1. J Endocrinol. 2013 Oct 4;219(2):119-29. doi: 10.1530/JOE-13-0141. Print 2013. Evidence for a role of sterol 27-hydroxylase in glucocorticoid metabolism in vivo. Vögeli I, Jung HH, Dick B, Erickson SK, Escher R, Funder JW, Frey FJ, Escher G. Department of Nephrology, Hypertension and Clinical Pharmacology, University Hospital Berne, CH-3010 Berne, Switzerland Department of Neurology, University Hospital Zurich, Zurich, Switzerland Department of Medicine, University of California, San Francisco, California, USA Department of Internal Medicine, Emmental Hospital, Burgdorf, Switzerland Prince Henry's Institute, Clayton 3168, Victoria, Australia. The intracellular availability of glucocorticoids is regulated by the enzymes 11β-hydroxysteroid dehydrogenase 1 (HSD11B1) and 11β-hydroxysteroid dehydrogenase 2 (HSD11B2). The activity of HSD11B1 is measured in the urine based on the (tetrahydrocortisol+5α-tetrahydrocortisol)/tetrahydrocortisone ((THF+5α-THF)/THE) ratio in humans and the (tetrahydrocorticosterone+5α-tetrahydrocorticosterone)/tetrahydrodehydrocorticost erone ((THB+5α-THB)/THA) ratio in mice. The cortisol/cortisone (F/E) ratio in humans and the corticosterone/11-dehydrocorticosterone (B/A) ratio in mice are markers of the activity of HSD11B2. In vitro agonist treatment of liver X receptor (LXR) down-regulates the activity of HSD11B1. Sterol 27-hydroxylase (CYP27A1) catalyses the first step in the alternative pathway of bile acid synthesis by hydroxylating cholesterol to 27-hydroxycholesterol (27-OHC). Since 27-OHC is a natural ligand for LXR, we hypothesised that CYP27A1 deficiency may up-regulate the activity of HSD11B1. In a patient with cerebrotendinous xanthomatosis carrying a loss-of-function mutation in CYP27A1, the plasma concentrations of 27-OHC were dramatically reduced (3.8 vs 90-140 ng/ml in healthy controls) and the urinary ratios of (THF+5α-THF)/THE and F/E were increased, demonstrating enhanced HSD11B1 and diminished HSD11B2 activities. Similarly, in Cyp27a1 knockout (KO) mice, the plasma concentrations of 27-OHC were undetectable (<1 vs 25-120 ng/ml in Cyp27a1 WT mice). The urinary ratio of (THB+5α-THB)/THA was fourfold and that of B/A was twofold higher in KO mice than in their WT littermates. The (THB+5α-THB)/THA ratio was also significantly increased in the plasma, liver and kidney of KO mice. In the liver of these mice, the increase in the concentrations of active glucocorticoids was due to increased liver weight as a consequence of Cyp27a1 deficiency. In vitro, 27-OHC acts as an inhibitor of the activity of HSD11B1. Our studies suggest that the expression of CYP27A1 modulates the concentrations of active glucocorticoids in both humans and mice and in vitro. PMID: 24096962 [PubMed - in process] 2. Eur J Med Genet. 2013 Sep 28. pii: S1769-7212(13)00207-3. doi: 10.1016/j.ejmg.2013.09.008. [Epub ahead of print] Mutation in CYP27A1 identified in family with coronary artery disease. Inanloorahatloo K, Zand Parsa AF, Huse K, Rasooli P, Davaran S, Platzer M, Fan JB, Amini S, Steemers F, Elahi E. School of Biology, College of Science, University of Tehran, Tehran, Iran; Genome Analysis, Leibniz Institute for Age Research - Fritz Lipmann Institute, Jena, Germany. Coronary artery disease (CAD) is a leading cause of death worldwide. Myocardial infarction is the most severe outcome of CAD. Despite extensive efforts, the genetics of CAD is poorly understood. We aimed to identify the genetic cause of CAD in a pedigree with several affected individuals. Exome sequencing led to identification of a mutation in CYP27A1 that causes p.Arg225His in the encoded protein sterol 27-hydroxylase as the likely cause of CAD in the pedigree. The enzyme is multifunctional, and several of its functions including its functions in vitamin D metabolism and reverse cholesterol transport (RCT) are relevant to the CAD phenotype. Measurements of vitamin D levels suggested that the mutation does not affect CAD by affecting this parameter. We suggest that the mutation may cause CAD by affecting RCT. Screening of all coding regions of the CYP27A1 in 100 additional patients led to finding four variations (p.Arg14Gly, p.Arg26Lys, p.Ala27Arg, and p.Val86Met) in seven patients that may contribute to their CAD status. CYP27A1 is the known causative gene of cerebrotendinous xanthomatosis, a disorder which is sometimes accompanied by early onset atherosclerosis. This and the observation of potentially harmful variations in unrelated CAD patients provide additional evidence for the suggested causative role of the p.Arg225His mutation in CAD. Copyright © 2013. Published by Elsevier Masson SAS. PMID: 24080357 [PubMed - as supplied by publisher] 3. Medicina (B Aires). 2013;73 Suppl 1:49-54. [Therapeutic developments in chronic ataxias]. [Article in Spanish] Buompadre MC. Servicio de Neurología Infantil, Hospital de Pediatría Prof. Dr. J. P. Garrahan, Buenos Aires. E-mail: mcelestebuompa@hotmail.com. Autosomal recessive cerebellar ataxias belong to a broader group of disorders known as inherited ataxias. In most cases onset occurs before the age of 20. These neurological disorders are characterized by degeneration or abnormal development of the cerebellum and spinal cord. Currently, specific treatment is only available for some of the chronic ataxias, more specifically those related to a known metabolic defect, such as abetalipoproteinemia, ataxia with vitamin E deficiency, and cerebrotendinous xanthomatosis. Treatment based on a diet with reduced intake of fat, supplementation of oral vitamins E and A, and the administration of chenodeoxycholic acid could modify the course of the disease. Although for most of autosomal recessive ataxias there is no definitive treatment, iron chelators and antioxidants have been proposed to reduce the mitochondrial iron overload in Friederich's ataxia patients. Corticosteroids have been used to reduce ataxia symptoms in ataxia telangiectasia. Coenzyme Q10 deficiency associated with ataxia may be responsive to Co Q10 or ubidecarenone supplementations. Early treatment of these disorders may be associated with a better drug response. PMID: 24072051 [PubMed - in process] 4. Transl Psychiatry. 2013 Sep 3;3:e302. doi: 10.1038/tp.2013.76. Psychiatric manifestations in cerebrotendinous xanthomatosis. Fraidakis MJ. 1] Federation of Neurology, La Salpêtrière Hospital, Groupe Hopsitalier Pitié-Salpêtrière (GHPS), Paris, France [2] Department of Neurogenetics, La Salpêtrière Hospital, Groupe Hopsitalier Pitié-Salpêtrière (GHPS), Paris, France. Cerebrotendinous xanthomatosis (CTX) is a rare and severe, but treatable, inborn disorder of bile acid biosynthesis and sterol storage with autosomal recessive inheritance and variable clinical presentation. CTX treatment consists of chenodeoxycholic acid and must be started as early as possible to prevent permanent disability. Psychiatric manifestations are rare and non-specific, and often lead to significant diagnostic and treatment delay. Therefore, better recognition of the gamut of psychiatric manifestations in CTX can diminish the risk of misdiagnosis and irreversible neurological deterioration. We hereby describe the psychiatric features in CTX. A complete review of all published cases of CTX in the medical literature was undertaken and the case reports with psychiatric presentation were collected and analyzed. We also describe the psychiatric features in relation to the neurological semeiology in six patients with CTX diagnosed at the La Salpêtrière Hospital. We conclude that psychiatric manifestations in CTX follow a bimodal/bitemporal pattern, appearing early in the disease course in the form of a behavioral/personality disorder associated with learning difficulties or mental retardation, or manifesting in advanced disease in the setting of dementia as rich neuropsychiatric syndromes, such as frontal, orbitofrontal or frontotemporal syndromes of cortico-subcortical dementia encompassing behavioral/personality disturbance, affective/mood disorders or psychotic disorders. Behavioral/personality disturbance in childhood or adolescence, especially when accompanied by learning difficulties, should therefore lead to further investigation to exclude CTX, as early diagnosis and treatment is critical for prognosis. PMCID: PMC3784765 PMID: 24002088 [PubMed - in process] 5. Indian Heart J. 2013 Jul-Aug;65(4):491-2. doi: 10.1016/j.ihj.2013.06.012. Epub 2013 Jul 6. Tendon xanthomas as indicators of atherosclerotic burden on coronary arteries. Patil S, Kharge J, Bagi V, Ramalingam R. Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, India. The presence of tendon xanthomas is an almost certain indicator of familial hypercholesterolemia (FH). They also reflect coronary atherosclerotic burden and therefore must be treated aggressively. Tendon xanthomas also occur in two rare conditions, cerebrotendinous xanthomatosis and sitosterolemia, which are not easily confused with FH, can be easily differentiated with clinical history and biochemical tests. Copyright © 2013. Published by Elsevier B.V. PMID: 23993019 [PubMed - in process] 6. Clin Nucl Med. 2013 Aug 28. [Epub ahead of print] 99mTc-Sestamibi Thigh SPECT/CT Imaging for Assessment of Myopathy in Cerebrotendinous Xanthomatosis With Histopathological and Immunohistochemical Correlation. Chen SF, Chang CC, Huang SH, Lu CH, Chuang YC, Pan TL, Chang WN. From the Departments of *Neurology and †Nuclear Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center and Chang Gung University College of Medicine, Kaohsiung; and ‡School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan. PURPOSE: The aim of this study was to determine the effectiveness of using Tc-sestamibi thigh SPECT/CT imaging for evaluating myopathy in cerebrotendinous xanthomatosis (CTX). PATIENTS AND METHODS: Four genetically proven CTX patients (Family I, Cases I-1 and I-2; Family II, Cases II-1 and II-2) were included. They all underwent muscle biopsies for histopathologic and ultrastructural studies. Immunohistochemical staining for vinculin expression was also performed. Tc-sestamibi thigh SPECT/CT imaging was conducted on all 4 CTX patients, and both visual interpretation and muscle-to-background (M/B) ratio count were applied for assessment. Correlation analysis of the imaging findings and results of the ultrastructural and immunohistochemical studies was done. RESULTS: In the Tc-sestamibi thigh SPECT/CT imaging study, all 4 CTX cases had abnormal scores of visual interpretation and M/B ratios. The ultrastructural features of the skeletal muscle of the 4 CTX cases showed mitochondrial and membrane system abnormalities, with increased depositions of metabolites. They also had abnormal increases in vinculin expression after immunohistochemical staining of the skeletal muscle. CONCLUSIONS: This is the first report on the use of Tc-sestamibi thigh SPECT/CT imaging to assess the mitochondrial status of CTX. The imaging findings may have a correlation with the ultrastructural and immunohistochemical findings on skeletal muscle. Although the Tc-sestamibi thigh SPECT/CT imaging is not specific for CTX, this noninvasive in vivo assessment can be an important tool for the detection and follow-up study of skeletal muscle involvement in CTX. PMID: 23989447 [PubMed - as supplied by publisher] 7. Curr Opin Lipidol. 2013 Aug;24(4):283-7. doi: 10.1097/MOL.0b013e328362df13. Cerebrotendinous xanthomatosis. Björkhem I. Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. ingemar.bjorkhem@karolinska.se PURPOSE OF REVIEW: Cerebrotendinous xanthomatosis (CTX) is a rare neurological disease characterized by accumulation of cholesterol and cholestanol in brain and tendons caused by a mutation in the sterol 27-hydroxylase gene (CYP27A1). The mechanism behind the accumulation of cholestanol in the brain was recently clarified and a role of 27-hydroxycholesterol as a regulator of brain cholesterol homeostasis has been established. RECENT FINDINGS: There is a significant flux of the bile acid precursor 7α-hydroxy-4-cholesten-3-one across the blood-brain barrier in cy27-/- mice with its subsequent conversion into cholestanol. CTX patients with white matter lesions and vacuolation are described. CYP27A1 was identified as a candidate gene for sporadic amyotrophic lateral sclerosis (ALS). SUMMARY: The mechanism behind accumulation of cholestanol in brain and tendons of patients with CTX has been clarified but it is not known why this accumulation is associated with parallel accumulation of cholesterol and formation of xanthomas. Further studies are needed to understand why some patients with CTX develop white matter lesions in the brain. In view of the fact that CTX can present with upper motor neuronal signs it is interesting that CYP27 has been shown to be a candidate gene for sporadic ALS. PMID: 23759795 [PubMed - in process] 8. Rev Med Liege. 2013 Apr;68(4):171-6. [Cerebrotendinous xanthomatosis, a rare, severe, but treatable metabolic disorder]. [Article in French] Delstanche S, Deflandre T, Otto B, Tshibanda L, Simoni P, Moonen G. Service de Neurologie, CHU de Liege, Belgique. Cerebrotendinous xanthomatosis (CTX) is a rare and treatable autosomal recessive disease. The diagnosis should be suspected in the presence of a suggestive clinical triad characterized by early-onset cataract, tendinous xanthomata and neurological symptoms and signs, notably cerebellar ataxia, mental retardation and pyramidal syndrome.The diagnosis is confirmed by demonstrating an increased blood level of cholestanol, or/and by molecular genetic analysis.In typical cases, brain MRI shows bilateral hyperintensity of the cerebellar nucleus dentatus together with cerebral atrophy and leukoencephalopathy. The treatment is based on the administration of chenodeoxycholic acid. The aim is to restore the negative feedback on the enzymatic cascade altered by mutation in the gene CYP27 which induces a 27-hydroxylase deficiency PMID: 23755706 [PubMed - indexed for MEDLINE] 9. J Radiol Case Rep. 2013 Apr 1;7(4):1-9. doi: 10.3941/jrcr.v7i4.1338. Print 2013 Apr. Cerebrotendinous xanthomatosis--the spectrum of imaging findings. Pudhiavan A, Agrawal A, Chaudhari S, Shukla A. Department of Radiodiagnosis, M.G.M.M.C. & M.Y. Hospital, Indore, India. drpudhiavan@gmail.com Cerebrotendinous xanthomatosis (CTX), also known as Van Bogaert-Scherer-Epstein disease is a rare autosomal recessive genetic disorder of the lipid metabolism. To date, there are less than 300 cases reported worldwide. We present a case of a 30 year old male who presented with mental retardation and swelling of ankles, with the a spectrum of CTX imaging findings. Imaging studies were performed which included plain X-ray, Ultrasound(US) and Magnetic Resonance Imaging(MRI) of both the brain and ankles. These pointed towards the diagnosis of CTX with the entire spectrum of findings which was confirmed with biopsy and laboratory findings. CTX is a potentially treatable condition with replacement therapy, and hence early diagnosis before neurological deterioration is important. This is aided by the imaging findings which are conclusive forte diagnosis of CTX. PMCID: PMC3661428 PMID: 23705046 [PubMed - in process] 10. J Inherit Metab Dis. 2013 Jul;36(4):687-702. doi: 10.1007/s10545-013-9618-y. Epub 2013 May 23. The neuropsychiatry of inborn errors of metabolism. Walterfang M, Bonnot O, Mocellin R, Velakoulis D. Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health, Parkville, Australia. mark.walterfang@mh.org.au A number of metabolic disorders that affect the central nervous system can present in childhood, adolescence or adulthood as a phenocopy of a major psychiatric syndrome such as psychosis, depression, anxiety or mania. An understanding and awareness of secondary syndromes in metabolic disorders is of great importance as it can lead to the early diagnosis of such disorders. Many of these metabolic disorders are progressive and may have illness-modifying treatments available. Earlier diagnosis may prevent or delay damage to the central nervous system and allow for the institution of appropriate treatment and family and genetic counselling. Metabolic disorders appear to result in neuropsychiatric illness either through disruption of late neurodevelopmental processes (metachromatic leukodystrophy, adrenoleukodystrophy, GM2 gangliosidosis, Niemann-Pick type C, cerebrotendinous xanthomatosis, neuronal ceroid lipofuscinosis, and alpha mannosidosis) or via chronic or acute disruption of excitatory/inhibitory or monoaminergic neurotransmitter systems (acute intermittent porphyria, maple syrup urine disease, urea cycle disorders, phenylketonuria and disorders of homocysteine metabolism). In this manuscript we review the evidence for neuropsychiatric illness in major metabolic disorders and discuss the possible models for how these disorders result in psychiatric symptoms. Treatment considerations are discussed, including treatment resistance, the increased propensity for side-effects and the possibility of some treatments worsening the underlying disorder. PMID: 23700255 [PubMed - in process] 11. Indian J Orthop. 2013 Mar;47(2):200-3. doi: 10.4103/0019-5413.108918. Cerebrotendinous xanthomatosis. Vadapalli S. Department of Orthopaedics, Konaseema Institute of Medical Sciences (KIMS), Amalapuram, East Godavari District, Andhra Pradesh, India. Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid storage disorder affecting the biosynthetic pathway of bile acids, leading to increased cholestanol formation and its accumulation in various tissues. Patients can present with tendon xanthomas, gait abnormalities, osteoporosis with or without a pathological fracture, diminished vision, intractable diarrhoea, seizures, ataxia, psychosis, and mental retardation. We report a 20-year-old man who presented with multiple recurrent tendon swellings and seizures. The earlier diagnosis and treatment helps in preventing the devastating neurological sequalae of this sinister condition. Treatment with chenodeoxycholic acid is crucial in preventing the progression of this rare disorder. PMCID: PMC3654472 PMID: 23682184 [PubMed] 12. Clin Neuropharmacol. 2013 May-Jun;36(3):78-83. doi: 10.1097/WNF.0b013e318288076a. Neurological outcome in cerebrotendinous xanthomatosis treated with chenodeoxycholic acid: early versus late diagnosis. Yahalom G, Tsabari R, Molshatzki N, Ephraty L, Cohen H, Hassin-Baer S. The Parkinson Disease and Movement Disorders Clinic, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel-Hashomer, Israel. OBJECTIVE: To present the long-term neurological outcome of Jewish Israeli patients with cerebrotendinous xanthomatosis (CTX) after several years of chenodeoxycholic acid (CDCA) treatment. METHODS: A cross sectional observational study of all patients with a diagnosis of CTX followed in a referral outpatient clinic during the years 2003-2012. RESULTS: Eighteen patients (10 men) from 11 families were enrolled. Sixteen patients were included in the analysis (2 patients had low compliance for treatment). The mean ± SD age at last evaluation was 35.0 ± 9.2 years (range, 16-45 years). After their diagnosis, at age 22.6 ± 10.8 years, all patients were treated with CDCA. Patients who started treatment after the age of 25 years had worse outcome and were significantly more limited in ambulation (P = 0.004) and more cognitively impaired (P = 0.047). Five patients who started treatment after 25 years of age continued to deteriorate despite CDCA treatment. CONCLUSIONS: Beginning CDCA treatment as early as possible is crucial to preventing neurological damage and deterioration in CTX. After significant neurological pathology is established, the effect of treatment is limited and deterioration may continue. PMID: 23673909 [PubMed - in process] 13. Neuropathol Appl Neurobiol. 2013 May 10. doi: 10.1111/nan.12058. [Epub ahead of print] Cerebrotendinous xanthomatosis with the c.379C>T (p.R127W) mutation in the CYP27A1 gene associated with premature age-associated limbic tauopathy. Kapás I, Katkó M, Harangi M, Paragh G, Balogh I, Kóczi Z, Regelsberger G, Molnár MJ, Kovacs GG. Semmelweis University, Neuropathology and Prion Disease Reference Centre, Budapest, Hungary; Department of Neurology, County Hospital, Vác, Hungary. PMID: 23659550 [PubMed - as supplied by publisher] 14. Parkinsonism Relat Disord. 2013 Aug;19(8):764-5. doi: 10.1016/j.parkreldis.2013.04.003. Epub 2013 Apr 25. Blepharospasm as a new feature of cerebrotendinous xanthomatosis. Lagarde J, Sedel F, Degos B. PMID: 23623195 [PubMed - in process] 15. Handb Clin Neurol. 2013;113:1437-55. doi: 10.1016/B978-0-444-59565-2.00013-7. Metabolic neuropathies and myopathies. D'amico A, Bertini E. Molecular Medicine and Unit of Neuromuscular and Neurodegenerative Diseases, IRCCS-Children's Hospital Bambino Gesù, Rome, Italy. Inborn errors of metabolism may impact on muscle and peripheral nerve. Abnormalities involve mitochondria and other subcellular organelles such as peroxisomes and lysosomes related to the turnover and recycling of cellular compartments. Treatable causes are β-oxidation defects producing progressive neuropathy; pyruvate dehydrogenase deficiency, porphyria, or vitamin B12 deficiency causing recurrent episodes of neuropathy or acute motor deficit mimicking Guillain-Barré syndrome. On the other hand, lysosomal (mucopolysaccharidosis, Gaucher and Fabry diseases), mitochondriopathic (mitochondrial or nuclear mutations or mDNA depletion), peroxisomal (adrenomyeloneuropathy, Refsum disease, sterol carrier protein-2 deficiency, cerebrotendinous xanthomatosis, α-methylacyl racemase deficiency) diseases are multisystemic disorders involving also the heart, liver, brain, retina, and kidney. Pathophysiology of most metabolic myopathies is related to the impairment of energy production or to abnormal production of reactive oxygen species (ROS). Main symptoms are excercise intolerance with myalgias, cramps and recurrent myoglobinuria or limb weakness associated with elevation of serum creatine kinase. Carnitine palmitoyl transferase deficiency, followed by acid maltase deficiency, and lipin deficiency, are the most common cause of isolated rhabdomyolysis. Metabolic myopathies are frequently associated to extra-neuromuscular disorders particularly involving the heart, liver, brain, retina, skin, and kidney. Copyright © 2013 Elsevier B.V. All rights reserved. PMID: 23622366 [PubMed - in process] 16. Genet Med. 2013 Sep;15(9):673-83. doi: 10.1038/gim.2013.28. Epub 2013 Mar 28. Hereditary ataxias: overview. Jayadev S, Bird TD. Department of Neurology, University of Washington, Seattle, Washington, USA. The hereditary ataxias are a highly heterogeneous group of disorders phenotypically characterized by gait ataxia, incoordination of eye movements, speech, and hand movements, and usually associated with atrophy of the cerebellum. There are more than 35 autosomal dominant types frequently termed spinocerebellar ataxia and typically having adult onset. The most common subtypes are spinocerebellar ataxia 1, 2, 3, 6, and 7, all of which are nucleotide repeat expansion disorders. Autosomal recessive ataxias usually have onset in childhood; the most common subtypes are -Friedreich, ataxia-telangiectasia, ataxia with oculomotor apraxia type 1, and ataxia with oculomotor apraxia type 2. Four autosomal recessive types have dietary or biochemical treatment modalities (ataxia with vitamin E deficiency, cerebrotendinous xanthomatosis, Refsum, and coenzyme Q10 deficiency), whereas there are no specific treatments for other ataxias. Diagnostic genetic testing is complicated because of the large number of relatively uncommon subtypes with extensive phenotypic overlap. However, the best testing strategy is based on assessing relative frequencies, ethnic predilections, and recognition of associated phenotypic features such as seizures, visual loss, or associated movement abnormalities. PMID: 23538602 [PubMed - in process] 17. J Am Podiatr Med Assoc. 2013 Mar-Apr;103(2):152-5. Cerebrotendinous xanthomatosis presenting with bilateral achilles tendon xanthomata: a case report. Mirzanli C, Esenyel CZ, Ozturk K, Baris A, Imren Y. Department of Orthopaedics and Traumatology, Vakif Gureba Research and Training Hospital, Istanbul, Turkey. cuneytmirzanli@yahoo.vom Xanthomas are described as deposits in the skin and subcutaneous tissues. Mostly known as pseudotumors, xanthomas consist of connective tissue containing mainly cholesterol, triglycerides, and numerous foamy macrophages. Bilateral Achilles tendon xanthomata is pathognomonic for cerebrotendinous xanthomatosis in the case of normal cholesterol levels but increased cholestanol levels in serum. In this article, we present findings regarding bilateral xanthomas of Achilles tendons in a patient with cerebrotendinous xanthomatosis. PMID: 23536508 [PubMed - in process] 18. Rev Neurol (Paris). 2013 Feb;169 Suppl 1:S63-9. doi: 10.1016/S0035-3787(13)70062-6. [Inborn errors of metabolism in adult neurology]. [Article in French] Sedel F. Département de Neurologie, centre de référence maladies lysosomales, Unité fonctionnelle neurométabolique bio-clinique et génétique, Hôpital Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, 47 Boulevard de l'Hôpital, 75651 Paris cedex 13, France. frederic.sedel@psl.aphp.fr Inborn errors of metabolism (IEM) are caused by mutations in genes coding for enzymes and other proteins involved in cell metabolism. Many IEM can be treated effectively. Although IEM have usually been considered pediatric diseases, they can present at any age, mostly with neurological and psychiatric symptoms, and therefore constitute an integral subspeciality of neurology. However, although they are increasingly being recognized, IEM remain rare, and the care for patients should be optimized in specialized reference centers. Since the number of different diseases is very large, the diagnostic approach needs to be rigorous, starting at the clinics and calling upon the additional help of neuroradiology, biochemistry and molecular biology. In practice, it is important for the neurologist to recognize: (1) when to start suspecting an IEM; and (2) how to correlate a given clinical presentation with one of the five major groups of diseases affecting the nervous system. These five groups may be classified as: (a) energy metabolism disorders such as respiratory chain disorders, pyruvate dehydrogenase deficiency, GLUT1 deficiency, fatty-acid β-oxidation defects, and disorders involving key cofactors such as electron transfer flavoprotein, thiamine, biotin, riboflavin, vitamin E and coenzyme Q10; (b) intoxication syndromes such as porphyrias, urea-cycle defects, homocystinurias, organic acidurias and amino acidopathies; (c) lipid-storage disorders such as lysosomal storage disorders (Krabbe disease, metachromatic leukodystrophy, Niemann - Pick disease type C, Fabry disease and Gaucher's disease), peroxisomal disorders (adrenomyeloneuropathy, Refsum disease, disorders of pristanic acid metabolism, peroxisome biogenesis disorders), Tangier disease and cerebrotendinous xanthomatosis; (d) metal-storage diseases such as iron, copper and manganese metabolic disorders; and (e) neurotransmitter metabolism defects, including defects of serotonin, dopamine and glycine metabolism. Copyright © 2013 Elsevier Masson SAS. All rights reserved. PMID: 23452774 [PubMed - indexed for MEDLINE] 19. BMJ Case Rep. 2013 Feb 14;2013. pii: bcr2012006641. doi: 10.1136/bcr-2012-006641. 'Hot cross bun' sign in a case of cerebrotendinous xanthomatosis: a rare neuroimaging observation. Jain RS, Sannegowda RB, Agrawal A, Hemrajani D, Jain R, Mathur T. Department of Neurology, SMS Medical College Hospital, Jaipur, Rajasthan, India. drrsjain@yahoo.com We report a 25-year-old young man presenting with cognitive decline, pancerebellar features, spastic quadriparesis, bilateral cataract (operated) and tendo-Achilles swelling (xanthoma). The CT of the head showed bilateral cerebellar hypodensities. There were bilateral cerebellar hypointensities involving dentate nuclei on T1-weighted images with corresponding hyperintensities on T2-weighted MRI. Additionally, an interesting MRI finding-'hot cross bun' appearance was seen in pons which has not been reported in the literature so far. Biopsy from tendo-Achilles confirmed xanthoma. He was treated with chenodeoxycholic acid following which he showed improvement in cognition and weakness. PMID: 23417372 [PubMed - indexed for MEDLINE] 20. Ophthalmology. 2013 May;120(5):956-60. doi: 10.1016/j.ophtha.2012.10.032. Epub 2013 Jan 31. Juvenile cataract morphology in 3 siblings not yet diagnosed with cerebrotendinous xanthomatosis. Khan AO, Aldahmesh MA, Mohamed JY, Alkuraya FS. Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. arif.khan@mssm.edu PURPOSE: Cerebrotendinous xanthomatosis is a progressive neurodegenerative storage disease caused by recessive CYP27A1 mutations and is characterized by abnormal deposition of cholestanol and cholesterol in multiple tissues, including the lens and brain. Oral chenodeoxycholic acid is preventive and can be therapeutic, but is not used optimally because the condition typically is diagnosed late or not at all. When affected children demonstrate lens opacities, ophthalmologists have the unique potential to facilitate earlier diagnosis and treatment by recognizing the juvenile cataract phenotype. This study highlights the morphology of lens opacities in a family with genetically confirmed disease. DESIGN: Prospective case series. PARTICIPANTS: Four siblings and their 2 parents, who are first cousins. METHODS: Ophthalmic examination, general physical examination, and exome sequencing guided by homozygosity analysis. MAIN OUTCOME MEASURES: Ophthalmic findings, general clinical findings, and results of CYP27A1 candidate gene testing. RESULTS: Two sisters, each visually symptomatic before 10 years of age, had a unique pattern of bilateral fleck deposits throughout the lens with significant posterior capsular cataract. When initially examined at 8 years of age, their then-asymptomatic younger brother had the same bilateral fleck deposits with minimal posterior capsular opacity; 1 year later, he demonstrated anterior capsular opacity and became symptomatic. Both asymptomatic parents had few but distinct similar flecks localized at or near the anterior Y-suture, whereas an asymptomatic sister did not. Genetic analysis revealed homozygosity for a known CYP27A1 mutation (c.1263+1G → A) in the 3 symptomatic siblings, heterozygosity for the mutation in the 2 parents, and no mutation in the asymptomatic sister. When specifically questioned, the 3 affected children had experienced recurrent bouts of diarrhea in early childhood, which is a common feature of the disease. CONCLUSIONS: An unusual pattern of fleck lenticular deposits was seen in affected children. With time, capsular opacities (posterior only or posterior and anterior) developed and caused visual symptoms. Such juvenile lenticular findings should raise suspicion for this treatable metabolic disorder, especially when in the context of recurrent diarrhea during early childhood. Asymptomatic fleck-like opacities at or near the anterior Y-suture may be a carrier sign. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. PMID: 23375591 [PubMed - indexed for MEDLINE] 21. Ugeskr Laeger. 2013 Jan 28;175(5):285-6. [Cerebrotendinous xanthomatosis is a rare disorder, which requires a specific treatment]. [Article in Danish] Blaabjerg M, Marjanovic D. Neurologisk Afdeling, Odense Universitetshospital, Sdr. Boulevard 29,5000 Odense C, Denmark. morten.blaabjerg@ouh.regionsyddanmark.dk Cerebrotendinous xanthomatosis (CTX) is a rare, but treatable lipid storage disorder caused by mutation in the CYP27A1 gene. The disorder results in deposition of cholestanol in various tissues. The classical CTX phenotype includes diarrhoea, juvenile cataract, xanthoma and progressive neurological symptoms. Studies have shown that progression of symptoms can be halted or even reversed, if treatment with chenodeoxycholic acid is initiated early. The diagnosis of CTX is often delayed due to lack of awareness of the disease. We describe the history, clinical features, biochemical, genetic and magnetic resonance imaging findings of the first reported case of CTX in Denmark. PMID: 23369332 [PubMed - indexed for MEDLINE] 22. Neurol India. 2012 Nov-Dec;60(6):643-4. doi: 10.4103/0028-3886.105202. Mutation analysis of cerebrotendinous xanthomatosis in an Indian case. Shah K, Mathew V, Gallus GN, Dotti MT, Federico A, Danda S. PMID: 23287330 [PubMed - in process] 23. Calcif Tissue Int. 2013 Mar;92(3):282-6. doi: 10.1007/s00223-012-9677-3. Epub 2012 Dec 2. Long-term bone density evaluation in cerebrotendinous xanthomatosis: evidence of improvement after chenodeoxycholic acid treatment. Martini G, Mignarri A, Ruvio M, Valenti R, Franci B, Del Puppo M, Federico A, Nuti R, Dotti MT. Department of Internal Medicine, Endocrine-Metabolic Sciences and Biochemistry, University of Siena, Siena, Italy. martinig@unisi.it Cerebrotendinous xanthomatosis (CTX) is known to be associated with osteoporosis and a higher incidence of bone fractures. However, the underlying pathogenesis is still unknown, and the effects of long-term replacement therapy with chenodeoxycholic acid (CDCA) on bone mineral density (BMD) have not been fully investigated. We studied 11 CTX patients aged 13-43 years. We performed dual-energy X-ray absorptiometry and assessed serum cholestanol and 25-hydroxyvitamin D (25-OHD) concentrations both at the time of diagnosis and after long-term treatment with CDCA. At baseline, we found low BMD in nine patients, cholestanol elevation in all subjects, and 25-OHD decrease in nine. After a mean follow-up time of 30 months (range 24-36), no substantial clinical changes including bone fractures occurred; and we detected a significant increase of both planar and volumetric BMD as well as normalization of plasma cholestanol levels and increase of serum 25-OHD. Densitometric improvement following CDCA introduction was not correlated to changes of biochemical parameters. Our study confirms the presence of low bone mass in CTX and demonstrates that long-term CDCA treatment increases bone mineral content. In this respect, improvement of vitamin D intestinal absorption secondary to bile acid restoration could play an important role. Moreover, our data strongly suggest the utility of periodic bone density evaluation in CTX patients. PMID: 23212544 [PubMed - indexed for MEDLINE] 24. Neurol Sci. 2013 Sep;34(9):1693-6. doi: 10.1007/s10072-012-1262-z. Epub 2012 Dec 5. Brain metabolism changes after therapy with chenodeoxycholic acid in a case of cerebrotendinous xanthomatosis. Caroppo P, D'Agata F, Mignarri A, Stromillo ML, Dotti MT, Mongini T. Department of Neuroscience, University of Turin, Via Cherasco, 15, 10126, Turin, Italy, paolacaroppo@libero.it. PMID: 23212406 [PubMed - in process] 25. Mov Disord. 2012 Dec;27(14):1769-74. doi: 10.1002/mds.25229. Epub 2012 Nov 2. Atypical parkinsonism and cerebrotendinous xanthomatosis: report of a family with corticobasal syndrome and a literature review. Rubio-Agusti I, Kojovic M, Edwards MJ, Murphy E, Chandrashekar HS, Lachmann RH, Bhatia KP. Sobell Department for Movement Disorders and Motor Neuroscience, UCL Institute of Neurology, London, United Kingdom. Cerebrotendinous xanthomatosis is an autosomal recessive inborn error of cholesterol metabolism. It presents with systemic and neurological symptoms, rarely including parkinsonism. Presented here are a clinical description of a new family with cerebrotendinous xanthomatosis and parkinsonism and a review of 13 additional cases reported in the literature. The index case developed corticobasal syndrome, previously not reported in cerebrotendinous xanthomatosis. His brother had parkinsonism with cerebellar features and cognitive impairment. In a literature review, median age of onset of parkinsonism was found to be 40 years. Nearly all patients had other neurological symptoms: cognitive (93%), pyramidal (93%), or cerebellar (53%). All patients had walking difficulties, with falls in 27%. Systemic features were common: cataracts (93%) or tendon xanthomata (87%). Frequent MRI abnormalities included cerebellar atrophy (100%), cerebral atrophy (80%), and dentate nuclei signal changes (80%). Functional dopaminergic imaging often demonstrated presynaptic denervation. Improvement with levodopa was frequent (91%) but mild. Progressive neurological decline occurred in 92% of patients despite treatment with chenodeoxycholic acid. Cerebrotendinous xanthomatosis should be considered in the differential diagnosis of atypical parkinsonism, including corticobasal syndrome, particularly with early age of onset and in the context of a complex neurological phenotype. Tendon xanthomata, early-onset cataracts, and radiological findings of cerebellar atrophy with lesions of the dentate nuclei are useful clinical clues. Symptomatic treatment with levodopa may help, but progressive neurological decline is frequent despite treatment with chenodeoxycholic acid. Copyright © 2012 Movement Disorder Society. PMID: 23124517 [PubMed - indexed for MEDLINE] 26. Mov Disord. 2012 Dec;27(14):1805-10. doi: 10.1002/mds.25206. Epub 2012 Oct 31. Myoclonus and dystonia in cerebrotendinous xanthomatosis. Lagarde J, Roze E, Apartis E, Pothalil D, Sedel F, Couvert P, Vidailhet M, Degos B. AP-HP Département de Neurologie, Hôpital de la Salpêtrière, Paris, France. BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an inherited neurometabolic disorder. The main neurological manifestations of the disease are pyramidal syndrome, ataxia, peripheral neuropathy, cognitive impairment, epilepsy, and psychiatric disturbances. Myoclonic dystonia has been reported on in the setting of various neurometabolic diseases. Anecdotal reports describe movement disorders associated with CTX, but no dystonia with myoclonic events. METHODS: We collected clinical, biochemical, electrophysiological, neuroradiological, and genetic data of 6 patients with myoclonus and mild dystonia associated with CTX. From a systematic literature review, we analyzed 31 patients with movement disorders secondary to CTX. RESULTS: Our 6 patients presented distal myoclonus with mild dystonia of the upper limbs. Myoclonus was of subcortical origin, based on neurophysiological recordings, and differed from oromandibular myoclonus previously described in CTX patients. CONCLUSIONS: These results expand the phenotype of CTX and suggest that myoclonus and/or dystonia are underdiagnosed. In keeping with our findings, tremors previously observed in CTX patients might actually correspond to myoclonic events. We hypothesize that a dysfunction of the dentate nuclei-basal ganglia pathway may be involved. Copyright © 2012 Movement Disorder Society. PMID: 23115103 [PubMed - indexed for MEDLINE] 27. Biochimie. 2013 Mar;95(3):448-54. doi: 10.1016/j.biochi.2012.02.029. Epub 2012 Mar 1. Five decades with oxysterols. Björkhem I. Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden. ingemar.bjorkhem@karolinska.se I have been involved in research on oxysterols since 1963 and this review is intended to cover some of the most important aspects of this work. The first project dealed with 7α-hydroxy-4-cholesten-3-one. My successful synthesis of this steroid with high specific radioactivity allowed a demonstration that it is a bile acid precursor. The mechanism of conversion of 7α-hydroxycholesterol into 7α-hydroxy-4-cholesten-3-one was investigated and I concluded that only one enzyme is required and that no isomerase is involved. Accumulation of 7α-hydroxy-4-cholesten-3-one in patients with lack of sterol 27-hydroxylase (Cerebrotendinous xanthomatosis was shown to be an important pathogenetic factor. This disease is characterized by cholestanol-containing xanthomas in tendons and brain and we could show that most of this cholestanol is formed from 7α-hydroxy-4-cholesten-3-one. We also showed that 7α-hydroxy-4-cholesten-3-one passes the blood-brain barrier. In contrast to cholesterol itself, side-chain oxidized oxysterols have a high capacity to pass lipophilic membranes. We demonstrated conversion of cholesterol into 27-hydroxycholesterol to be a significant mechanism for elimination of cholesterol from macrophages. We also showed that conversion of cholesterol into 24S-hydroxycholesterol is important for elimination of cholesterol from the brain. Side-chain oxidized oxysterols have a high capacity to affect critical genes in cholesterol turnover in vitro. Most of the published in vitro experiments with oxysteroids are highly unphysiological, however. Mouse models studied in my laboratory with high or low levels of 27-hydroxycholesterol have little or no disturbances in cholesterol homeostasis. 24S-hydroxycholesterol is an efficient ligand to LXR and suggested to be important for cholesterol homeostasis in the brain. We recently developed a mouse model with markedly increased levels of this oxysterol in circulation and brain. This overexpression had however only a very modest effect on cholesterol turnover. We concluded that oxysterols are not the master regulators of cholesterol homeostasis in vivo suggested previously. Copyright © 2012 Elsevier Masson SAS. All rights reserved. PMID: 23111110 [PubMed - indexed for MEDLINE] 28. Ceylon Med J. 2012 Sep;57(3):128-9. doi: 10.4038/cmj.v57i3.4708. Two siblings with cerebrotendinous xanthomatosis. Kottahachchi DC, Balasooriya BL, Panangala L, Ranawaka UK. University Medical Unit, Teaching Hospital, Ragama, Sri Lanka. dula_k@yahoo.com PMID: 23086033 [PubMed - in process] 29. J Med Syst. 2012 Nov;36 Suppl 1:S25-36. doi: 10.1007/s10916-012-9887-2. Epub 2012 Oct 20. Summarizing phenotype evolution patterns from report cases. Taboada M, Alvarez V, Martínez D, Pilo B, Robinson PN, Sobrido MJ. Department of Electronics and Computer Science, University of Santiago de Compostela, Santiago de Compostela, Spain. maria.taboada@usc.es The need to represent and manage time is implicit in several reasoning processes in medicine. However, this is predominantly obvious in the field of many neurodegenerative disorders, which are characterized by insidious onsets, progressive courses and variable combinations of clinical manifestations in each patient. Therefore, the availability of tools providing high level descriptions of the evolution of phenotype manifestations from patient data is crucial to promote early disease recognition and optimize the diagnostic process. Although many case reports published in the literature do not provide exhaustive temporal information except only key time references, such as disease onset, diagnosis or monitoring time, automatically comparing cases described by temporal clinical manifestation sequences can provide valuable knowledge about the data evolution. In this paper, we demonstrate the usefulness of representing patient case reports of a neurodegenerative disorder as a set of temporal clinical manifestations semantically annotated with a domain phenotype ontology and registered with a time-stamped value. Novel techniques are presented to query and match sets of different manifestation sequences from multiple patient cases, with the aim of automatically inferring phenotype evolution patterns of generic patients for clinical studies. The method was applied to 25 patient report cases from a Spanish study of the domain of cerebrotendinous xanthomatosis. Five evolution patterns were automatically generated to analyze the patient data. The results were evaluated against 49 relevant conclusions drawn from the study, with a precision of 93 % and a recall of 70 %. PMID: 23085966 [PubMed - indexed for MEDLINE] 30. BMJ Case Rep. 2012 Sep 21;2012. pii: bcr2012006202. doi: 10.1136/bcr-2012-006202. Cerebrotendinous xanthomatosis: a rare disorder with a rare presentation. Agrawal NK, Garg S. Department of Endocrinology and Metabolism, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India. drnkavns@gmail.com A young man was brought for mental retardation, frequent non-bloody diarrhoea and swellings at ankles and elbow. He became bed-ridden due to cataract, mental retardation and pain in the back and lower limb. There were repeated pathological fractures and vitamin D deficiency without renal dysfunction. There were low low-density lipoprotein and triglyceride levels. MRI of the brain revealed hypointense lesions in cerebellar white matter, heterogenous hyperintensity in dentate nucleus and adjacent white matter, right basal ganglia and in the periventricular region with diffuse cerebral atrophy. T1-weighted MRI (ankle region) revealed bilaterally thickened and irregular achilles tendons with hyperintense masses surrounded by patchy hypointensities. A similar xanthomatous lesion (cholestanol deposits) was also present in the sacral region. Vitamin D and calcium supplementation and chenodeoxycholic acid therapy improved pain at lower limbs and body weight. Cerebrotendinous xanthomatosis is a rare autosomal-recessive familial mutation of the sterol 27 hydroxylase causing lipid metabolic disease. PMID: 23001091 [PubMed - in process] 31. J Neurol. 2013 Jan;260(1):268-74. doi: 10.1007/s00415-012-6630-3. Epub 2012 Aug 10. Polyneuropathy in cerebrotendinous xanthomatosis and response to treatment with chenodeoxycholic acid. Ginanneschi F, Mignarri A, Mondelli M, Gallus GN, Del Puppo M, Giorgi S, Federico A, Rossi A, Dotti MT. Section of Neurology and Clinical Neurophysiology, Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Viale Bracci 2, 53100, Siena, Italy. Polyneuropathy has been reported in cerebrotendinous xanthomatosis (CTX), although its nature and possible association with certain genotypes and phenotypes are unclear. The effect of chronic administration of chenodeoxycholic acid (CDCA) on peripheral nerve conduction parameters is still debated. We report clinical, laboratory, and electrophysiological findings in 35 CTX patients. Twenty-six subjects (74.2 %) showed peripheral nerve abnormalities. Polyneuropathy was predominantly axonal (76.9 % of patients) and generally mild. No correlation was found between its presence and clinical or biochemical data. In polyneuropathic patients, CDCA treatment improved electrophysiological conduction parameters, irrespective of the duration of therapy. Improvement mainly concerned nerve conduction velocities, whereas most nerve amplitudes remained unchanged. This means that CDCA treatment did not influence the number of axons activated by maximum electrical stimulation but increased the conduction of the still-excitable fibers. Our findings may suggest that CDCA treatment promotes myelin synthesis in nerve fibers with residual unaffected axons. The effect of therapy may therefore depend largely on the extent of irreversible structural damage to axons. PMID: 22878431 [PubMed - indexed for MEDLINE] 32. BMC Med Inform Decis Mak. 2012 Jul 31;12:78. doi: 10.1186/1472-6947-12-78. Querying phenotype-genotype relationships on patient datasets using semantic web technology: the example of Cerebrotendinous xanthomatosis. Taboada M, Martínez D, Pilo B, Jiménez-Escrig A, Robinson PN, Sobrido MJ. Department of Electronics and Computer Science, University of Santiago de Compostela, Edificio Monte da Condesa, Spain. maria.taboada@usc.es BACKGROUND: Semantic Web technology can considerably catalyze translational genetics and genomics research in medicine, where the interchange of information between basic research and clinical levels becomes crucial. This exchange involves mapping abstract phenotype descriptions from research resources, such as knowledge databases and catalogs, to unstructured datasets produced through experimental methods and clinical practice. This is especially true for the construction of mutation databases. This paper presents a way of harmonizing abstract phenotype descriptions with patient data from clinical practice, and querying this dataset about relationships between phenotypes and genetic variants, at different levels of abstraction. METHODS: Due to the current availability of ontological and terminological resources that have already reached some consensus in biomedicine, a reuse-based ontology engineering approach was followed. The proposed approach uses the Ontology Web Language (OWL) to represent the phenotype ontology and the patient model, the Semantic Web Rule Language (SWRL) to bridge the gap between phenotype descriptions and clinical data, and the Semantic Query Web Rule Language (SQWRL) to query relevant phenotype-genotype bidirectional relationships. The work tests the use of semantic web technology in the biomedical research domain named cerebrotendinous xanthomatosis (CTX), using a real dataset and ontologies. RESULTS: A framework to query relevant phenotype-genotype bidirectional relationships is provided. Phenotype descriptions and patient data were harmonized by defining 28 Horn-like rules in terms of the OWL concepts. In total, 24 patterns of SWQRL queries were designed following the initial list of competency questions. As the approach is based on OWL, the semantic of the framework adapts the standard logical model of an open world assumption. CONCLUSIONS: This work demonstrates how semantic web technologies can be used to support flexible representation and computational inference mechanisms required to query patient datasets at different levels of abstraction. The open world assumption is especially good for describing only partially known phenotype-genotype relationships, in a way that is easily extensible. In future, this type of approach could offer researchers a valuable resource to infer new data from patient data for statistical analysis in translational research. In conclusion, phenotype description formalization and mapping to clinical data are two key elements for interchanging knowledge between basic and clinical research. PMCID: PMC3444309 PMID: 22849591 [PubMed - indexed for MEDLINE] 33. Free Radic Biol Med. 2013 Jun;59:69-84. doi: 10.1016/j.freeradbiomed.2012.07.027. Epub 2012 Jul 27. Analytical strategies for characterization of oxysterol lipidomes: liver X receptor ligands in plasma. Griffiths WJ, Crick PJ, Wang Y, Ogundare M, Tuschl K, Morris AA, Bigger BW, Clayton PT, Wang Y. Institute of Mass Spectrometry, College of Medicine, Swansea University, Swansea SA2 8PP, UK. w.j.griffiths@swansea.ac.uk Bile acids, bile alcohols, and hormonal steroids represent the ultimate biologically active products of cholesterol metabolism in vertebrates. However, intermediates in their formation, including oxysterols and cholestenoic acids, also possess known, e.g., as ligands to nuclear and G-protein-coupled receptors, and unknown regulatory activities. The potential diversity of molecules originating from the cholesterol structure is very broad and their abundance in biological materials ranges over several orders of magnitude. Here we describe the application of enzyme-assisted derivatization for sterol analysis (EADSA) in combination with liquid chromatography-electrospray ionization-mass spectrometry to define the oxysterol and cholestenoic acid metabolomes of human plasma. Quantitative profiling of adult plasma using EADSA leads to the detection of over 30 metabolites derived from cholesterol, some of which are ligands to the nuclear receptors LXR, FXR, and pregnane X receptor or the G-protein-coupled receptor Epstein-Barr virus-induced gene 2. The potential of the EADSA technique in screening for inborn errors of cholesterol metabolism and biosynthesis is demonstrated by the unique plasma profile of patients suffering from cerebrotendinous xanthomatosis. The analytical methods described are easily adapted to the analysis of other biological fluids, including cerebrospinal fluid, and also tissues, e.g., brain, in which nuclear and G-protein-coupled receptors may have important regulatory roles. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22846477 [PubMed - in process] 34. Nihon Naika Gakkai Zasshi. 2012 May 10;101(5):1397-400. [Case report: A case of cerebrotendinous xanthomatosis with multiple large soft tissue tumors]. [Article in Japanese] Umemoto Y, Ueno H, Hara N, Nakamura T, Ohtsuki T, Yanase T, Yamawaki T, Matsumoto M. Department of Neurology, Hiroshima University Hospital, Japan. PMID: 22693862 [PubMed - indexed for MEDLINE] 35. Epilepsy Behav. 2012 Jul;24(3):380-1. doi: 10.1016/j.yebeh.2012.04.121. Epub 2012 May 30. Early-onset epilepsy as the main neurological manifestation of cerebrotendinous xanthomatosis. Pedroso JL, Pinto WB, Souza PV, Santos LT, Abud IC, Avelino MA, Barsottini OG. Department of Neurology, Universidade Federal de São Paulo, São Paulo, Brazil. zeluizpedroso@yahoo.com.br Cerebrotendinous xanthomatosis (CTX) is a rare inherited metabolic disorder, which usually presents with diverse systemic manifestations (ophthalmologic, cardiac, and dermatologic symptoms), and neurological dysfunction, such as neuropsychiatric symptoms, cognitive decline, and ataxia. Epilepsy is rarely seen as the main neurological manifestation of CTX. Herein, we describe a middle-aged woman with epilepsy since childhood as the only neurological symptom associated with the classical systemic manifestations of CTX. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22658436 [PubMed - indexed for MEDLINE] 36. Acta Neurol Belg. 2012 Sep;112(3):287-9. doi: 10.1007/s13760-012-0064-7. Epub 2012 Apr 17. Cerebrotendinous xanthomatosis presenting with asymmetric parkinsonism: a case with I-123-FP-CIT SPECT imaging. Schotsmans K, De Cauwer H, Baets J, Ceyssens S, van den Hauwe L, Deconinck T, Helsen G. Department of Neurology, Antwerp University Hospital, University of Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium. Cerebrotendinous xanthomatosis (CTX) is a rare inherited neurometabolic disease. Clinical symptoms are caused by increased deposition of cholestanol and cholesterol in various tissues. Progressive neurological symptoms are one of the principal manifestations. We report the case of a 44-year-old man who presented with asymmetric parkinsonism. In addition, there were mild bilateral pyramidal signs and a mild polyneuropathy. Brain MRI showed bilateral lesions in the dentate nucleus of the cerebellum and in the substantia nigra. Nuclear brain imaging using I-123-FP-CIT demonstrated an asymmetric reduced presynaptic dopaminergic function of the putamen and caudate nucleus, correlating well with his lateralized bradykinetic-rigid syndrome. CTX was diagnosed based on an increased plasma level of cholestanol, typical cerebellar brain lesions and the causative genetic mutation. CTX presenting with parkinsonism is considered rare and data on the neuroimaging of the dopaminergic deficit are limited. PMID: 22527785 [PubMed - indexed for MEDLINE] 37. PLoS One. 2012;7(4):e35333. doi: 10.1371/journal.pone.0035333. Epub 2012 Apr 11. Mapping of gene expression reveals CYP27A1 as a susceptibility gene for sporadic ALS. Diekstra FP, Saris CG, van Rheenen W, Franke L, Jansen RC, van Es MA, van Vught PW, Blauw HM, Groen EJ, Horvath S, Estrada K, Rivadeneira F, Hofman A, Uitterlinden AG, Robberecht W, Andersen PM, Melki J, Meininger V, Hardiman O, Landers JE, Brown RH Jr, Shatunov A, Shaw CE, Leigh PN, Al-Chalabi A, Ophoff RA, van den Berg LH, Veldink JH. Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands. Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 × 10(-51)) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS. PMCID: PMC3324559 PMID: 22509407 [PubMed - indexed for MEDLINE] 38. World J Gastroenterol. 2012 Mar 14;18(10):1067-76. doi: 10.3748/wjg.v18.i10.1067. Differential diagnosis in patients with suspected bile acid synthesis defects. Haas D, Gan-Schreier H, Langhans CD, Rohrer T, Engelmann G, Heverin M, Russell DW, Clayton PT, Hoffmann GF, Okun JG. Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children´s Hospital, Heidelberg D-69120, Germany. dorothea.haas@med.uni-heidelberg.de AIM: To investigate the clinical presentations associated with bile acid synthesis defects and to describe identification of individual disorders and diagnostic pitfalls. METHODS: Authors describe semiquantitative determination of 16 urinary bile acid metabolites by electrospray ionization-tandem mass spectrometry. Sample preparation was performed by solid-phase extraction. The total analysis time was 2 min per sample. Authors determined bile acid metabolites in 363 patients with suspected defects in bile acid metabolism. RESULTS: Abnormal bile acid metabolites were found in 36 patients. Two patients had bile acid synthesis defects but presented with atypical presentations. In 2 other patients who were later shown to be affected by biliary atresia and cystic fibrosis the profile of bile acid metabolites was initially suggestive of a bile acid synthesis defect. Three adult patients suffered from cerebrotendinous xanthomatosis. Nineteen patients had peroxisomal disorders, and 10 patients had cholestatic hepatopathy of other cause. CONCLUSION: Screening for urinary cholanoids should be done in every infant with cholestatic hepatopathy as well as in children with progressive neurological disease to provide specific therapy. PMCID: PMC3296980 PMID: 22416181 [PubMed - indexed for MEDLINE] 39. Neuroradiology. 2012 Jun;54(6):649-51. doi: 10.1007/s00234-012-1026-8. Epub 2012 Mar 15. Cerebrotendinous xanthomatosis with progressive cerebellar vacuolation : six-year MRI follow-up. Mignarri A, Dotti MT, Del Puppo M, Gallus GN, Giorgio A, Cerase A, Monti L. PMID: 22415344 [PubMed - indexed for MEDLINE] 40. Clin Neurol Neurosurg. 2012 Sep;114(7):1021-3. doi: 10.1016/j.clineuro.2012.01.032. Epub 2012 Feb 13. A case of cerebrotendinous xanthomatosis presenting with epilepsy as an initial symptom with a novel V413D mutation in the CYP27A1 gene. Koyama S, Kawanami T, Tanji H, Arawaka S, Wada M, Saito N, Kato T. Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. skoyama@med.id.yamagata-u.ac.jp PMID: 22336472 [PubMed - indexed for MEDLINE] 41. Neurol Neurochir Pol. 2011 Nov-Dec;45(6):600-3. Cerebrotendinous xanthomatosis: a rare cause of spinocerebellar syndrome. Ostrowska M, Banaszkiewicz K, Kiławiec A, Róg T, Lütjohann D, Szczudlik A. Department of Neurology, Jagiellonian University Medical Medical College, Krakow, Poland. mostroff@interia.pl A 34-year-old patient demonstrating pyramidal and cerebellar signs, accompanied by epilepsy, peripheral neuropathy, mental retardation and bilateral cataract was diagnosed with cerebrotendinous xanthomatosis based on the clinical picture, magnetic resonance imaging of the brain and serum sterol analysis. Tendon xanthomas were not observed in this case. After establishing the diagnosis, treatment with chenodeoxycholic acid and statin was introduced. During the next two years of the follow-up, serum cholestanol and 7α-hydroxycholesterol levels decreased in response to the therapy, but this was not reflected in the patient's neurological condition, which was slowly progressing. Treatment effectiveness in cerebrotendinous xanthomatosis is variable, notably better in patients who had started therapy before the injury to the nervous system took place. The present case report points to cerebrotendinous xanthomatosis as a rare cause of spinocerebellar syndrome, which might be treatable if diagnosed in early life. PMID: 22212991 [PubMed - indexed for MEDLINE] 42. Am J Med Sci. 2012 Apr;343(4):332-3. doi: 10.1097/MAJ.0b013e31823cf6d8. Cerebrotendinous xanthomatosis revealed in drug-resistant epilepsy diagnostic workup. Kauffman MA, Gonzalez-Morón D, Consalvo D, Kochen S. Consultorio de Neurogenética, Centro Universitario de Neurología JM Ramos Mejia, Buenos Aires, Argentina. marcelokauffman@conicet.gov.ar Cerebrotendinous xanthomatosis (CTX) is a treatable disorder of bile acid production caused by mutations in the mitochondrial enzyme sterol 27-hydroxilase. This inborn error of bile acid metabolism results in lipid pathologic accumulation in multiple tissues. Progressive neuropsychiatric disturbances are a frequent manifestation of this disease. Although seizures have been frequently noticed as part of CTX manifestations, there have not been reports of CTX being diagnosed in drug-resistant epilepsy diagnostic workup nor of seizure response to chenodeoxycholic acid treatment. Here, the authors present a case of a drug-resistant epilepsy patient with a complex phenotype where a diagnosis of CTX was done and showed a significant reduction in seizure frequency after chenodeoxycholic acid supplementation. This report illustrates the importance of considering treatable neurometabolic disorders in epileptic patients showing complex phenotypes. PMID: 22197981 [PubMed - indexed for MEDLINE] 43. Neurosci Lett. 2012 Jan 11;506(2):322-6. doi: 10.1016/j.neulet.2011.11.036. Epub 2011 Dec 2. The bile steroid chenodeoxycholate is a potent antagonist at NMDA and GABA(A) receptors. Schubring SR, Fleischer W, Lin JS, Haas HL, Sergeeva OA. Heinrich-Heine University, Medical Faculty, Molecular Neurophysiology, D-40225 Dusseldorf, Germany. The bile steroids (BS) cholic acid and chenodeoxycholic acid are produced in hepatocytes and in the brain. Nothing is known about neuronal actions of BS. Deficiency in a 27-hydroxylase enzyme coincides with reduced production of chenodeoxycholic acid (CDCA) and a relative increase in cholic acid in an inherited lipid storage disease, cerebrotendinous xanthomatosis, characterized by neurological dysfunctions, which can be treated by dietary CDCA. We have examined the modulation of hypothalamic network activity by nine common BS. Cholate and CDCA significantly reduced the firing of hypothalamic neurons and synchronized network activity with CDCA being nearly 10 times more potent. The synthetic BS dehydrocholate synchronized the activity without affecting the firing rate. Gabazine, a GABA(A) receptor antagonist, occluded synchronization by BS. Whole-cell patch clamp recordings revealed a block of NMDA- and GABA(A)-receptors by BS. Potencies of nine common BS differed between NMDA and GABA(A) receptors, however in both cases they correlated with BS affinities for albumin but not with their lipophilicity, supporting a direct action at ligand gated ion channels. GABAergic synaptic currents displayed a faster decay under BS. Our data provide new insight into extrahepatic functions of BS revealing their neuroactive potential. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID: 22155097 [PubMed - indexed for MEDLINE] 44. Orthopedics. 2011 Dec 6;34(12):e960-4. doi: 10.3928/01477447-20111021-28. Bilateral Achilles tendon enlargement. Huang L, Miao XD, Yang DS, Tao HM. Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Cerebrotendinous xanthomatosis is a rare, autosomal-recessive, lipid-storage disease with accumulation of cholestanol in most tissues, particularly within the Achilles tendons. It has been characterized both clinically and biochemically, and recently from the molecular biological aspect as well. Juvenile cataract, childhood diarrhea, mental retardation, cerebellar ataxia, and tendon xanthomas are the most prominent features of this disease. Bilateral symmetrical firm masses of Achilles tendons may be the first symptom the patient recognizes because it can jeopardize his or her ability to walk. However, the treatment strategies for tendon tumors vary. In a recent case, we diagnosed the disease properly, according to the clinical manifestations and the radiological and laboratory examinations. The genetic mutation was characterized by analyzing sterol 27-hydroxylase from the patient's family (located on nucleotide 599) and led to a nonsense mutation. It is a unique type of mutation that has never been reported to our knowledge. Tendon lesions are characterized by the loss of muscle fibers and accumulation of lipid products. To help the patient regain the strength of the Achilles tendon and walking abilities, a large area of tendon tumor was excised, followed by reconstruction with a tibialis posterior allograft, which is the second strongest tendon in the foot and ankle. Although the use of this type of graft is uncommon, the final result was satisfactory. At the 10-month follow-up examination, the patient could walk easily without pain. This case report suggests that the surgical procedure will provide an alternative for the repair of large-area degenerative Achilles tendons. Copyright © 2011, SLACK Incorporated. PMID: 22146219 [PubMed - indexed for MEDLINE] 45. Best Pract Res Clin Rheumatol. 2011 Oct;25(5):683-701. doi: 10.1016/j.berh.2011.10.016. Miscellaneous non-inflammatory musculoskeletal conditions. Rare thesaurismosis and xanthomatosis. Chalès G, Coiffier G, Guggenbuhl P. INSERM UMR 991, Service de Rhumatologie, Hôpital Sud, CHU, Rennes, France. gerard.chales@chu-rennes.fr The focus will be on xanthomatosis, a tissue danger signal which needs to be recognized by the clinician, and its relationship with monogenetic lipoprotein disorders (cholesterol, triglycerides), bile acid and sterol metabolism, particularly on metabolic pathways and genetics as well as on musculoskeletal and cardiovascular involvement, and their implications for clinical management. The critical question is to assess coronary heart disease risk, requiring correct identification of the pattern of lipoprotein disorders and of the causes (primary or secondary). Familial hypercholesterolemia must be suspected in adults and children with raised total cholesterol, especially when there is a personal or a family history of premature coronary heart disease, usually requiring potent statins to achieve adequate LDL-cholesterol lowering, even if we do not know safety of long-term therapy and whether treatments of dyslipidemia early in life prevent cardiovascular diseases in adulthood. Cerebrotendinous xanthomatosis is a treatable disease and must be suspected if there is a history of infantile chronic diarrhea and/or juvenile cataracts, even in the absence of tendon xanthomas. Current evidence for the prevention and screening, diagnosis, and treatment of dyslipidemia are available for the clinicians. Copyright © 2011 Elsevier Ltd. All rights reserved. PMID: 22142747 [PubMed - indexed for MEDLINE] 46. Gen Hosp Psychiatry. 2012 Sep-Oct;34(5):578.e1-4. doi: 10.1016/j.genhosppsych.2011.10.008. Epub 2011 Nov 30. Fluoxetine-responsive depression in a Chinese cerebrotendinous xanthomatosis. Chen Q, Liu W, Jiang B, Yu R, Li X, Li H. Department of Psychiatry, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China. Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive, lipid storage disorder which is extremely rare in the Chinese population. It is characterized by progressive neurologic dysfunction and enlargement of tendon xanthomas, and is often accompanied with neuropsychiatric symptoms. Few reports are available regarding depression and antidepressant medication in CTX patients. Here, we report a Chinese case of CTX associated with fluoxetine-responsive major depression. Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22133984 [PubMed - indexed for MEDLINE] 47. FEBS J. 2012 May;279(9):1516-33. doi: 10.1111/j.1742-4658.2011.08432.x. Epub 2011 Dec 22. Cytochrome P450s in the synthesis of cholesterol and bile acids--from mouse models to human diseases. Lorbek G, Lewinska M, Rozman D. Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. The present review describes the transgenic mouse models that have been designed to evaluate the functions of the cytochrome P450s involved in cholesterol and bile acid synthesis, as well as their link with disease. The knockout of cholesterogenic Cyp51 is embrionally lethal, with symptoms of Antley-Bixler syndrome occurring in mice, whereas the evidence for this association is conflicting in humans. Disruption of Cyp7a1 from classic bile acid synthesis in mice leads to either increased postnatal death or a milder phenotype with elevated serum cholesterol. The latter is similar to the case in humans, where CYP7A1 mutations associate with high plasma low-density lipoprotein and hepatic cholesterol content, as well as deficient bile acid excretion. Disruption of Cyp8b1 from an alternative bile acid pathway results in the absence of cholic acid and a reduced absorption of dietary lipids; however, the human CYP8B1 polymorphism fails to explain differences in bile acid composition. Unexpectedly, apparently normal Cyp27a1(-/-) mice still synthesize bile acids that originate from the compensatory pathway. In humans, CYP27A1 mutations cause cerebrotendinous xanthomatosis, suggesting that only mice can compensate for the loss of alternative bile acid synthesis. In line with this, Cyp7b1 knockouts are also apparently normal, whereas human CYP7B1 mutations lead to a congenital bile acid synthesis defect in children or spastic paraplegia in adults. Mouse knockouts of the brain-specific Cyp46a1 have reduced brain cholesterol excretion, whereas, in humans, CYP46A1 polymorphisms associate with cognitive impairment. At present, cytochrome P450 family 39 is poorly characterized. Despite important physiological differences between humans and mice, mouse models prove to be an invaluable tool for understanding the multifactorial facets of cholesterol and bile acid-related disorders. © 2011 The Authors Journal compilation © 2011 FEBS. PMID: 22111624 [PubMed - indexed for MEDLINE] 48. BMC Neurol. 2011 Oct 21;11:130. doi: 10.1186/1471-2377-11-130. 2 Novel deletions of the sterol 27-hydroxylase gene in a Chinese Family with Cerebrotendinous Xanthomatosis. Tian D, Zhang ZQ. Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, 6 Tiantan Xili, Chongwen District, Beijing 100050, China. BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare lipid-storage disease. We investigated the clinic manifestation, histopathology and sterol 27-hydroxylase gene (CYP27A1) in a Chinese family with Cerebrotendinous Xanthomatosis (CTX). CASE PRESENTATION: A 36-year-old female with typical CTX clinical manifestation had Spindle-shaped lipid crystal clefts in xanthomas and "onion-like demyelination" in sural nerve. The patient was compound heterozygote carrying two deletions in exon 1 (c.73delG) and exon 2 (c.369_375delGTACCCA). The family memebers were carriers. CONCLUSIONS: A Chinese family with Cerebrotendinous Xanthomatosis had typical clinical manifestation. CYP27A1 mutations were found in the proband and all other family members. PMCID: PMC3226568 PMID: 22018287 [PubMed - indexed for MEDLINE] 49. Eur J Med Genet. 2012 Jan;55(1):71-4. doi: 10.1016/j.ejmg.2011.08.003. Epub 2011 Sep 16. Three siblings with Cerebrotendinous Xanthomatosis: a novel mutation in the CYP27A1 gene. Suh S, Kim HK, Park HD, Ki CS, Kim MY, Jin SM, Kim SW, Hur KY, Kim KW, Kim JH. Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Gangnam-Gu, Seoul 135-710, Republic of Korea. Cerebrotendinous Xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease caused by sterol 27-hydroxylase (CYP27) deficiency. We report three CTX siblings that shared a novel mutation of the CYP27A1 gene. These siblings presented with elevated cholestanol levels and typical manifestations such as tendon xanthomas, cataracts, osteopenia, mental retardation, cerebellar ataxia and peripheral neuropathy. All shared the same genetic mutation, c.1146_1151delins and c.1214G>A of CYP27A1. All were treated with 750 mg/day chenodeoxycholic acid (CDCA). In conclusion, one should consider the possibility of CTX in any individual with normocholesterolemic xanthomatosis, early-onset cataracts, mental retardation, cerebellar ataxia and peripheral neuropathy. Copyright © 2011 Elsevier Masson SAS. All rights reserved. PMID: 21958693 [PubMed - indexed for MEDLINE] 50. Clin Genet. 2012 Jan;81(1):24-8. doi: 10.1111/j.1399-0004.2011.01793.x. Epub 2011 Oct 16. Extreme xanthomatosis in patients with both familial hypercholesterolemia and cerebrotendinous xanthomatosis. Huijgen R, Stork AD, Defesche JC, Peter J, Alonso R, Cuevas A, Kastelein JJ, Duran M, Stroes ES. Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Two unrelated individuals were referred to Lipid Clinics in The Netherlands and Chile with extreme xanthomatosis and hypercholesterolemia. Both were diagnosed with heterozygous familial hypercholesterolemia (heFH) after molecular genetic analysis of the low-density lipoprotein (LDL) receptor gene. Since heFH by itself could not account for the massive xanthomas, the presence of an additional hereditary lipid or lipoprotein disorder was suspected. Further genetic analysis revealed homozygozity for mutations in the sterol 27-hydroxylase gene, confirming the diagnosis of cerebrotendinous xanthomatosis (CTX). Markedly, the typical neurological manifestations of CTX were absent, suggestive of a protective role of LDL-receptor deficiency against the severe neurological consequences of CTX. © 2011 John Wiley & Sons A/S. PMID: 21955034 [PubMed - indexed for MEDLINE] 51. Pract Neurol. 2011 Oct;11(5):296-300. doi: 10.1136/practneurol-2011-000003. A neurological rarity not to be missed: cerebrotendinous xanthomatosis. Rafiq M, Sharrack N, Shaw PJ, Hadjivassiliou M. Department of Neurology, Royal Hallamshire Hospital, Sheffield, UK. PMID: 21921005 [PubMed - indexed for MEDLINE] 52. Arch Ophthalmol. 2011 Aug;129(8):1087-8. doi: 10.1001/archophthalmol.2011.219. Cerebrotendinous xanthomatosis: a treatable disease with juvenile cataracts as a presenting sign. Monson DM, DeBarber AE, Bock CJ, Anadiotis G, Merkens LS, Steiner RD, Stout AU. Casey Eye Institute, Portland, OR, USA. PMCID: PMC3366103 PMID: 21825196 [PubMed - indexed for MEDLINE] 53. J Neurol. 2012 Feb;259(2):364-6. doi: 10.1007/s00415-011-6167-x. Epub 2011 Jul 19. Leukodystrophy with a cerebellar cystic aspect and intracranial atherosclerosis: an atypical presentation of cerebrotendinous xanthomatosis. Androdias G, Vukusic S, Gignoux L, Boespflug-Tanguy O, Acquaviva C, Zabot MT, Couvert P, Carrie A, Confavreux C, Labauge P. PMID: 21769531 [PubMed - indexed for MEDLINE] 54. Parkinsonism Relat Disord. 2012 Jan;18(1):99-101. doi: 10.1016/j.parkreldis.2011.06.004. Epub 2011 Jul 20. Parkinsonism as neurological presentation of late-onset cerebrotendinous xanthomatosis. Mignarri A, Falcini M, Vella A, Giorgio A, Gallus GN, Del Puppo M, Vattimo A, Federico A, Dotti MT. Neurology and Neurometabolic Unit, Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy. PMID: 21764626 [PubMed - indexed for MEDLINE] 55. Chem Phys Lipids. 2011 Sep;164(6):530-4. doi: 10.1016/j.chemphyslip.2011.05.001. Epub 2011 Jun 6. Monitoring of 7α-hydroxy-4-cholesten-3-one during therapy of cerebrotendinous xanthomatosis: a case report. Matysik S, Orsó E, Black A, Ahrens N, Schmitz G. Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany. Cerebrotendinous xanthomatosis (CTX) is a rare, inherited autosomal-recessive lipid-storage disorder caused by 27-hydroxylase deficiency. In this study, we report of a 30-year old man with this disorder who was treated using chenodeoxycholic acid, simvastatin, and low-density lipoprotein (LDL) apheresis. The LDL apheresis was performed weekly for nine months. The first subjective improvement was reported by the patient after his fourth LDL-apheresis. Spasticity, gait disturbances, and his entire psychomotoric test results had improved tremendously. His fine motoric skills have been regained. The efficacy of LDL-apheresis was monitored using quantitative determination of 7α-OH-4-cholesten-3-one in plasma based on a LC-MS/MS method. The clearance efficacy of 7α-hydroxy-4-cholesten-3-one from the patient's plasma per LDL-apheresis varied between 8% and 53% but returned to the initial high levels after seven days (mean value 241 ng/mL). A slight negative trend in the plasma concentration could be derived over the period of nine months. Copyright © 2011. Published by Elsevier Ireland Ltd. PMID: 21679699 [PubMed - indexed for MEDLINE] 56. Eur J Neurol. 2011 Oct;18(10):1203-11. doi: 10.1111/j.1468-1331.2011.03439.x. Epub 2011 Jun 4. Cerebrotendinous xanthomatosis in Spain: clinical, prognostic, and genetic survey. Pilo-de-la-Fuente B, Jimenez-Escrig A, Lorenzo JR, Pardo J, Arias M, Ares-Luque A, Duarte J, Muñiz-Pérez S, Sobrido MJ. Division of Neurology, Hospital del Sureste, Ronda del Sur s/n, Arganda del Rey, Madrid, Spain. bpilodelafuente@yahoo.es BACKGROUND AND PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by mutations in the CYP27A1 gene resulting in sterol-27-hydroxylase deficiency. Current information about CTX is based mainly on case reports, with only few large series reported. Although perceived as a potentially treatable condition, efficacy of chenodeoxycholic acid plus statin therapy remains unclear. To perform a nationwide survey of confirmed cases, with a thorough analysis of genotype-phenotype data and prognostic factors. METHODS: Retrospective review of the clinical and epidemiological aspects and mutations of all the patients diagnosed since 1992 in the main reference centers for genetic testing of CTX in Spain. RESULTS: Twenty-five patients from 19 families were identified. An average delay of 19 years was observed between symptom onset and clinical diagnosis. Two main clinical subgroups were recognizable: a classic form (cerebellar and other supratentorial symptoms) and a spinal form (chronic myelopathy). Cholestanol levels did not correlate with clinical presentation, severity or response to therapy. Despite treatment, five patients died during follow-up, one to 4 years after diagnosis. Thirteen different mutations were identified, with a higher frequency of p.R395C in Northwestern Spain and p.R405W in Southern Spain. None of the mutations could be associated with a particular clinical feature combination or prognosis. CONCLUSIONS: This is the first nationwide extensive series of CTX reported in Spain. The higher number of cases in some areas suggests a possible founder effect. Spinal forms had a less severe prognosis. A delayed diagnosis could contribute to the lack of significant response to treatment. © 2011 The Author(s). European Journal of Neurology © 2011 EFNS. PMID: 21645175 [PubMed - indexed for MEDLINE] 57. BMC Neurol. 2011 May 31;11:63. doi: 10.1186/1471-2377-11-63. Neuromuscular abnormality and autonomic dysfunction in patients with cerebrotendinous xanthomatosis. Chen SF, Tsai NW, Chang CC, Lu CH, Huang CR, Chuang YC, Chang WN. Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare lipid-storage disease. Neuromuscular abnormality and autonomic system (ANS) dysfuction in CTX are rarely examined in large-scale studies in the literature. We studied the peripheral nervous system, myopathology, and autonomic system of four CTX patients and performed a literature review of the reported CTX patients with peripheral neuropathy. METHODS: Four biochemically and genetically confirmed CTX patients, belonging to two families, were included for study and all received nerve conduction study (NCS), muscle biopsy for histopathologic and ultrastructural study, skin biopsy for intraepidermal nerve fiber (INEF) density measurement, autonomic testings including sympathetic skin response, R-R interval variation and head-up tilt test using an automated tilt table to record the changes of blood pressure and heart rate in different postures. The Q-Sweat test was also applied for the detection of sweat amount and onset time of response. The clinical characteristics, study methods and results of 13 studies of peripheral neuropathy in CTX patients in the literature were also recorded for analysis. RESULTS: The results of NCS study showed axonal sensory-motor polyneuropathy in three CTX cases and mixed axonal and demyelinating sensor-motor polyneuropathy in one. The myopathological and histopathologic studies revealed mild denervation characteristics, but the ultrastructural study revealed changes of mitochondria and the membranous system, and increased amounts of glycogen, lipofuscin and lipid deposition. The ANS study revealed different degrees of abnormalities in the applied tests and the INEF density measurement showed small fiber neuropathy in three of the four CTX patients. The literature review of peripheral neuropathy in CTX revealed different types of peripheral neuropathy, of which axonal peripheral neuropathy was the most common. CONCLUSIONS: Peripheral neuropathy, especially the subtype of axonal sensori-motor neuropathy, is common in patients with CTX. Evidence of lipid metabolic derangement in CTX can be reflected in ultrastructural studies of muscles. With an adequate multi-parametric evaluation, a high incidence of ANS abnormalities can be seen in this rare lipid-storage disease, and a high incidence of small fiber involvement is also reflected in the IENF density measurement of skin biopsies. PMCID: PMC3119170 PMID: 21627786 [PubMed - indexed for MEDLINE] 58. J Orthop Sci. 2011 Nov;16(6):825-7. doi: 10.1007/s00776-011-0072-0. Epub 2011 May 7. A compound heterozygous mutation of CYP27A1 gene in a Taiwanese patient with cerebrotendinous xanthomatosis. Chen WC, Wu KC, Hu CH, Chern TC, Jou IM. Department of Emergency Medicine, College of Medicine, National Cheng-Kung University and Hospital, Tainan, Taiwan. PMID: 21553098 [PubMed - indexed for MEDLINE] 59. Parkinsonism Relat Disord. 2011 Aug;17(7):570-2. doi: 10.1016/j.parkreldis.2011.04.006. Epub 2011 Apr 29. Botulinum toxin-responsive oromandibular dystonia in cerebrotendinous xanthomatosis. Posada IJ, Ramos A. PMID: 21531161 [PubMed - indexed for MEDLINE] 60. Muscle Nerve. 2011 Apr;43(4):531-6. doi: 10.1002/mus.21905. Neurophysiological study in cerebrotendinous xanthomatosis. Pilo B, de Blas G, Sobrido MJ, Navarro C, Grandas F, Barrero FJ, Moya MA, Jimenez-Escrig A. Neurology Division, Hospital del Sureste, c/ Ronda del Sur s/n, 28500 Madrid, Spain. bpilodelafuente@yahoo.es INTRODUCTION: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal-recessive disease due to mutations of the 27α-hydroxylase. It is characterized by cataracts, xanthomas, and neurological manifestations. Polyneuropathy has been reported, although it is unclear whether it is axonal or demyelinating. METHODS: We report clinical and neurophysiological results of 13 patients with CTX diagnosed in Spain. RESULTS: In 8 patients (62%), peripheral neuropathy was demonstrated (4 demyelinating, 3 axonal, and 1 mixed; 3 predominantly motor and 5 sensorimotor). All patients had clinical signs/symptoms of peripheral neuropathy. Upper limb somatosensory evoked potentials (SSEPs) were affected in 38% of patients, and lower limb SSEPs in 67%. Fifty percent of patients had delayed brainstem auditory evoked potentials, and 43% had affected visual evoked potentials. DISCUSSION: In this series, polyneuropathy was predominantly sensorimotor and demyelinating. Neurophysiological studies correlated only partially with clinical follow-up. Therefore, we recommend neurophysiological follow-up studies only if clinical symptoms are present. Copyright © 2011 Wiley Periodicals, Inc. PMID: 21404287 [PubMed - indexed for MEDLINE] 61. Neurologia. 2011 Sep;26(7):397-404. doi: 10.1016/j.nrl.2010.12.009. Epub 2011 Feb 22. [Usefulness of cholestanol levels in the diagnosis and follow-up of patients with cerebrotendinous xanthomatosis]. [Article in Spanish] Pilo de la Fuente B, Sobrido MJ, Girós M, Pozo L, Lustres M, Barrero F, Macarrón J, Díaz M, Jiménez-Escrig A. Sección de Neurología, Hospital del Sureste, Arganda del Rey, Madrid, España. bpilodelafuente@yahoo.es INTRODUCTION: cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disease caused by a deficiency of mitochondrial enzyme sterol 27-hydrolylase. Such a deficiency results in a reduced production of chenodeoxycholic acid and in an increased formation of cholestanol. It is clinically characterized by cataracts, diarrhoea, xanthomas, premature arteriosclerosis and a number of progressive neurological symptoms. Although cholestanol levels are used for the diagnosis of CTX, their correlation with the clinical symptoms and their prognostic usefulness have not been assessed so far. METHODS: we reviewed 14 CTX patients diagnosed between 1995 and 2008 in two reference centres for the genetic diagnosis of this disorder, whose cholestanol levels had been recorded. We studied the main demographic, clinical and therapeutical data and their correlation with plasma cholestanol levels. RESULTS: the average cholestanol level at diagnosis was 105.8 μmol/l. These levels did not correlate with any neurological symptoms or with disability at diagnosis scored by the EDSS. After treatment, all patients achieved a significant reduction in plasma cholestanol levels (average reduction of 91 μmol/l in an average follow-up of 34 months), although only one patient remained clinically stable. CONCLUSIONS: high cholestanol levels are very useful for diagnosis of CTX but they do not have a prognostic value (they do not correlate with severity). Normalisation of cholestanol levels is not always associated with clinical stabilisation. However, follow-up of cholestanol levels can be useful for the dose adjustment. 2010 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved. PMID: 21345536 [PubMed - indexed for MEDLINE] 62. J Hepatol. 2011 Oct;55(4):885-95. doi: 10.1016/j.jhep.2010.12.037. Epub 2011 Feb 18. Insufficient bile acid signaling impairs liver repair in CYP27(-/-) mice. Meng Z, Liu N, Fu X, Wang X, Wang YD, Chen WD, Zhang L, Forman BM, Huang W. Division of Gene Regulation and Drug Discovery, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA. BACKGROUND & AIMS: Previous studies indicate that bile acids (BAs) promote normal liver regeneration and repair after injury. However, the impact of insufficient BA signaling, which is observed in patients with BA sequestrant medication or cerebrotendinous xanthomatosis (CTX) disease, on liver injury is still unknown. Our aim is to determine the outcomes of reduced BA levels upon liver injury. METHODS: Seventy percent partial hepatectomy (PH) and carbon tetrachloride (CCl(4)) treatment were performed using CYP27(-/-) mice, a genetic animal model with low BA levels. The liver repair of CYP27(-/-) mice after the treatments was characterized by histological staining, chemical analysis, and quantitative real-time PCR. RESULTS: CYP27(-/-) mice exhibited enhanced CCl(4)-induce liver injury, and defective liver regeneration and prolonged steatosis after 70% PH. Due to the insufficient BA signaling, farnesoid X receptor (FXR) activities were significantly reduced in CYP27(-/-) livers after 70% PH. Activation of FXR by either 0.2% cholic acid feeding or oral infusion of an FXR agonist greatly promoted liver regeneration in CYP27(-/-) mice. CONCLUSIONS: Normal physiological levels of BAs are required for liver repair. Patients with BA sequestrant medications or CTX disease due to CYP27 gene mutations may have an increased risk of liver failure, and treatment with FXR ligands can promote liver regeneration of patients with low BA levels. Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. PMID: 21334403 [PubMed - indexed for MEDLINE] 63. Clinics (Sao Paulo). 2010;65(11):1217-8. Cerebrotendinous xanthomatosis: a treatable hereditary neuro-metabolic disease. Cerqueira AC, Nardi AE, Bezerra JM. PMCID: PMC2999723 PMID: 21243300 [PubMed - indexed for MEDLINE] 64. BMJ Case Rep. 2011 Sep 5;2011. pii: bcr0820114582. doi: 10.1136/bcr.08.2011.4582. Cerebrotendinous xanthomatosis: a rare genetic disorder. Bhojwani RA, Khot R. Medicine department, Government Medical college, Nagpur, India. rohan9_88@yahoo.com A 32-year-old male patient presented with uncontrolled convulsions to the emergency room. He had epilepsy since childhood and was on tablet phenytoin sodium 100 mg three times a day. However, on detailed history elicitation and clinical examination, he was found to have a constellation of findings. He had multiple swellings over both the lower limbs and upper limbs at the site of various tendon insertions (xanthomas), mental retardation, speech disturbance, bilateral pyramidal tract involvement and bilateral cataracts. Based on clinical features, a diagnosis of cerebrotendinous xanthomatosis: a relatively rare genetic disorder was suspected, and later on confirmed histopathologically. PMCID: PMC3176383 PMID: 22679194 [PubMed - indexed for MEDLINE] 65. J Chromatogr B Analyt Technol Biomed Life Sci. 2011 May 15;879(17-18):1384-92. doi: 10.1016/j.jchromb.2010.11.019. Epub 2010 Nov 23. Profiling sterols in cerebrotendinous xanthomatosis: utility of Girard derivatization and high resolution exact mass LC-ESI-MS(n) analysis. DeBarber AE, Sandlers Y, Pappu AS, Merkens LS, Duell PB, Lear SR, Erickson SK, Steiner RD. Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, United States. debarber@ohsu.edu In this study we profile free 3-oxo sterols present in plasma from patients affected with the neurodegenerative disorder of sterol and bile acid metabolism cerebrotendinous xanthomatosis (CTX), utilizing a combination of charge-tagging and LC-ESI-MS(n) performed with an LTQ-Orbitrap Discovery instrument. In addition, we profile sterols in plasma from 24-month-old cyp27A1 gene knockout mice lacking the enzyme defective in CTX. Charge-tagging was accomplished by reaction with cationic Girard's P (GP) reagent 1-(carboxymethyl) pyridinium chloride hydrazide, an approach uniquely suited to studying the 3-oxo sterols that accumulate in CTX, as Girard's reagent reacts with the sterol oxo moiety to form charged hydrazone derivatives. The ability to selectively generate GP-tagged 3-oxo-4-ene and 3-oxo-5(H) saturated plasma sterols enabled ESI-MS(n) analysis of these sterols in the presence of a large excess (3 orders of magnitude) of cholesterol. Often cholesterol detected in biological samples makes it challenging to quantify minor sterols, with cholesterol frequently removed prior to analysis. We derivatized plasma (10 μl) without SPE removal of cholesterol to ensure detection of all sterols present in plasma. We were able to measure 4-cholesten-3-one in plasma from untreated CTX patients (1207±302 ng/ml, mean±SD, n=4), as well as other intermediates in a proposed pathway to 5α-cholestanol. In addition, a number of bile acid precursors were identified in plasma using this technique. GP-tagged sterols were identified utilizing high resolution exact mass spectra (±5 ppm), as well as MS(2) ([M](+)→) spectra that possessed characteristic neutral loss of 79Da (pyridine) fragment ions, and MS(3) ([M](+)→[M-79](+)→) spectra that provided additional structurally informative fragment ions. Copyright © 2010 Elsevier B.V. All rights reserved. PMCID: PMC3326078 PMID: 21168372 [PubMed - indexed for MEDLINE] 66. Clin Nucl Med. 2011 Jan;36(1):38-9. doi: 10.1097/RLU.0b013e3181feed83. SPECT imaging for brain improvement quantification in a patient with cerebrotendinous xanthomatosis. Selva-O'Callaghan A, Bardes I, Jacas C, Jubany L, Lorenzo-Bosquet C, Cuberas-Borrós G, Vilardell-Tarres M. Internal Medicine Department, Vall D'Hebron General Hospital, Barcelona, Spain. aselva@vhebron.net Cerebrotendinous xanthomatosis is a rare recessive autosomal disease caused by mutations of the sterol 27-hydroxylase gene (CYP27), which leads to reduced synthesis of bile acids, particularly chenodeoxycholic acid (Cali et al, J Biol Chem. 1991;266:7779-7783; Gallus et al, Neurol Sci. 2006;27:143-149). The disease is characterized by progressive neurologic dysfunction due to accumulation of cholestanol in neurologic tissues (Moghadasian et al, Arch Neurol. 2002;59:527-529; Selva-O'Callaghan et al, Rheumatology. 2007;46:1212-1213). Long-term treatment with chenodeoxycholic acid can arrest or even reverse progression of the disease (Pierre et al, J Inherit Metab Dis. In press).Brain SPECT with 740 MBq of Tc-99m ethyl cysteinate dimmer, using a double-head gamma camera (Siemens E.cam) with high-resolution, low-energy parallel collimators was performed in our patient at onset and 2 years after starting chenodeoxycholic acid treatment. SPECT acquisitions were performed using a 360-degree orbit, 1 image/30 seg/3 degree, and 128 × 128 matrix. Reconstruction was by means of filtered back-projection, Butterworth 5/0.25, without attenuation correction. Pre- and post-SPECT dicom images were reoriented into Talairach space using NeuroGam (Segami Corporation). To visually identify abnormal perfusion regions, volume render brain image was computed, where abnormal perfusion regions were found by comparing with age-matched normal database, and Brodmann areas (BA) were quantified. Pre- versus post-treatment changes were computed by means of relative percentage between counts. Post-treatment SPECT showed better perfusion than pretreatment SPECT with an increase between 5% and 10% in frontal cortex (BA 9, BA 24, BA 32, BA 46, BA 47), parietal cortex (BA 5, BA 31), and temporal cortex (BA 20, BA 22, BA 28, BA 36, BA 37, BA 38), and with an increase of more than 10% in frontal cortex (BA 45) and parietal cortex (BA 23). This case illustrates the benefit of bile acid therapy for halting and even reversing neurologic retardation in this condition. PMID: 21157207 [PubMed - indexed for MEDLINE] 67. J Cardiovasc Med (Hagerstown). 2012 Apr;13(4):281-3. doi: 10.2459/JCM.0b013e32834058b8. Acute myocardial infarction in patient with cerebrotendinous xanthomatosis: should these patients undergo stress tests during screening? Passaseo I, Cacciotti L, Pauselli L, Ansalone G. Cardiology Unit, Madre Giuseppina Vannini Hospital, Rome, Italy. ilaria.passaseo@gmail.com PMID: 21135585 [PubMed - indexed for MEDLINE] 68. J Neurol. 2011 May;258(5):783-90. doi: 10.1007/s00415-010-5829-4. Epub 2010 Nov 21. Clinical relevance and neurophysiological correlates of spasticity in cerebrotendinous xanthomatosis. Mignarri A, Rossi S, Ballerini M, Gallus GN, Del Puppo M, Galluzzi P, Federico A, Dotti MT. Neurometabolic Unit, Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Siena, Italy. Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disease due to defective activity of sterol 27-hydroxylase, with plasma and tissue cholestanol storage. Clinical phenotype is characterized by both systemic manifestations and neurological signs. Therapy with chenodeoxycholic acid (CDCA) suppresses abnormal bile acid synthesis. The purpose of the study was to assess the frequency and clinical relevance of spasticity in the CTX phenotype and to study the usefulness of transcranial magnetic stimulation (TMS) in detecting corticospinal tract damage and monitoring the effects of replacement therapy. Twenty-four CTX patients underwent clinical evaluation including general disability scores, pyramidal and cerebellar function scales, assessment of serum cholestanol and TMS. Nine patients who started CDCA therapy at baseline received clinical and neurophysiological follow up. All patients showed signs of pyramidal damage which were relevant for clinical disability in 18 out of 24 cases (75%), resulting in spastic paraparesis. TMS revealed corticospinal alterations even in subjects with mild clinical signs of corticospinal tract involvement. After CDCA treatment, serum cholestanol decreased to normal concentrations in all patients. Clinical picture was unchanged in seven out of nine cases; in two others pyramidal signs disappeared. A reduction in abnormal neurophysiological parameters was found. Spastic paraparesis is the most frequent and relevant neurological feature in CTX patients. Replacement treatment with CDCA can prevent the progression of pyramidal damage, especially if started early in the course of the disease. TMS represents a sensitive indicator of corticospinal tract dysfunction and subclinical improvements in pyramidal function after CDCA therapy. PMID: 21104094 [PubMed - indexed for MEDLINE] 69. Clin Neuropathol. 2010 Nov-Dec;29(6):361-4. Clinical imaging and neuropathological correlations in an unusual case of cerebrotendinous xanthomatosis. Wallon D, Guyant-Maréchal L, Laquerrière A, Wevers RA, Martinaud O, Kluijtmans LA, Yntema HG, Saugier-Veber P, Hannequin D. Department of Neurology, Rouen University Hospital, France. david.wallon@chu.rouen.fr Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disorder due to a deficiency of the mitochondrial enzyme sterol 27-hydroxylase (CYP 27) with reduced or no chenodeoxycholic synthesis. This deficiency leads to an accumulation of cholestanol in different sites such as the eye lens, central nervous system or tendons. We report a 64-year-old female patient with a progressive gait disorder associated with cognitive decline since the age of 59. The patient had no mental retardation, cataract or chronic diarrhea. Her family reported increasing behavioral modifications 10 years previously. Clinical examination revealed a spastic paraplegia and bilateral xanthomas on the Achilles tendons. Cerebral magnetic resonance imaging (MRI) revealed diffuse hyperintense T2 abnormalities in the pyramidal tracts from the internal capsules to the cerebral peduncles also Technetium-99m-ECD brain SPECT showed a severe cerebellar hypoperfusion. Serum cholestanol analysis was 7 µmol/l (N). After 2 years, she was bedridden and died of aspiration pneumonia. The neuropathological study confirmed the CTX diagnosis and the sequencing analysis revealed that she was compound heterozygous for two mutations in the CYP27A1 gene: 1435 C > T (exon 7) on one allele and a new mutation, 1017 G > C (exon 5) on the other. The interest of the present case is to report neuropathology findings strongly correlated with the MRI and SPECT abnormalities. PMID: 21073839 [PubMed - indexed for MEDLINE] 70. J Neurol Neurosurg Psychiatry. 2010 Nov;81(11):1189-93. doi: 10.1136/jnnp.2009.203364. Clinical relevance of brain volume changes in patients with cerebrotendinous xanthomatosis. Guerrera S, Stromillo ML, Mignarri A, Battaglini M, Marino S, Di Perri C, Federico A, Dotti MT, De Stefano N. Department of Neurological and Behavioural Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy. OBJECTIVE: To quantify total and regional brain damage in subjects with cerebrotendinous xanthomatosis (CTX) using MR based quantitative measures. BACKGROUND: CTX is a rare inherited disorder characterised by progressive neurological impairment. Appropriate therapy can slow disease progression. Measures of brain volume changes have been used in several neurological disorders due to their value in assessing disease outcome and monitoring patients' evolution. METHODS: 24 CTX patients underwent conventional MRI to measure total and regional brain volumes. In five CTX patients who started therapy at baseline, clinical and MRI examinations were repeated after 2 years. Clinical disability, overall cognitive performance and cerebellar function were evaluated using the modified Rankin Scale (RS), Mini Mental Status Examination (MMSE) and cerebellar functional system score (CB-FSS). RESULTS: Measures of normalised brain, cortical and cerebellar volumes were lower in CTX patients than in healthy controls (p<0.01). Instead, there were no differences in normalised white matter volumes between the two groups (p=0.1). At regional analysis, a significant volume decrease was found in each cortical region (p<0.01 for all regions). Normalised cortical volumes correlated closely with age (r=-0.9, p<0.0001), RS (r=-0.65, p<0.001) and MMSE (r=-0.60, p<0.01). Normalised cerebellar volumes correlated closely with CB-FSS scores (r=-0.58, p<0.01). In the five CTX patients followed over time, the annual brain volume decrease was -1.1 ± 0.2%. CONCLUSIONS: Cortical volume, rather than white matter volume, is diffusely decreased in CTX patients and correlates closely with the patient's clinical status. These data provide evidence for the presence of clinically relevant neuronal-axonal damage in the brains of CTX patients. PMID: 20972203 [PubMed - indexed for MEDLINE] 71. Orphanet J Rare Dis. 2010 Oct 6;5:27. doi: 10.1186/1750-1172-5-27. A novel mutation in the sterol 27-hydroxylase gene of a woman with autosomal recessive cerebrotendinous xanthomatosis. Schneider H, Lingesleben A, Vogel HP, Garuti R, Calandra S. Department of Neurology, University of Technology Dresden, University Clinic, Fetscherstr 74, 01307 Dresden, Germany. hauke.schneider@uniklinikum-dresden.de Mutations of the gene encoding the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1 gene) cause defects in the cholesterol pathway to bile acids that lead to the storage of cholestanol and cholesterol in tendons, lenses and the central nervous system. This disorder is the cause of a clinical syndrome known as cerebrotendinous xanthomatosis (CTX). Since 1991 several mutations of the CYP27A1 gene have been reported. We diagnosed the clinical features of CTX in a caucasian woman. Serum levels of cholestanol and 7α-hydroxycholesterol were elevated and the concentration of 27-hydroxycholesterol was reduced. Bile alcohols in the urine and faeces were increased. The analysis of the CYP27A1 gene showed that the patient was a compound heterozygote carrying two mutations both located in exon 8. One mutation is a novel four nucleotide deletion (c.1330-1333delTTCC) that results in a frameshift and the occurrence of a premature stop codon leading to the formation of a truncated protein of 448 amino acids. The other mutation, previously reported, is a C - > T transition (c. c.1381C > T) that converts the glutamine codon at position 461 into a termination codon (p.Q461X). These truncated proteins are expected to have no biological function being devoid of the cysteine residue at position 476 of the normal enzyme that is crucial for heme binding and enzyme activity. PMCID: PMC2958880 PMID: 20925952 [PubMed - indexed for MEDLINE] 72. J Neurol Neurosurg Psychiatry. 2011 Jun;82(6):703-4. doi: 10.1136/jnnp.2009.196444. Epub 2010 Jul 26. Visualisation of treatment response in a case of cerebrotendinous xanthomatosis. Seidel S, Kasprian G, Prayer D, Krssák M, Sycha T, Auff E. PMID: 20660914 [PubMed - indexed for MEDLINE] 73. Br J Anaesth. 2010 Aug;105(2):237-8. doi: 10.1093/bja/aeq188. Cerebrotendinous xanthomatosis and anaesthesia. Habaragamuwa BW, Bajekal R. PMID: 20627886 [PubMed - indexed for MEDLINE] 74. BMC Neurol. 2010 Jul 6;10:59. doi: 10.1186/1471-2377-10-59. Multi-parametric neuroimaging evaluation of cerebrotendinous xanthomatosis and its correlation with neuropsychological presentations. Chang CC, Lui CC, Wang JJ, Huang SH, Lu CH, Chen C, Chen CF, Tu MC, Huang CW, Chang WN. Department of Neurology, Chang Gung Memorial Hospital-Kaohsiung Medical Center and Chang Gung University College of Medicine, Niaosung, Taiwan. BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder. Recent studies show that brain damage in CTX patients extends beyond the abnormalities observed on conventional magnetic resonance imaging (MRI). We studied the MRI and 99 mTc-ethyl cysteinate dimer single photon emission computed tomography (SPECT) findings of CTX patients and made a correlation with the neuropsychological presentations. METHODS: Diffusion tensor imaging (DTI) and 3D T1-weighted images of five CTX patients were compared with 15 age-matched controls. Voxel-based morphometry (VBM) was use to delineate gray matter (GM) and white matter (WM) volume loss. Fractional anisotropy (FA), mean diffusivity (MD), and eigenvalues derived from DTI were used to detect WM changes and correlate with neuropsychological results. SPECT functional studies were used to correlate with GM changes. RESULTS: Cognitive results showed that aside from moderate mental retardation, the patient group performed worse in all cognitive domains. Despite the extensive GM atrophy pattern, the cerebellum, peri-Sylvian regions and parietal-occipital regions were correlated with SPECT results. WM atrophy located in the peri-dentate and left cerebral peduncle areas corresponded with changes in diffusion measures, while axial and radial diffusivity suggested both demyelinating and axonal changes. Changes in FA and MD were preceded by VBM in the corpus callosum and corona radiata. Cognitive results correlated with FA changes. CONCLUSION: In CTX, GM atrophy affected the perfusion patterns. Changes in WM included atrophy, and axonal changes with demyelination. Disconnection of major fiber tracts among different cortical regions may contribute to cognitive impairment. PMCID: PMC2909944 PMID: 20602799 [PubMed - indexed for MEDLINE] 75. Intern Med. 2010;49(12):1127-31. Epub 2010 Jun 15. Identification of a novel missense mutation in the sterol 27-hydroxylase gene in two Japanese patients with cerebrotendinous xanthomatosis. Nozue T, Higashikata T, Inazu A, Kawashiri MA, Nohara A, Kobayashi J, Koizumi J, Yamagishi M, Mabuchi H. Division of Cardiology, Department of Internal Medicine, Yokohama Sakae Kyosai Hospital, Federation of National Public Service Personnel Mutual Associations, Yokohama, Japan. nozue2493@yahoo.co.jp Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive sterol storage disease caused by a mutated sterol 27-hydroxylase (CYP27A1) gene. We analyzed the CYP27A1 gene in two Japanese CTX patients. The CYP27A1 gene was amplified by PCR and screened by PCR-SSCP. The nucleotide sequence was analyzed to confirm mutations. Case 1 was a compound heterozygote for Arg104Gln in exon 2 and Arg441Gln in exon 8. To our knowledge, this is the first report in which the Arg104Gln mutation is identified in CTX patients. Probably case 2 would be a compound heterozygote for Arg441Trp in exon 8 and a mutation that was not identified. PMID: 20558929 [PubMed - indexed for MEDLINE] 76. J Lipid Res. 2010 Sep;51(9):2722-30. doi: 10.1194/jlr.M008326. Epub 2010 May 28. On the mechanism of accumulation of cholestanol in the brain of mice with a disruption of sterol 27-hydroxylase. Båvner A, Shafaati M, Hansson M, Olin M, Shpitzen S, Meiner V, Leitersdorf E, Björkhem I. Department of Laboratory Medicine, Division of Clincial Chemistry, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden. The rare disease cerebrotendinous xanthomatosis (CTX) is due to a lack of sterol 27-hydroxylase (CYP27A1) and is characterized by cholestanol-containing xanthomas in brain and tendons. Mice with the same defect do not develop xanthomas. The driving force in the development of the xanthomas is likely to be conversion of a bile acid precursor into cholestanol. The mechanism behind the xanthomas in the brain has not been clarified. We demonstrate here that female cyp27a1(-/-) mice have an increase of cholestanol of about 2.5- fold in plasma, 6-fold in tendons, and 12-fold in brain. Treatment of cyp27a1(-/-) mice with 0.05% cholic acid normalized the cholestanol levels in tendons and plasma and reduced the content in the brain. The above changes occurred in parallel with changes in plasma levels of 7alpha-hydroxy-4-cholesten-3-one, a precursor both to bile acids and cholestanol. Injection of a cyp27a1(-/-) mouse with (2)H(7)-labeled 7alpha-hydroxy-4-cholesten-3-one resulted in a significant incorporation of (2)H(7)-cholestanol in the brain. The results are consistent with a concentration-dependent flux of 7alpha-hydroxy-4-cholesten-3-one across the blood-brain barrier in cyp27a1(-/-) mice and subsequent formation of cholestanol. It is suggested that the same mechanism is responsible for accumulation of cholestanol in the brain of patients with CTX. PMCID: PMC2918454 PMID: 20511491 [PubMed - indexed for MEDLINE] 77. Biochem Biophys Res Commun. 2010 May 21;396(1):46-9. doi: 10.1016/j.bbrc.2010.02.140. Cerebrotendinous xanthomatosis: an inborn error in bile acid synthesis with defined mutations but still a challenge. Björkhem I, Hansson M. Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institutet, Karolinska University Hospital Huddinge, S-14186 Huddinge, Sweden. ingemar.bjorkhem@karolinska.se Cerebrotendinous xanthomatosis [CTX] is a rare disease characterized by the accumulation of cholesterol and cholestanol in brain and tendons caused by a mutation in the sterol 27-hydroxylase gene [CYP27A1] involved in bile acid synthesis. Disruption of this gene in mice does not give rise to xanthomas. The gene defect leads to reduced bile acid synthesis with a compensatory increase in the activity of the rate-limiting enzyme in bile acid synthesis, cholesterol 7alpha-hydroxylase. This leads to a marked accumulation of 7alpha-hydroxylated bile acid precursors, in particular 7alpha-hydroxy-4-cholesten-3-one. The latter oxysterol passes the blood-brain barrier and is an efficient precursor to cholestanol. The activity of cholesterol 7alpha-hydroxylase is normalized by treatment with bile acids. Such treatment reduces the xanthomas in CTX patients in parallel with decreased cholestanol levels. The relationship between the accumulation of cholestanol and the development of cholesterol-rich xanthomas has however not been clarified and a suitable animal model is still lacking. 2010 Elsevier Inc. All rights reserved. PMID: 20494109 [PubMed - indexed for MEDLINE] 78. J Lipid Res. 2010 Sep;51(9):2489-503. doi: 10.1194/jlr.R006338. Epub 2010 May 13. Genetic connections between neurological disorders and cholesterol metabolism. Björkhem I, Leoni V, Meaney S. Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden. ingemar.bjorkhem@karolinska.se Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Over the last decade, evidence has accumulated that disturbances in cholesterol metabolism are associated with the development of various neurological conditions. In addition to genetically defined defects in cholesterol synthesis, which will be covered in another review in this Thematic Series, defects in cholesterol metabolism (cerebrotendinous xanthomatosis) and intracellular transport (Niemann Pick Syndrome) lead to neurological disease. A subform of hereditary spastic paresis (type SPG5) and Huntington's disease are neurological diseases with mutations in genes that are of importance for cholesterol metabolism. Neurodegeneration is generally associated with disturbances in cholesterol metabolism, and presence of the E4 isoform of the cholesterol transporter apolipoprotein E as well as hypercholesterolemia are important risk factors for development of Alzheimer's disease. In the present review, we discuss the links between genetic disturbances in cholesterol metabolism and the above neurological disorders. PMCID: PMC2918434 PMID: 20466796 [PubMed - indexed for MEDLINE] 79. Indian J Pediatr. 2010 Jun;77(6):697-8. doi: 10.1007/s12098-010-0070-9. Epub 2010 May 7. Cerebrotendinous xanthomatosis. Kamate M, Chetal V, Hattiholi V. Department of Pediatrics, KLE University's JN Medical College, Belgaum, India. drmaheshkamate@gmail.com We describe two adolescent Indian siblings with cerebrotendinous xanthomatosis with cognitive impairment, progressive neurological deterioration, juvenile cataracts and chronic diarrhea. Both patients had bilateral Achilles tendon xanthomata. Rapid progression of disease was an unusual finding in these cases. Magnetic resonance imaging showed characteristic signal alterations in cerebellar hemispheres, brainstem and posterior cerebral white matter. PMID: 20454938 [PubMed - indexed for MEDLINE] 80. Ophthalmic Genet. 2010 Jun;31(2):73-6. doi: 10.3109/13816810903584963. Cerebrotendinous xanthomatosis (CTX): an association of pulverulent cataracts and pseudo-dominant developmental delay in a family with a splice site mutation in CYP27A1--a case report. Bourkiza R, Joyce S, Patel H, Chan M, Meyer E, Maher ER, Reddy MA. Department of Ophthalmology, Barts and the London NHS Trust, London, UK. rbourkiza@doctors.org.uk PURPOSE: A 15-year-old boy with developmental delay presented to the pediatric ophthalmology clinic with bilateral pulverulent cataracts. The family was examined for developmental delay, cataracts and systemic problems. METHODS: The parents were consanguineous and originally from Bangladesh. All the children were born in the UK. The mother and 5 children had developmental delay. Three children had global developmental delay, diarrhea and pulverulent cataracts. Two children had microcephaly, developmental delay, constipation and no cataracts. The mother did not have microcephaly, cataracts or gastrointestinal problems. Linkage analysis via autozygosity testing was performed for detection of loci and candidate genes. The patients with cataracts were segregated with homozygous mutations in the CYP27A1 (G to A substitution at position +1 of intron 6). RESULTS: The complex nature of this family's findings suggested that it had an unusual autosomal dominant condition with variable expression. Autozygosity testing demonstrated that three members had Cerebrotendinous xanthomatosis (CTX), which is inherited in an autosomal recessive manner. The aetiology of the developmental delay in other family members remains unknown. CONCLUSIONS: Cerebrotendinous xanthomatosis is a rare autosomal recessive condition that can result in neurological deficits and early death if left untreated. In view of the reversible nature of the condition with appropriate treatment, there needs to be a high level of suspicion of CTX for any child with cataracts and developmental delay even if the pattern of inheritance is not straightforward at initial assessment. PMID: 20450308 [PubMed - indexed for MEDLINE] 81. CNS Spectr. 2010 Apr;15(4):231-6. Cerebrotendinous xanthomatosis presenting with severe externalized disorder: improvement after one year of treatment with chenodeoxycholic Acid. Bonnot O, Fraidakis MJ, Lucanto R, Chauvin D, Kelley N, Plaza M, Dubourg O, Lyon-Caen O, Sedel F, Cohen D. Groupe Hospitalier Pitie Salpetriere, Paris, France. Cerebrotendinous xanthomatosis (CTX) is a rare inborn disorder of sterol storage with autosomal recessive inheritance and a variable clinical presentation. We describe two siblings with an early psychiatric presentation of CTX-associated attention-deficit/hyperactivity disorder and oppositional defiant disorder, also associated with a mild intellectual disability and major behavioral impairments. In both cases, treatment with chenodeoxycholic acid improved externalized symptoms and a partial recovery of cognitive impairments was observed. This suggests that CTX is potentially reversible, demonstrating the need for early diagnosis and treatment of this disorder before irreversible neurological lesions can occur. PMID: 20414172 [PubMed - indexed for MEDLINE] 82. Eur J Neurol. 2010 Oct;17(10):1259-62. doi: 10.1111/j.1468-1331.2010.03002.x. Four novel CYP27A1 mutations in seven Italian patients with CTX. Gallus GN, Dotti MT, Mignarri A, Rufa A, Da Pozzo P, Cardaioli E, Federico A. Department of Neurological, Neurosurgical and Behavioural Sciences, Medical School, University of Siena, Siena, Italy. BACKGROUND AND PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease, because of sterol 27-hydroxylase deficiency. Clinical manifestations of CTX are tendon xanthomas, juvenile cataracts, osteoporosis, diarrhoea and multiple progressive neurological dysfunctions. More than 300 patients with CTX have been reported to date worldwide and about fifty different mutations identified in CYP27A1 gene. This study describes the clinical and laboratory findings of seven new patients. METHODS: We report the molecular and clinical characterization of seven new Italian patients with CTX carrying four novel mutations. RESULTS: We identified four novel mutations located in different exons, in particular in the region of exons 2-5 of the CYP27A1 gene. Phenotypical expression did not differ from classical CTX presentation except for absence of tendon xanthomas in two patients. © 2010 The Author(s). European Journal of Neurology © 2010 EFNS. PMID: 20402754 [PubMed - indexed for MEDLINE] 83. J Assoc Physicians India. 2009 Oct;57:716-7. Cerebrotendinous xanthomatosis: a treatable neurodegenerative disease. Sandeep P, Jayakrishnan C, Sadanan S, Sreekumar S, Thulasidharan NK. Department of Medicine, Govt. Medical College, Calicut. Cerebrotendinous xanthomatosis is one of the rare forms of treatable hereditary neurodegenerative disorders. It is due to a defect in hydroxylation of cholesterol side chain that impairs oxidative cleavage of cholesterol leading to excess accumulation of cholesterol. Here we present such a case which presented to us with recurrent generalized tonic clonic seizures. He is under treatment for the same and has not neurologically deteriorated since then. PMID: 20329433 [PubMed - indexed for MEDLINE] 84. Cerebrotendinous Xanthomatosis. Federico A, Dotti MT, Gallus GN. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013. 2003 Jul 16. DISEASE CHARACTERISTICS: Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease characterized by infantile-onset diarrhea, childhood-onset cataract, adolescent- to young adult-onset tendon xanthomas, and adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures). Chronic diarrhea from infancy may be the earliest clinical manifestation. In approximately 75% of affected individuals, cataracts are the first finding, often appearing in the first decade of life. Xanthomas appear in the second or third decade; they occur on the Achilles tendon, the extensor tendons of the elbow and hand, the patellar tendon, and the neck tendons. Xanthomas have been reported in the lung, bones, and central nervous system. Some individuals show mental impairment from early infancy, whereas the majority have normal or only slightly subnormal intellectual function until puberty; dementia with slow deterioration in intellectual abilities occurs in the 20s in more than 50% of individuals. Neuropsychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicide attempts may be prominent. Pyramidal signs (i.e., spasticity) and/or cerebellar signs almost invariably become evident between ages 20 and 30 years. DIAGNOSIS/TESTING: CTX is diagnosed by clinical findings and biochemical testing. The biochemical abnormalities that distinguish CTX from other conditions with xanthomas include: high plasma and tissue cholestanol concentration, normal-to-low plasma cholesterol concentration; decreased chenodeoxycholic acid; increased concentration of bile alcohols and their glyconjugates; and increased concentrations of cholestanol and apolipoprotein B in cerebrospinal fluid. CYP27A1 is the only gene in which mutations are known to cause cerebrotendinous xanthomatosis. MANAGEMENT: Treatment of manifestations: Long-term treatment with chenodeoxycholic acid (CDCA) normalizes bile acid synthesis, normalizes plasma and CSF concentration of cholestanol, and improves neurophysiologic findings. Inhibitors of HMG-CoA reductase alone or in combination with CDCA are also effective in decreasing cholestanol concentration and improving clinical signs; however, they may induce muscle damage. Cataract extraction is typically required in at least one eye by age 50 years. Epilepsy, spasticity, and parkinsonism are treated symptomatically. Surveillance: Annual neurologic and neuropsychological evaluation, cholestanol plasma concentration, brain MRI, echocardiogram, and assessment of total body density (TBD). Evaluation of relatives at risk: Early diagnosis by biochemical testing or molecular genetic testing if the two disease-causing mutations in the family are known allows for early treatment that may prevent or limit disease manifestations. GENETIC COUNSELING: CTX is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if both disease-causing mutations in the family are known. PMID: 20301583 [PubMed] 85. AJNR Am J Neuroradiol. 2010 Aug;31(7):1347-9. doi: 10.3174/ajnr.A1885. Epub 2010 Feb 11. MR spectroscopy detects lipid peaks in cerebrotendinous xanthomatosis. Embiruçu EK, Otaduy MC, Taneja AK, Leite CC, Kok F, Lucato LT. Department of Neurology, Clinics Hospital of the University of Sao Paulo, School of Medicine, Sao Paulo, Brazil. CTX is a rare lipid-storage disease. Novel MRS findings from 3 patients, using a short TE, were the presence of lipid peaks at 0.9 and 1.3 ppm in the depth of the cerebellar hemisphere; this might represent an additional marker of disease that is CNS-specific and noninvasive. A decrease in NAA concentration was also detected and attributed to neuroaxonal damage. One patient presented an increase in mIns concentration, pointing to gliosis and astrocytic proliferation. PMID: 20150306 [PubMed - indexed for MEDLINE] 86. J Am Chem Soc. 2010 Feb 24;132(7):2222-32. doi: 10.1021/ja9080265. Oxysterols from free radical chain oxidation of 7-dehydrocholesterol: product and mechanistic studies. Xu L, Korade Z, Porter NA. Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, USA. Free radical chain oxidation of highly oxidizable 7-dehydrocholesterol (7-DHC), initiated by 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), was carried out at 37 degrees C in benzene for 24 h. Fifteen oxysterols derived from 7-DHC were isolated and characterized with 1D and 2D NMR spectroscopy and mass spectrometry. A mechanism that involves abstraction of hydrogen atoms at C-9 and/or C-14 is proposed to account for the formation of all of the oxysterols and the reaction progress profile. In either the H-9 or H-14 mechanism, a pentadienyl radical intermediate is formed after abstraction of H-9 or H-14 by a peroxyl radical. This step is followed by the well-precedented transformations observed in peroxidation reactions of polyunsaturated fatty acids such as oxygen addition, peroxyl radical 5-exo cyclization, and S(H)i carbon radical attack on the peroxide bond. The mechanism for peroxidation of 7-DHC also accounts for the formation of numerous oxysterol natural products isolated from fungal species, marine sponges, and cactaceous species. In a cell viability test, the oxysterol mixture from 7-DHC peroxidation was found to be cytotoxic to Neuro2a neuroblastoma cells in the micromolar concentration range. We propose that the high reactivity of 7-DHC and the oxysterols generated from its peroxidation may play important roles in the pathogenesis of Smith-Lemli-Opitz syndrome, X-linked dominant chondrodysplasia punctata, and cerebrotendinous xanthomatosis, all of these being metabolic disorders characterized by an elevated level of 7-DHC. PMCID: PMC2839323 PMID: 20121089 [PubMed - indexed for MEDLINE] 87. Mov Disord. 2010 Mar 15;25(4):452-8. doi: 10.1002/mds.22979. Cerebrotendinous xanthomatosis patients with and without parkinsonism: clinical characteristics and neuroimaging findings. Su CS, Chang WN, Huang SH, Lui CC, Pan TL, Lu CH, Chuang YC, Huang CR, Tsai NW, Hsieh MJ, Chang CC. Department of Neurology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. Parkinsonism in cerebrotendinous xanthomatosis (CTX) is rare. There are no published studies with imaging findings of dopamine transporter using (99m)Tc-[2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3,2,1] oct-2-yl] methyl] (2-mercaptoethyl) amino] ethyl] amino]-ethanethiolato(3-)-N2,N2,S2,S2]oxo-[1R-(exo-exo)] ((99m)Tc-TRODAT-1) SPECT in CTX patients. This report is on the clinical details of five genetically-proven CTX patients (two with and three without parkinsonism). Imaging findings using cranial magnetic resonance (MR) imaging and (99m)Tc-TRODAT-1 SPECT are also shown. Clinical correlation of neuroimaging findings and clinical presentations was made. A literature review of the clinical and neuroimaging features of eight CTX patients with parkinsonism reported in the English literature is also presented. The parkinsonian features of our two cases and the other eight reported cases occurred before the age of 50 years. The MR imaging study showed variable findings, in which, besides the common diffuse cerebral and cerebellar white matter lesions shown in CTX, several focal brain lesions were also noted. Of the focal lesions, substantia nigra abnormalities were seen only in the two cases with parkinsonism. The (99m)Tc-TRODAT-1 SPECT study showed different degrees of unilateral or bilateral abnormalities in the striatal binding in both visual and semiquantitative assessments. parkinsonism can be one of the neurologic presentations of CTX. Even though abnormal findings of the substantia nigra were detected in both of our CTX patients with parkinsonism, basal ganglion lesions have not been uniformly described in MR imaging findings of reported CTX patients with parkinsonism. (99m)Tc-TRODAT-1 SPECT study can be of value in the detection of striatal involvement, and the study results also suggest pre-synaptic dopamine neuron involvement in CTX patients with parkinsonism. PMID: 20108380 [PubMed - indexed for MEDLINE] 88. BMJ Case Rep. 2010 Nov 5;2010. pii: bcr0220102736. doi: 10.1136/bcr.02.2010.2736. Cerebrotendinous xanthomatosis associated with immune thrombocytopenia. El Husseiny NM. Department of Internal Medicine, Cairo University, Giza, Egypt. dr_noha2002@yahoo.com Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease inherited in a autosomal recessive way. CTX is characterised by childhood-onset cataract, adolescent to young adult-onset tendon xanthomas and adult-onset progressive neurological dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs and seizures). Xanthomas appear in the second or third decade; they occur on the Achilles tendon, the extensor tendons of the elbow and hand, the patellar tendon and the neck tendons. The biochemical abnormalities that distinguish CTX from other conditions with xanthomas include high plasma and tissue cholestanol concentration, normal-to-low plasma cholesterol concentration and decreased chenodeoxycholic acid. Long-term treatment of individuals with CTX with chenodeoxycholic acid (CDCA) normalises bile acid synthesis, normalises plasma and cerebrospinal fluid concentration of cholestanol, and improves neurophysiological findings. Inhibitors of 3-hydroxy 3-methyl glutaryl coenzyme A reductase alone or in combination with CDCA are also effective in decreasing cholestanol concentration and improving clinical signs; however, they may induce muscle symptoms. PMCID: PMC3028412 PMID: 22791847 [PubMed - indexed for MEDLINE] 89. Indian J Radiol Imaging. 2009 Oct-Dec;19(4):314-7. doi: 10.4103/0971-3026.57218. Case Report: Cerebrotendinous xanthomatosis. Karandikar AA, Pushparajan S, Unni MN, Srinivas R. Department of Radiology, Kerala Institute of Medical Sciences, Trivandrum, Kerala, India. Cerebrotendinous xanthomatosis is a rare genetic disorder. We present and discuss the clinical, radiological, and histopathologic findings in a 36-year-old woman who had juvenile cataract, childhood diarrhea, mental retardation, cerebellar ataxia, and bilateral Achilles tendon xanthomas. She was thoroughly investigated radiologically and biopsy confirmed the diagnosis of xanthomas. PMCID: PMC2797749 PMID: 19881113 [PubMed] 90. Clin Chim Acta. 2010 Jan;411(1-2):43-8. doi: 10.1016/j.cca.2009.09.036. Epub 2009 Oct 3. ESI-MS/MS quantification of 7alpha-hydroxy-4-cholesten-3-one facilitates rapid, convenient diagnostic testing for cerebrotendinous xanthomatosis. DeBarber AE, Connor WE, Pappu AS, Merkens LS, Steiner RD. Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA. debarber@ohsu.edu BACKGROUND: The genetic disorder cerebrotendinous xanthomatosis (CTX) frequently remains undiagnosed for many years. Left untreated CTX is associated with the development of cataracts, xanthomas and severe neurological dysfunction. The method routinely used to screen for CTX is GC-based measurement of elevated 5alpha-cholestanol from hydrolyzed plasma. A plasma test for CTX utilizing ESI-MS/MS methodology would be beneficial. METHODS: Development of rapid, simple LC-ESI-MS/MS methodology to test plasma for CTX is described. Two hour Girard derivatization allowed for 7alpha-hydroxy-4-cholesten-3-one quantification by isotope dilution LC-ESI-MS/MS within 12 min from un-hydrolyzed affected patient plasma (5 microl). RESULTS: Adequate sensitivity and reproducibility were achieved for quantification of 7alpha-hydroxy-4-cholesten-3-one, which demonstrated improved utility as a diagnostic marker of disease and to monitor treatment compared to 5alpha-cholestanol. The mean plasma concentration of 7alpha-hydroxy-4-cholesten-3-one in untreated CTX-affected patients (n=6) was 107-fold that in unaffected subjects (n=9), with the lowest concentration in affected patients >10-fold the highest concentration in unaffected subjects. CONCLUSION: Quantification of the bile acid precursor 7alpha-hydroxy-4-cholesten-3-one with LC-ESI-MS/MS is a novel approach to improved diagnostic testing of plasma for CTX, amenable to high-throughput analysis and automated sample handling. Development of ESI-MS/MS methodology should make CTX testing more widely available and facilitate easier diagnosis of CTX. PMID: 19808031 [PubMed - indexed for MEDLINE] 91. Atherosclerosis. 2010 Mar;209(1):39-41. doi: 10.1016/j.atherosclerosis.2009.09.015. Epub 2009 Sep 16. An alternative pathway of reverse cholesterol transport: the oxysterol 27-hydroxycholesterol. Weingärtner O, Laufs U, Böhm M, Lütjohann D. Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany. oweingartner@aol.com Reverse cholesterol transport, although not well understood, is an important mechanism in the pathophysiology of atherosclerosis. Macrophages can eliminate some cholesterol from atherosclerotic lesions by an oxidative mechanism involving sterol 27-hydroxylase. Patients with inherited "cerebrotendinous xanthomatosis" lack sterol 27-hydroxylase (CYP27A1) and develop severe premature atherosclerosis despite normal serum cholesterol concentrations. Thus, it has been speculated that sterol 27-hydroxylase is an anti-atherosclerotic enzyme. Here, we report the case of a 25-year-old patient who presented to our emergency room with an acute non-ST elevation myocardial infarction due to severe coronary heart disease. Lipid analysis revealed dramatically increased 27-hydroxycholesterol and low high-density lipoprotein (HDL)-cholesterol levels. Previous reports suggest that 27-hydroxylase is upregulated to protect peripheral cells from severe cholesterol accumulation, especially in cases of ineffective reverse cholesterol transport due to low HDL-cholesterol levels. Our findings indicate that oxysterols could play an important and so far underestimated role in reverse cholesterol transport. PMID: 19801147 [PubMed - indexed for MEDLINE] 92. Biomed Chromatogr. 2010 Jun;24(6):600-5. doi: 10.1002/bmc.1332. Determination of serum cholestanol by semi-micro high-performance liquid chromatography with electrochemical detection. Hojo K, Hakamata H, Takahashi A, Hosokawa YY, Kusu F. Department of Analytical Chemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Horinouchi 1432-1, Hachioji, Tokyo 192-0392, Japan. A simple and sensitive method that dose not require derivatization for determining cholestanol has been developed using HPLC with electrochemical detection (HPLC-ECD). The current peak height was linearly related to the amount of cholestanol injected, ranging from 1 to 200 muM (r = 0.999). The detection limit (S/N = 3) of cholestanol was 0.23 muM (1.2 pmol). Total cholestanol in control human and mouse serum was determined by the present method with a recovery rate of more than 90% and an RSD (n = 5) of less than 7.3%. Further, this method was successfully applied to monitor experimental hypercholestanolemia in mice fed a high-cholestanol diet, an animal model of cerebrotendinous xanthomatosis (CTX). In conclusion, we found this method to be both simple and useful for the determination of cholestanol in serum, helping in the diagnosis of CTX. Copyright 2009 John Wiley & Sons, Ltd. PMID: 19795364 [PubMed - indexed for MEDLINE] 93. Rev Med Chil. 2009 Jun;137(6):815-20. doi: /S0034-98872009000600013. Epub 2009 Sep 4. [Cerebrotendinous xanthomatosis: report of one case]. [Article in Spanish] Filippi J, Irarrázaval S, Peredo P, Mellado P. Departamento de Ortopedia y Traumatología, Pontificia Universidad Católica de Chile, Santiago, Chile. jfilippi@med.puc.cl Cerebrotendinous xanthomatosis is an inherited autosomal recessive disease caused by a mutation in the gene for the sterol 27-hydroxylase enzyme, which determines the accumulation of plasmatic cholestanol in various tissues. The natural history of this disease is characterized by chronic diarrhea beginning in childhood, cataract in youth, tendinous xanthomas in adulthood and later progressive neurological dysfunction manifested as dementia, psychiatric disorders, cerebellar, pyramidal or extra pyramidal signs or seizures. We report a 39 year-old male with a history of diarrhea during childhood and bilateral cataracts requiring surgery at 20 years of age, who evolves later with psychiatric disorders and bilateral increased volume in Achules tendons. High levels of plasmatic cholestanol and magnetic resonance imaging confirmed the diagnosis of this disease. PMID: 19746285 [PubMed - indexed for MEDLINE] 94. Pediatr Endocrinol Rev. 2009 Sep;7(1):6-11. Cerebrotendinous xanthomatosis (CTX): a treatable lipid storage disease. Keren Z, Falik-Zaccai TC. Institute of Human Genetics, Western Galilee Hospital, Naharia, Israel. kzohar76@gmail.com Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease with multi-organ involvement. The clinical manifestations usually start at infancy and develop during the first and second decades of life; infantile-onset diarrhea may be the earliest clinical manifestation of CTX. Additional clinical manifestations are juvenile cataracts, tendon xanthomas, and multiple progressive neurological symptoms. Systemic manifestations that are often found include osteoporosis, heart involvement and premature arteriosclerosis. CTX is caused by mutations in the sterol 27 hydroxylase gene (CYP27) on chromosome 2q35-qter, which is responsible for conversion of cholesterol to cholic and chenodeoxycholic acid. Reduced synthesis of cholic and chenodeoxycholic acid results in failed feedback inhibition of cholesterol production, which in turn leads to increased serum cholestanol concentration and elevated urinary bile alcohols. Early treatment with chenodeoxycholic acid (CDCA) prevents the clinical symptoms and prevents deterioration. Although CTX is rare world wide, genetic islands of high frequency have been reported. In this review we would like to familiarize the reader with this fatal inborn error of metabolism that is possibly under-diagnosed and is preventable once recognized and treated. PMID: 19696711 [PubMed - indexed for MEDLINE] 95. Actas Dermosifiliogr. 2009 Apr;100(3):222-6. [Cerebrotendinous xanthomatosis: report of 4 patients]. [Article in Spanish] Ferrándiz-Pulido C, Bartralot R, Girós M, Bassas P, Heras C, Bodet D, Savall R, García-Patos V. Servicio de Dermatología, Hospital Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, España. 40879cfp@comb.es Cerebrotendinous xanthomatosis (CTX) is an uncommon autosomal recessive disease caused by mutation of the CYP27A1 gene. It is characterized by the presence of xanthomas in different tissues, principally brain and tendon, due to the accumulation of beta-cholestanol. Diagnosis is confirmed by measurement of serum beta-cholestanol and urinary bile alcohol levels. Therapy with chenodeoxycholic acid has been shown to be the most effective treatment and can halt progression of the disease. We present 4 patients with a history of neurological disorders since childhood and who were diagnosed with CTX after developing tendon xanthomas. Although diagnostic suspicion depends to a large extent on recognition of tendon xanthomas, these are not an early sign of the disease, which can present with neurological disorders, cataracts, and chronic diarrhea. Early diagnosis of CTX therefore rests on measurement of serum beta-cholestanol levels, even in absence of tendon xanthomas. PMID: 19457308 [PubMed - indexed for MEDLINE] 96. Ned Tijdschr Geneeskd. 2009 Apr 11;153(15):726-7. [The right medicine for cerebrotendinous xanthomatosis]. [Article in Dutch] Verrips A, Wevers RA, van Spronsen FJ, Sikkens H. Canisius-Wilhelmina Ziekenhuis, Kinderneurologisch Centrum, Nijmegen. a.verrips@cwz.nl PMID: 19452779 [PubMed - indexed for MEDLINE] 97. Mov Disord. 2009 Jul 15;24(9):1397-9. doi: 10.1002/mds.22585. Oromandibular dystonia as a complication of cerebrotendinous xanthomatosis. Alcalay R, Wu S, Patel S, Frucht S. PMID: 19373932 [PubMed - indexed for MEDLINE] 98. J Inherit Metab Dis. 2009 Apr;32(2):309. doi: 10.1007/s10545-009-1147-3. Epub 2009 Mar 9. Children with cataract and chronic diarrhoea: cerebrotendinous xanthomatosis. Cruysberg JR. PMID: 19266310 [PubMed - indexed for MEDLINE] 99. J Inherit Metab Dis. 2008 Dec;31 Suppl 2:S241-5. doi: 10.1007/s10545-008-0815-z. Epub 2008 Dec 27. Prospective treatment of cerebrotendinous xanthomatosis with cholic acid therapy. Pierre G, Setchell K, Blyth J, Preece MA, Chakrapani A, McKiernan P. Department of Inherited Metabolic Disease, Birmingham Children's Hospital NHS Trust, Steelhouse Lane, Birmingham, B4 6NH, UK. marsha2000_tt@yahoo.com Cerebrotendinous xanthomatosis (CTX) OMIM#213700 is a rare disorder of bile acid synthesis caused by deficiency of the enzyme sterol 27-hydroxylase. It results in deficiency of bile acids and accumulation of abnormal bile alcohols and accelerated cholesterol synthesis. CTX usually presents in the second or third decade with slowly progressive neurological dysfunction, cerebellar ataxia and premature atherosclerosis. Treatment with bile acid supplementation improves but does not completely reverse the neurological signs and symptoms. However, CTX is now known to be associated with a period of neonatal cholestasis. If it is diagnosed at this point, treatment may prevent the onset of neurological problems. We present the case histories and developmental findings in two affected siblings treated from infancy. We plan to continue regular neurodevelopmental reviews. PMID: 19125350 [PubMed - indexed for MEDLINE] 100. Pediatrics. 2009 Jan;123(1):143-7. doi: 10.1542/peds.2008-0192. Chronic diarrhea and juvenile cataracts: think cerebrotendinous xanthomatosis and treat. Berginer VM, Gross B, Morad K, Kfir N, Morkos S, Aaref S, Falik-Zaccai TC. Department of Neurology, Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba, Israel. Cerebrotendinous xanthomatosis is an autosomal recessive disease of bile acid synthesis caused by 27-hydroxylase deficiency. Treatment with chenodeoxycholic acid normalizes cholestanol concentrations and abrogates progression of the disease. We present 4 patients with cerebrotendinous xanthomatosis within 1 family who were treated with chenodeoxycholic acid for 14 years. Two young sisters started treatment at the preclinical stage before the appearance of major symptoms. Their 2 older uncles, who had already developed the complete phenotypic form of cerebrotendinous xanthomatosis when diagnosed, commenced treatment at the same time as the sisters, thus establishing a natural control group. After 14 years of chenodeoxycholic acid therapy, the cholestanol levels of all 4 patients decreased to normal levels (<6 microg/mL). Both sisters remained asymptomatic. Only moderate improvement in symptoms was observed in their uncles. In this long-term study, prompt preclinical administration of chenodeoxycholic acid in early childhood completely prevented the cerebrotendinous xanthomatosis phenotype in 2 sisters. Pediatricians should be aware of this diagnostic possibility of cerebrotendinous xanthomatosis in children presenting with chronic diarrhea and juvenile cataracts. Prevention is particularly significant in light of the availability of early genetic diagnosis and the devastating effects of this illness if not treated. PMID: 19117873 [PubMed - indexed for MEDLINE] 101. Genet Med. 2008 Dec;10(12):903-9. doi: 10.1097/GIM.0b013e31818d0e0f. Population screening in a Druze community: the challenge and the reward. Falik-Zaccai TC, Kfir N, Frenkel P, Cohen C, Tanus M, Mandel H, Shihab S, Morkos S, Aaref S, Summar ML, Khayat M. Institute of Human Genetics, Western Galilee Hospital-Nahariya, Israel. Tzipora.Falik@naharia.health.gov.il PURPOSE: The Druze community is characterized by consanguinity and endogamy, and by reluctance to genetic testing and technological interventions for the prevention of birth defects. Multiple patients with four rare and severe inborn errors of metabolism cerebrotendinous xanthomatosis, prolidase deficiency, argininosuccinate lyase deficiency, and carbamyl phosphate synthetase I deficiency were identified in an isolated Druze village in northern Israel. The aims of this study were to identify couples at risk for four inherited diseases, and to prevent birth defects in a community presenting religious and cultural obstacles to genetic testing. METHODS: A genetic screening and counseling program in a high-risk community. RESULTS: The 1425 residents who attended group genetic counseling sessions between 2003 and 2007 consented to genetic testing. We identified 217 carriers for either one or two disease causing mutations. High carrier frequencies for cerebrotendinous xanthomatosis, prolidase deficiency, argininosuccinate lyase deficiency, and carbamyl phosphate synthetase I deficiency were identified as 1:11, 1:21, 1:41, and 1:95, respectively. Fifty-eight percent (125) of the carriers' spouses agreed to genetic counseling and testing. Ten couples at risk for affected offspring were identified and offered prenatal genetic counseling and diagnosis. CONCLUSIONS: The genetic screening program, the first of its kind reported in a Druze community, was well received. We expect this program to increase awareness of genetic counseling, to contribute to disease prevention, and to serve as a model for other isolated communities. PMID: 19092443 [PubMed - indexed for MEDLINE] 102. Neurologia. 2008 Oct;23(8):530-1. [Cerebrotendinous xanthomatosis]. Romero JO, Callejón JR, Alonso G. Sección de Neurologia, Hospital Torrecárdenas, Almería. PMID: 19034999 [PubMed - indexed for MEDLINE] 103. Expert Rev Neurother. 2008 Nov;8(11):1731-41. doi: 10.1586/14737175.8.11.1731. Inherited metabolic disorders and cerebral infarction. Kalidas K, Behrouz R. Department of Neurology, University of South Florida College of Medicine, Tampa, FL 33606, USA. kkalidas@health.usf.edu The association of genetic factors and cerebral infarction (CI) has long been established. A positive family history alone is a recognized risk factor for CI and vascular events in general. However, there are certain inherited conditions that further increase the risk of stroke. These conditions are generally metabolic and mitochondrial genetic defects that have variable modes of inheritance. This article reviews major inherited metabolic disorders that predispose an individual to CI. Ten main conditions will be discussed: Fabry's disease, cerebrotendinous xanthomatosis, tangier disease, familial hypercholesterolemia, homocystinuria, methylmalonic acidemia, glutaric aciduria type I, propionic acidemia, ornithine transcarbamylase deficiency and mitochondrial encephalopathy, lactic acidosis and stroke-like phenomenon. PMID: 18986243 [PubMed - indexed for MEDLINE] 104. J Inherit Metab Dis. 2008 Dec;31 Suppl 2:S387-93. doi: 10.1007/s10545-008-0963-1. Epub 2008 Oct 24. Elevated cholesterol precursors other than cholestanol can also be a hallmark for CTX. de Sain-van der Velden MG, Verrips A, Prinsen BH, de Barse M, Berger R, Visser G. Department of Metabolic and Endocrine Diseases, University Medical Centre Utrecht, HP KC 02.069.1, Lundlaan 6 3584 CX, Utrecht, The Netherlands. M.G.deSain@umcutrecht.nl Cerebrotendinous xanthomatosis (CTX) is an inborn error of bile acid synthesis in which hepatic conversion of cholesterol to cholic and chenodeoxycholic acids is impaired. Patients have abnormal bile alcohols in urine, normal to increased plasma cholesterol concentrations and increased concentrations of plasma cholestanol. Little is known about cholesterol precursors in CTX, however. We studied cholesterol and phytosterol profiles in two siblings with CTX during follow-up. While cholesterol concentrations were low in both patients, plasma cholestanol was 6-fold higher compared to control values. In addition, both siblings had a more than 100-fold increase in 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC). Lathosterol, lanosterol and sitosterol were increased in both patients while concentrations of desmosterol and campesterol were normal. In addition, plasma lathosterol/cholesterol ratios were significantly elevated. After treatment with chenodeoxycholate, both patients showed a marked decrease in cholestanol, 7DHC, 8DHC, lathosterol, lanosterol and sitosterol. In addition, the lathosterol/cholesterol ratio normalized, indicating that overall cholesterol synthesis was sufficiently suppressed. This study shows that elevated cholesterol precursors, other than cholestanol, can be a hallmark for CTX. PMID: 18949577 [PubMed - indexed for MEDLINE] 105. Neurology. 2008 Jul 8;71(2):e4. doi: 10.1212/01.wnl.0000316806.01406.74. Teaching neuroimage: cerebrotendinous xanthomatosis. Mehta BP, Shmerling RH. Department of Neurology, Massachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. bmehta@partners.org PMID: 18606959 [PubMed - indexed for MEDLINE] 106. Nat Clin Pract Gastroenterol Hepatol. 2008 Aug;5(8):456-68. doi: 10.1038/ncpgasthep1179. Epub 2008 Jun 24. Mechanisms of disease: Inborn errors of bile acid synthesis. Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine and The Children's Hospital, CO 80045, USA. Inborn errors of bile acid synthesis are rare genetic disorders that can present as neonatal cholestasis, neurologic disease or fat-soluble-vitamin deficiencies. There are nine known defects of bile acid synthesis, including oxysterol 7alpha-hydroxylase deficiency, Delta(4)-3-oxosteroid-5beta-reductase deficiency, 3beta-hydroxy-Delta(5)-C(27)-steroid dehydrogenase deficiency, cerebrotendinous xanthomatosis (also known as sterol 27-hydroxylase deficiency), alpha-methylacyl-CoA racemase deficiency, and Zellweger syndrome (also known as cerebrohepatorenal syndrome). These diseases are characterized by a failure to produce normal bile acids and an accumulation of unusual bile acids and bile acid intermediaries. Individuals with inborn errors of bile acid synthesis generally present with the hallmark features of normal or low serum bile acid concentrations, normal gamma-glutamyl transpeptidase concentrations and the absence of pruritus. Failure to diagnose any of these conditions can result in liver failure or progressive chronic liver disease. If recognized early, many patients can have a remarkable clinical response to oral bile acid therapy. PMID: 18577977 [PubMed - indexed for MEDLINE] 107. Orthopade. 2008 Jul;37(7):704-8. doi: 10.1007/s00132-008-1275-8. [Cerebrotendinous xanthomatosis. Hereditary lipid storage disease leading to bilateral swelling of Achilles tendon]. [Article in German] Zacherl M, Sourij H, Beham A, Emberger W, Leithner A, Windhager W. Universitätsklinik für Orthopädie, Medizinische Universität, Graz. max_zacherl@hotmail.com Cerebrotendinous xanthomatosis is a rare hereditary lipid storage disease characterised by deposits of cholestanol. In a female patient with bilateral swelling of the Achilles tendon who underwent biopsy, cerebrotendinous xanthomatosis was confirmed by combining disease patterns. She suffered from ataxia, depression, epilepsy, reduced intelligence, bilateral cataracts, gallstones, and atherosclerosis. Concentration of serum cholestanol was 10 times higher than normal. As causal therapy, ursodeoxycholic acid and statin drugs were prescribed to halt progression. PMID: 18483801 [PubMed - indexed for MEDLINE] 108. J Neurol. 2008 Jun;255(6):839-42. doi: 10.1007/s00415-008-0729-6. Epub 2008 May 6. Cerebrotendinous xanthomatosis: neuropathological findings. Pilo de la Fuente B, Ruiz I, Lopez de Munain A, Jimenez-Escrig A. Division of Neurology, Virgen del Puerto Hospital, Paraje de Valcorchero s/n Plasencia, 10600 Céceres, Spain. bpilodelafuente@yahoo.es Cerebrotendinous xanthomatosis is an inherited autosomal recessive lipid storage disease caused by a 27-hydroxylase enzyme deficiency, characterised clinically by tendon xanthomas, premature cataracts, chronic diarrhoea and progressive neurologic dysfunction. The disease is very uncommon and there are very few pathological descriptions. We report a 52-year-old male who presented with a neuropsychiatric disorder and cognitive decline. Despite treatment the patient developed optic atrophy, parkinsonism and dementia and died. The autopsy revealed a nonspecific brain and cerebellar atrophy. Under microscopic examination, lipid crystal clefts, neuronal loss, demyelination, reactive astrocytosis and perivascular macrophages were found. These findings suggest the limited reversibility of the disease, and its poor prognosis, specially if treatment is not started early. PMID: 18458861 [PubMed - indexed for MEDLINE] 109. Ned Tijdschr Geneeskd. 2008 Mar 15;152(11):632-6. [Bilateral cataract in childhood years: always an indication for screening on a metabolic disorder]. [Article in Dutch] Wijburg MT, Wenniger-Prick LJ, Bosch AM, Visser G, Bams-Mengerink A. Universitair Medisch Centrum Utrecht, divisie Kinderen, Huispost KC 03.063.0, Lundlaan 6, 3584 EA Utrecht. In three young patients who presented with bilateral cataracts the cause proved to be an inherited metabolic disease. The first patient was a newborn aged 7 weeks, in whom galactokinase deficiency was diagnosed. The second patient was a boy aged 8 years with cerebrotendinous xanthomatosis. The third patient was a girl who was diagnosed with cataracts at the age of 3 months. At the age of 4 years the diagnosis 'rhizomelic chondrodysplasia punctata' was established. Screening for metabolic disorders in all children with bilateral cataracts is essential, as in some disorders progressive and severe symptoms can be avoided with timely initiation of treatment. In addition, diagnosis allows for family studies and genetic counselling to take place. This may result in prevention of disease by early therapeutic intervention and prenatal screening. PMID: 18410025 [PubMed - indexed for MEDLINE] 110. Neurology. 2008 Jan 29;70(5):402-4. doi: 10.1212/01.wnl.0000280460.28039.3d. The first cerebrotendinous xanthomatosis family from Argentina: a new mutation in CYP27A1 gene. Szlago M, Gallus GN, Schenone A, Patiño ME, Sfaelo Z, Rufa A, Da Pozzo P, Cardaioli E, Dotti MT, Federico A. FESEN, Laboratorio de Neuroquímica, Buenos Aires, Argentina. PMID: 18227423 [PubMed - indexed for MEDLINE] 111. Acta Univ Carol Med Monogr. 2008;154:5-101. Noncholesterol sterols. Vecka M, Zak A, Tvrzická E. Charles University in Prague, First Faculty of Medicine, Clinical Department of Gastroenterology and Hepatology, Prague. marvec@volny.cz Although most of us are more or less familiar with the term "cholesterol", the world of sterols is far more complicated and interesting. Apart from cholesterol, many non-cholesterol sterols can be found in human plasma and these sterols serve many important functions in human organism. They are either derived from endogenous biosynthesis of cholesterol or they come from dietary sources (phytosterols). The sole cholesterol molecule is used for keeping our cell membranes fit, for signalization purposes as well as a precursor for bile acids and steroid hormones. The compounds prior to cholesterol in its biosynthetic pathway were identified as vitamin D3 precursor, meiosis activating sterols and nowadays it seems that they could play a role in cholesterol homeostasis. The sterols from ingested vegetable sources, the phytosterols, are expelled from enterocytes and thus indirectly help our gut in coping with abundant cholesterol in the lumen. Higher plants synthesize many phytosterols, but in marine organisms, we can find other innumerous sterol molecules. The diversity of sterol molecules produced and resistance of their tetracyclic core to enzymatic activities implies crucial importance of sterols during the ontogenesis of multicellular organisms. First oxygen appeared on the Earth app. 2.7 billion years ago and since that time, every new life form took the advantage of oxygen needed also for build-up of sterol molecules. The last decades changed our view to the sterol molecules on almost at all levels of their appearance in human body. In the gut, the absorption of sterols was proven to be protein dependent and the quest for the transporter was successful. The general concepts of intracellular homeostasis of cholesterol have been described including the covalent interaction unbelievable so far - cholesterol and a protein. The clinical importance of non-cholesterol sterols rises with the effort to discover underlying facts about the causes of atherosclerosis. The compound in question, cholesterol, seems to be involved, but it sounds not to be crucial per se. The fact that the accumulation of phytosterols in sitosterolemia enhances the probability of early atherosclerosis onset further supports the hypothesis about some sterol (or steroid) compound being responsible on the molecular level for triggering the pathobiochemical cascade of events leading to atherosclerosis. Understanding the processes taking place in the enterocyte during the absorption of sterols resulted in synthesis of selective inhibitors at the level of sterol translocation into the enterocyte, sterol esterification and chylomicron packing, which are in different phases of clinical testing. The studies in the last part of the monograph represent the clinical potential of the analyses of non-cholesterol sterols. In well-defined groups, these analytes enables us to assess the changes in the homeostasis of cholesterol, which can be reflected in the concentration of total cholesterol. Furthermore, the high concentrations of some plasma sterols could point to the inborn errors of cholesterol biosynthesis (Smith-Laemli-Opitz syndrome), transport (sitosterolemia) or metabolization (cerebrotendinous xanthomatosis). Some issues concerning the research on the non-cholesterol sterols still remain unanswered - it is not known why some of the enzymes of the cholesterol biosynthesis (seladin-1, sterol D14 reductase) have other functions, qualitative aspects of sterol absorption are not satisfactorily explained and exact reason for expulsion of phytosterols from human body is not clear. Nevertheless, the authors hope that the presented facts can broaden the reader's perspective about the area, which is usually hidden beneath the cholesterol molecule. PMID: 19283968 [PubMed - indexed for MEDLINE] 112. J Assoc Physicians India. 2007 Sep;55:655-7. Cerebrotendinous xanthomatosis: a treatable cause of metabolic ataxia. Mukherjee AA, Chawla BP, Rathi SS, Puthran RS. Department of Medicine, K.J. Somaiya Medical College and Research Centre, Sion, Mumbai. Cerebrotendinous xanthomatosis is an exceptionally rare condition in Indian subcontinent, however, it is potentially treatable if diagnosed. We present and discuss the clinical presentation and investigations in a case of cerebrotendinous xanthomatosis (CTX). PMID: 18051740 [PubMed - indexed for MEDLINE] 113. Rev Neurol (Paris). 2007 Oct;163(10):884-96. [Treatable hereditary neuro-metabolic diseases]. [Article in French] Sedel F, Lyon-Caen O, Saudubray JM. Fédération des maladies du système nerveux, Groupe Hospitalier Pitié-Salpêtrière, Paris. frederic.sedel@psl.aphp.fr Hereditary metabolic diseases may appear during adolescence or young adulthood, revealed by an apparently unexplained neurological or psychiatric disorder. Certain metabolic diseases respond to specific treatments and should be identified early, particularly in emergency situations where rapid introduction of a treatment can avoid fatal outcome or irreversible neurological damage. The main diseases leading to an acute neurological syndrome in the adult are urea cycle disorders, homocysteine metabolisms disorders and porphyria. More rarely, Wilson's disease, aminoacid diseases, organic aciduria, or pyruvate dehydrogenase deficiency, beta-oxidation disordes or biotin metabolism may be involved. Most emergency situations can be screen correctly with simple tests (serum ammonia, homocysteine, lactate, urinary prophyrines, acylcarnitine pattern, amino acid and organic acid chromatography). For chronic situations, the main treatable diseases are Wilson's disease, homocysteine, cerebrotendinous xanthomatosis, Refsum's disease, vitamin E deficiency, Gaucher's disease, Fabry's disease, and neurotransmitter metabolism disorders. We present treatable metabolic disorders as a function of the different clinical situations observed in adults. PMID: 18033024 [PubMed - indexed for MEDLINE] 114. Acta Cytol. 2007 Jul-Aug;51(4):654-6. Cerebrotendinous xanthomatosis: a case report. Srinivas BH, Patnayak R, Rao IS, Prayaga A, Khan AK, Narasimhlu G. Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Andhra Pradesh, India. BACKGROUND: Cerebrotendinous xanthomatosis is a rare, autosomal recessive, inherited lipid storage disease characterized by accumulation of cholestanol and cholesterol in most tissues. The disease is caused by mutations in the sterol 27-hydroxylase gene, leading to a block in bile synthesis, with accumulation of substrates for this enzyme, including cholesterol, resulting in an increase in the conversion of cholesterol to cholestanol. CASE: A 26-year-old woman presented with gradually increasing bilateral ankle swelling. She had a history of bilateral cataracts and left-sided hemiparesis. She had mental retardation, with a history of delayed milestone development. Her serum cholesterol levels were elevated. Aspiration of both ankle swellings revealed histiocytes and many foreign body giant cells. There were numerous rectangular to rhomboid crystals in the background. CONCLUSION: Very few articles are available on the cytologic features of tendinous xanthomas; hence we tried to highlight these features. PMID: 17718147 [PubMed - indexed for MEDLINE] 115. Metabolism. 2007 Sep;56(9):1248-55. Mutational analysis of CYP27A1: assessment of 27-hydroxylation of cholesterol and 25-hydroxylation of vitamin D. Gupta RP, Patrick K, Bell NH. Department of Medicine, Medical University of South Carolina, Strom Thurmond Research Building, Charleston, SC 29403, USA. The CYP27A1 gene encodes a mitochondrial enzyme that modulates the acidic biosynthetic pathway for bile acids beginning with the 27-hydroxylation of cholesterol. CYP27A1 also 25-hydroxylates vitamin D(3). Gene mutations cause cerebrotendinous xanthomatosis (CTX), an autosomal recessive disorder, and may cause 25-hydroxyvitamin D deficiency and early-onset osteoporosis and fractures in affected patients. To examine the effects of mutations of CYP27A1 on vitamin D and cholesterol hydroxylating activity, recombinant CYP27A1 and mutant complementary DNAs produced by site-directed mutagenesis were stably expressed in either Escherichia coli or COS-1 cells. Activities of wild-type and mutant enzymes were determined with cholesterol, vitamin D(3), and 1alpha-hydroxyvitamin D(3) (1alphaOHD(3)) as substrates. Of the 15 mutants tested, 11 expressed protein and 4 expressed little or no protein. Functional heme activity, estimated by reduced CO difference spectra at 450 nm, was absent in 12 mutants. When expressed in E. coli, 3 mutants, K226R, D321G, and P408S, each known to cause clinically CTX, showed modest decreases in reduced CO spectra peak and either no change or decreases of less than 50% in hydroxylation of cholesterol, vitamin D(3), and 1alphaOHD(3) compared with wild type. When expressed transiently in COS-1 cells, each of these mutants showed 25-hydroxylation activity for 1alphaOHD(3) as well as wild type. Thus, 3 mutants, K226R, D321G, and P408S, known to occur clinically with nonfunctioning mutants, hydroxylated cholesterol, vitamin D(3), and 1alphaOHD(3). How they contribute to the pathogenesis of CTX despite being biologically active in vitro remains to be determined. PMCID: PMC2707179 PMID: 17697869 [PubMed - indexed for MEDLINE] 116. J Inherit Metab Dis. 2007 Oct;30(5):631-41. Epub 2007 Aug 10. Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. Sedel F, Baumann N, Turpin JC, Lyon-Caen O, Saudubray JM, Cohen D. Federation of Nervous System Diseases, Hôpital de la Salpêtrière, 47 Boulevard de l'Hôpital, 75651, Paris cedex 13, France. frederic.sedel@psl.aphp.fr Comment in J Inherit Metab Dis. 2007 Oct;30(5):627. Inborn errors of metabolism (IEMs) may present in adolescence or adulthood as a psychiatric disorder. In some instances, an IEM is suspected because of informative family history or because psychiatric symptoms form part of a more diffuse clinical picture with systemic, cognitive or motor neurological signs. However, in some cases, psychiatric signs may be apparently isolated. We propose a schematic classification of IEMs into three groups according to the type of psychiatric signs at onset. Group 1 represents emergencies, in which disorders can present with acute and recurrent attacks of confusion, sometimes misdiagnosed as acute psychosis. Diseases in this group include urea cycle defects, homocysteine remethylation defects and porphyrias. Group 2 includes diseases with chronic psychiatric symptoms arising in adolescence or adulthood. Catatonia, visual hallucinations, and aggravation with treatments are often observed. This group includes homocystinurias, Wilson disease, adrenoleukodystrophy and some lysosomal disorders. Group 3 is characterized by mild mental retardation and late-onset behavioural or personality changes. This includes homocystinurias, cerebrotendinous xanthomatosis, nonketotic hyperglycinaemia, monoamine oxidase A deficiency, succinic semialdehyde dehydrogenase deficiency, creatine transporter deficiency, and alpha and beta mannosidosis. Because specific treatments should be more effective at the 'psychiatric stage' before the occurrence of irreversible neurological lesions, clinicians should be aware of atypical psychiatric symptoms or subtle organic signs that are suggestive of an IEM. Here we present an overview of IEMs potentially revealed by psychiatric problems in adolescence or adulthood and provide a diagnostic strategy to guide metabolic investigations. PMID: 17694356 [PubMed - indexed for MEDLINE] 117. Intern Med. 2007;46(15):1259-61. Epub 2007 Aug 2. Cerebrotendinous xanthomatosis with cerebellar ataxia as the chief symptom. Okuma H, Kitagawa Y, Tokuoka K, Takagi S. Department of Neurology, Tokai University Tokyo Hospital. ookuma@tok.u-tokai.ac.jp PMID: 17675781 [PubMed - indexed for MEDLINE] 118. Redox Rep. 2007;12(3):119-24. Cerebrotendinous xanthomatosis: case report with evidence of oxidative stress. Gonzalez-Cuyar LF, Hunter B, Harris PL, Perry G, Smith MA, Castellani RJ. Department of Pathology, University of Maryland, Baltimore, Maryland, USA. Cerebrotendinous xanthomatosis is an autosomal recessive disorder of bile acid synthesis, characterized by mutation in the mitochondrial enzyme 27-hydroxylase that leads to an accumulation of cholestanol and cholesterol. Characterized clinically by premature bilateral cataracts, slowly progressive neurological deterioration with dementia, cerebellar and brainstem signs, peripheral neuropathy, and seizures, the disease presents pathologically with lipid granulomata with foamy histiocytes and cholesterol clefts. Replacement therapy with chenodeoxycholic acid slows progression of the disease but does not reverse neurological deficits. Here, we present the case of a 49-year-old woman diagnosed at autopsy with cerebrotendinous xanthomatosis, on the basis of bilateral Achilles tendon granulomas, and typical foamy histiocytic infiltration of the brain, most severe in the dentate nucleus, and a typical clinical presentation. To investigate the pathological manifestations of this disease further, we performed immunohistochemistry for N(epsilon)-(carboxymethyl)-lysine, an indicator of oxidative damage, and found strong labeling of cytoplasmic material within histiocytes. In summary, this case of undiagnosed cerebrotendinous xanthomatosis during life emphasizes the need for a greater awareness of the disease, and early diagnosis and treatment. Further, the involvement of oxidative stress in cerebrotendinous xanthomatosis indicates that combined therapy with chenodeoxycholic acid and antioxidants may improve clinical outcome. PMID: 17623518 [PubMed - indexed for MEDLINE] 119. Saudi Med J. 2007 Jul;28(7):1113-8. Cerebrotendinous xanthomatosis in a Saudi Arabian family-genotyping and long-term follow-up. Price Evans DA, Salah KA, Mobrad MA, Mitchell WD, Olin M, Eggertsen G. Department of Medicine, C123 Riyadh Military Hospital, PO Box 7897, Riyadh 11159, Kingdom of Saudi Arabia, and Department of Medical Laboratory Services & Technology, Huddinge University Hospital, Sweden. daperkh@hotmail.com A Saudi Arabian family is described in which there were 2 siblings with typical features of cerebral xanthomatosis CTX including premature cataracts, xanthomata of the Achilles tendons, neuro-psychiatric disturbances, and atherosclerosis. The 2 patients were homozygous for a point mutation in the mitochondrial 27-hydroxylase gene CYP27A1, OMIM 606530 located in the splice site of intron 6, where G was exchanged for A IVS6+1G>A. Their parents were cousins, 5 siblings were healthy, 2 were heterozygous for the mutation, and one showed the wild-type genotype. The father was heterozygous for the mutation, while the other family members were not tested. The progress of the 2 CTX patients over 14 years is described; firstly when they were receiving treatment with chenodeoxycholic acid; when this medication was not available, and later when it was restored. A hereditary hyperlipidemia was also present in this family. It is suggested that when this occurs with CTX, a more serious illness results that merits more aggressive dual therapy. PMID: 17603722 [PubMed - indexed for MEDLINE] 120. Dtsch Med Wochenschr. 2007 Jul 29;132(27):1463-6. [Cerebrotendinous xanthomatosis]. [Article in German] Burghaus L, Liu W, Haupt WF. Klinik und Poliklinik für Neurologie, Universität zu Köln, Köln, Germany. lothar.burghaus@uk-koeln.de HISTORY AND CLINICAL FINDINGS: A 43-year-old woman had since childhood suffered from progressive dementia. Gait ataxia and mild polyneuropathy were noted in the neurological examination. She also had painful xanthomas of the achilles tendons. A bilateral cataract operation had been performed during adolescence. INVESTIGATIONS: An elevated concentration of cholestanol and a normal cholesterol level were found in the blood samples. The cerebral computed tomography revealed slight cerebral atrophy, predominantly affecting the cerebellum. Neurophysiological tests detected a sensory polyneuropathy in the legs. In addition the electroencephalogram showed a generalized slowing of electrical activity. DIAGNOSIS, TREATMENT AND COURSE: Clinical findings and laboratory values indicated the diagnosis of a cerebrotendinous xanthomatosis. After initiation of a drug therapy, based on a combination of an HMG-CoA-reductase inhibitor (simvastatin 20 mg/day) and a bile acid, chenodeoxycholic acid (15 mg/kg/day), further progression of the disease was prevented. CONCLUSION: The diagnosis of cerebrotendinous xanthomatosis is easily made in patients presenting all clinical symptoms expected in the disease. However, up to 30% of the patients do not show severe xanthomas. Especially in early stages of the disease the diagnosis may be difficult. Treatment can be efficacious and should be started as early as possible to prevent irreversible damage, particularly in the nervous system. PMID: 17583829 [PubMed - indexed for MEDLINE] 121. Biochim Biophys Acta. 2007 Jul;1771(7):839-44. Epub 2007 May 1. Rifampicin-induced CYP3A4 activation in CTX patients cannot replace chenodeoxycholic acid treatment. Szalat A, Gershkovich P, Ben-Ari A, Shaish A, Liberman Y, Boutboul E, Gotkine M, Hoffman A, Harats D, Leitersdorf E, Meiner V. Department of Internal Medicine B and the Center for Research Prevention and Treatment of Atherosclerosis, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Cerebrotendinous xanthomatosis (CTX) is a rare neurodegenerative disorder with cholestanol accumulation resulting from mutations in the sterol 27-hydroxylase gene (CYP27A). Conventional treatment includes chenodeoxycholic acid and HMG-CoA reductase inhibitors. Mice with disrupted Cyp27A (Cyp27 KO) do not show elevated cholestanol levels nor develop CTX manifestations. This phenomenon was proposed to be due to murine CYP3A overexpression leading to an alternative pathway for degradation of bile alcohols including cholestanol. Our objective was to examine the influence of CYP3A4 induction on cholestanol elimination in CTX patients. Rifampicin (600 mg/day x 7 days), known to induce the PXR, and thereby to increase CYP3A activity, was used. The degree of CYP3A4 induction was assessed by comparing midazolam pharmacokinetics before and after rifampicin treatment. Cholestanol levels and cholestanol/cholesterol ratios were assayed during the experimental period and compared to a 3 weeks period without treatment. The results show that despite 60% increase in CYP3A4 activity following rifampicin treatment, there is no significant change in cholestanol levels. We conclude that up-regulated expression of CYP3A affects cholestanol elimination in mice differently as compared to its effect in CTX patients. Therefore, CYP3A4 inducers cannot replace chenodeoxycholic acid for the treatment of CTX. PMID: 17553741 [PubMed - indexed for MEDLINE] 122. J Intern Med. 2007 May;261(5):504-10. Unique patient with cerebrotendinous xanthomatosis. Evidence for presence of a defect in a gene that is not identical to sterol 27-hydroxylase. Hansson M, Olin M, Floren CH, von Bahr S, van't Hooft F, Meaney S, Eggertsen G, Björkhem I. Division of Clinical Chemistry, Karolinska University Hospital, Huddinge, Sweden. Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder believed to be exclusively caused by mutations in the CYP27A1 gene coding for the enzyme sterol 27-hydroxylase. Common findings in CTX are tendon xanthomas, cataracts and progressive neurological dysfunction. Here, we characterize an adult female patient with tendon xanthomas and classic biochemical findings of CTX (i.e. high levels of bile alcohols and cholestanol and extremely low levels of 27-hydroxycholesterol in plasma). Additionally, sterol 27-hydroxylase activity in cultured monocyte-derived macrophages from this patient was <5% of normal. Sequencing the CYP27A1 gene uncovered that the patient is heterozygous for two previously undescribed base substitutions in exon 8, C478A and C479A, which are expected to affect the haeme-binding domain of the enzyme. When expressed in HEK293 cells, the corresponding protein had only 8% of normal enzymatic activity. No other mutation was found in the open reading frame of the CYP27A1 gene, intron-exon boundaries or in the 5'-untranslated region up to 5000 bp distal to the translational start site. Sequencing mRNA isolated from leucocytes from the patient revealed a 1 : 1 ratio of mutated and nonmutated species, with total mRNA levels that were not significantly different from the controls. It is concluded that the patient is heterozygous for two mutations affecting one allele of the CYP27A1 gene and with at least one additional yet undefined gene that is of critical importance for the activity of sterol 27-hydroxylase. PMID: 17444890 [PubMed - indexed for MEDLINE] 123. Neurophysiol Clin. 2007 Jan-Mar;37(1):47-9. Epub 2007 Feb 16. Cerebrotendinous xanthomatosis: no involvement of the autonomic nervous system in a case with severe neuropathy. Geraldes R, Santos-Bento M, de Carvalho M. PMID: 17418358 [PubMed - indexed for MEDLINE] 124. Clin Chim Acta. 2007 May 1;380(1-2):81-8. Epub 2007 Jan 24. High-throughput urine screening for Smith-Lemli-Opitz syndrome and cerebrotendinous xanthomatosis using negative electrospray tandem mass spectrometry. Pitt JJ. VCGS Pathology, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia. james.pitt@ghsv.org.au BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) and cerebrotendinous xanthomatosis (CTX) are disorders affecting cholesterol metabolism. Currently, diagnosis relies on clinical recognition and specific and complex biochemical testing. METHODS: A rapid, high-throughput urine test, suitable for mass screening for these two disorders, was developed using flow injection negative electrospray tandem mass spectrometry with multiple reaction monitoring. Cholestane-pentol glucuronide, a known marker for CTX, was measured and a steroid sulfate with a proposed keto-pregnadien-diol structure was identified and measured for SLOS. Measurement of the two markers was readily incorporated into an existing tandem mass spectrometry method for diagnosing inborn errors of amino and organic acid metabolism. RESULTS: Levels in affected patients were well separated from 1738 controls, ranging from 6.7 to 100 times the 99.7th percentile of controls in SLOS patients (n=3) and 7.3 to 24 times the 99.7th percentile of controls in CTX patients (n=4). CONCLUSIONS: The addition of testing for SLOS and CTX to a routine tandem mass spectrometry urine screening program simplifies the diagnosis of these two disorders and further extends the range of inborn errors of metabolism detected by this technique. PMID: 17341417 [PubMed - indexed for MEDLINE] 125. J Lipid Res. 2007 May;48(5):1167-74. Epub 2007 Feb 26. On the mechanism of cerebral accumulation of cholestanol in patients with cerebrotendinous xanthomatosis. Panzenboeck U, Andersson U, Hansson M, Sattler W, Meaney S, Björkhem I. Institute of Pathophysiology, Center of Molecular Medicine, Medical University of Graz, Graz, Austria, and Division of Clinical Chemistry, Karolinska University Hospital, Karolinska Institutet, Huddinge, Sweden. The most serious consequence of sterol 27-hydroxylase deficiency in humans [cerebrotendinous xanthomatosis (CTX)] is the development of cholestanol-containing brain xanthomas. The cholestanol in the brain may be derived from the circulation or from 7alpha-hydroxylated intermediates in bile acid synthesis, present at 50- to 250-fold increased levels in plasma. Here, we demonstrate a transfer of 7alpha-hydroxy-4-cholesten-3-one across cultured porcine brain endothelial cells (a model for the blood-brain barrier) that is approximately 100-fold more efficient than the transfer of cholestanol. Furthermore, there was an efficient conversion of 7alpha-hydroxy-4-cholesten-3-one to cholestanol in cultured neuronal and glial cells as well as in monocyte-derived macrophages of human origin. It is concluded that the continuous intracellular production of cholestanol from a bile acid precursor capable of rapidly passing biomembranes, including the blood-brain barrier, is likely to be of major importance for the accumulation of cholestanol in patients with CTX. Such a mechanism also fits well with the observation that treatment with chenodeoxycholic acid, which normalizes the level of the bile acid precursor, results in a reduction of cholestanol-containing xanthomas even in the brain. PMID: 17325385 [PubMed - indexed for MEDLINE] 126. Neuropathology. 2007 Feb;27(1):62-6. Cerebrotendinous xanthomatosis with a compound heterozygote mutation and severe polyneuropathy. Wang Z, Yuan Y, Zhang W, Zhang Y, Feng L. Department of Neurology, First Hospital of Peking University, China. Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessively inherited lipid storage disorder with multiple system involvement and has been reported worldwide. Here we report a Chinese family with CTX and present the pathological findings within peripheral nerves and CYP27A1 gene mutation analysis. We also review the published literature to discuss the clinical presentation and classification of neuropathy in this disease. PMID: 17319284 [PubMed - indexed for MEDLINE] 127. Nihon Naika Gakkai Zasshi. 2007 Jan 10;96(1):150-2. [Cerebrotendinous xanthomatosis with minimal change nephrotic syndrome]. [Article in Japanese] Matsumoto M, Kabashima N, Serino R, Tokunaga M, Oikawa S, Shibata T, Otsuji Y, Tamura M. Department of Cardiology and Nephrology, University of Occupational and Environmental Health, Kitakyushu. PMID: 17305069 [PubMed - indexed for MEDLINE] 128. J Radiol. 2006 Dec;87(12 Pt 1):1883-6. [Imaging of cerebrotendinous xanthomatosis]. [Article in French] Nagi S, Bouchriha M, Sebaï R, Marrakchi-Turki Z, Zouaoui W, Mrabet H, Megdiche H, Ben Slama C, Touibi S. Service de Neuroradiologie, Institut National de Neurologie, Tunis, Tunisie. sonia.nagi@rns.tn Cerebrotendinous xanthomatosis is a rare lipid storage disorder due tocaused by an autosomal recessive inherited defect of the hepatic mitochondrial sterol 27 hydroxylase. It's characterized by accumulation of cholestanol and cholesterol in many tissues, in particular tendons and brain, with tendon xanthomas, juvenile cataracts, and neurological abnormalities. MR imaging showed typical bilateral and symmetrical involvement of the dentate nuclei. Early and long- term treatment may improve neurologic function. The authors present a case of cerebrotendinous xanthomatosis and describe ultrasound, computed tomography, and magnetic resonance findings. PMID: 17213773 [PubMed - indexed for MEDLINE] 129. Neurology. 2006 Dec 12;67(11):E20. Cerebrotendinous xanthomatosis. Schöls L, Nägele T, Schüle R, Berg D. Department of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, D-72076 Tübingen, Germany. Ludger.Schoels@uni-tuebingen.de PMID: 17159091 [PubMed - indexed for MEDLINE] 130. Indian J Dermatol Venereol Leprol. 2006 Sep-Oct;72(5):364-6. Cerebrotendinous xanthomatosis: need for early diagnosis. Muhammed K, Nandakumar G, Saritha S. Department of Dermatology and Venereology, Government Medical College, Kozhikode--673 008, Kerala, India. drmuhammedk@rediffmail.com Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid storage disease characterized by widespread tissue deposition of two neutral sterols, cholestanol and cholesterol, resulting in tendinous xanthomas, juvenile cataracts, progressive neurological defects and premature death from arteriosclerosis. The primary biochemical defect is deficiency of hepatic mitochondrial enzyme sterol-27-hydroxylase which catalyses the hydroxylation of cholestanol (5-alpha dehydro derivative of cholesterol) and this deficiency decreases bile acid synthesis. Substantial elevation of serum cholestanol and urinary bile alcohols with low to normal plasma cholesterol concentration establishes the diagnosis. Cerebrotendinous xanthomatosis is exceptionally rare in the Indian population. We are reporting a woman with this rare disorder, who was on antiepileptic and antipsychotic drugs for a prolonged period and whose original condition went undiagnosed. She presented with xanthomas on the Achilles tendons and the upper end of tibia. She was mentally subnormal and her serum cholestanol level was raised. Her younger sister too was severely affected by this disorder. Early treatment with chenodeoxycholic acid is known to prevent disease progression. PMID: 17050932 [PubMed - indexed for MEDLINE] 131. J Lipid Res. 2007 Jan;48(1):185-92. Epub 2006 Oct 1. Cholestanol metabolism in patients with cerebrotendinous xanthomatosis: absorption, turnover, and tissue deposition. Bhattacharyya AK, Lin DS, Connor WE. Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA, USA. To study the metabolism of cholestanol in patients with cerebrotendinous xanthomatosis (CTX), we measured the cholestanol absorption, the cholesterol and cholestanol turnover, and the tissue content of sterols in two patients. Cholestanol absorption was approximately 5.0%. The rapid exchangeable pool of cholestanol was 233 mg, and the total exchangeable pool was 752 mg. The production rate of cholestanol in pool A was 39 mg/day. [4-14C]cholestanol was detected in the xanthomas, but neither [4-14C]cholestanol nor [4-14C]cholesterol was detected in peripheral nerves biopsied at 49 and 97 days after [4-14C]cholesterol given intravenously. Of the 18 tissues analyzed at biopsy and autopsy, the cholestanol content varied from 0.09 mg/g in psoas muscle to 76 mg/g in a cerebellar xanthoma. With the assumption that the cholestanol-to-cholesterol ratio is 1.0, the relative cholestanol-to-cholesterol ratio varied from 1.0 in plasma and liver to 30.0 in the cerebellar xanthoma; cholestanol was especially high in nerve tissue. Our data indicate that CTX patients absorb cholestanol from the diet. They have a higher than normal cholestanol production rate. Cholestanol was derived from cholesterol. In CTX patients, the blood-brain barrier was intact to the passage of [4-14C]cholesterol and [4-14C]cholestanol. The deposition of large amounts of cholestanol (up to 30% of total sterols in cerebellum) in nerve tissues must have an important role in the neurological symptoms in CTX patients. In view of the intact blood-brain barrier, several other explanations for the large amounts of cholestanol in the brain were postulated. PMID: 17012751 [PubMed - indexed for MEDLINE] 132. Neurol Sci. 2006 Jun;27(2):143-9. Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Gallus GN, Dotti MT, Federico A. Department of Neurological and Behavioural Sciences, Medical School, University of Siena, Viale Bracci 2, I-53100, Siena, Italy. Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease due to defective activity of the mitochondrial enzyme sterol 27-hydroxylase. In 1991, sterol 27-hydroxylase gene (CYP27A1) was localised on the long arm of chromosome 2 [1]. Clinical characteristics of CTX are diarrhoea, cataracts, tendon xanthomas and neurological manifestations including dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, and seizures. More than 300 patients with CTX have been reported to date worldwide and about 50 different mutations identified in the CYP27A1 gene. Almost all mutations lead to the absence or inactive form of the sterol 27-hydroxylase. In this review, according with the aims of this section of the journal, we describe the different pathogenetic mutations in the CYP27A1 gene and the main clinical and pathogenetic aspects that may help clinical neurologists in the diagnosis of CTX. PMID: 16816916 [PubMed - indexed for MEDLINE] 133. J Bone Joint Surg Am. 2006 Jun;88(6):1340-4. Cerebrotendinous xanthomatosis: a rare cause of bilateral Achilles tendon swelling and ataxia. A case report. Brodsky JW, Beischer AD, Anat D, East C, Soltero E, Tint GS, Salen G, Silverman J. Baylor University Medical Center, 411 North Washington Avenue, Suite 7000, Dallas, TX 75246, USA. PMID: 16757769 [PubMed - indexed for MEDLINE] 134. Skeletal Radiol. 2007 Feb;36(2):171-5. Epub 2006 May 20. Cerebrotendinous xanthomatosis presenting with bilateral Achilles tendon xanthomata. Smithard A, Lamyman MJ, McCarthy CL, Gibbons CL, Cooke PJ, Athanasou N. Tumour Surgery, Nuffield Orthopaedic Centre, Windmill Road, Oxford, OX3 7LD, UK, We report on a case of a 36-year-old lady who presented with large, painful soft-tissue swellings of both Achilles tendons. MRI demonstrated fusiform enlargement involving the Achilles tendons bilaterally. The tendons returned heterogeneous signal intensity characterised by a diffuse reticulated appearance. The right tendon mass was treated with a wide marginal excision and Achilles tendon reconstruction. The histology confirmed Achilles tendon xanthoma. Further metabolic investigation revealed the patient to have a rare autosomal recessive condition called cerebrotendinous xanthomatosis (CTX). Her brother was also affected. CTX is easily treatable if diagnosed early, and should be suspected in patients presenting with bilateral Achilles tendon xanthomas and normal plasma lipid levels. PMID: 16715243 [PubMed - indexed for MEDLINE] 135. Biochemistry. 2006 Apr 11;45(14):4396-404. Distinct binding of cholesterol and 5beta-cholestane-3alpha,7alpha,12alpha-triol to cytochrome P450 27A1: evidence from modeling and site-directed mutagenesis studies. Mast N, Murtazina D, Liu H, Graham SE, Bjorkhem I, Halpert JR, Peterson J, Pikuleva IA. Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555-1031, USA. Cytochrome P450 27A1 (P450 27A1 or CYP27A1) is an important enzyme that participates in different pathways of cholesterol degradation as well as in the activation of vitamin D(3). Several approaches were utilized to investigate how two physiological substrates, cholesterol and 5beta-cholestane-3alpha,7alpha,12alpha-triol, interact with CYP27A1. The enzyme active site was first probed spectrally by assessing binding of the two substrates and five substrate analogues followed by computer modeling and site-directed mutagenesis. The computer models suggest that the spatial positions and orientations of cholesterol and 5beta-cholestane-3alpha,7alpha,12alpha-triol are different in the enzyme active site. As a result, some of the active site residues interact with both substrates, although they are situated differently relative to each steroid, and some residues bind only one substrate. Mutation of the overlapping substrate-contact residues (W100, H103, T110, M301C, V367, I481, and V482) affected CYP27A1 binding and enzyme activity in a substrate-dependent manner and allowed identification of several important side chains. T110 is proposed to interact with the 12alpha-hydroxyl of 5beta-cholestane-3alpha,7alpha,12alpha-triol, whereas V367 seems to be crucial for correct positioning of the cholesterol C26 methyl group and for regioselective hydroxylation of this substrate. Distinct binding of the CYP27A1 substrates may provide insight into why phenotypic manifestations of cerebrotendinous xanthomatosis, a disease associated with CYP27A1 deficiency, are so diverse. PMID: 16584175 [PubMed - indexed for MEDLINE] 136. J Neurol Sci. 2006 Apr 15;243(1-2):83-6. Epub 2006 Jan 30. Could steroids mask the diagnosis of cerebrotendinous xanthomatosis? Siman-Tov T, Meiner V, Gadoth N. Department of Neurology, Meir General Hospital Kfar-Saba, and the Sackler Faculty of Medicine, Tel-Aviv University, Israel. Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis, caused by impaired hydroxylation of cholesterol side chains due to deficiency of the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1), leading to accumulation of cholestanol and cholesterol in brain and other tissues. Elevated plasma cholestanol serves as a key marker for the clinical diagnosis of CTX. In the present report we describe a young man with CTX who was on high dose steroids for a misdiagnosed chronic inflammatory demyelinating polyneuropathy (CIDP) and had normal level of serum cholestanol. When steroids were discontinued, markedly elevated serum cholestanol was measured concomitant with marked clinical worsening. This observation may imply that steroids can lower plasma cholestanol, possibly by directly inducing residual CYP27A1 activity or by inducing alternative pathways for cholestanol elimination. PMID: 16445943 [PubMed - indexed for MEDLINE] 137. Proteomics. 2006 Feb;6(3):1029-37. New insights into the pathological mechanisms of cerebrotendinous xanthomatosis in the Taiwanese using genomic and proteomic tools. Wang PW, Chang WN, Lu CH, Chao D, Schrag C, Pan TL. Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid-storage disorder caused by a deficiency of the mitochondrial sterol 27-hydroxylase. Genetic analysis utilizing SSCP and direct DNA sequencing identified a new mutation. One base-pair of cytosine was deleted at codon 326 on exon 2 of CYP27 in all CTX patients while their father was heterozygotic. This novel point deletion predicts a frameshift in mRNA (Pro(102) -->Leu) and results in the appearance of a premature termination codon (TGA) to substitute for Val(106) (GTG). To characterize the pathological mechanism of CTX patients, the protein profiles of serum and leukocytes extracted from these subjects were presented by means of proteomic technologies including 2-DE and MALDI-TOF analysis. According to the results, the amount of vinculin, ABP-280, talin and vimentin in leukocytes of CTX patients had changed significantly, reflecting the changes in membrane dynamics concerning cholestanol accumulation. The expression of target proteins in CTX patients and control was further verified by western blotting which indicated the same tendency as 2-DE data. This is the first paper to integrate both genomic and proteomic concepts for analyzing the possible mechanism of CTX and provides more information for related study in the future. PMID: 16372260 [PubMed - indexed for MEDLINE] 138. Clin Neuropathol. 2005 Nov-Dec;24(6):276-83. Inherited cholesterol lipidosis: cerebrotendinous xanthomatosis (van Bogaert Scherer Epstein disease). A clinicopathological study. Isenhardt K, Schmitt R, Nagel A, Drach L, Schlote W. Department of Neurology, Klinikum Aschaffenburg, University of Würzburg, Germany. Klaus.Isenhardt@klinikum-aschaffenburg.de Cerebrotendinous xanthomathosis (CTX) is a rare autosomal-recessively transmitted disease of the lipid storage system with an array of general and neurological symptoms, based on the pathological storage of cholestanol and cholesterol. The histologic manifestations are foamy cell granulomata and cholesterol crystals within various tissues, associated with a loss of both nerve cells and demyelination inside the CNS. We present a case of CTX with clinical progression as well as the pathomorphologic autopsy findings. The CNS affection in our case will be demonstrated and the pathogenesis be discussed. Medical treatment of CTX is possible but with variable success. In the case shown, the patient profited only marginally from a long-term application of chenodeoxycholic acid. PMID: 16320823 [PubMed - indexed for MEDLINE] 139. Am J Med Genet A. 2005 Dec 1;139A(2):114-7. Unusual cerebrotendinous xanthomatosis with fronto-temporal dementia phenotype. Guyant-Maréchal L, Verrips A, Girard C, Wevers RA, Zijlstra F, Sistermans E, Vera P, Campion D, Hannequin D. Department of Neurology, Rouen University Hospital, France. Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP27). We report a 53-year-old man, with an unusual phenotype of CTX. He had xanthomas since adolescence. He had no mental retardation and developed at 44 years a progressive neuropsychiatric phenotype, suggestive of fronto-temporal dementia according to clinical Neary criteria. Cataract and ataxia were absent. Cerebral MRI revealed diffuse hyperintense T2 abnormalities in the supratentorial white matter without cerebellar atrophy or lesions, while Technetium-99m-ECD brain SPECT revealed a severe cerebellar hypoperfusion. Serum cholestanol level was elevated with excessive urinary bile alcohols excretion. Mutation analysis revealed that he was compound heterozygous for two mutations in the CYP27A1 gene: 1016 C > T (exon 5) on one allele and a novel mutation, 1435C > G (exon 8) on the other allele. A follow-up study was conducted to evaluate the effects of chenodeoxycholic acid (CDCA) and simvastatin treatment during 3 years. In spite of this treatment, cognitive functions declined but no other signs of neurological deterioration appeared. Copyright 2005 Wiley-Liss, Inc. PMID: 16278884 [PubMed - indexed for MEDLINE] 140. Rev Med Interne. 2005 Dec;26(12):992-3. Epub 2005 Oct 4. [Hypertrophy of the atrial septum in the cerebrotendinous xanthomatosis]. [Article in French] Frih-Ayed M, Boughammoura-Bouatay A, Ben Hamda K, Chebel S, Ben Farhat M. PMID: 16236394 [PubMed - indexed for MEDLINE] 141. Arch Neurol. 2005 Sep;62(9):1459-63. Cerebrotendinous xanthomatosis: possible higher prevalence than previously recognized. Lorincz MT, Rainier S, Thomas D, Fink JK. Department of Neurology, University of Michigan, Ann Arbor, 48109, USA. BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare but treatable neurodegenerative disorder caused by 27-sterol hydroxylase (CYP27) deficiency. OBJECTIVE: To describe clinical features and results of genetic analysis in a family with CTX. DESIGN: Case report. SETTING: University hospital. Subjects A 54-year-old woman with CTX, her family members, and 115 white control subjects. MAIN OUTCOME MEASURES: Results of clinical evaluation and magnetic resonance imaging of the brain in the affected subject; results of mutation analysis of the CYP27 coding sequence in the patient, her parents, and the control subjects. RESULTS: The proband and her affected sibling had classic features of CTX, including presenile cataracts, tendon xanthomas, diarrhea, and a complex neurodegenerative disorder. They were somewhat atypical, however, because their cataracts were congenital, cognitive impairment had been noted in childhood, and the white matter involvement was more severe than usual. The proband was shown to be homozygous for CYP27 mutation R362C. Similar analysis of 115 control subjects identified 1 subject who was a heterozygous carrier for this same CYP27 mutation. CONCLUSIONS: The prevalence of CTX due to CYP27 mutation R362C alone is approximately 1 per 50,000 among white individuals. Although the disorder is rare, this incidence is substantially greater than previously recognized. Greater awareness of CTX is important because specific treatment is available. PMID: 16157755 [PubMed - indexed for MEDLINE] 142. Neurology. 2005 Apr 26;64(8):1476. Cerebrotendinous xanthomatosis: a treatable ataxia. Clemen CS, Spottke EA, Lütjohann D, Urbach H, von Bergmann K, Klockgether T, Dodel R. Center for Biochemistry, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931 Koeln, Germany. christoph.clemen@uni-koeln.de PMID: 15851751 [PubMed - indexed for MEDLINE] 143. J Pediatr Gastroenterol Nutr. 2005 Apr;40(4):481-6. Mutation in the sterol 27-hydroxylase gene associated with fatal cholestasis in infancy. von Bahr S, Björkhem I, Van't Hooft F, Alvelius G, Nemeth A, Sjövall J, Fischler B. Department of Clinical Chemistry, Huddinge University Hospital, Karolinska Institutet, Stockholm, Sweden. Erratum in J Pediatr Gastroenterol Nutr. 2005 Jul;41(1):144. BACKGROUND: Inborn errors of bile acid synthesis are rare but potentially treatable causes of neonatal cholestasis. We here present a cholestatic infant with an ongoing cytomegalovirus infection who despite intensive treatment died of severe liver disease at 4 months of age. METHODS: The urinary steroids were investigated by electrospray mass spectrometry and gas chromatography mass spectrometry. Oxysterols in plasma were analysed by isotope dilution mass spectrometry. Mutations in the sterol 27-hydroxylase gene were detected by PCR. RESULTS: Glucuronidated bile alcohols, which are known to be excreted by patients with cerebrotendinous xanthomatosis (CTX) were detected in the urine. Analysis of plasma revealed markedly reduced levels of 27-hydroxycholesterol. Mutation analysis showed the presence of a stop codon in exon 7, confirming the diagnosis of CTX, a rare disease not previously diagnosed in Sweden. CONCLUSIONS: Fetal and neonatal deaths among siblings of patients with CTX have been reported previously and the present case supports the contention that reduced activity of the sterol 27-hydroxylase may predispose to the development of neonatal cholestasis. The associated viral infection may have further precipitated the liver disease. Since CTX, like other inborn errors of bile acid synthesis may be treated with bile acids an early diagnosis is essential. Thus, the analysis of urine by electrospray mass spectrometry is highly recommended in the investigation of patients with neonatal cholestasis. PMID: 15795599 [PubMed - indexed for MEDLINE] 144. Metabolism. 2005 Mar;54(3):335-44. Isotopomer spectral analysis of intermediates of cholesterol synthesis in patients with cerebrotendinous xanthomatosis. Clarenbach JJ, Lindenthal B, Dotti MT, Federico A, Kelleher JK, von Bergmann K. Department of Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany. Four patients with cerebrotendinous xanthomatosis (CTX) and 2 healthy controls received a constant proximal intraduodenal infusion of 1- 13 C-acetate as a stable-isotope-labeled marker of sterol synthesis. One patient was treated with pravastatin (20 mg twice daily) and another patient with chenodeoxycholic acid (250 mg tid). Every hour, venous blood and duodenal samples were obtained. Stable-isotope enrichment of neutral and polar sterols in serum and bile was assessed by gas chromatography/mass spectrometry. Isotopomer spectral analysis was performed on cholesterol, lathosterol, Delta-8-cholesterol, methylsterol, and lanosterol. Stable-isotope labeling of cholestanol, bile acids, and bile alcohols was analyzed by assessing the change over time of the ratio of M + 3 to M + 0. Eleven hours after marker infusion, we found up to 50% newly synthesized lathosterol in serum and up to 80% in bile, with similar results for other cholesterol precursors. In cholesterol, stable-isotope labeling could be demonstrated in all study subjects with a more prominent labeling in bile than in serum. No stable-isotope labeling was detected in cholestanol. Only minor stable-isotope incorporation was detectable in polar sterols in some subjects. Therapy with pravastatin did not have any effect on fractional or absolute synthesis rates or on the concentrations of cholestanol or cholesterol precursors compared to untreated patients with CTX. In contrast, therapy with chenodeoxycholic acid markedly lowered the concentrations of cholestanol and cholesterol precursors, led to a disappearance of bile alcohols, and reduced absolute synthesis rates of lathosterol. Isotopomer spectral analysis proved to be a powerful method to assess the endogenous synthesis of cholesterol precursors in patients with CTX. Higher fractional synthesis in bile than in serum may be due to the size of the pools in bile vs serum. Cholestanol exhibits no marker uptake and is therefore probably synthesized from preformed cholesterol. Biliary cholesterol secretion in patients with CTX is decreased compared to healthy controls. PMID: 15736111 [PubMed - indexed for MEDLINE] 145. Arq Neuropsiquiatr. 2004 Dec;62(4):1085-9. Epub 2004 Dec 15. Cerebrotendinous xanthomatosis: report of two Brazilian brothers. Lange MC, Zétola VF, Teive HA, Scola RH, Trentin AP, Zavala JA, Pereira ER, Raskin S, Werneck LC, Sistermans EA. Serviço de Neurologia, Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brazil. Cerebrotendinous xanthomatosis is a treatable rare autossomal recessive disease characterized by lipid storage secondary to a sterol 27-hydroxylase deficiency in the formation of cholic and chenodeoxycholic acids. We describe two Brazilian brothers with cognitive impairement and chronic diarrhea. One of them also presents bilateral cataracts. Neurological findings were progressive walking deficit, limb ataxia and pyramidal signs. Both patients had bilateral Achilles tendon xanthomata. Magnetic resonance image showed signal alterations in cerebellar hemispheres. We describe these cases with molecular genetic analysis confirming diagnosis and comparing with previous literature. The CYP27A1 gene study showed a C1187T mutation on exon 6. PMID: 15608974 [PubMed - indexed for MEDLINE] 146. J Lipid Res. 2005 Feb;46(2):287-96. Epub 2004 Dec 1. Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis. Honda A, Salen G, Matsuzaki Y, Batta AK, Xu G, Hirayama T, Tint GS, Doy M, Shefer S. Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki 310-0852, Japan. akihonda-gi@umin.ac.jp Cerebrotendinous xanthomatosis (CTX), sterol 27-hydroxylase (CYP27A1) deficiency, is associated with markedly reduced chenodeoxycholic acid (CDCA), the most powerful activating ligand for farnesoid X receptor (FXR). We investigated the effects of reduced CDCA on FXR target genes in humans. Liver specimens from an untreated CTX patient and 10 control subjects were studied. In the patient, hepatic CDCA concentration was markedly reduced but the bile alcohol level exceeded CDCA levels in control subjects (73.5 vs. 37.8 +/- 6.2 nmol/g liver). Cholesterol 7alpha-hydroxylase (CYP7A1) and Na+/taurocholate-cotransporting polypeptide (NTCP) were upregulated 84- and 8-fold, respectively. However, small heterodimer partner (SHP) and bile salt export pump were normally expressed. Marked CYP7A1 induction with normal SHP expression was not explained by the regulation of liver X receptor alpha (LXRalpha) or pregnane X receptor. However, another nuclear receptor, hepatocyte nuclear factor 4alpha (HNF4alpha), was induced 2.9-fold in CTX, which was associated with enhanced mRNA levels of HNF4alpha target genes, CYP7A1, 7alpha-hydroxy-4-cholesten-3-one 12alpha-hydroxylase, CYP27A1, and NTCP. In conclusion, the coordinate regulation of FXR target genes was lost in CTX. The mechanism of the disruption may be explained by a normally stimulated FXR pathway attributable to markedly increased bile alcohols with activation of HNF4alpha caused by reduced bile acids in CTX liver. PMID: 15576845 [PubMed - indexed for MEDLINE] 147. Neurol Sci. 2004 Oct;25(4):185-91. Normalisation of serum cholestanol concentration in a patient with cerebrotendinous xanthomatosis by combined treatment with chenodeoxycholic acid, simvastatin and LDL apheresis. Dotti MT, Lütjohann D, von Bergmann K, Federico A. Department of Neurological and Behavioural Sciences, University of Siena, Viale Bracci, Siena, Italy. The concentrations of serum cholesterol, cholestanol and non-cholesterol sterols were measured in a patient with cerebrotendinous xanthomatosis under different therapeutic regimens. During treatment with chenodeoxycholic acid (CDCA) (750 mg/day) plus simvastatin (20 mg/day) for two years cholesterol and cholestanol concentrations averaged 188+/-10 mg/dl and 0.54+/-0.03 mg/dl. Thereafter treatment with simvastatin was discontinued. During treatment with low-density lipoprotein (LDL)-apheresis plus CDCA for 33 weeks, cholestanol concentrations reached almost normal levels (0.48+/-0.03 mg/dl immediately before and 0.32+/-0.02 mg/dl directly after LDL-apheresis, n=6). A further reduction of cholesterol and cholestanol was achieved by addition of simvastatin (20 mg/day). Cholesterol and cholestanol concentrations before and after LDL-apheresis during this treatment period averaged 122+/-4 mg/dl and 55+/-10 mg/dl, and 0.42+/-0.02 mg/dl and 0.18+/-0.06 mg/dl, respectively. Despite the consistent reduction of cholestanol to normal or even subnormal levels, a definite improvement of clinical symptoms was not noted. Our results suggest caution in the recourse to an aggressive cholestanol lowering therapy. PMID: 15549503 [PubMed - indexed for MEDLINE] 148. J Lipid Res. 2005 Jan;46(1):76-85. Epub 2004 Nov 1. Role of CYP27A in cholesterol and bile acid metabolism. Dubrac S, Lear SR, Ananthanarayanan M, Balasubramaniyan N, Bollineni J, Shefer S, Hyogo H, Cohen DE, Blanche PJ, Krauss RM, Batta AK, Salen G, Suchy FJ, Maeda N, Erickson SK. Department of Medicine, University of California, San Francisco, CA 94143, USA. The CYP27A gene encodes a mitochondrial cytochrome P450 enzyme, sterol 27-hydroxylase, that is expressed in many different tissues and plays an important role in cholesterol and bile acid metabolism. In humans, CYP27A deficiency leads to cerebrotendinous xanthomatosis. To gain insight into the roles of CYP27A in the regulation of cholesterol and bile acid metabolism, cyp27A gene knockout heterozygous, homozygous, and wild-type littermate mice were studied. In contrast to homozygotes, heterozygotes had increased body weight and were mildly hypercholesterolemic, with increased numbers of lipoprotein particles in the low density lipoprotein size range. Cyp7A expression was not increased in heterozygotes but was in homozygotes, suggesting that parts of the homozygous phenotype are secondary to increased cyp7A expression and activity. Homozygotes exhibited pronounced hepatomegaly and dysregulation in hepatic cholesterol, bile acid, and fatty acid metabolism. Hepatic cholesterol synthesis and synthesis of bile acid intermediates were increased; however, side chain cleavage was impaired, leading to decreased bile salt concentrations in gallbladder bile. Expression of Na-taurocholate cotransporting polypeptide, the major sinusoidal bile salt transporter, was increased, and that of bile salt export pump, the major canalicular bile salt transporter, was decreased. Gender played a modifying role in the homozygous response to cyp27A deficiency, with females being generally more severely affected. Thus, both cyp27A genotype and gender affected the regulation of hepatic bile acid, cholesterol, and fatty acid metabolism. PMID: 15520450 [PubMed - indexed for MEDLINE] 149. Nervenarzt. 2004 Jun;75(6):608. [Cerebrotendinous xanthomatosis--a treatable metabolic disorder]. [Article in German] Sperhake JP, Matschke J. Comment on Nervenarzt. 2002 Dec;73(12):1160-6. PMID: 15257383 [PubMed - indexed for MEDLINE] 150. J Atheroscler Thromb. 2004;11(3):167-72. Enhanced susceptibility of LDL to oxidative modification in a CTX patient:- role of chenodeoxycholic acid in xanthoma formation. Kinoshita M, Kawamura M, Fujita M, Hirota D, Suda T, Taki M, Kusano J, Takao K, Takenaka H, Kubota S, Teramoto T. Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan. makkino@med.teikyo-u.ac.jp Cerebrotendinous xanthomatosis (CTX) is a rare familial sterol storage disease, causing multiple xanthomas in tendons and the brain. The underlying biochemical defect is a lack of the hepatic mitochondrial cholesterol 27-hydroxylase involved in the normal biosynthesis of bile acid, resulting in reduced biosynthesis of chenodeoxycholic acid (CDCA). It has been reported that administration of CDCA to CTX patients improves neurological disorders and xanthomas of the Achilles tendon. The present study investigated the effect of CDCA on the mechanism of cholesterol accumulation in macrophages, the major cells in xanthoma. The LDL from the patients in this study was significantly more susceptible to oxidative modification than normal LDL, and supplement therapy with CDCA resulted in an improvement in the susceptibility to oxidative modification. In the incubation of CDCA with plasma, 13% of the CDCA added to serum was recovered in the LDL fraction. In addition, supplementation with CDCA enhanced cholesteryl ester transfer protein (CETP) activity and reduced high-density-lipoprotein cholesterol levels in the plasma. This evidence suggests that the multiple xanthomas observed in CTX may be induced by increased oxidized LDL and the low activity of CETP, both of which are caused by a lack of CDCA. PMID: 15256768 [PubMed - indexed for MEDLINE] 151. J Intern Med. 2004 Jun;255(6):680-3. Coronary heart disease in a patient with cerebrotendinous xanthomatosis. Valdivielso P, Calandra S, Durán JC, Garuti R, Herrera E, González P. Unidad de Lípidos y Dermatología, Hospital Clínico Universitario 'Virgen de la Victoria', Málaga, Spain. valdivielso@uma.es Coronary heart disease is a prevalent condition and a leading cause of death in developed countries. Most cases are due to the cluster of classical risk factors, such as smoking, diabetes, high blood pressure and dyslipidaemia. However, a few patients develop severe and premature arteriosclerosis in spite of absence of common risk factors. Here, we present the clinical, analytical and molecular features of a 36-years-old man who died from advanced ischaemic heart disease as a result of cerebrotendinous xanthomatosis (CTX), a rare condition characterized by elevation in plasma and most tissues of cholestanol and where neurological impairment is the hallmark of this disease. We discuss the relevance of heart disease and the mechanism leading to accelerate arteriosclerosis is CTX. PMID: 15147532 [PubMed - indexed for MEDLINE] 152. Metabolism. 2004 May;53(5):556-62. Hydrophilic 7 beta-hydroxy bile acids, lovastatin, and cholestyramine are ineffective in the treatment of cerebrotendinous xanthomatosis. Batta AK, Salen G, Tint GS. Department of Medicine, University of Medicine and Dentistry, New Jersey Medical School, Newark, NJ, USA. We compared the effect of treatments with hydrophilic bile acids (ursodeoxycholic and ursocholic acids), cholestyramine, and lovastatin versus chenodeoxycholic acid in 4 patients with cerebrotendinous xanthomatosis (CTX). Bile acids and bile alcohols in plasma, bile, and urine before and after treatment were quantitated by gas-liquid chromatography. Untreated, all patients showed abnormal biliary bile acid composition: cholic acid (72.7%) and chenodeoxycholic acid (6.2%), and polyhydroxylated C(27)-bile alcohols (10.0%), and elevated plasma cholestanol levels. Treatment with hydrophobic chenodeoxycholic acid inhibited abnormal bile acid synthesis (virtual disappearance of C(27)-bile alcohols from plasma, bile, and urine and marked reduction of plasma cholestanol levels). Hydrophilic ursodeoxycholic and ursocholic acids did not inhibit abnormal bile acid synthesis, while cholestyramine increased abnormal bile acid synthesis (continued increased formation of polyhydroxylated C(27)-bile alcohols and further elevation of plasma cholestanol levels). Lovastatin did not affect abnormal bile acid synthesis or reduce plasma cholestanol levels. The results demonstrate that impaired side-chain oxidation in bile acid synthesis due to mutations of Cyp27 results in increased formation of polyhydroxylated C(27)-bile alcohols and cholestanol in CTX. Hydrophobic chenodeoxycholic acid, but not cholestyramine, lovastatin, or hydrophilic 7beta-hydroxy acids, inhibited the abnormal synthetic pathway. The role of chenodeoxycholic acid in downregulating abnormal bile acid synthesis in CTX is emphasized. PMID: 15131757 [PubMed - indexed for MEDLINE] 153. Clin Invest Med. 2004 Feb;27(1):42-50. Cerebrotendinous xanthomatosis: clinical course, genotypes and metabolic backgrounds. Moghadasian MH. Department of Human Nutritional Sciences and National Centre for Agri-food Research in Medicine, University of Manitoba, Winnipeg, Man. mmoghadasian@sbrc.ca Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive metabolic disease. It has been reported in more than 200 people worldwide. This review covers the epidemiologic, biochemical and molecular characteristics of the disease, its clinical symptoms and treatment. A search of MEDLINE, using the keywords cerebrotendinous xanthomatosis, brain xanthoma, tendon xanthoma, cholestanol, cholesterol and bile alcohol for articles covering clinical manifestations, laboratory findings, pathology, molecular defects and treatment of CTX, revealed 175 patients with documented CTX. Of these patients, 56% were female. The incidence of tendon xanthomas was 71%, cataracts 92%, low intelligence 81% and other neurologic symptoms 100%. Several genetic studies have revealed mutations in the sterol 27-hydroxylase gene, resulting in markedly diminished activity of the enzyme in CTX patients. This genetic defect is associated with elevated plasma cholestanol levels and consequently its accumulation in the brain, lens, tendons and other tissues. The disease can be treated by the administration of chenodeoxycholic acid, a cost-effective therapy that will considerably reduce the socioeconomic burden of treating patients with CTX. The mechanism of cholestanol accumulation in affected tissues and its pathogenesis are undefined and therefore warrant further investigation. PMID: 15061585 [PubMed - indexed for MEDLINE] 154. J Neurol. 2004 Jan;251(1):105-7. Spinal phenotype of cerebrotendinous xanthomatosis--a pitfall in the diagnosis of multiple sclerosis. Bartholdi D, Zumsteg D, Verrips A, Wevers RA, Sistermans E, Hess K, Jung HH. PMID: 14999499 [PubMed - indexed for MEDLINE] 155. Neurol India. 2003 Dec;51(4):556-8. Cerebrotendinous xanthomatosis with oromandibular dyskinesia. Bordia S, Saifee AA. Department of Neurology, RNT Medical College, Udaipur, India. We present an unusual case of cerebrotendinous xanthomatosis in a female elderly patient with recurrent TM joint dislocation and oromandibular dyskinesia. PMID: 14742951 [PubMed - indexed for MEDLINE] 156. Mol Genet Metab. 2004 Feb;81(2):144-6. Cerebrotendinous xanthomatosis in a Hong Kong Chinese kinship with a novel splicing site mutation IVS6-1G>T in the sterol 27-hydroxylase gene. Mak CM, Lam KS, Tan KC, Ma OC, Tam S. Division of Clinical Biochemistry, Queen Mary Hospital, Hong Kong SAR, China. makm@ha.org.hk We reported a Hong Kong Chinese proband with Cerebrotendinous Xanthomatosis in which a novel acceptor splicing site mutation (IVS6-1G>T) was identified. Family screening revealed the same mutation in his elder brother and the youngest sister. All the three affected siblings were compound heterozygous for IVS6-1G>T and a known missense mutation R372Q (GenBank Accession No. M62401). Significant phenotypic variation was noted among them that the youngest sister was still symptom-free at the time of writing. PMID: 14741198 [PubMed - indexed for MEDLINE] 157. Singapore Med J. 2003 Sep;44(9):488; author reply 489. Article: Cerebrotendinous Xanthomatosis in three siblings from a Chinese family. Cruysberg JR. PMID: 14740780 [PubMed - indexed for MEDLINE] 158. Neurol India. 2003 Sep;51(3):401-3. Cerebrotendinous xanthomatosis: neuroimaging findings in two siblings from an Indian family. Gaikwad SB, Garg A, Mishra NK, Gupta V, Srivastava A, Sarkar C. Department of Neuroradiology, Neurosciences Center, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110029. sgaikwad_63@yahoo.com Cerebrotendinous xanthomatosis (CTX) is exceptionally rare in the Indian population. We present and discuss the clinical, radiological and histopathologic findings in 2 siblings with CTX. Both the patients had juvenile cataract, mental retardation and marked cerebellar ataxia. The Achilles tendon swelling was present in only 1 patient (Case 2). MR imaging showed typical bilateral and symmetrical involvement of the dentate nuclei, inferior olives, brainstem and cerebellar hemispheric white matter. Although the diagnosis of CTX was made in the 3rd decade in both our cases, early diagnosis is possible if neuroimaging is done in the early course of the disease. PMID: 14652454 [PubMed - indexed for MEDLINE] 159. J Neurol Sci. 2003 Dec 15;216(1):179-82. Combined treatment with LDL-apheresis, chenodeoxycholic acid and HMG-CoA reductase inhibitor for cerebrotendinous xanthomatosis. Ito S, Kuwabara S, Sakakibara R, Oki T, Arai H, Oda S, Hattori T. Department of Neurology (D3), Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, 260-8670, Chiba, Japan. s_yonezu@ka2.so-net.ne.jp The effects of combined treatment with low-density lipoprotein (LDL)-apheresis, chenodeoxycholic acid (CDCA) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor were studied in 2 patients with cerebrotendinous xanthomatosis. Patient 1 was initially treated with LDL-apheresis alone: serum cholestanol levels decreased by 50% after each apheresis, but returned to their initial levels within 2 weeks. After an addition of CDCA administration, the serum cholestanol levels steadily decreased, resulting in slight improvement of neurological symptoms. Patient 2 received a combined treatment with LDL-apheresis, CDCA and HMG-CoA reductase inhibitor. This combination showed less LDL-apheresis-dependent fluctuation and more rapid decrease of serum cholestanol levels than those in Patient 1, resulting in improvement and stabilization of the symptoms. Our results suggest that LDL-apheresis in combination with CDCA and HMG-CoA reductase inhibitor may have beneficial effects and can be one of the treatment options. PMID: 14607320 [PubMed - indexed for MEDLINE] 160. J Med Food. 2003 Fall;6(3):217-24. Cholestanol metabolism, molecular pathology, and nutritional implications. Seyama Y. Department of Nutrition and Food Science, Faculty of Human Life and Environmental Sciences, Ochanomizu University, Tokyo, Japan. yousuke@cc.ocha.ac.jp Cholestanol, not cholesterol, is a minor component in the human body and in foods, but an increase in cholestanol concentration in serum induces a pathological condition named cerebrotendinous xanthomatosis (CTX). In our investigation of this disease for more than 25 years, a procedure for quantification of cholestanol by high-performance liquid chromatography and an assay method for sterol 27-hydroxylase were established, and several mutations of the CYP 27 gene in 10 CTX families were identified. We also established experimental animal models with symptoms of CTX by feeding a high cholestanol diet. Corneal dystrophy and gallstones were produced in mice, and an apoptosis of cerebellar neuronal cells was observed in rats. We propose the following underlying mechanism of CTX pathogenesis: When cholesterol in the plasma membrane is replaced by cholestanol to some extent, the membrane fluidity is reduced, and the calcium channel fails to open, inducing cell death. CTX patients are treated with oral administration of chenodeoxycholic acid, which reduces the cholestanol concentration in serum. Cholestanol has a toxic effect, and an imbalance of the cholesterol/cholestanol ratio in plasma membrane is suspected to cause the disturbance of calcium channel function of the membrane. PMID: 14585188 [PubMed - indexed for MEDLINE] 161. J Child Neurol. 2003 Sep;18(9):633-8. Cerebrotendinous xanthomatosis: clinical manifestations, diagnostic criteria, pathogenesis, and therapy. Federico A, Dotti MT. Department of Neurological and Behavioural Sciences, Medical School, University of Siena, Viale Bracci 2, 53100 Siena, Italy. federico@unisi.it In this report, we review the clinical, biochemical, pathophysiologic, and therapeutic aspects of cerebrotendinous xanthomatosis. We stress the importance of early diagnosis and treatment. In addition, we describe our experience in treating patients with chenodeoxycholic acid, an essential drug for this disorder that is no longer available. PMID: 14572142 [PubMed - indexed for MEDLINE] 162. J Neurol Neurosurg Psychiatry. 2003 Sep;74(9):1335. Cerebrotendinous xanthomatosis. Castelnovo G, Jomir L, Bouly S. Department of Neurology, Caremeau Hospital, CHU Nimes, France. giovanni.castelnova@chu_nimes.fr PMCID: PMC1738654 PMID: 12933951 [PubMed - indexed for MEDLINE] 163. J Lipid Res. 2003 Aug;44(8):1515-22. Epub 2003 Jun 1. On the substrate specificity of human CYP27A1: implications for bile acid and cholestanol formation. Norlin M, von Bahr S, Bjorkhem I, Wikvall K. Department of Pharmaceutical Biosciences, University of Uppsala, Box 578, S-751 23 Uppsala, Sweden. The mitochondrial sterol 27-hydroxylase (CYP27A1) is required for degradation of the C27-sterol side chain in bile acid biosynthesis. CYP27A1 seems, however, to have roles beyond this, as illustrated by patients with a deficient sterol 27-hydroxylase due to mutations of the CYP27A1 gene [cerebrotendinous xanthomatosis (CTX)]. These subjects have symptoms ranging from accumulation of bile alcohols and cholestanol to accelerated atherosclerosis and progressive neurologic impairment. The present work describes a detailed investigation on the substrate specificity of recombinant human CYP27A1. In accordance with some previous work with rat liver mitochondria, the activity in general increased with the polarity of the substrate. An obvious example was the finding that cholesterol was 27-hydroxylated more efficiently than cholesterol oleate but less efficiently than cholesterol sulfate. The oxysterols 24S-hydroxycholesterol and 25-hydroxycholesterol were 27-hydroxylated less efficiently than cholesterol, possibly due to steric hindrance. Surprisingly, sterols with a 3-oxo-Delta4 structure were found to be hydroxylated at a much higher rate than the corresponding sterols with a 3beta-hydroxy-Delta5 structure. The rates of hydroxylation of the sterols were: 7alpha-hydroxy-4-cholesten-3-one>4-cholesten-3-one>7alpha-hydroxycholesterol>24-h ydroxy-4-cholesten-3-one> cholesterol>25-hydroxy-4-cholesten-3-one>24-hydroxycholesterol>or=25-hydroxychole sterol. The possibility is discussed that the findings may have implications for oxysterol-mediated regulation of gene expression. The very high activity of CYP27A1 towards the cholestanol precursor 4-cholesten-3-one may be of importance in connection with the accumulation of cholestanol in patients with CTX. PMID: 12777473 [PubMed - indexed for MEDLINE] 164. Pathology. 2003 Apr;35(2):141-4. An autopsy case of gallbladder cancer developing in a Japanese man with cerebrotendinous xanthomatosis: genetic analysis of the sterol 27-hydroxylase and p53 genes. Kato H, Koyabu S, Aoki S, Tamai T, Sugawa M, Watanabe M, Shiraishi T. Department of Internal Medicine, Owase General Hospital, Owase, Mie, Japan. kato2001@clin.medic.mie-u.ac.jp Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid-storage disorder characterised by xanthomas, neurological dysfunctions and premature atherosclerosis. A case of a well differentiated adenocarcinoma of the gallbladder occurring in a 57-year-old Japanese man with CTX, confirmed clinically, biochemically and at autopsy is reported together with analyses of the sterol 27-hydroxylase (CYP27) and p53 genes. A missense mutation of the p53 (G for C) was detected in the gallbladder adenocarcinoma. Direct sequence analysis also showed a silent mutational substitution of unknown significance, C for A, in CYP27 at codon 89. In the past, CTX patients have only demonstrated this infrequently, indicating no direct relationship between CYP27 dysfunction and tumour development. Thus, the present case of gallbladder cancer appears to be a chance occurrence. PMID: 12745462 [PubMed - indexed for MEDLINE] 165. AJNR Am J Neuroradiol. 2003 Mar;24(3):495-500. Quantification of brain damage in cerebrotendinous xanthomatosis with magnetization transfer MR imaging. Inglese M, De Stefano N, Pagani E, Dotti MT, Comi G, Federico A, Filippi M. Neuroimaging Research Unit, Department of Neuroscience, Milan, Italy. BACKGROUND AND PURPOSE: Conventional MR imaging for quantification of brain damage in monitoring the evolution of cerebrotendinous xanthomatosis (CTX) has limitations. Magnetization transfer (MT) MR imaging is overcoming these limitations. Using MT MR imaging, we sought to quantify, in vivo, the extent of brain and cerebellar damage in patients with CTX, with the ulimate goal to investigate the magnitude of the correlation between MT MR imaging findings and clinical disability. METHODS: Conventional and MT MR images of the brain were obtained in nine patients with CTX and in 10 sex- and age-matched healthy volunteers. MT ratio histograms were derived of the whole brain, brain normal-appearing white matter (NAWM), brain normal-appearing gray matter (NAGM), cerebellar NAWM, and cerebellar NAGM. Clinical disability was measured by using the Expanded Disability Status Scale (EDSS). RESULTS: Average MT ratio and peak heights of the whole brain, brain NAWM, and brain NAGM histograms in patients with CTX were significantly lower than the corresponding quantities in the control subjects. All cerebellar NAGM MT ratio histogram-derived metrics and average MT ratio of the cerebellar NAWM histogram in patients with CTX were also significantly lower than the corresponding quantities in the control subjects. Strong correlations were found between the EDSS score and a composite whole-brain MT ratio histogram score (r = 0.77, P <.01) and a composite brain white matter MT ratio histogram score (r = 0.71, P <.03). A strong correlation was also found between the cerebellar functional system score and a composite cerebellar NAWM score (r = 0.72, P <.02). CONCLUSION: The quantitative assessment of brain damage in patients with CTX with use of MT MR imaging can provide powerful measures of disease outcome. PMID: 12637303 [PubMed - indexed for MEDLINE] 166. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):833-8. Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance. Dussault I, Yoo HD, Lin M, Wang E, Fan M, Batta AK, Salen G, Erickson SK, Forman BM. Division of Molecular Medicine and Department of Diabetes and Gonda Diabetes Research Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA. The nuclear receptor PXR (pregnane X receptor) is a broad-specificity sensor that recognizes a wide variety of synthetic drugs and xenobiotic agents. On activation by these compounds, PXR coordinately induces a network of transporters, cytochrome P450 enzymes, and other genes that effectively clear xenobiotics from the liver and intestine. Like PXR, the majority of its target genes also possess a broad specificity for exogenous compounds. Thus, PXR is both a sensor and effector in a well integrated and generalized pathway for chemical immunity. Although it is clear that PXR responds to numerous foreign compounds, it is unclear whether it possesses an endogenous ligand. To address this issue, we noted that there is substantial overlap in the substrate specificities of PXR and its critical CYP3A target gene. This prompted us to ask whether endogenous CYP3A substrates also serve as PXR ligands. We demonstrate that 5beta-cholestane-3alpha,7alpha,12alpha-triol (triol), a cholesterol-derived CYP3A substrate, is a potent PXR agonist that effectively induces cyp3a expression in mice. This defines a critical salvage pathway that can be autoinduced to minimize triol accumulation. In contrast, triol can accumulate to very high levels in humans, and unlike mice, these people develop the severe clinical manifestations of cerebrotendinous xanthomatosis. The reason for these dramatic species differences has remained unclear. We now demonstrate that triol fails to activate human PXR or induce the CYP3A-salvage pathway. This explains why humans are more susceptible to sterol accumulation and suggests that synthetic ligands for human PXR could be used to treat cerebrotendinous xanthomatosis and other disorders of cholesterol excess. PMCID: PMC298687 PMID: 12569201 [PubMed - indexed for MEDLINE] 167. J Inherit Metab Dis. 2002 Oct;25(6):501-13. Mutations in the sterol 27-hydroxylase gene (CYP27A) cause hepatitis of infancy as well as cerebrotendinous xanthomatosis. Clayton PT, Verrips A, Sistermans E, Mann A, Mieli-Vergani G, Wevers R. Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, University College London and Great Ormond Street Hospital for Children NHS Trust, London, UK. p.clayton@ich.ucl.ac.uk Follow-up investigations were undertaken on a previously reported patient who had severe familial giant cell hepatitis in infancy associated with substantially increased urinary excretion of bile alcohol glucuronides. By the age of 11 years, he had developed a profile of cholanoids in plasma and urine that closely resembled the pattern seen in cerebrotendinous xanthomatosis (CTX). Sequencing of the sterol 27-hydroxylase gene (CYP27A) showed that he was homozygous for a deletion (525/526delG) that causes a frameshift and a premature stop codon. This genotype has previously been described in an adult female with classical symptoms of CTX (tendon xanthomata, cataracts and deteriorating cognitive function). A review of past medical histories of a group of patients with CTX revealed that prolonged neonatal cholestatic jaundice was common. The family histories also revealed fetal and neonatal deaths among siblings of patients with CTX. We conclude that defective activity of cholesterol 27-hydroxylase can lead to neonatal cholestatic jaundice ('hepatitis of infancy'), which may be self-limiting. After a latent period, however, progressive accumulation of cholesterol and cholestanol can lead to the xanthomata, neurodegeneration, cataracts and atherosclerosis that are typical of CTX. PMID: 12555943 [PubMed - indexed for MEDLINE] 168. J Assoc Physicians India. 2002 Sep;50:1196-7. Cerebrotendinous xanthomatosis. Sen A, Ghosh B, Kundu TN, Das SK, Sengupta SR. Department of Dermatology, Institute of Postgraduate Medicine and Research, Kolkata. PMID: 12516712 [PubMed - indexed for MEDLINE] 169. Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):223-8. Epub 2002 Dec 30. Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor. Goodwin B, Gauthier KC, Umetani M, Watson MA, Lochansky MI, Collins JL, Leitersdorf E, Mangelsdorf DJ, Kliewer SA, Repa JJ. Nuclear Receptor Discovery Research, GlaxoSmithKline Inc., Five Moore Drive, Research Triangle Park, NC 27709, USA. Sterol 27-hydroxylase (CYP27A1) is required for bile acid synthesis by both the classical and alternate pathways. Cyp27a1(-/-) mice exhibit a dramatic increase in the activity of cytochrome P450 3A (CYP3A), which catalyzes side-chain hydroxylations of bile acid intermediates, thereby facilitating their excretion in the bile and urine. We examine the role of the nuclear xenobiotic receptor PXR (pregnane X receptor) in this process. We demonstrate that expression of Cyp3a11 and other established PXR target genes is increased in the Cyp27a1(-/-) mice. WhenCyp27a1(-/-) mice are fed a diet containing either cholic acid or chenodeoxycholic acid, expression of CYP7A1, which catalyzes the rate-limiting step in bile acid biosynthesis, is strongly suppressed. In parallel, the induction of Cyp3a11 observed in these mice is reversed, suggesting that bile acid intermediates serve as PXR activators. In support of this hypothesis, three potentially toxic sterols (7alpha-hydroxy-4-cholesten-3-one, 5beta-cholestan-3alpha,7alpha,12alpha-triol, and 4-cholesten-3-one), including two that are known to accumulate in Cyp27a1(-/-) mice, are efficacious activators of mouse PXR. All three compounds are more potent activators of mouse PXR than of human PXR, which may explain in part why humans who lack functional CYP27A1 do not display a corresponding increase in CYP3A activity and are stricken with the disease cerebrotendinous xanthomatosis. Taken together, these results reveal the existence of a feedforward regulatory loop by which potentially toxic bile acid intermediates activate PXR and induce their own metabolism. In addition, this study demonstrates that animal models with alterations in gene expression can be used to identify endogenous ligands for orphan nuclear receptors. PMCID: PMC140933 PMID: 12509506 [PubMed - indexed for MEDLINE] 170. Neurologia. 2002 Dec;17(10):647-50. [Cerebrotendinous xanthomatosis without tendinous xanthomas: presentation of two cases]. [Article in Spanish] Campdelacreu J, Muñoz E, Cervera A, Jaumà S, Girós M, Tolosa E. Servei de Neurologia, ICMSN, Hospital Clínic de Barcelona, Spain. Cerebrotendinous xanthomatosis (CTX) is a genetic disorder caused by a 27-hydroxilase enzyme deficiency, leading to beta-cholestanol storage in many body tissues. Clinically, the disease is characterised by the presence of tendinous xanthomas, juvenile cataracts and progressive neurologic dysfunction. The diagnosis requires beta-cholestanol quantification in serum. We report two siblings with a history of photosensitive epilepsy of childhood onset, who developed progressive spastic paraparesis and cataracts in their third decade of life. They were diagnosed to have CTX in spite of the absence of tendinous xanthomas. Cranial and spinal MRI only showed bilateral high intensity signal in the dentate nuclei in the T2-weighted and proton-density sequences. Our patients presented with a progressive spastic paraparesis. The delay in the diagnosis in our case could be due to the absence of tendinous xanthomas and late-onset cataracts. The recognition of the disease is important, because the treatment with chenodeoxycholic acid induces a decrement of beta-cholestanol levels in serum and could prevent the progression of the disease. PMID: 12487962 [PubMed - indexed for MEDLINE] 171. Nervenarzt. 2002 Dec;73(12):1160-6. [Cerebrotendinous xanthomatosis, a treatable metabolic disorder]. [Article in German] Heller R, Grau AJ, Schäbitz WR, Schwaninger M. Neurologische Klinik, Universität Heidelberg. royheller@hotmail.com Comment in Nervenarzt. 2004 Jun;75(6):608. Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis which can be clinically diagnosed and specifically treated. It is an underdiagnosed disorder worldwide.Here,we describe two women who were diagnosed with CTX during their forties after symptoms had already developed 15 years earlier. Both patients showed gait ataxia, spastic paraparesis, polyneuropathy, bilateral premature cataracts, tendon xanthomas, and cognitive deficits. One of the patients had also chronic diarrhea. The deficiency of the mitochondrial enzyme sterol 27-hydroxylase results in a virtual absence of chenodeoxycholic acid. This leads to excessive production of cholestanol and cholesterol and accumulation of these sterols in many tissues, especially the eye lens, central nervous system,and tendons. The determination of a high cholestanol serum level allows the diagnosis,which can be confirmed through genetic analysis. Early diagnosis of CTX is important, since an effective therapy is available. Long-term therapy with chenodeoxycholic acid is effective for CTX, mainly in prevention of further deterioration. PMID: 12486565 [PubMed - indexed for MEDLINE] 172. Arch Neurol. 2002 Dec;59(12):1975. Cerebrotendinous xanthomatosis: juvenile cataract and chronic diarrhea before the onset of neurologic disease. Cruysberg JR. Comment on Arch Neurol. 2002 Apr;59(4):527-9. PMID: 12470193 [PubMed - indexed for MEDLINE] 173. Mov Disord. 2002 Nov;17(6):1396-7. Early-onset parkinsonism in cerebrotendinous xanthomatosis. Grandas F, Martín-Moro M, Garcia-Muñozguren S, Anaya F. Comment on Mov Disord. 2000 Sep;15(5):1017-9. PMID: 12465096 [PubMed - indexed for MEDLINE] 174. J Clin Pathol. 2002 Nov;55(11):859-61. Specificity of the commonly used enzymatic assay for plasma cholesterol determination. Moghadasian MH, Frohlich JJ, Scudamore CH. Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, Canada. mhmoghad@interchange.ubc.ca AIM: To assess the specificity and sensitivity of the commonly used enzymatic colorimetric test for plasma cholesterol determination. METHODS: Interference with an enzymatic method for cholesterol measurement by several non-cholesterol sterols (beta sitosterol, campesterol, stigmasterol, stigmastanol, desmosterol, and lathosterol) was assessed. Some of these compounds are present in plasma at higher than normal concentrations either in rare genetic disorders, such as phytosterolaemia, or after the consumption of phytosterol enriched foods. RESULTS: The non-cholesterol sterols were detected by the assay in a linear manner. There was no competitive interference in the presence of cholesterol. CONCLUSIONS: This crossreactivity may affect the diagnosis and treatment of non-cholesterol dyslipidaemias, including phytosterolaemia and cerebrotendinous xanthomatosis. Similarly, changes in plasma lipid compositions after the consumption of phytosterol enriched foods cannot be specifically determined by this enzymatic assay. Until a more specific enzymatic assay is developed, alternative methods such as gas chromatography should be used to differentiate between cholesterol and non-cholesterol sterols. PMCID: PMC1769797 PMID: 12401826 [PubMed - indexed for MEDLINE] 175. J Intern Med. 2002 Sep;252(3):259-64. Cerebrotendinous xanthomatosis: molecular characterization of two Scandinavian sisters. Rystedt E, Olin M, Seyama Y, Buchmann M, Berstad A, Eggertsen G, Björkhem I. Division of Clinical Chemistry, Huddinge University Hospital, Karolinska Institutet, Stockholm, Sweden. ingemar.bjorkhem@chemlab.hs.sll.se Cerebrotendinous xanthomatosis (CTX) is a hereditary disorder, which is inherited as an autosomally recessive disease, causing production of cholesterol and cholestanol xanthomas and mental retardation. The disease is caused by mutations in the gene for sterol 27-hydroxylase (CYP27A1). The only CTX patients diagnosed in Scandinavia are two Norwegian sisters from a consanguineous marriage. Here we have characterized the mutation and its functional consequences for the enzyme. Analysis of genomic DNA from cultured fibroblasts identified a base exchange C > T in position 1441, causing arginine at amino acid position 441 to be replaced by tryptophan. The same mutation was introduced by mutagenesis in the complimentary DNA (cDNA) for CYP27, ligated into the expression vector pcDNA4/HisMax and transfected into HEK293 cells. The mutated enzyme had less than 5% of the enzyme activity compared with the native enzyme. No abnormal catalytic products could be identified in the cell culture medium. Probably the mutation affects the haem binding within the holoenzyme. The mutation has also previously been reported in a Japanese family. This is the second example of a CTX-causing mutation that has been recognized in more than one population. PMID: 12270007 [PubMed - indexed for MEDLINE] 176. J Neurol. 2002 Sep;249(9):1311-2. Mutation of the sterol 27-hydroxylase gene ( CYP27A1) in a Taiwanese family with cerebrotendinous xanthomatosis. Lee MJ, Huang YC, Sweeney MG, Wood NW, Reilly MM, Yip PK. PMID: 12242561 [PubMed - indexed for MEDLINE] 177. Chang Gung Med J. 2002 May;25(5):334-40. Cerebrotendinous xanthomatosis with psychiatric disorders: report of three siblings and literature review. Lee Y, Lin PY, Chiu NM, Chang WN, Wen JK. Department of Psychiatry, Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ROC. Cerebrotendinous xanthomatosis (CTX), a rare familial lipid metabolic disease inherited via an autosomal recessive trait, is caused by mutations of the sterol 27-hydroxylase gene. Psychiatric disorders may occur in patients with CTX. In Taiwan, Chang et al presented patients with CTX. However, there has not been a case presented about CTX with psychiatric disorders in Taiwan. We present three siblings in one family with CTX combined with moderate mental retardation. One of the siblings had long-term depressed mood, irritability, poor appetite, insomnia, fatigability, and pessimistic thinking and was diagnosed as dysthymic disorder. After 2.5 years of antidepressant treatment at our outpatient clinic, the depressive symptoms of the dysthymic sibling improved greatly. However, the results of the IQ tests of the three siblings did not change after effective treatments for physical manifestations of CTX. In addition, the authors reviewed the literature of CTX combined with psychiatric disorders. PMID: 12141707 [PubMed - indexed for MEDLINE] 178. Arterioscler Thromb Vasc Biol. 2002 Jul 1;22(7):1129-35. Mechanism of accumulation of cholesterol and cholestanol in tendons and the role of sterol 27-hydroxylase (CYP27A1). von Bahr S, Movin T, Papadogiannakis N, Pikuleva I, Rönnow P, Diczfalusy U, Björkhem I. Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden. OBJECTIVE: Tendon xanthomas are deposits of lipids and connective tissue commonly found in hypercholesterolemic patients. Macrophages are likely to be responsible for the lipid accumulation. Normolipidemic patients with the rare disease cerebrotendinous xanthomatosis, lacking the enzyme sterol 27-hydroxylase (CYP27A1), develop prominent xanthomas in tendons and brain containing both cholestanol and cholesterol, with a cholestanol:cholesterol ratio higher than that in the circulation. Because of its ability to convert cholesterol into polar metabolites that leave the cells faster, CYP27A1 has been suggested to be an antiatherogenic enzyme. The hypothesis was tested that tendons contain CYP27A1 that may be of importance for the normal efflux of both steroids. METHODS AND RESULTS: Western blotting and combined gas chromatography-mass spectrometry showed that human tendons contain significant amounts of CYP27A1 and its product, 27-hydroxycholesterol. Immunohistochemistry showed that CYP27A1 is present in macrophages and tenocytes. The tendons also contained cholestanol, with a cholestanol:cholesterol ratio slightly higher than that in the circulation. Recombinant human CYP27A1, and cultured human macrophages containing this enzyme, had similar activity toward cholesterol and cholestanol. After loading of macrophages with labeled cholesterol and cholestanol, there was an efflux of these steroids in both unmetabolized and 27-oxygenated form, resulting in a significant cellular accumulation of cholestanol compared with cholesterol. CONCLUSION: The results are consistent with the possibility that CYP27A1 is of importance for the efflux of both cholesterol and cholestanol from tendons. PMID: 12117727 [PubMed - indexed for MEDLINE] 179. Clin Genet. 2002 Mar;61(3):185-91. Two novel mutations in the sterol 27-hydroxylase gene causing cerebrotendinous xanthomatosis. Lamon-Fava S, Schaefer EJ, Garuti R, Salen G, Calandra S. Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, and Division of Endocrinology, Metabolism, and Molecular Biology, New England Medical Center, Boston, MA, USA. Cerebrotendinous xanthomatosis (CTX) is a rare recessive autosomal disease caused by mutations of the sterol 27-hydroxylase gene. Clinically, CTX is characterized by tendon xanthomas, cataracts and progressive neurological deficits. Because of the disruption of the 27-hydroxylase activity, CTX patients have elevated plasma levels of cholestanol, a by-product of abnormal bile acid synthesis. The present authors describe a female patient with CTX. The proband in this study presented with elevated cholestanol levels, markedly reduced mitochondrial 27-hydroxylase activity and altered bile acid composition. The 27-hydroxylase gene was analysed for mutations by polymerase chain reaction amplification of the exons and the splice-junction regions of the gene. The proband was found to be a compound heterozygote for two different mutations which have not been previously described: (1) a G --> A transition at nucleotide 455 that is responsible for converting a glycine to a glutamic acid residue at amino acid position 112 (G112E); and (2) a five-nucleotide deletion in exon 5 (from nucleotide 965 to 969) that is responsible for a shift in the reading frame and the insertion of a premature codon at position 296, and consequently, the synthesis of a truncated protein lacking the heme-binding and andrenodoxin-binding domains. Long-term (18-year) treatment of the proband with chenodeoxycholic acid (750 mg day-1) has been effective in preventing any progression of the disease. PMID: 12000359 [PubMed - indexed for MEDLINE] 180. J Lipid Res. 2002 May;43(5):665-70. 25R,26-Hydroxycholesterol revisited: synthesis, metabolism, and biologic roles. Javitt NB. Department of Pediatrics and Medicine, NYU School of Medicine, New York, NY 10016, USA. norman.javitt@med.nyu.edu The CYP27 gene is expressed in arterial endothelium, macrophages, and other tissues. The gene product generates sterol intermediates that function as ligands for nuclear receptors prior to their transport to the liver for metabolism, mostly to bile acids. Most attention has been given to 27-hydroxycholesterol as a ligand for LXR activated receptors and to chenodeoxycholic acid as a ligand for farnesoid X activated receptors (FXRs). Expression of the pathway in macrophages is essential for normal reverse cholesterol transport. Thus, ABC transporter activity is upregulated, which enhances cholesterol efflux. Absence of these mechanisms probably accounts for the accelerated atherosclerosis that occurs in cerebrotendinous xanthomatosis. Accumulation of 27-hydroxycholesterol in human atheroma is puzzling and may reflect low levels of oxysterol 7alpha-hydroxylase activity in human macrophages. The same enzyme determines the proportion of mono-, di-, and tri-hydroxy bile acids synthesized in the liver. Oxysterol 7alpha-hydroxylase deficiency is a molecular basis for cholestatic liver disease. Chenodeoxycholic acid, the major normal end product, downregulates expression of cholesterol 7alpha-hydroxylase via the FXR/short heterodimer protein nuclear receptor and thus limits total bile acid production. The challenge is to quantify in a physiologic setting the magnitude of the pathway in different tissues and to further evaluate the biologic roles of all the intermediates that may function as ligands for orphan nuclear receptors or via other regulatory mechanisms. PMID: 11971935 [PubMed - indexed for MEDLINE] 181. Arch Neurol. 2002 Apr;59(4):527-9. Cerebrotendinous xanthomatosis: a rare disease with diverse manifestations. Moghadasian MH, Salen G, Frohlich JJ, Scudamore CH. Healthy Heart Program, St Paul's Hospital, Suite 180, 1081 Burrard St, Vancouver, British Columbia, Canada V6Z 1Y6. mhmoghad@interchange.ubc.ca Comment in Arch Neurol. 2002 Dec;59(12):1975. This mini-review deals with a new appraisal of cerebrotendinous xanthomatosis. In addition to neurologic symptoms, patients with cerebrotendinous xanthomatosis develop cataracts, diarrhea, Achilles tendon xanthoma, atherosclerotic vascular disease, and many other abnormalities. Although the pathophysiology of the disease is not completely understood, excess production and consequent accumulation of cholestanol in tissues may play a crucial role. Chenodeoxycholic acid is the most effective therapy. The causative role and detrimental effects (at a low plasma level) of cholestanol merit further investigation. PMID: 11939886 [PubMed - indexed for MEDLINE] 182. J Assoc Physicians India. 2002 Mar;50:450-1. Cerebrotendinous xanthomatosis. Jayabal A, Jayavelu A, Dhanaraj M. Department of Neurology, Stanley Medical College and Hospital, Chennai. PMID: 11922243 [PubMed - indexed for MEDLINE] 183. Clin Genet. 2002 Jan;61(1):77-8. A Japanese patient with cerebrotendinous xanthomatosis has different mutations within two functional domains of CYP27. Toba H, Fukuyama R, Sasaki M, Shiga K, Ishibashi S, Fushiki S. PMID: 11903362 [PubMed - indexed for MEDLINE] 184. Cerebrovasc Dis. 2002;13 Suppl 2:21-30. Imaging of white matter lesions. Barkhof F, Scheltens P. Department of Radiology, Vrije University Medical Centre, Amsterdam, The Netherlands. f.barkhof@vumc.nl Magnetic resonance imaging (MRI) is very sensitive for the detection of white matter lesions (WML), which occur even in normal ageing. Intrinsic WML should be separated from physiological changes in the ageing brain, such as periventricular caps and bands, and from dilated Virchow-Robin spaces. Genuine WML are best seen with T2-weighted sequences such as long TR dual-echo spin-echo or FLAIR (fluid-attenuated inversion recovery); the latter has the advantage of easily separating WML from CSF-like lesions. Abnormal T2 signal in MRI is not specific, and can accompany any change in tissue composition. In the work-up of WML in small vessel disease, magnetic resonance angiography can be used to rule out (concomitant) large vessel disease, and diffusion-weighted MRI to identify new ischaemic lesions (amidst pre-existing old WML). The differential diagnosis of WML includes hereditary leukodystrophies and acquired disorders. The leukodystrophies that can present in adult age include metachromatic leukodystrophy, globoid cell leukodystrophy, adrenomyeloneuropathy, mitochondrial disorders, vanishing white matter, and cerebrotendinous xanthomatosis. These metabolic disorders typically present with symmetrical abnormalities that can be very diffuse, often with involvement of brainstem and cerebellum. Only the mitochondrial disorders tend to be more asymmetric and frequently involve the grey matter preferentially. Among the acquired white matter disorders, hypoxic-ischaemic causes are by far the most prevalent and without further clinical clues there is no need to even consider the next most common disorder, i.e. multiple sclerosis (MS). Among the nonischaemic disorders, MS is far more common than vasculitis, infection, intoxication and trauma. While vasculitis can mimic small vessel disease, MS has distinctive features with preferential involvement of the subcortical U-fibres, the corpus callosum, temporal lobes and the brainstem/cerebellum. Spinal cord lesions are very common in MS, but do not occur in normal ageing nor in small vessel disease. Copyright 2002 S. Karger AG, Basel PMID: 11901239 [PubMed - indexed for MEDLINE] 185. J Inherit Metab Dis. 2001 Dec;24(7):696-706. Cerebrotendinous xanthomatosis: heterogeneity of clinical phenotype with evidence of previously undescribed ophthalmological findings. Dotti MT, Rufa A, Federico A. Unit of Neurometabolic Diseases and Research Center for Diagnosis, Prevention and Therapy of Neurohandicap, University of Siena, Italy. Cerebrontendinous xanthomatosis (CTX) is a rare autosomal recessive neurometabolic disease involving lipid metabolism. The classical phenotype is characterized by neurological dysfunction, tendon xanthomas and juvenile cataracts. Other ophthalmological findings have occasionally been reported. To gain more insight into the type and frequency of ophthalmological alterations in this multisystem metabolic disorder, we examined 13 CTX patients. Besides cataracts, found in all cases, the second most frequent ocular abnormality was paleness of the optic disk, which was found in 6 patients and was probably previously underestimated. Signs of premature retinal senescence were also observed. We discuss the possible relation between these ocular manifestations and the metabolic defect. PMID: 11804206 [PubMed - indexed for MEDLINE] 186. J Chromatogr A. 2001 Nov 23;935(1-2):203-36. Plasma non-cholesterol sterols. Kuksis A. Banting and Best Department of Medical Research, University of Toronto, Canada. arnis.kuksis@utoronto.ca Increased levels of plasma sterols other than cholesterol can serve as markers for abnormalities in lipid metabolism associated with clinical disease. Premature atherosclerosis and xanthomatosis occur in two rare lipid storage diseases, Cerebrotendinous xanthomatosis (CTX) and sitosterolemia. In CTX, cholestanol is present in all tissues. In sitosterolemia, dietary campesterol and sitosterol accumulate in plasma and red blood cells. Plasma accumulation of oxo-sterols is associated with inhibition of bile acid synthesis and other abnormalities in plasma lipid metabolism. Inhibition of cholesterol biosynthesis is associated with plasma appearance of precursor sterols. The increases in non-cholesterol sterols, while highly significant, represent only minor changes in plasma sterols, which require capillary gas-liquid chromatography and MS for effective detection, identification and quantification. PMID: 11762775 [PubMed - indexed for MEDLINE] 187. Eur J Biochem. 2001 Dec;268(24):6607-15. Structure-function analysis of CYP27B1 and CYP27A1. Studies on mutants from patients with vitamin D-dependent rickets type I (VDDR-I) and cerebrotendinous xanthomatosis (CTX). Sawada N, Sakaki T, Kitanaka S, Kato S, Inouye K. Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Japan. We have determined eight types of missense mutants of CYP27B1 from Japanese vitamin D-dependent rickets type I (VDDR-I) patients [Kitanaka, S., Takeyama, K., Murayama, A., Sato, T., Okumura, K., Nogami, M., Hasegawa, Y., Niimi, H., Yanagisawa, J., Tanaka, T. & Kato, S. (1998) New England J. Med., 338, 653-661 and Kitanaka, S., Murayama, A., Sakaki, T., Inouye, K., Seino, Y., Fukumoto, S., Shima, M., Yukizane, S., Takayanagi, M., Niimi, H., Takeyama, K. & Kato, S. (1999) J. Clin. Endocrine Metab., 84, 4111-4117]. None of the CYP27B1 mutants showed 1alpha-hydroxylase activity towards 25-hydroxyvitamin D3. Thus, it was assumed that the mutated amino-acid residues play important roles in the 1alpha-hydroxylase activity, such as substrate binding, activation of molecular oxygen, interaction with adrenodoxin, and folding of the cytochrome P450 structure. To examine our hypothesis, we generated various mutants of CYP27B1 and studied their enzymatic properties. In addition, the corresponding mutations were introduced to CYP27A1, which belongs to the same family as CYP27B1. As CYP27A1 showed much higher expression level than CYP27B1 in Escherichia coli, further analysis including heme-binding and substrate-binding was performed with CYP27A1 in place of CYP27B1. Western blot analysis, spectral analysis including reduced CO-difference spectra and substrate-induced difference spectra, and enzymatic analysis of the mutant CYP27A1 gave information on the structure-function relationships of both CYP27A1 and CYP27B1. Although the sequence alignment suggested that Arg107, Gly125, and Pro497 of CYP27B1 might be involved in substrate binding, the experimental data strongly suggested that mutations of these amino-acid residues destroyed the tertiary structure of the substrate-heme pocket. It was also suggested that Arg389 and Arg453 of CYP27B1 were involved in heme-propionate binding, and Asp164 stabilized the four-helix bundle consisting of D, E, I and J helices, possibly by forming a salt bridge. Thr321 was found to be responsible for the activation of molecular oxygen. PMID: 11737215 [PubMed - indexed for MEDLINE] 188. J Lipid Res. 2001 Dec;42(12):2030-8. Oxidized plant sterols in human serum and lipid infusions as measured by combined gas-liquid chromatography-mass spectrometry. Plat J, Brzezinka H, Lütjohann D, Mensink RP, von Bergmann K. Maastricht University, Department of Human Biology, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. J.Plat@HB.UNIMAAS.NL Some oxidized forms of cholesterol (oxysterols) are thought to be atherogenic and cytotoxic. Because plant sterols are structurally related to cholesterol, we examined whether oxidized plant sterols (oxyphytosterols) could be identified in human serum and soy-based lipid emulsions. We first prepared both deuterated and nondeuterated reference compounds. We then analyzed by gas-liquid chromatography-mass spectrometry the oxyphytosterol concentrations in serum from patients with phytosterolemia or cerebrotendinous xanthomatosis, in a pool serum and in two lipid emulsions. 7-Ketositosterol, 7 beta-hydroxysitosterol, 5 alpha, 6 alpha-epoxysitosterol, 3 beta,5 alpha,6 beta-sitostanetriol, and probably also 7 alpha-hydroxysitosterol were present in markedly elevated concentrations in serum from phytosterolemic patients only. Also, campesterol oxidation products such as 7 alpha-hydroxycampesterol and 7 beta-hydroxycampesterol were found. Interestingly, sitosterol was oxidized for approximately 1.4% in phytosterolemic serum, which is rather high compared with the approximate 0.01% oxidatively modified cholesterol normally seen in human serum. The same oxyphytosterols were also found in two lipid emulsions in which the ratio of oxidized sitosterol to sitosterol varied between 0.038 and 0.041. In conclusion, we have shown that oxidized forms of plant sterols are present in serum from phytosterolemic patients and two frequently used soy-based lipid emulsions. Currently, it is unknown whether oxyphytosterols affect health, as has been suggested for oxysterols. However, 7 beta-hydroxycholesterol may be one of the more harmful oxysterols, and both sitosterol and campesterol were oxidized into 7 beta-hydroxysitosterol and 7 beta-hydroxycampesterol. The relevance of these findings therefore deserves further exploration. PMID: 11734576 [PubMed - indexed for MEDLINE] 189. Neurology. 2001 Nov 13;57(9):1743. Cerebrotendinous xanthomatosis. Federico A, Dotti MT. Comment on Neurology. 2000 Aug 22;55(4):601. PMID: 11706139 [PubMed - indexed for MEDLINE] 190. J Neurol Sci. 2001 Sep 15;190(1-2):29-33. Cerebrotendinous xanthomatosis: 11-year treatment with chenodeoxycholic acid in five patients. An electrophysiological study. Mondelli M, Sicurelli F, Scarpini C, Dotti MT, Federico A. Servizio di EMG ASL 7, Siena, Italy. We report the electrophysiological follow-up of five cerebrotendinous xanthomatosis patients treated for 11 years with chenodeoxycholic acid (CDCA). Nerve conduction velocity (NCV) was reduced in three cases. P100 latency of visual evoked potentials was delayed in four cases, interpeaks I-III and I-V of brainstem auditory evoked potentials (BAEPs) was increased in two and interpeak N13-20 of upper limb somatosensory evoked potentials (SEPs) was slowed in one. After 4 months of therapy with CDCA, NCV was normal and did not show any significant change during the 11 years of observation. Central motor conduction time of motor evoked potentials (MEPs) and N24-P40 interpeak latency of lower limb SEPs were increased in five and four cases, respectively, in spite of 2/3-year treatment with CDCA. Improvement of evoked potentials, especially of MEPs and SEPs, was slower and continued over the whole 11-year period. The size of xanthomas slightly decreased in some patients during treatment and the clinical manifestations stabilized, avoiding progressive worsening, but there was no significant improvement in neurological deficit. Two sisters of patients who never took CDCA showed progressive worsening of clinical manifestations, upper limb SEPs and BAEPs. PMID: 11574103 [PubMed - indexed for MEDLINE] 191. Ned Tijdschr Geneeskd. 2001 Sep 1;145(35):1673-7. [Cerebrotendinous xanthomatosis]. [Article in Dutch] Verrips A. Universitair Medisch Centrum St Radboud, Interdisciplinair Kinderneurologisch Centrum, Postbus 9101, 6500 HB Nijmegen. a.verrips@ckskg.azn.nl A 24-year-old woman and a 13-year-old boy had suffered from diarrhoea, walking disorders, visual complaints and other complaints for many years. Once the suspicion of cerebrotendinous xanthomatosis (CTX) had been confirmed with biochemical and genetic tests and treatment with chenodeoxycholic acid had been started, the diarrhoea disappeared and the neurological symptoms lessened. CTX is a rare, autosomal recessive metabolic disease. The clinical hallmarks are: bilateral juvenile cataract, chronic diarrhoea, progressive neurological symptoms and signs, and tendon xanthomas. The phenotypic variability often hinders the clinical diagnosis. The biochemical diagnosis can be made by determining the serum cholestanol level and the excretion of urinary bile alcohols, followed by a mutation analysis. CTX is a treatable disease and therefore an early diagnosis is important. PMID: 11561482 [PubMed - indexed for MEDLINE] 192. Lab Invest. 2001 Sep;81(9):1173-83. Advances in experimental dyslipidemia and atherosclerosis. Moghadasian MH, Frohlich JJ, McManus BM. Healthy Heart Program, Department of Pathology and Laboratory Medicine, St. Paul's Hospital and the University of British Columbia, Vancouver, British Columbia, Canada. mhmoghad@interchange.ubc.ca Among the models of dyslipidemia and atherosclerosis, a number of wild-type, naturally defective, and genetically modified animals (rabbits, mice, pigeons, dogs, pigs, and monkeys) have been characterized. In particular, their similarities to and differences from humans in respect to relevant biochemical, physiologic, and pathologic conditions have been evaluated. Features of atherosclerotic lesions and their specific relationship to plasma lipoprotein particles have been critically reviewed and summarized. All animal models studied have limitations: the most significant advantages and disadvantages of using a specific animal species are outlined here. New insights in lipid metabolism and genetic background with regard to variations in pathogenesis of dyslipidemia-associated atherogenesis have also been reviewed. Evidence suggests that among wild-type species, strains of White Carneau pigeons and Watanabe Heritable Hyperlipidemic and St. Thomas's Hospital rabbits are preferable to the cholesterol-fed wild-type animal species in dyslipidemia and atherosclerosis research. Evidence for the usefulness of both wild-type and transgenic animals in studying the involvement of inflammatory pathways and Chlamydia pneumoniae infection in pathogenesis of atherosclerosis has also been summarized. Transgenic mice and rabbits are excellent tools for studying specific gene-related disorders. However, despite these significant achievements in animal experimentation, there are no suitable animal models for several rare types of fatal dyslipidemia-associated disorders such as phytosterolemia and cerebrotendinous xanthomatosis. An excellent model of diabetic atherosclerosis is unavailable. The question of reversibility of atherosclerosis still remains unanswered. Further work is needed to overcome these deficiencies. PMID: 11555665 [PubMed - indexed for MEDLINE] 193. Acta Paediatr. 2001 Jul;90(7):828-9. Cerebrotendinous xanthomatosis presenting as "chologenic diarrhoea". Bindl L, Lütjohann D, Lentze MJ, von Bergmann K. PMID: 11519995 [PubMed - indexed for MEDLINE] 194. J Inherit Metab Dis. 2001 Jun;24(3):379-92. Frontal lobe dementia with abnormal cholesterol metabolism and heterozygous mutation in sterol 27-hydroxylase gene (CYP27). Sugama S, Kimura A, Chen W, Kubota S, Seyama Y, Taira N, Eto Y. Department of Psychiatry, Amekudai Hospital, Okinawa, Japan. Of the primary dementing disorders that cause frontotemporal dementia, the best-known is Pick disease. We report on a 44-year-old woman with progressive frontal lobe dementia and spastic paraplegia. Examination revealed increased serum levels of cholestanol with abnormal cholesterol metabolism and a heterozygous mutation of the sterol 27-hydroxylase gene (CYP27). Biochemical findings were compatible with cerebrotendinous xanthomatosis (CTX); however, the clinical manifestations were very dissimilar. To our knowledge, a symptomatic carrier of this mutation among CTX patients has not been reported. We speculate that the present patient has a previously undescribed neurodegenerative disease related to abnormal cholesterol metabolism with this heterozygous mutation. PMID: 11486904 [PubMed - indexed for MEDLINE] 195. J Am Acad Dermatol. 2001 Aug;45(2):292-5. Cerebrotendinous xanthomatosis. Bel S, García-Patos V, Rodríguez L, Selva A, Díaz P, Wolthers BG, Castells A. Department of Dermatology, Hospitals Vall d'Hebron, Barcelona, Spain. Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid-storage disease caused by mutations in the sterol 27-hydroxylase gene. The accumulation of cholestanol in various tissues characterizes this disease. Diagnosis is based on determination of urinary bile alcohols. Therapy with chenodeoxycholic acid may arrest the progression of the disease. A 55-year-old woman presented with a slowly progressive paraparesia and two firm subcutaneous tumors over the knees. Her medical history revealed difficulty in standing and walking since infancy, bilateral juvenile cataracts, and mental retardation. Histopathologic examination of one subcutaneous tumor was consistent with tendinous xanthoma. Substantial elevation of urinary bile alcohols confirmed the diagnosis. Treatment with oral chenodeoxycholic acid was started, with only mild improvement of spasticity. Recognition of tendon xanthomas in a young patient with neurologic symptoms or cataracts (or both) is crucial to start early treatment and to avoid irreversible neurologic sequelae. PMID: 11464194 [PubMed - indexed for MEDLINE] 196. J Biol Chem. 2001 Sep 14;276(37):34579-85. Epub 2001 Jul 13. Side chain hydroxylations in bile acid biosynthesis catalyzed by CYP3A are markedly up-regulated in Cyp27-/- mice but not in cerebrotendinous xanthomatosis. Honda A, Salen G, Matsuzaki Y, Batta AK, Xu G, Leitersdorf E, Tint GS, Erickson SK, Tanaka N, Shefer S. Department of Gastroenterology, University of Tsukuba, Tsukuba-city 305-8575, Japan. The accumulation of various 25-hydroxylated C(27)-bile alcohols in blood and their excretion in urine are characteristic features of cerebrotendinous xanthomatosis (CTX) a recessively inherited inborn error of bile acid synthesis caused by mutations in the mitochondrial sterol 27-hydroxylase (CYP27) gene. These bile alcohols may be intermediates in the alternative cholic acid side chain cleavage pathway. The present study was undertaken to identify enzymes and reactions responsible for the formation of these bile alcohols and to explain why Cyp27(-/-) mice do not show CTX-related abnormalities. Microsomal activities of 5beta-cholestane-3alpha,7alpha,12alpha-triol 25- and 26-hydroxylases, 5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol 23R-, 24S-, and 27-hydroxylases and testosterone 6beta-hydroxylase, a marker enzyme for CYP3A, in Cyp27(-/-) mice livers were markedly up-regulated (5.5-, 3.5-, 6.5-, 7.5-, 2.9-, and 5.4-fold, respectively). In contrast, these enzyme activities were not increased in CTX. The activities of 5beta-cholestane-3alpha,7alpha,12alpha-triol 25- and 26-hydroxylases and 5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol 23R-, 24R-, 24S-, and 27-hydroxylases were strongly correlated with the activities of testosterone 6beta-hydroxylase in control human liver microsomes from eight unrelated donors. Troleandomycin, a specific inhibitor of CYP3A, markedly suppressed these microsomal side chain hydroxylations in both mouse and human livers in a dose-dependent manner. In addition, experiments using recombinant overexpressed human CYP3A4 confirmed that these microsomal side chain hydroxylations were catalyzed by a single enzyme, CYP3A4. The results demonstrate that microsomal 25- and 26-hydroxylations of 5beta-cholestane-3alpha,7alpha,12alpha-triol and microsomal 23R-, 24R-, 24S-, and 27-hydroxylations of 5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol are mainly catalyzed by CYP3A in both mice and humans. Unlike Cyp27(-/-) mice, CYP3A activity was not up-regulated despite marked accumulation of 5beta-cholestane-3alpha,7alpha,12alpha-triol in CTX. PMID: 11454857 [PubMed - indexed for MEDLINE] 197. Endocr Pract. 2001 May-Jun;7(3):225. Visual vignette. A case presentation: cerebrotendinous xanthomatosis. Budavari AI, Whitaker MD. Division of Endocrinology, Mayo Clinic Scottsdale, Arizona, USA. PMID: 11430306 [PubMed - indexed for MEDLINE] 198. Singapore Med J. 2001 Jan;42(1):30-2. Cerebrotendinous xanthomatosis in three siblings from a Chinese family. Ko KF, Lee KW. Department of Medicine, Kwong Wah Hospital, Kowloon, Hong Kong. Cerebrotendinous xanthomatosis (CTX) is exceptionally rare in the Chinese population. We reported a 31-year-old Chinese male in Hong Kong, who has the characteristic features of cerebrotendinous xanthomatosis including the multiple xanthomas of tendons, mental retardation, bilateral cataracts, cerebellar ataxia and spasticity of the left arm, high concentrations of plasma phytosterols and abnormal MR of brain. On screening the family, two other siblings of 27 and 29 respectively, have tendon xanthomas and high plasma phytosterols. An extensive search of the international medical literature, including the Medline, has revealed only one other case report of cerebrotendinous xanthomatosis in Taiwan. CTX is a potentially treatable disease. It is hoped by alertness, early diagnosis and treatment can be made, and hence prevent further progression of the disease. PMID: 11361235 [PubMed - indexed for MEDLINE] 199. Nihon Rinsho. 2001 Mar;59 Suppl 3:348-52. [Cerebrotendinous xanthomatosis]. [Article in Japanese] Inoue K, Kubota S, Seyama Y. Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo. PMID: 11347094 [PubMed - indexed for MEDLINE] 200. Clin Chim Acta. 2001 Apr;306(1-2):63-9. Clinical and biochemical features, molecular diagnosis and long-term management of a case of cerebrotendinous xanthomatosis. Burnett JR, Moses EA, Croft KD, Brown AJ, Grainger K, Vasikaran SD, Leitersdorf E, Watts GF. Department of Core Clinical Pathology and Biochemistry, Royal Perth Hospital, Perth, Australia. Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive sterol storage disease characterised clinically by juvenile bilateral cataracts, progressive neurological dysfunction, and formation of tendon xanthomata. We describe the clinical and biochemical features, molecular diagnosis and long-term management of the first reported Australasian case of CTX. Molecular analysis confirmed the diagnosis of CTX and demonstrated that the patient was homozygous for a G-->A transition in the splice donor site of intron 4 of the sterol 27-hydroxylase gene. Serum cholestanol concentrations were decreased with the HMG-CoA reductase inhibitor simvastatin alone and greater reductions were achieved after the addition of the bile acid chenodeoxycholic acid; suggesting a synergistic effect of this combination. Despite serum cholestanol concentrations remaining within the low-normal range, there has been no significant improvement in mental and physical abilities or in EEG abnormalities with 5 years of treatment. Metabolism of radiolabeled 7-ketocholesterol to aqueous soluble products was absent in CTX-derived macrophages. Consistent with this finding, plasma 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol, and 7-ketocholesterol concentrations were increased in the CTX subject compared with controls. PMID: 11282095 [PubMed - indexed for MEDLINE] 201. Neurology. 2001 Mar 13;56(5):695-6. Chenodeoxycholic treatment of cerebrotendinous xanthomatosis. Samenuk P, Koffman BM. Erratum in Neurology 2001 May 22;56(10):1425. Comment on Neurology. 2000 Aug 22;55(4):601. PMID: 11245734 [PubMed - indexed for MEDLINE] 202. J Lipid Res. 2001 Feb;42(2):291-300. Differences in hepatic levels of intermediates in bile acid biosynthesis between Cyp27(-/-) mice and CTX. Honda A, Salen G, Matsuzaki Y, Batta AK, Xu G, Leitersdorf E, Tint GS, Erickson SK, Tanaka N, Shefer S. Department of Gastroenterology, University of Tsukuba, Tsukuba City 305-8575, Japan. Cerebrotendinous xanthomatosis (CTX) is a rare, recessively inherited lipid storage disease characterized by a markedly reduced production of chenodeoxycholic acid and an increased formation of 25-hydroxylated bile alcohols and cholestanol. Patients with this disease are known to have mutations in the sterol 27-hydroxylase (Cyp27) gene. However, one study showed that mice with a disrupted Cyp27 gene did not have any CTX-related clinical or biochemical abnormalities. To explore the reason, hepatic cholesterol, cholestanol, and 12 intermediates in bile acid biosynthetic pathways were quantified in 10 Cyp27(-/-) and 7 Cyp27(+/+) mice, two CTX patients (untreated and treated with chenodeoxycholic acid), and four human control subjects by high resolution gas chromatography-mass spectrometry. Mitochondrial 27-hydroxycholesterol and 5beta-cholestane-3alpha,7alpha,12alpha,27-tetrol were virtually absent in both Cyp27(-/-) mice and CTX patients. In Cyp27(-/-) mice, microsomal concentrations of intermediates in the early bile acid biosynthetic pathway (7alpha-hydroxycholesterol, 7alpha-hydroxy-4-cholesten-3-one, 7alpha,12alpha-dihydroxy-4-cholesten-3-one, and 5beta-cholestane-3alpha,7alpha,12alpha-triol), 25-hydroxylated bile alcohols (5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol, 5beta-cholestane-3alpha,7alpha,12alpha,23R,25-pentol, and 5beta-cholestane-3alpha,7alpha,12alpha,24R, 25-pentol), and cholestanol were all significantly elevated compared with those in Cyp27(+/+) mice, although the levels were lower than those in untreated CTX patients. The intermediate levels in early bile acid biosynthesis were more elevated in male (16;-86% of CTX) than in female Cyp27(-/-) mice (7-30% of CTX). In contrast, 25-hydroxylated bile alcohol concentrations were not significantly different between male and female Cyp27(-/-) mice and were considerably lower (less than 14%) than those in CTX patients.These results suggest that 1) in Cyp27(-/-) mice, especially in females, classic bile acid biosynthesis via 7alpha-hydroxycholesterol is not stimulated as much as in CTX patients; and 2) formed 25-hydroxylated bile alcohols are more efficiently metabolized in Cyp27(-/-) mice than in CTX patients. PMID: 11181760 [PubMed - indexed for MEDLINE] 203. J Lipid Res. 2001 Feb;42(2):159-69. Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees. Lee MH, Hazard S, Carpten JD, Yi S, Cohen J, Gerhardt GT, Salen G, Patel SB. Division of Endocrinology, Medical University of South Carolina, Charleston 29403, USA. Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid biosynthesis. Clinically, CTX patients present with tendon xanthomas, juvenile cataracts, and progressive neurological dysfunction and can be diagnosed by the detection of elevated plasma cholestanol levels. CTX is caused by mutations affecting the sterol 27-hydroxylase gene (CYP27 ). CTX has been identified in a number of populations, but seems to have a higher prevalence in the Japanese, Sephardic Jewish, and Italian populations. We have assembled 12 previously unreported pedigrees from the United States. The CYP27 locus had been previously mapped to chromosome 2q33-qter. We performed linkage analyses and found no evidence of genetic heterogeneity. All CTX patients showed segregation with the CYP27 locus, and haplotype analysis and recombinant events allowed us to precisely map CYP27 to chromosome 2q35, between markers D2S1371 and D2S424. Twenty-three mutations were identified from 13 probands analyzed thus far; 11 were compound heterozygotes and 2 had homozygous mutations. Of these, five are novel mutations [Trp100Stop, Pro408Ser, Gln428Stop, a 10-base pair (bp) deletion in exon 1, and a 2-bp deletion in exon 6 of the CYP27 gene]. Three-dimensional structural modeling of sterol 27-hydroxylase showed that, while the majority of the missense mutations disrupt the heme-binding and adrenodoxin-binding domains critical for enzyme activity, two missense mutations (Arg94Trp/Gln and Lys226Arg) are clearly located outside these sites and may identify a potential substrate-binding or other protein contact site. PMCID: PMC1418947 PMID: 11181744 [PubMed - indexed for MEDLINE] 204. J Neurol Sci. 2001 Jan 1;182(2):95-7. Diphenylpyraline-responsive parkinsonism in cerebrotendinous xanthomatosis: long-term follow up of three patients. Ohno T, Kobayashi S, Hayashi M, Sakurai M, Kanazawa I. Department of Neurology, Division of Neuroscience, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. skoba@med.juntendo.ac.jp A long-term follow-up study was made of three patients with cerebrotendinous xanthomatosis (CTX) associated with parkinsonism, two of whom were siblings. Besides typical CTX symptoms, all three patients showed severe parkinsonism. This observation has been rarely reported in CTX. The fact that the two siblings showed parkinsonism strongly suggests the genetic propensity to parkinsonism in these CTX patients. Positron emission tomography studies of the two patients revealed presynaptic dysfunction of the nigro-striatal dopaminergic system. Treatment with the reductase inhibitor hydroxymethyl glutaryl coenzyme successfully corrected the serum cholestanol level in the early stage of the disease, which, however, did not arrest the progression of clinical symptoms, particularly their parkinsonism. Clinically, levodopa had a little effect on parkinsonism, whereas an antihistamine drug, diphenylpyraline hydrochloride (DPP) had excellent effects on all three patients throughout the long-term follow up. The mechanism of the action of DPP on parkinsonism is unclear, however, the drug seems to be a therapeutic choice for treating parkinsonism in CTX. PMID: 11137513 [PubMed - indexed for MEDLINE] 205. Brain. 2001 Jan;124(Pt 1):121-31. Magnetic resonance imaging and spectroscopic changes in brains of patients with cerebrotendinous xanthomatosis. De Stefano N, Dotti MT, Mortilla M, Federico A. Institute of Neurological Sciences, Neurometabolic Unit, NMR Centre and Centre for the Diagnosis, Prevention and Therapy of Neuro-handicap, University of Siena, Italy. Cerebrotendinous xanthomatosis (CTX) is a rare disorder due to an inherited defect in the metabolic pathway of cholesterol. Early diagnosis of the disease is particularly important as patients benefit from therapy with chenodeoxycholic acid. Although the disease is clinically characterized by the concomitant presence of tendon xanthomas, juvenile cataracts and progressive neurological impairment, clinical features may vary greatly. Neuroradiological studies have suggested that the bilateral abnormality of the dentate nuclei could be typical of this disease. However, this finding has been seen inconsistently on conventional MRI. The dynamic of the CNS pathology in CTX is complex, and whether demyelination or axonopathy has primary importance in the pathogenesis of CTX pathology is not known. To clarify both neuroradiological and pathological issues, we performed combined brain MRI and spectroscopy examinations on 12 CTX patients. On conventional MRIs, bilateral hyperintensities of the dentate nuclei were clearly seen in nine out of 12 patients on T(2) -weighted MRIs, but were evident in all patients using a FLAIR sequence. On proton magnetic resonance (MR) spectroscopy, significant decreases in N: -acetylaspartate resonance intensities (P: <0.0001) and increases in lactate MR signals (P<0.05) were found in the group of CTX patients in large volumes of interest localized above the lateral brain ventricles and in the cerebellar hemispheres. Cerebral values of N -acetylaspartate resonance intensities showed a close correlation with patients' disability (Spearman rank correlation = -0.78, P<0.005). These results suggest that MR abnormalities in the dentate nuclei may be evident consistently in patients with CTX. Proton MR spectroscopy data demonstrated widespread axonal damage (as shown by the decrease in N -acetylaspartate) and diffuse brain mitochondrial dysfunction (as shown by the increase in brain parenchymal lactate) in patients with CTX. The close correlation seen between values of the putative axonal marker N-acetylaspartate and patients' disability scores suggests that proton MR spectroscopy can provide a useful measure of disease outcome in CTX. PMID: 11133792 [PubMed - indexed for MEDLINE] 206. Radiology. 2000 Dec;217(3):869-76. Cerebrotendinous xanthomatosis: the spectrum of imaging findings and the correlation with neuropathologic findings. Barkhof F, Verrips A, Wesseling P, van Der Knaap MS, van Engelen BG, Gabreëls FJ, Keyser A, Wevers RA, Valk J. Depts of Radiology, Academic Hospital "Vrije Universiteit," De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands. f.barkhof@azvu.nl PURPOSE: To describe imaging findings and their neuropathologic correlate in patients with cerebrotendinous xanthomatosis (CTX). MATERIALS AND METHODS: Computed tomographic (CT) and magnetic resonance (MR) images in 24 patients with symptoms (mean age at time of imaging, 37 years; mean disease duration, 18 years) were reviewed for site and frequency of brain, spinal cord, and Achilles tendon involvement. Two patients died, and imaging findings were compared with postmortem neuropathologic findings. RESULTS: Apart from nonspecific supratentorial atrophy and deep white matter changes, more typical hyperintense lesions were seen on T2-weighted images in the dentate nucleus (in 79% of patients), globus pallidus, substantia nigra, and inferior olive and extended into adjacent white matter as disease progressed. In these locations, lipid crystal clefts and perivascular macrophages, neuronal loss, demyelination, fibrosis, and reactive astrocytosis were found at microscopic examination. Hypointensity was sometimes found on T2-weighted images in the dentate nucleus and was related to deposition of hemosiderin and calcifications. CT depicted fewer lesions; all had low attenuation, except for the calcifications. Spinal cord MR imaging revealed increased signal intensity in the lateral and dorsal columns on T2-weighted images. Achilles tendon xanthomas displayed intermediate signal intensity on T1- and T2-weighted images. CONCLUSION: The typical pattern of MR imaging findings reflects the classic histopathologic findings and should prompt the diagnosis of CTX. PMID: 11110956 [PubMed - indexed for MEDLINE] 207. Mov Disord. 2000 Sep;15(5):1017-9. Cerebrotendinous xanthomatosis with predominant parkinsonian syndrome: further confirmation of the clinical heterogeneity. Dotti MT, Federico A, Garuti R, Calandra S. Institute of Neurology, Unit of Neurometabolic Diseases, University of Siena, Italy. Comment in Mov Disord. 2002 Nov;17(6):1396-7. PMID: 11009219 [PubMed - indexed for MEDLINE] 208. Eur Radiol. 2000;10(7):1204. Computed tomography and ultrasound of the achilles tendon in cerebrotendinous xanthomatosis. Ortega Herrera R, Santiago FR, Artalejo Martinez de la Victor. PMID: 11003423 [PubMed - indexed for MEDLINE] 209. Neurology. 2000 Aug 22;55(4):601. Neuroimages: cerebrotendinous xanthomatosis. Fleck JD, Biller J, Mathews VP. Comment in Neurology. 2001 Nov 13;57(9):1743. Neurology. 2001 Mar 13;56(5):695-6. PMID: 10953208 [PubMed - indexed for MEDLINE] 210. J Chromatogr B Biomed Sci Appl. 2000 Jun 9;742(2):345-52. A new method for determination of serum cholestanol by high-performance liquid chromatography with ultraviolet detection. Halperin G, Elisaf M, Leitersdorf E, Harats D. Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel-Hashomer, Israel. We developed a method for the determination of serum 5alpha-cholestan-3beta-ol (cholestanol). The sterols were derivatized to the 4'-bromobenzenesulfonyl esters and heated in isopropanol. The cholesterol-4'-bromobenzenesulfonate was solvolyzed to cholesteryl isopropyl ether, but the derivatized cholestanol did not change and could be measured in a high-performance liquid chromatographic system equipped with a UV detector at 235 nm. On the other hand, the resulting cholesteryl isopropyl ether, having different absorbance and chromatographic mobility was not detected. This method was used for measuring cholestanol levels in patients with cerebrotendinous xanthomatosis (CTX), liver cirrhosis and serum from healthy control subjects. Reproducibility, linearity and recovery tests were done on 0.3 ml of serum samples containing >2 microg/ml cholestanol, using stigmastanol as an internal standard (I.S.). Determining cholestenol by this method can be used for diagnosis and follow-up of patients with CTX and various liver diseases. PMID: 10901139 [PubMed - indexed for MEDLINE] 211. Neuromuscul Disord. 2000 Aug;10(6):407-14. Cerebrotendinous xanthomatosis. Controversies about nerve and muscle: observations in ten patients. Verrips A, van Engelen BG, ter Laak H, Gabreëls-Festen A, Janssen A, Zwarts M, Wevers RA, Gabreëls FJ. Departments of Paediatric Neurology, University Hospital Nijmegen, PO Box 9101, 6500 HB, The, Nijmegen, Netherlands. a.verrips@ckskg.azn.nl Neuromuscular characteristics were documented in ten patients with biochemically and genetically confirmed cerebrotendinous xanthomatosis. An array of genotypes was found in these patients. Only one patient complained of muscle weakness, while clinical signs of peripheral neuropathy were present in six patients. Electromyogram showed predominantly axonal neuropathy in seven patients. Neurogenic changes were seen in muscle biopsies of nine patients. Sural nerve biopsies of three patients showed features of axonal neuropathy. In addition, in one patient, extensive onion bulb formation was seen, which is indicative of a primarily demyelinating process. Five patients had normal mitochondrial respiratory chain enzyme activity. It is concluded that myopathy is not a feature of cerebrotendinous xanthomatosis and that the most prominent neuromuscular abnormality is sensorimotor axonal polyneuropathy. PMID: 10899446 [PubMed - indexed for MEDLINE] 212. Rinsho Shinkeigaku. 2000 Mar;40(3):222-6. [A case of familial type IIa hypercholesterolemia with the clinical features similar to cerebrotendinous xanthomatosis]. [Article in Japanese] Sakae N, Taniwaki T, Arakawa K, Yamada T, Kira J. Department of Neurology, Faculty of Medicine, Kyusyu University. A 63-years-old woman noticed unsteady gait at the age of 56 years and then developed dysarthria two years later. A general physical examination at age 56 revealed mild hypertrophy of both Achilles tendons. On neurological examination, she had scanning speech, moderate limb and truncal ataxia, and moderate hyperreflexia of all limbs. A soft tissue X-ray examination disclosed hypertrophy of both Achilles tendons with multiple punctate calcification. Brain MRI showed diffuse cerebellar atrophy. Motor evoked potentials in the right limb disclosed a prolonged central conduction time. Blood chemistry showed familial type IIa hypercholesterolemia (cholesterol 320 mg/dl, and LDL-cholesterol 245 mg/dl), yet cholestanol level was normal. A examination of CTX gene mutation at hot spots revealed no mutation. Her mother and two siblings also had hypertrophy of Achilles tendons as well as type IIa hypercholesterolemia. In addition, the one sibling showed mild ataxia of lower limbs, respectively. This report suggests a possible link between familial type IIa hypercholesterolemia and cerebellar degeneration syndrome clinically mimicking CTX. PMID: 10885331 [PubMed - indexed for MEDLINE] 213. J Biol Chem. 2000 Sep 8;275(36):27627-33. Sterol 27-hydroxylase acts on 7-ketocholesterol in human atherosclerotic lesions and macrophages in culture. Brown AJ, Watts GF, Burnett JR, Dean RT, Jessup W. Cell Biology Group, Heart Research Institute, Sydney 2050, Australia. andrew.brown@email.swmed.edu 27-Hydroxycholesterol (27OH) is the major oxysterol in human atherosclerotic lesions, followed by 7-ketocholesterol (7K). Whereas 7K probably originates nonenzymically, 27OH arises by the action of sterol 27-hydroxylase, a cytochrome P450 enzyme expressed at particularly high levels in the macrophage and proposed to represent an important pathway by which macrophages eliminate excess cholesterol. We hypothesized and here show that 27-hydroxylated 7-ketocholesterol (270H-7K) is present in human lesions, probably generated by the action of sterol 27-hydroxylase on 7K. Moreover, [(3)H]27OH-7K was produced by human monocyte-derived macrophages (HMDMs) supplied with [(3)H]7K but not in HMDMs from a patient with cerebrotendinous xanthomatosis (CTX) shown to have a splice-junction mutation of sterol 27-hydroxylase. Whereas [(3)H]27OH-7K was predominantly secreted into the medium, [(3)H]-27OH formed from [(3)H]-cholesterol was mostly cell-associated. The majority of supplied [(3)H]7K was metabolized beyond 27OH-7K to aqueous-soluble products (apparently bile acids derived from the sterol 27-hydroxylase pathway). Metabolism to aqueous-soluble products was ablated by a sterol 27-hydroxylase inhibitor and absent in CTX cells. Sterol 27-hydroxylase therefore appears to represent an important pathway by which macrophages eliminate not only cholesterol but also oxysterols such as 7K. The fact that 7K (and cholesterol) still accumulates in lesions and foam cells indicates that this pathway may be perturbed in atherosclerosis and affords a new opportunity for the development of therapeutic strategies to regress atherosclerotic lesions. PMID: 10869358 [PubMed - indexed for MEDLINE] 214. Trends Endocrinol Metab. 2000 Jul;11(5):180-3. Sterol 27-hydroxylase deficiency: a rare cause of xanthomas in normocholesterolemic humans. Björkhem I, Leitersdorf E. Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, SE-141 86 Huddinge, Sweden. Ingemar.Bjorkhem@chemlab.hs.sll.se Cerebrotendinous xanthomatosis is characterized by the accumulation of cholestanol and cholesterol in xanthomas and brain causing a number of severe symptoms. More than 20 different mutations have been identified in the gene encoding sterol 27-hydroxylase. Defects in the gene lead to reduced bile acid biosynthesis, with accumulation of 7 alpha-hydroxylated intermediates, one of which is a precursor to cholestanol. The disease can be treated successfully with chenodeoxycholic acid, which reduces the upregulation of cholesterol 7 alpha-hydroxylase and, therefore, the formation of cholestanol. Disruption of the gene encoding sterol 27-hydroxylase in mice does not have the same metabolic consequences as in humans. PMID: 10856919 [PubMed - indexed for MEDLINE] 215. Rofo. 2000 Mar;172(3):301-2. [Cerebrotendinous xanthomatosis in a 12-year-old patient with growth disorder]. [Article in German] Fiebach JB. PMID: 10809535 [PubMed - indexed for MEDLINE] 216. Eur Radiol. 2000;10(4):576-8. MRI of the brain in cerebrotendinous xanthomatosis (van Bogaert-Scherer-Epstein disease). Vanrietvelde F, Lemmerling M, Mespreuve M, Crevits L, De Reuck J, Kunnen M. Department of Radiology, University Hospital Gent, Belgium. The clinical, biochemical and magnetic resonance imaging findings of two patients with cerebrotendinous xanthomatosis are reported. This is a rare hereditary disease. Early recognition of this entity is important in view of the existing treatment possibilities. Magnetic resonance imaging findings typically include a bilateral and almost symmetrical increase of the signal intensity on the T2-weighted images in the cerebellar and periventricular cerebral white matter, the basal ganglia, the dentate nuclei and the brainstem as well as cerebellar and cerebral atrophy. PMID: 10795535 [PubMed - indexed for MEDLINE] 217. Brain. 2000 May;123 ( Pt 5):908-19. Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Verrips A, Hoefsloot LH, Steenbergen GC, Theelen JP, Wevers RA, Gabreëls FJ, van Engelen BG, van den Heuvel LP. Department of Neurology, University Hospital Nijmegen, Nijmegen, The Netherlands. Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP 27), due to mutations in its gene. In this study we report on mutations in 58 patients with CTX out of 32 unrelated families. Eight of these were novel mutations, two of which were found together with two already known pathogenic mutations. Twelve mutations found in this patient group have been described in the literature. In the patients from 31 families, mutations were found in both alleles. In the literature, 28 mutations in 67 patients with CTX out of 44 families have been described. Pooling our patient group and the patients from the literature together, 37 different mutations in 125 patients out of 74 families were obtained. Identical mutations have been found in families from different ethnic backgrounds. In 41% of all the patients, CYP 27 gene mutations are found in the region of exons 6-8. This region encodes for adrenodoxin and haem binding sites of the protein. Of these 125 patients, a genotype-phenotype analysis was done for 79 homozygous patients harbouring 23 different mutations, out of 45 families. The patients with compound heterozygous mutations were left out of the genotype-phenotype analysis. The genotype-phenotype analysis did not reveal any correlation. PMID: 10775536 [PubMed - indexed for MEDLINE] 218. Arch Neurol. 2000 Apr;57(4):520-4. Presence of diarrhea and absence of tendon xanthomas in patients with cerebrotendinous xanthomatosis. Verrips A, van Engelen BG, Wevers RA, van Geel BM, Cruysberg JR, van den Heuvel LP, Keyser A, Gabreëls FJ. Department of Neurology, University Hospital of Nijmegen, The Netherlands. A.Verrips@ckskg.azn.nl BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder of bile acid synthesis. A diagnosis of CTX should be considered in patients with premature bilateral cataracts, intractable diarrhea, neurological signs and symptoms, and tendon xanthomas, especially in the Achilles tendons. The prevalence of these signs and symptoms increases with age. OBJECTIVES: To investigate signs and symptoms, age at onset, and age at diagnosis in 32 patients with biochemically and genetically confirmed CTX, and to compare this clinical spectrum with reports in the literature. METHODS: Retrospective analysis of records of all patients with CTX at our hospital (27 adults and 5 children). After a MEDLINE search in the English, French, and German literature, 181 patients with CTX (165 adults and 16 children) were identified worldwide. RESULTS: Of our 32 patients with CTX, 31 (97%) had cataracts and neurological signs and symptoms, predominantly pyramidal signs (26 [81%]); 21 (66%) had low intelligence and 18 (56%) had cerebellar signs. Only 13 (41%) had visible or palpable tendon xanthomas at the time of diagnosis. In total, 16 patients (50%) had chronic, intractable diarrhea that started in childhood. These findings were in contrast with the literature, where tendon xanthomas were reported in 89% and diarrhea in only 2 patients. CONCLUSIONS: We believe that CTX is underdiagnosed worldwide. We recommend that the presence of 2 of the 4 clinical hallmarks of CTX prompt thorough metabolic screening, including determination of urine bile alcohol excretion and serum cholestanol level, because CTX is a treatable disease. PMID: 10768627 [PubMed - indexed for MEDLINE] 219. Int J Legal Med. 2000;113(2):110-3. Sudden death due to cerebrotendinous xanthomatosis confirmed by mutation analysis. Sperhake JP, Matschke J, Orth U, Gal A, Püschel K. Institut für Rechtsmedizin, Universität Hamburg, Germany. sperhake@uke.uni-hamburg.de A case of sudden death of a 52-year-old mentally retarded Caucasian male is described where the rectal temperature was 43.4 degrees C 3 h postmortem. The autopsy revealed cerebrotendinous xanthomatosis (CTX), a rare hereditary metabolic disorder, as the primary disease. The diagnosis was confirmed by postmortem identification of two mutations (compound heterozygosity for R237X and IVS6+1G-->A) in the sterol 27-hydroxylase (CYP27) gene. Both mutations have already been described in patients with CTX and can be considered the most likely cause of the disease. The pathomechanism of the excessive hyperthermia could not be completely elucidated. PMID: 10741487 [PubMed - indexed for MEDLINE] 220. Br J Dermatol. 2000 Feb;142(2):378-80. Cerebrotendinous xanthomatosis: report of a case. Nakamura S, Tamura T, Takahashi H, Ishida-Yamamoto A, Hashimoto Y, Kuroda K, Iizuka H. PMID: 10730784 [PubMed - indexed for MEDLINE] 221. Clin Genet. 1999 Nov;56(5):405-6. Cerebrotendinous xanthomatosis without xanthomas. Gilad R, Lampl Y, Lev D, Sadeh M. PMID: 10668932 [PubMed - indexed for MEDLINE] 222. J Lab Clin Med. 2000 Dec;136(6):457-67. Smith-Lemli-Opitz syndrome and other sterol disorders among Finns with developmental disabilities. Nissinen MJ, Gylling H, Kaski M, Tammisto P, Mieskonen S, Ignatius J, Miettinen TA. Department of Medicine, University of Helsinki, Finland. Smith-Lemli-Opitz syndrome (SLOS) is an inherited disorder of cholesterol metabolism in which 7- and 8-dehydrocholesterols are accumulated in blood and tissues. Diagnosis of SLOS and other disorders in cholesterol metabolism (eg, cerebrotendinous xanthomatosis, phytosterolemia, desmosterolosis, and X-linked dominant Conradi-Hünermann-Happle syndrome) can be performed by gas-liquid chromatographic analysis of serum sterols. To elucidate their involvement in developmental disability, we evaluated serum sterols in two study groups: developmentally disabled subjects in long-term care (N = 322) and newborns and young children (N = 49) with features of SLOS in the Finnish population of 5 million. Only 1 SLOS case (type II) was found from among the 49 children. Seven additional adult cases (type I) with a wide range of clinical features and the serum sterol abnormalities characteristic of SLOS were detected from among the developmentally disabled subjects. The frequency of SLOS in the latter group was relatively high (7 in 322). No other hereditary sterol disorders were found, but two subgroups with low serum cholesterol precursor sterols and high serum plant sterols were identified. Several subjects, including the 7 SLOS patients, used ample medication and had abnormalities in serum sterol concentrations. Thus, among the subjects taking melperone, a high serum delta8-cholestenol level suggests an interference by the drug with cholesterol synthesis. Our results emphasize the importance of analyzing the serum sterols of developmentally disabled subjects to diagnose SLOS and of finding putative undiagnosed disorders in sterol metabolism associated with these clinical conditions. PMID: 11128747 [PubMed - indexed for MEDLINE] 223. J Neurol Neurosurg Psychiatry. 1999 Nov;67(5):675-7. Mutation of the sterol 27-hydroxylase gene (CYP27) results in truncation of mRNA expressed in leucocytes in a Japanese family with cerebrotendinous xanthomatosis. Shiga K, Fukuyama R, Kimura S, Nakajima K, Fushiki S. Department of Dynamic Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan. OBJECTIVES: A Japanese family with cerebrotendinous xanthomatosis (CTX) was investigated for a sequence alteration in the sterol 27-hydroxylase gene (CYP27). The expression of CYP27 has been mostly explored using cultured fibroblasts, prompting the examination of the transcripts from blood leucocytes as a simple and rapid technique. METHODS: An alteration in CYP27 of the proband was searched for by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and subsequent sequencing. Samples of RNA were subjected to reverse transcription PCR (RT-PCR) and the product of the proband was amplified with nested primers and sequenced. RESULTS: A homozygous G to A transition at the 5' end of intron 7 was detected in the patient. In RT-PCR analysis, only a truncated transcript was detected in the patient, whereas both normal and truncated transcripts were detected in the siblings. The sequencing of the patient's cDNA fragment disclosed a direct conjuction of exon 6 and exon 8. CONCLUSION: The mutation at splice donor site and the truncation of mRNA were identical with those of a recently reported Italian patient, although different in symptomatology. The application of blood leucocytes can be a simple technique on analysing a constructive abnormality of CYP27 mRNA. PMCID: PMC1736608 PMID: 10519880 [PubMed - indexed for MEDLINE] 224. Lipids. 1999 Apr;34(4):395-405. Anomalous enantioselectivity in the sharpless asymmetric dihydroxylation reaction of 24-nor-5beta-cholest-23-ene-3alpha,7alpha,12alpha-triol: synthesis of substrates for studies of cholesterol side-chain oxidation. Ertel NH, Dayal B, Rao K, Salen G. Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA. Recently we described a block in bile acid synthesis in cerebrotendinous xanthomatosis (CTX), a lipid storage disease related to an inborn error of bile acid metabolism. In this disease a defect in hepatic microsomal (24S) hydroxylation blocks the transformation of 5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol into (24S) 5beta-cholestane-3alpha,7alpha,12alpha,24,25- pentol and cholic acid. Mitochondrial cholesterol 27-hydroxylation has also been reported to be abnormal in CTX subjects, but the relative importance of the enzymatic defect in this alternative microsomal pathway (namely, the 24S hydroxylation of 5beta-cholestane-3alpha,7alpha, 12alpha,25-tetrol relative to the abnormality in mitochondrial 27-hydroxylase) has not been established in CTX. To delineate the sequence of side-chain hydroxylations and the enzymatic block in bile acid synthesis, we synthesized the (23R and 23S) 24-nor-5beta-cholestane-3alpha,7alpha, 12alpha,23,25-pentols utilizing a modified Sharpless asymmetric dihydroxylation reaction on 24-nor-5beta-cholest-23-ene-3alpha, 7alpha, 12alpha-triol, a C26 analog of the naturally occurring C27 bile alcohol, 5beta-cholest-24-ene-3alpha,7alpha,12alpha-triol . Stereospecific conversion of the unsaturated 24-nor triol to the corresponding chiral compounds (23R and 23S), 24-nor-5beta-cholestane-3alpha,7alpha,12alpha,23 ,25-pentols, was quantitative. However, conversion of the unsaturated 24-nor triol to the chiral nor-pentols had absolute stereochemistry opposite to the products predicted by the Sharpless steric model. The absolute configurations and enantiomeric excess of the C26 nor-pentols and the C27 pentols (synthesized from 5beta-cholest-24-ene-3alpha,7alpha,12alpha-triol for comparison) were confirmed by nuclear magnetic resonance and lanthanide-induced circular dichroism Cotton effect measurements. These results may contribute to a better understanding of the role of the 24S-hydroxylation vs. 27-hydroxylation step in cholic acid biosynthesis. PMID: 10443973 [PubMed - indexed for MEDLINE] 225. Brain. 1999 Aug;122 ( Pt 8):1589-95. Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis. Verrips A, Nijeholt GJ, Barkhof F, Van Engelen BG, Wesseling P, Luyten JA, Wevers RA, Stam J, Wokke JH, van den Heuvel LP, Keyser A, Gabreëls FJ. Departments of Neurology, Pathology and Laboratory of Pediatrics and Neurology, University Hospital Nijmegen, Utrecht, The Netherlands. A.Verrips@czzoneu.azn.nl We describe seven Dutch patients from six families with a slowly progressive, mainly spinal cord syndrome that remained for many years the sole expression of cerebrotendinous xanthomatosis (CTX). MRI demonstrated white matter abnormalities in the lateral and dorsal columns of the spinal cord. Post-mortem examination of one of the patients showed extensive myelin loss in these columns. An array of genotypes was found in these patients. We conclude that 'spinal xanthomatosis' is a clinical and radiological separate entity of CTX that should be included in the differential diagnosis of 'chronic myelopathy'. PMID: 10430841 [PubMed - indexed for MEDLINE] 226. J Neurol Neurosurg Psychiatry. 1999 Aug;67(2):195-8. Mutations producing premature termination of translation and an amino acid substitution in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis associated with parkinsonism. Wakamatsu N, Hayashi M, Kawai H, Kondo H, Gotoda Y, Nishida Y, Kondo R, Tsuji S, Matsumoto T. First Department of Internal Medicine, School of Medicine, The University of Tokushima, Tokushima, Japan. nwake@inst-hsc.pref.aichi.jp OBJECTIVES: Mutational analysis of the sterol 27-hydroxylase (CYP27) gene was performed on three patients from two Japanese families who had cerebrotendinous xanthomatosis (CTX) associated with parkinsonism. METHODS: Clinical evaluations, brain MRI studies, and laboratory analyses were completed on the three patients. The CYP27 gene was analysed for mutations by PCR amplification of gene segments followed by direct sequencing. RESULTS: Two different, homozygous mutations were identified in these families. One is a novel transition, substituting T for G at Glu162 (GAG) resulting in a stop codon (TAG). The other is also a transition, substituting T for C at Arg441 (CGG) resulting in Trp (TGG). The second is located in two amino acids ahead of the heme ligand binding site (Cys443) of the protein likely rendering it non-functional. It is the most common CTX mutation in Japanese patients. CONCLUSIONS: CTX with parkinsonism is caused by mutations with a severe impact on enzyme function. The two mutations described here are likely to cause loss of function because they are chain terminating or affect an essential site in the protein. PMCID: PMC1736478 PMID: 10406988 [PubMed - indexed for MEDLINE] 227. Biochem Biophys Res Commun. 1999 Mar 5;256(1):198-203. Cholestanol induces apoptosis of cerebellar neuronal cells. Inoue K, Kubota S, Seyama Y. Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. Cerebrotendinous xanthomatosis (CTX) is a hereditary lipid storage disease characterized by hyper-cholestanolemia, cerebellar ataxia, xanthoma, and cataract. We hypothesized that cholestanol in serum of CTX patients might induce neuronal cell death in the cerebellum and eventually lead to cerebellar ataxia. To gain support for this hypothesis we developed hyper-cholestanolemia rats by feeding cholestanol. Neuronal cells, especially Purkinje cells in the cerebellum were stained by Sudan black B only in the cholestanol-fed rats, indicating the deposit of cholestanol in cerebellum. To examine effects of cholestanol in vitro, cerebellar neuronal cells were cultured with cholestanol. The cholestanol concentration increased and the viability decreased in cells cultured with cholestanol. Apoptosis was evident in cells cultured with cholestanol more frequently than in control cells, determined using the terminal deoxynucleotidyl transferase (TdT) dUTP nick end-labeling (TUNEL) method. As activities of interleukin-1beta-converting enzyme (ICE) and CPP32 protease were increased in cells cultured with cholestanol, all these data taken together suggest that cholestanol induced apoptosis of cerebellar neuronal cells. Our observations may explain the mechanism of cerebellar ataxia of CTX patients. Copyright 1999 Academic Press. PMID: 10066446 [PubMed - indexed for MEDLINE] 228. Metabolism. 1999 Feb;48(2):233-8. Effect of simvastatin in addition to chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis. Verrips A, Wevers RA, Van Engelen BG, Keyser A, Wolthers BG, Barkhof F, Stalenhoef A, De Graaf R, Janssen-Zijlstra F, Van Spreeken A, Gabreëls FJ. Dutch Cerebrotendinous Xanthamatosis Research Group, University Hospital Nijmegen, The Netherlands. The effects of combination therapy with chenodeoxycholic acid (CDCA) and simvastatin on serum cholestanol, low-density lipoprotein (LDL) cholesterol, and lathosterol levels were investigated in seven adult patients with cerebrotendinous xanthomatosis (CTX) who were on long-term treatment with CDCA. The patients were treated with a combination of CDCA 750 mg daily and an increasing dose of simvastatin from 10 mg to 40 mg daily for a period of 6 months. We found a significant effect of this combination therapy compared with CDCA alone in terms of decreasing the serum cholestanol and LDL cholesterol levels, particularly with a daily dose of 40 mg simvastatin. The mean cholestanol level decreased from 9.27 micromol/L (baseline) to 6.69 micromol/L (40 mg simvastatin), while the mean LDL cholesterol level decreased from 5.08 mmol/L (baseline) to 3.04 mmol/L (40 mg simvastatin). No side effects were reported, and there were no effects on the clinical condition, cerebral magnetic resonance imaging (MRI), visual evoked potentials, and electroencephalographic features. We conclude that a combination of 750 mg CDCA and 40 mg simvastatin daily is effective to further reduce serum cholestanol, LDL cholesterol, and lathosterol in adult CTX patients treated with long-term CDCA. Whether this combination treatment will be effective for the long-term prevention of neurological deterioration and atherosclerosis remains to be established. PMID: 10024088 [PubMed - indexed for MEDLINE] 229. Intern Med. 1998 Nov;37(11):922-6. Pulmonary manifestations in cerebrotendinous xanthomatosis. Kawabata M, Kuriyama M, Mori S, Sakashita I, Osame M. Third Department of Internal Medicine, Kagoshima University School of Medicine. Comment in Intern Med. 1998 Nov;37(11):901-2. We investigated five cases with cerebrotendinous xanthomatosis (CTX) with particular reference to biochemical and pathological pulmonary disorders. To date, few reports discuss the pathophysiology of pulmonary disorders of CTX patients. This study is the first investigation of such pulmonary disorders. All 5 patients had no pulmonary symptoms and no disturbances on radiological studies and pulmonary function tests. However, in bronchoalveolar lavage (BAL) fluids, many cells with cruciform reflexes, which is characteristic of intracellular sterol accumulation, were found under phase contrast microscopy. Biochemically, cholestanol was found to be increased in the BAL fluid as well as in serum. Pathological findings of transbronchial lung biopsy (TBLB) samples disclosed foamy macrophages and small granulomas in alveolar septa. In conclusion, the lung was apparently involved in CTX, and the lesions were characterized with the accumulation of foamy and giant cells with a high concentration of cholestanol, which likely results in the formation of foreign body granulomas. PMID: 9868952 [PubMed - indexed for MEDLINE] 230. J Neurol. 1998 Nov;245(11):723-6. Cerebrotendinous xanthomatosis: evidence of lipomatous hypertrophy of the atrial septum. Dotti MT, Mondillo S, Plewnia K, Agricola E, Federico A. University of Siena, Institute of Neurological Sciences, Unit of Neurometabolic Diseases, Italy. dotti@unisi.it Premature atherosclerosis and cardiac complications have been reported among the systemic manifestations of cerebrotendinous xanthomatosis (CTX), a rare bile acid disorder with predominantly neurological features. In some cases, myocardial infarction has been the cause of sudden death. We examined nine CTX patients to determine whether they also had clinical or subclinical signs of cardiovascular disorders. In four of them, transthoracic echocardiography showed thickening of the interatrial septum compatible with lipomatous hypertrophy. The unexpected association of the two abnormalities is unlikely to be coincidental and suggests that careful cardiac examination should be considered, even in the absence of clinical manifestations. PMID: 9808240 [PubMed - indexed for MEDLINE] 231. Biochemistry. 1998 Oct 27;37(43):15050-6. A novel Arg362Ser mutation in the sterol 27-hydroxylase gene (CYP27): its effects on pre-mRNA splicing and enzyme activity. Chen W, Kubota S, Ujike H, Ishihara T, Seyama Y. Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Japan. A novel C to A mutation in the sterol 27-hydroxylase gene (CYP27) was identified by sequencing amplified CYP27 gene products from a patient with cerebrotendinous xanthomatosis (CTX). The mutation changed the adrenodoxin cofactor binding residue 362Arg to 362Ser (CGT 362Arg to AGT 362Ser), and was responsible for deficiency in the sterol 27-hydroxylase activity, as confirmed by expression of mutant cDNA into COS-1 cells. Quantitative analysis showed that the expression of CYP27 gene mRNA in the patient represented 52.5% of the normal level. As the mutation occurred at the penultimate nucleotide of exon 6 (-2 position of exon 6-intron 6 splice site) of the gene, we hypothesized that the mutation may partially affect the normal splicing efficiency in exon 6 and cause alternative splicing elsewhere, which resulted in decreased transcript in the patient. Transfection of constructed minigenes, with or without the mutation, into COS-1 cells confirmed that the mutant minigene was responsible for a mRNA species alternatively spliced at an activated cryptic 5' splice site 88 bp upstream from the 3' end of exon 6. Our data suggest that the C to A mutation at the penultimate nucleotide of exon 6 of the CYP27 gene not only causes the deficiency in the sterol 27-hydroxylase activity, but also partially leads to alternative pre-mRNA splicing of the gene. To our knowledge, this is the first report regarding effects on pre-mRNA splicing of a mutation at the -2 position of a 5' splice site. PMID: 9790667 [PubMed - indexed for MEDLINE] 232. Neurology. 1998 Sep;51(3):865-7. Genetic analysis enables definite and rapid diagnosis of cerebrotendinous xanthomatosis. Chen W, Kubota S, Teramoto T, Ishida S, Ohsawa N, Katayama T, Takeda T, Kuroda K, Yahara O, Kusuhara T, Neshige R, Seyama Y. Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Japan. Mutations in the sterol 27-hydroxylase gene (CYP27) cause cerebrotendinous xanthomatosis (CTX). Early diagnosis of CTX is crucial because treatment with chenodeoxycholic acid can prevent or reverse some of the neurologic disability associated with the disease. We report the identification of three types of mutations (Arg441Trp, Arg372Gln, and Arg441Gln) in the CYP27 gene in five patients with suspected CTX from four unrelated families by restriction endonuclease analysis. PMID: 9748042 [PubMed - indexed for MEDLINE] 233. Ryoikibetsu Shokogun Shirizu. 1998;(19 Pt 2):285-8. [27-Hydroxylase deficiency (cerebrotendinous xanthomatosis)]. [Article in Japanese] Miyamoto K, Setoguchi T. Department of Surgery 1, Miyazaki Medical College. PMID: 9645063 [PubMed - indexed for MEDLINE] 234. Ryoikibetsu Shokogun Shirizu. 1998;(19 Pt 2):111-4. [Cerebrotendinous xanthomatosis (CTX)]. [Article in Japanese] Kinoshita M, Teramoto T. Department of Internal Medicine, Teikyo University School of Medicine. PMID: 9645021 [PubMed - indexed for MEDLINE] 235. J Biol Chem. 1998 Jun 12;273(24):14805-12. Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted sterol 27-hydroxylase gene. Rosen H, Reshef A, Maeda N, Lippoldt A, Shpizen S, Triger L, Eggertsen G, Björkhem I, Leitersdorf E. Department of Molecular Virology, Faculty of Medicine, Hebrew University, 91120 Jerusalem, Israel. Sterol 27-hydroxylase is important for the degradation of the steroid side chain in conversion of cholesterol into bile acids and has been ascribed a regulatory role in cholesterol homeostasis. Its deficiency causes the autosomal recessive disease cerebrotendinous xanthomatosis (CTX), characterized by progressive dementia, xanthomatosis, and accelerated atherosclerosis. Mice with a disrupted cyp27 (cyp27(-/-)) had normal plasma levels of cholesterol, retinol, tocopherol, and 1,25-dihydroxyvitamin D. Excretion of fecal bile acids was decreased (<20% of normal), and formation of bile acids from tritium-labeled 7alpha-hydroxycholesterol was less than 15% of normal. Compensatory up-regulation of hepatic cholesterol 7alpha-hydroxylase and hydroxymethylglutaryl-CoA reductase (9- and 2-3-fold increases in mRNA levels, respectively) was found. No CTX-related pathological abnormalities were observed. In CTX, there is an increased formation of 25-hydroxylated bile alcohols and cholestanol. In bile and feces of the cyp27(-/-) mice only traces of bile alcohols were found, and there was no cholestanol accumulation. It is evident that sterol 27-hydroxylase is more important for bile acid synthesis in mice than in humans. The results do not support the contention that 27-hydroxylated steroids are critical for maintenance of cholesterol homeostasis or levels of vitamin D metabolites in the circulation. PMID: 9614081 [PubMed - indexed for MEDLINE] 236. Eur J Pediatr. 1998 Apr;157(4):313-6. Treatment and follow-up of children with cerebrotendinous xanthomatosis. van Heijst AF, Verrips A, Wevers RA, Cruysberg JR, Renier WO, Tolboom JJ. Department of Paediatrics, University Hospital Nijmegen, The Netherlands. A.vanHeijst@CKSKG@azn.nl The clinical spectrum and the effects of treatment over a period of 5 years in five children with cerebrotendinous xanthomatosis (CTX) are described. In all children biochemical, neuroradiological, and neurophysiological studies were done. CTX was diagnosed and effects of therapy were evaluated by determination of the serum cholestanol/cholesterol ratio (CCR) and the urinary excretion of bile alcohols. All children were treated with chenodeoxycholic acid (15 mg/kg/day) in three divided oral doses. Diarrhoea and juvenile cataract were the main clinical features. Psychomotor retardation, pyramidal and cerebellar signs were also found. After starting treatment, biochemical abnormalities normalized and diarrhoea disappeared. After 1 year of therapy there was no further delay in motor development, and in three children the intelligence quotient improved. EEG abnormalities disappeared. After 5 years of therapy the children are in a stable clinical condition.CONCLUSION: The clinical, biochemical and neurophysiological abnormalities in five children with CTX showed a remarkable improvement after starting treatment with chenodeoxycholic acid. The early diagnosis of CTX and the start of treatment with chenodeoxycholic acid has prevented neurological deterioration for a period of 5 years. PMID: 9578968 [PubMed - indexed for MEDLINE] 237. Biochemistry. 1998 Mar 31;37(13):4420-8. Silent nucleotide substitution in the sterol 27-hydroxylase gene (CYP 27) leads to alternative pre-mRNA splicing by activating a cryptic 5' splice site at the mutant codon in cerebrotendinous xanthomatosis patients. Chen W, Kubota S, Teramoto T, Nishimura Y, Yonemoto K, Seyama Y. Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 1130033, Japan. A functionally silent nucleotide substitution of the sterol 27-hydroxylase gene (CYP 27), identified in two families with cerebrotendinous xanthomatosis (CTX), was confirmed to cause alternative pre-mRNA splicing of the gene. Full-length RT-PCR analysis of the CYP 27 gene in a patient from one of the CTX families revealed one major and an additional faint band. Sequence analysis of the cloned RT-PCR product showed three species of cDNA: 3' terminal 13 bp of exon 2 deleted cDNA, exon 2 skipped cDNA, and full-length cDNA with a functionally silent G to T mutation at codon 112 (GGG 112Gly to GGT 112Gly). Only a single base change was identified by genomic DNA sequence analysis of the CYP 27 gene in the patient: T replaced G at the third position of codon 112, 13 bp upstream from the 3' terminus of exon 2. Transfection of constructed minigenes, with or without the mutation, confirmed that this silent mutation resulted in alternative pre-mRNA splicing by activating a cryptic 5' splice site around the mutant codon. The mutation was also identified in two patients from another CTX family, with a compound heterozygous pattern of A for G substitution at codon 372, a mutation reported previously by our group. The results elucidate a novel molecular basis for the CTX and suggest the significance of a silent nucleotide substitution with regard to pre-RNA splicing. PMID: 9521761 [PubMed - indexed for MEDLINE] 238. J Lipid Res. 1998 Mar;39(3):509-17. Alternative pre-mRNA splicing of the sterol 27-hydroxylase gene (CYP 27) caused by a G to A mutation at the last nucleotide of exon 6 in a patient with cerebrotendinous xanthomatosis (CTX). Chen W, Kubota S, Seyama Y. Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Japan. A recently identified G to A mutation at the last nucleotide of exon 6 of the sterol 27-hydroxylase gene (CYP 27) in a patient with cerebrotendinous xanthomatosis (CTX) was shown here to cause alternative pre-mRNA splicing of the gene. Northern blot analysis of the patient's RNA revealed a broadened band in the human CYP 27 mRNA region compared to that of the normal sample, indicating that there may exist differently spliced mRNA species in the patient. RT-PCR produced three fragments in the patient, one was full-length size and the other two were of smaller sizes. Sequence analysis confirmed that the nucleotide of the full-length size was identical to that of the normal full-length cDNA, except for the G to A mutation at codon 362, which corresponds to the last nucleotide of exon 6. One of the smaller size species lacked exon 6 and the other was absent from the 3' terminal 88 bp of exon 6 due to the use of an activated cryptic 5' splice site in exon 6. The correctly spliced mRNA harbouring the G to A mutation was responsible for the deficiency of the sterol 27-hydroxylase activity, as confirmed by transfection experiment. Transfection of constructed minigenes, with or without the mutation, showed that correctly spliced mRNA was observed in the normal minigene while the mutant minigene was differently spliced. This is the first report of a G to A substitution at the last nucleotide of an exon resulting in both normal and abnormal pre-mRNA splicings, including exon skipping and activating of a coding region cryptic 5' splice site. The results reveal a new molecular basis for the CTX and provide information on aberrant splicing of pre-mRNA in multi-exon genes. PMID: 9548584 [PubMed - indexed for MEDLINE] 239. J Lipid Res. 1997 Nov;38(11):2322-34. Four novel mutations of sterol 27-hydroxylase gene in Italian patients with cerebrotendinous xanthomatosis. Garuti R, Croce MA, Tiozzo R, Dotti MT, Federico A, Bertolini S, Calandra S. Dipartimento di Scienze Biomediche, Università di Modena, Italy. We report the characterization of eight mutations of sterol 27-hydroxylase gene (CYP27) in five Italian patients with cerebrotendinous xanthomatosis, who were found to be compound heterozygotes. Four mutations (C --> T at nt 45 of exon 4, G(+1) --> A in intron 6, G(+5) --> T in intron 7, and G(-1) --> A in intron 7) are novel. The C --> T at nt 45 of exon 4 converts the arginine codon into a stop codon thus generating a truncated protein of 198 amino acids. The three splice site mutations reduced the content of CYP27 mRNA in skin fibroblasts to very low or undetectable levels and generated minute amounts of abnormal mRNAs. The G(+1) --> A transition in intron 6 produced three abnormal mRNAs. In the first, the 5' half of exon 6 joins to exon 7, skipping 89 bp of exon 6, and in the second, exon 5 joins directly to exon 7. The predicted translation products of these mRNAs are truncated proteins. In the third abnormal mRNA, exon 5 joins to exon 8 with an in-frame deletion of 246 bp. The G(+5) --> T transversion in intron 7 generates a single abnormal mRNA in which exon 6 joins directly to exon 8, with a frameshift and a premature stop codon. In the G(-1) --> A transition in intron 7, two mRNAs are generated. In the first, the retention of the whole intron 7 causes a frameshift and a premature stop codon; in the second, the joining of exon 7 to exon 8 is associated with an in-frame deletion of the first 6 nucleotides. All these novel mutations are predicted to produce structurally abnormal enzymatic proteins with no measurable biological activity. PMID: 9392430 [PubMed - indexed for MEDLINE] 240. Hum Genet. 1997 Aug;100(2):284-6. Exon skipping in the sterol 27-hydroxylase gene leads to cerebrotendinous xanthomatosis. Verrips A, Steenbergen-Spanjers GC, Luyten JA, Wevers RA, Wokke JH, Gabreëls FJ, Wolthers BG, van den Heuvel LP. Department of Neurology, University Hospital Nijmegen, The Netherlands. A.Verrips@czzoneu.azn.nl We report a new mutation in the sterol 27-hydroxylase (CYP 27) gene in a Dutch family with cerebrotendinous xanthomatosis: a G-->A transition in the splice donor site in intron 4. This mutation leads to skipping of exon 4, resulting in a loss of 66 amino acids in the CYP 27 enzyme molecule. PMID: 9254865 [PubMed - indexed for MEDLINE] 241. Chest. 1997 Jul;112(1):273-4. Pulmonary lymphangioleiomyomatosis and cerebrotendinous xanthomatosis: is there a link? Dormans TP, Verrips A, Bulten J, Cox N. Department of Internal Medicine, University Hospital Nijmegen, The Netherlands. A 41-year-old woman had progressive shortness of breath. Cerebrotendinous xanthomatosis was diagnosed 4 years before. An open-lung biopsy showed the simultaneous presence of cerebrotendinous xanthomatosis and pulmonary lymphangioleiomyomatosis. This is perhaps the first time the coincidental occurrence of these two diseases is described. PMID: 9228390 [PubMed - indexed for MEDLINE] 242. J Lipid Res. 1997 May;38(5):870-9. Novel homozygous and compound heterozygous mutations of sterol 27-hydroxylase gene (CYP27) cause cerebrotendinous xanthomatosis in three Japanese patients from two unrelated families. Chen W, Kubota S, Kim KS, Cheng J, Kuriyama M, Eggertsen G, Björkhem I, Seyama Y. Department of Physiological Chemistry and Nutrition, Faculty of Medicine, Japan. The autosomal recessively inherited cholesterol metabolic disease, cerebrotendinous xanthomatosis (CTX), is caused by mutations in the sterol 27-hydroxylase gene. Three Japanese CTX patients from two unrelated families were studied genetically. By DNA sequence analysis a novel mutation of A for G substitution at amino acid position 372 (CGG 372Arg to CAG 372Gln) was identified in one of the CTX families. The mutation was also found in two patients from the other family, with a compound heterozygous pattern of A for G substitution at amino acid position 441 (CGG 441Arg to CAG 441Gln). The latter mutation was the same as previously reported by our group (J. Lipid Res. 1994. 35: 1031-1039). As the two mutations changed the restriction enzyme sites, rapid screening methods were developed for the detection of the carriers. Transfection of the two mutant cDNAs into COS cells resulted in markedly reduced sterol 27-hydroxylase activity. These results indicate that the two mutations are responsible for the deficiency of the sterol 27-hydroxylase activity in these patients. The features of mutations identified till now in Japanese CTX patients are also reviewed. PMID: 9186905 [PubMed - indexed for MEDLINE] 243. Steroids. 1997 May;62(5):451-4. Rapid hydrogenation of unsaturated sterols and bile alcohols using microwaves. Dayal B, Ertel NH, Rapole KR, Asgaonkar A, Salen G. Medical Service, Department of Veterans Affairs Medical Center, East Orange, New Jersey 07018, USA. This paper describes an operationally simple, rapid hydrogenation of unsaturated sterols and bile alcohols in a domestic microwave oven. This has been achieved by the addition of catalytic amounts of Pd/C in methylene chloride/propylene glycol solvents in the presence of ammonium formate followed by microwave irradiation. It is suggested that this methodology will be helpful in the identification of saturated and unsaturated sterols with different side-chain structures in rare diseases: sitosterolemia, cerebrotendinous xanthomatosis (CTX), as well as atherosclerosis and diabetes mellitus. Sterols, such as cholesterol, campesterol, sitosterol, and bile alcohols with unsaturated side chains, were converted to their reduced congeners with high yield and purity. PMID: 9178433 [PubMed - indexed for MEDLINE] 244. Steroids. 1997 May;62(5):409-14. 7 beta-hydroxy bile alcohols: facile synthesis and 2D 1H NMR studies of 5 beta-cholestane-3 alpha, 7 beta, 12 alpha, 25-tetrol. Dayal B, Ertel NH, Padia J, Rapole KR, Salen G. Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, USA. A rapid and easily performed procedure for the synthesis of 5 beta-cholestane-3 alpha, 7 beta, 12 alpha, 25-tetrol by means of an efficient homologation sequence of the intermediate, 3 alpha, 7 beta, 12 alpha-triformyloxy-24-oxo-25-diazo-25-homo-5 beta-cholane is described. The reaction sequence involved treating the intermediate, alpha-diazoketone in methanol with 3% AgNO3 or Ag2O, anhydrous Na2CO3, Na2S2O/H2O resulting in the formation of homoursocholic acid in high yield. Esterification of the homoursocholic acid in methanol containing a catalytic amount of methanesulfonic acid under microwave irradiation conditions gave methyl homourscholate. The subsequent treatment of methyl homoursocholate with methyl magnesium iodide provided 5 beta-cholestane-3 alpha, 7 beta, 12 alpha, 25-tetrol in 88% yield. The products and synthetic intermediates prepared in these studies were fully characterized by the results of 1D and 2D NMR, and high-resolution mass spectral studies. These studies will help in further investigation of the defect of cholic acid biosynthesis in patients with cerebrotendinous xanthomatosis (CTX) as well as other inborn errors of bile acid metabolism. PMID: 9178427 [PubMed - indexed for MEDLINE] 245. Phys Ther. 1997 May;77(5):534-52. Rehabilitation of balance in two patients with cerebellar dysfunction. Gill-Body KM, Popat RA, Parker SW, Krebs DE. Graduate Programs in Physical Therapy, MGH Institute of Health Professions, Boston, MA 02114, USA. The treatment of two patients with cerebellar dysfunction is described. One patient was a 36-year-old woman with a 7-month history of dizziness and unsteadiness following surgical resection of a recurrent pilocystic astrocytoma located in the cerebellar vermis. The other patient was a 48-year-old man with cerebrotendinous xanthomatosis (CTX) and diffuse cerebellar atrophy, and a 10-year history of progressive gait and balance difficulties. Each patient was treated with a 6-week course of physical therapy that emphasized the practice of activities that challenged stability. The patient with the cerebellar tumor resection also performed eye-head coordination exercises. Each patient had weekly therapy and performed selected balance retraining exercises on a daily basis at home. Measurements taken before and after treatment for each patient included self-perception of symptoms, clinical balance tests, and stability during selected standing and gait activities; for the patient with the cerebellar tumor resection, vestibular function tests and posturography were also performed. Both patients reported improvements in symptoms and demonstrated similar improvements on several kinematic indicators of stability during gait. The patient with the cerebellar tumor resection improved on posturography following treatment, whereas the patient with CTX improved on clinical balance tests. This case report describes two individualized treatment programs and documents functional improvements in two patients with different etiologies, durations, and clinical presentations of cerebellar dysfunction. The outcomes suggest that patients with cerebellar lesions, acute or chronic, may be able to learn to improve their postural stability. PMID: 9149763 [PubMed - indexed for MEDLINE] 246. J Formos Med Assoc. 1997 Mar;96(3):225-7. Failure in the treatment of long-standing osteoporosis in cerebrotendinous xanthomatosis. Chang WN, Lui CC. Department of Neurology, Chang Gung Memorial Hospital-Kaohsiung, Taiwan, ROC. We evaluated the therapeutic effect of combined therapy with chenodeoxycholic acid, calcium carbonate, and sodium bicarbonate on long-standing osteoporsis in three siblings (two women and one man, aged 30-38 yr) with cerebrotendinous xanthomatosis (CTX). The evaluation was based on the measurement of bone mineral density (BMD) before and after 3 years of combined therapy. Clinically, the therapeutic effect was quite limited (almost no change in BMD values), and did not parallel the marked decrease in serum cholestanol level (normalization of serum levels). While the reason for the therapeutic failure in our patients is not known, it is possible that delay in starting treatment may have been a factor. Measurement of BMD for evaluation of therapeutic effect in long-standing osteoporosis in CTX patients is of little practical value. PMID: 9080765 [PubMed - indexed for MEDLINE] 247. Neurology. 1997 Jan;48(1):258-60. A novel mutation in the sterol 27-hydroxylase gene of a Pakistani family with autosomal recessive cerebrotendinous xanthomatosis. Ahmed MS, Afsar S, Hentati A, Ahmad A, Pasha J, Juneja T, Hung WY, Ahmad A, Choudhri A, Saya S, Siddique T. Department of Neurology, Northwestern University Medical School, Chicago, IL 60611, USA. Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of lipid storage with prominent neurologic features. The disease is associated with mutations in CYP27, which encodes mitochondrial sterol 27-hydroxylase, an enzyme that catalyzes the oxidation of sterol intermediates during bile acid synthesis. The loss of this enzyme results in accumulation of cholestanol in the nervous system and other tissues. Six different mutations have been previously described in CTX. We analyzed a Pakistani family, which included four affected individuals with clinical characteristics of CTX, for mutations in CYP27. The exons of CYP27 in the family DNA were amplified by polymerase chain reaction (PCR) and analyzed for mutations by band shifts (single stranded conformational polymorphism [SSCP]) and DNA sequencing. The PCR product for exon 4 showed an SSCP change in this family. The DNA of affected individuals showed an abnormal mobility pattern interpreted as homozygous for the mutation. One non-affected sibling was homozygous for the normal migrating pattern, whereas the parents and another non-affected sibling were heterozygous. The sequence of exon 4 of affected individuals showed a substitution of C to T in codon 237, thus substituting arginine to a stop codon. This mutation would terminate the translation, which may result in a protein half the size of the wild type rendering it practically inactive. PMID: 9008528 [PubMed - indexed for MEDLINE] 248. Rev Neurol. 1996 Dec;24(136):1535-8. [Cerebrotendinous xanthomatosis: utility of nuclear magnetic resonance image in the follow-up and response to treatment]. [Article in Spanish] Cuende E, Gómez-Rz de Mendarozqueta M, Vesga JC, Saracíbar N, Ibáñez-Avilés A, Castellano-Hurtado C. INTRODUCTION: Cerebrotendinous xanthomatosis is an inherited autosomal recessive lipid storage disease. Clinical features include tendon xanthomas, premature cataracts and progressive neurologic dysfunctions. Substantial elevation of serum cholestanol and urinary bile alcohols and their precursors establishes the diagnosis. Magnetic resonance image (MRI) is useful for diagnosis of cerebral and tendinous lesions. Treatment with chanodeoxycholic acid (CDCA) has been reported to correct biochemical abnormalities and to arrest and possibility to reverse the progression of the neurologic symptoms in some patients. CLINICAL CASE: We present the case of a 34-year-old male suffering from ataxia and enlargement of both Achilles tendons suggestive of cerebrotendinous xanthomatosis. The findings of elevated serum cholestanol and urinary bile alcohols confirmed clinical suspicious. Cranial and tendinous MRI evidenced cerebral, cerebellar, medullar and tendinous lesions. The patient received treatment with CDCA for 42 months (750 mg/day), with improvement in neurologic symptoms, correction of analytical parameters and cerebellar and medullar lesions at MRI. CONCLUSION: In cerebrotendinous xanthomatosis, treatment with CDCA reduces serum cholestanol and arrest neurologic symptoms progression. In accordance with clinical evolution and analytical normalization, we point out he utility of MRI in the surveillance and response to treatment with CDCA. PMID: 9064170 [PubMed - indexed for MEDLINE] 249. Hum Genet. 1996 Dec;98(6):735-7. Two new mutations in the sterol 27-hydroxylase gene in two families lead to cerebrotendinous xanthomatosis. Verrips A, Steenbergen-Spanjers GC, Luyten JA, van den Heuvel LP, Keyser A, Gabreëls FJ, Wevers RA. Department of Neurology, University Hospital Nijmegen, The Netherlands. This report concerns two new mutations in the sterol 27-hydroxylase gene in two patients with cerebrotendinous xanthomatosis (CTX). In a Surinam-Creole patient (patient A), a G deletion on position cDNA 546/547 in exon 3 led to a frameshift and the introduction of a premature termination codon. In a Dutch patient (patient B), a C-->T transition at position 496 in exon 3 also led to a premature termination codon. Patient A was homozygous for the mutation, whereas patient B was compound heterozygous, a C-->T transition also being found in exon 6 at position 1204. The two new mutations were confirmed by restriction analysis with the restriction enzymes FokI and MaeI, respectively. PMID: 8931710 [PubMed - indexed for MEDLINE] 250. Biochim Biophys Acta. 1996 Nov 15;1317(2):119-26. Genetic analysis of a Japanese cerebrotendinous xanthomatosis family: identification of a novel mutation in the adrenodoxin binding region of the CYP 27 gene. Chen W, Kubota S, Nishimura Y, Nozaki S, Yamashita S, Nakagawa T, Kameda-Takemura K, Menju M, Matsuzawa Y, Björkhem I, Eggertsen G, Seyama Y. Department of Physiological Chemistry and Nutrition, Faculty of Medicine, University of Tokyo, Japan. Cerebrotendinous xanthomatosis (CTX), an autosomal recessive lipid-storage hereditary disorder, is caused by mutations in the sterol 27-hydroxylase gene (CYP 27). A 24-year-old female Japanese CTX patient and her parents were studied for a CYP 27 mutation. Multiple xanthomas were the main complaint of the patient and plasma cholestanol level was markedly elevated. Sterol analysis of a xanthoma biopsy confirmed cholesterol and cholestanol deposition, and the cholestanol accounted for 8.1% of the total sterols. Sterol 27-hydroxylase activity in fibroblasts derived from the patient was undetectable, while the activities in fibroblasts from her mother and father were 54% and 41% of the normal level, respectively. Direct sequence analysis showed a missense mutation of A for G substitution in the CYP 27 gene at codon 362 (CGT 362Arg to CAT 362His) with a homozygous pattern in the patient, and a heterozygous pattern in the parents. The mutation, which eliminates a normal HgaI endonuclease site at position 1195 of the cDNA and is located at the adrenodoxin binding region of the gene, is most probably responsible for the decreased sterol 27-hydroxylase activity in this Japanese CTX family. The combined data strongly support that the primary enzymatic defect in CTX is the disruption of sterol 27-hydroxylase and that the disease is inherited in an autosomal recessive trait. PMID: 8950197 [PubMed - indexed for MEDLINE] 251. Acta Paediatr. 1996 Aug;85(8):932-6. Chronic diarrhoea as a dominating symptom in two children with cerebrotendinous xanthomatosis. van Heijst AF, Wevers RA, Tangerman A, Cruysberg JR, Renier WO, Tolboom JJ. Department of Paediatrics, University Hospital Nijmegen St Radboud, The Netherlands. The objective of this study was to describe diarrhoea as a dominating symptom of cerebrotendinous xanthomatosis (CTX), a lipid storage disease, and investigate its cause. Two children with chronic diarrhoea as the dominating symptom of CTX are presented. Before and after therapy with orally administered chenodeoxycholic acid (15 mg kg-1 24 h, in three divided doses) bile alcohol excretion in urine, serum cholestanol level, serum bile acid patterns and faecal bile acids were measured. All routine gastro-intestinal investigations before therapy were normal. Diarrhoea ceased immediately after starting treatment with chenodeoxycholic acid. Abnormal bile alcohol excretion in urine decreased rapidly during the first days and elevated serum cholestanol level normalized in 2 years. We postulate the presence of bile alcohols in the lumen of the gut as most likely cause for diarrhoea in CTX, since the rapid decrease of bile alcohol excretion is associated with prompt cessation of diarrhoea after starting treatment with chenodeoxycholic acid. PMID: 8863874 [PubMed - indexed for MEDLINE] 252. J Lipid Res. 1996 Jul;37(7):1459-67. Cerebrotendinous xanthomatosis caused by two new mutations of the sterol-27-hydroxylase gene that disrupt mRNA splicing. Garuti R, Lelli N, Barozzini M, Tiozzo R, Dotti MT, Federico A, Ottomano AM, Croce A, Bertolini S, Calandra S. Dipartimento di Scienze Biomediche, Università di Modena, Italy. Cerebrotendinous xanthomatosis (CTX) is an inherited sterol storage disease associated with the accumulation of cholestanol and cholesterol in various tissues. CTX is caused by a deficiency of sterol-27-hydroxylase, a mitochondrial enzyme that oxidizes the side chain of cholesterol in the pathway leading to the formation of bile acids. In the present study we report two mutations of sterol-27-hydroxylase gene (CYP27 gene) found in Italian CTX patients. Proband T.C. is homozygous for a G-->A transition at the first nucleotide of intron 7. This mutation causes the formation of minute amounts of an abnormal mRNA, in which exon 6 joins directly to exon 8 with the skipping of exon 7. The exon 6-exon 8 junction results in a frame shift, downstream from the codon for Arg362, which generates a string of 28 novel amino acids preceding a premature termination codon. Proband C.U. is homozygous for a G-->C transversion at the last nucleotide of exon 3. This mutation, which changes the consensus sequence of the 5' donor splice site, is associated with barely detectable levels of sterol-27-hydroxylase mRNA, of normal size, in proband fibroblasts. As both mutations change the sites for two restriction enzymes, rapid methods were devised for the identification of the healthy carriers among the probands' family members and for the screening of these mutations in other CTX patients. PMID: 8827518 [PubMed - indexed for MEDLINE] 253. J Neurol Sci. 1996 Jun;138(1-2):145-9. PET analysis of a case of cerebrotendinous xanthomatosis presenting hemiparkinsonism. Kuwabara K, Hitoshi S, Nukina N, Ishii K, Momose T, Kubota S, Seyama Y, Kanazawa I. Department of Neurology, Faculty of Medicine, University of Tokyo, Japan. We describe a 34-year-old Japanese woman presenting gait difficulty and Achilles tendon swelling. The patient was diagnosed as having cerebrotendinous xanthomatosis (CTX) based on the high serum cholestanol level and diminished enzymatic activity of 27-hydroxylase of fibroblasts from her skin. Her clinical presentation was atypical regarding the presence of hemiparkinsonism and absence of apparent cataract, dementia, and cerebellar ataxia. Although MRI studies could not detect any abnormality in the basal ganglia or midbrain, PET analysis using [18F]-6-fluoro-L-dopa revealed reduced uptake of dopamine into the putamen, suggesting the impairment of presynaptic dopaminergic neurons. PMID: 8791252 [PubMed - indexed for MEDLINE] 254. J Neurol Neurosurg Psychiatry. 1996 May;60(5):582-5. Cerebrotendinous xanthomatosis without tendon xanthomas mimicking Marinesco-Sjoegren syndrome: a case report. Siebner HR, Berndt S, Conrad B. Department of Neurology, Technical University of Munich, Germany. A 39 year old patient with cerebellar signs, juvenile cataracts, and dull normal intelligence had cerebrotendinous xanthomatosis without tendon xanthomas, diagnosed previously as Marinesco-Sjoegren syndrome. Cerebrotendinous xanthomatosis was proved by a greatly increased excretion of bile alcohols in the patient's urine. Cerebrotendinous xanthomatosis is a sterol storage disorder due to an autosomal recessive inherited defect of sterol 27-hydroxylase characterised by high cholestanol concentration in multiple tissues. If tendon xanthomas are not present, a diagnosis of cerebrotendinous xanthomatosis will often not be made, unless biochemical tests are performed. The clinical features of cerebrotendinous xanthomas strongly resembles Marinesco-Sjoegren syndrome. Marinesco-Sjoegren syndrome is a autosomal recessive disorder characterised by the triad cerebellar ataxia, congenital cataract, and mental retardation. Although a late onset after the first decade of life favours cerebrotendinous xanthomatosis as the underlying disease, a definite distinction between cerebrotendinous xanthomatosis without tendon xanthomas and Marinesco-Sjoegren syndrome based on clinical presentation may be difficult. It is considered that some patients with Marinesco-Sjoegren syndrome reported in the medical literature had cerebrotendinous xanthomatosis without tendon xanthomas. This is of crucial clinical relevance, because, by contrast with Marinesco-Sjoegren syndrome, treatment for cerebrotendinous xanthomatosis is already available. PMCID: PMC486377 PMID: 8778269 [PubMed - indexed for MEDLINE] 255. J Lipid Res. 1996 Mar;37(3):662-72. Partial deletion of the gene encoding sterol 27-hydroxylase in a subject with cerebrotendinous xanthomatosis. Garuti R, Lelli N, Barozzini M, Dotti MT, Federico A, Bertolini S, Calandra S. Dipartimento di Scienze Biomediche, Universitá di Modena, Italy. An Italian subject with cerebrotendinous xanthomatosis (CTX) was found to have a partial deletion of the gene encoding the enzyme sterol 27-hydroxylase (CYP27 gene). Southern blot analysis revealed that this deletion (approximately 2 kb) spans from intron 6 to the 3' flanking (3'FLK) region, eliminating exons 7-9, the last three exons of CYP27 gene. No sterol 27-hydroxylase mRNA was detected in proband cells, either by Northern blot analysis or by reverse transcription polymerase chain reaction (PCR). This suggests that the mutant mRNA devoid of the exon encoding the whole untranslated sequence (exon 9) might be rapidly degraded in the cytoplasm. We used inverse PCR to obtain a partial sequence of the 3'FLK region of the normal CYP27 gene; this allowed us to define the mechanism underlying the deletion. The established sequence was used to design suitable primers to perform step-wise sequences of a 1.7 kb segment of the 3'FLK region of the normal gene and of the deletion joint in the CTX patient. The analysis of the sequence data indicate that the deletion might result from a complex mechanism involving two intragenic recombinations between a) two 14 nucleotide complementary sequences, one in intron 6 and the other in the 3'FLK region: and b) AT-rich complementary sequences of the 3'FLK region, and a slipped mispairing between two 6 nucleotide direct repeats, one in intron 6 and the other in the 3'FLK region. Such repeats are brought close to each other by the formation of the stem-loops induced by the two intragenic recombinations. This is the first example of CTX caused by a rearrangement of CYP27 gene. PMID: 8728327 [PubMed - indexed for MEDLINE] 256. J Lipid Res. 1996 Mar;37(3):631-9. A novel mutation in the cytochrome P450(27) (CYP27) gene caused cerebrotendinous xanthomatosis in a Japanese family. Okuyama E, Tomita S, Takeuchi H, Ichikawa Y. Department of Biochemistry, Kagawa Medical School, Japan. Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disease caused by mutations in the cytochrome P450(27) (CYP27) gene. This disease is characterized by the accumulation of a bile alcohol, cholestanol, in diverse tissues. Accumulation in the central nervous system leads to neurological dysfunction including dementia, spinal cord paresis, and cerebellar ataxia. Accumulation in other tissues causes tendon xanthomas, premature atherosclerosis, and cataracts. In a Japanese family with CTX, we identified two points mutations in the CYP27 gene at different sites. One is a novel transversion, which substitutes G for C at Pro 368 (CCC) to Arg (CGC). The other is a transition, which substitutes A for G at Arg441 (CGG) to Gln (CAG), this being the same mutation that Kim et al. reported (1994. J. Lipid Res. 35: 1031 - 1039). Allele-specific polymerase chain reaction analysis indicated that the father and mother of this family, who themselves had no clinical manifestations of CTX, had the former and latter mutations heterozygously, respectively. On the other hand, the patients each had both mutations heterozygously. These results are highly suggestive, but not conclusive, that the newly identified transversion in the CYP27 gene accounts for the sterol 27-hydroxylase (EC 1.14.13.15) deficiency in these patients. PMID: 8728324 [PubMed - indexed for MEDLINE] 257. Recenti Prog Med. 1996 Mar;87(3):110-3. [Cerebrotendinous xanthomatosis. A case report]. [Article in Italian] Sabadini L, Gonnelli L, Anichini C, Funtò I, Marcolongo R, Dotti MG, Federico A. Istituto di Reumatologia, Università, Siena. We describe a patient with cerebrotendinous xanthomatosis (CTX) who saw a Rheumatologist because of joint and muscle pain in the lower limbs. Clinical examination did not reveal any classic joint disease; however, tendon lesions and clumsy gait were noted. The patient presented with a swollen Achilles tendon bilaterally and a parapareto-spastic gait; Babinski sign was positive on the right side, and hyperreflexia of both lower limbs could be demonstrated. As bilateral cataracts were present, we have interpreted the aforementioned signs as CTX with spinal involvement; mean plasma cholesterol was increased, thus confirming the diagnosis. The primary biochemical abnormality of this disease is a defect in the synthesis of bile acids; therefore, chenodeoxycholic acid (CDCA) has been tried, and beneficial effects following CDCA treatment, especially in the early stages of CTX, have been reported in the literature. We report this case because of the severity and the rarity of this disease, and also because of its hereditary transmission. Our aim is to underline the need of a precocious diagnosis, in order to prevent a further progression of the disease; this therapeutic goal can now be achieved, thanks to the therapeutic regimens recently developed. PMID: 8650430 [PubMed - indexed for MEDLINE] 258. Neurology. 1996 Feb;46(2):571-4. Japanese triplets with cerebrotendinous xanthomatosis are homozygous for a mutant gene coding for the sterol 27-hydroxylase (Arg441Trp). Nagai Y, Hirano M, Mori T, Takakura Y, Tamai S, Ueno S. Department of Medical Genetics, Nara Medical University, Nara, Japan. We present the first case of triplets with cerebrotendinous xanthomatosis (CTX). A C-to-T base change identified in the genomic DNA and cDNA encoding the sterol 27-hydroxylase led to replacement of arginine by tryptophan at position 441 (Arg441Trp) in the triplets. The triplets were homozygous and their mother was heterozygous for this mutant gene. The triplets exhibited an identical phenotypic expression, which was different from that of a sporadic CTX case with the same mutation. PMID: 8614539 [PubMed - indexed for MEDLINE] 259. Neurol Neurochir Pol. 1996;30 Suppl 2:121-6. Aspects of cerebrotendinous xanthomatosis (CTX). Berginer VM. Department of Neurology, Soroka Medical Centre and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. PMID: 9100250 [PubMed - indexed for MEDLINE] 260. QJM. 1996 Jan;89(1):55-63. Cerebrotendinous xanthomatosis: a family study of sterol 27-hydroxylase mutations and pharmacotherapy. Watts GF, Mitchell WD, Bending JJ, Reshef A, Leitersdorf E. University Department of Medicine, University of Western Australia, Perth. We examined the phenotypic characteristics, molecular genetics and optimal pharmacological treatment of cerebrotendinous xanthomatosis (CTX) in an English family with combined hyperlipidaemia. The proband presented in adulthood with classical clinical characteristics of CTX, a greater than tenfold elevation in plasma cholestanol and combined hyperlipidaemia. His brother also had typical features of CTX without the presence of dyslipidaemia. Genotyping revealed that the two brothers were compound heterozygotes for a novel missense mutation in exon 2 (R94Q) and for a recently described nonsense mutation in exon 5, of the sterol 27-hydroxylase gene (CYP27). Analysis of all available family members revealed that hyperlipidaemia did not co-segregate with the presence of a CYP27 mutant allele. Trial of therapy showed that the lowest plasma sterol and triglyceride concentrations and cholestanol:cholesterol ratio were achieved with the combination of chenodeoxycholic acid (CDCA) 750 mg/day, a primary bile acid, and simvastatin 40 mg/day, an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase. CDCA alone and simvastatin alone significantly lowered plasma cholestanol concentration, but the decrease was greater with the former. After 1 year there was significant improvement in both cognitive and motor function with regression of tendon xanthomata on computerized tomography. We conclude that CTX in this English pedigree is probably due to compound mutant alleles in CYP27, that combined hyperlipidaemia in this family is unrelated to CTX, and that this complicated condition responds optimally to the combination of CDCA and simvastatin. PMID: 8730343 [PubMed - indexed for MEDLINE] 261. Surv Ophthalmol. 1996 Jan-Feb;40(4):320-37. Cholesterol and cataracts. Cenedella RJ. Department of Biochemistry, Kirksville College of Osteopathic Medicine, Missouri, USA. Inherited defects in enzymes of cholesterol metabolism and use of drugs which inhibit lens cholesterol biosynthesis can be associated with cataracts in animals and man. The basis of this relationship apparently lies in the need of the lens to satisfy its sustained requirement for cholesterol by on-site synthesis, and impairing this synthesis can lead to alteration of lens membrane structure. Lens membrane contains the highest cholesterol content of any known membrane. The Smith-Lemli-Opitz syndrome, mevalonic aciduria, and cerebrotendinous xanthomatosis all involve mutations in enzymes of cholesterol metabolism, and affected patients can develop cataracts. Two established models of rodent cataracts are based on treatment with inhibitors of cholesterol biosynthesis. The long-term ocular safety of the very widely used vastatin class of hypocholesterolemic drugs is controversial. Some vastatins are potent inhibitors of cholesterol biosynthesis by animal lenses, can block cholesterol accumulation by these lenses and can produce cataracts in dogs. Whether these drugs inhibit cholesterol biosynthesis in human lenses at therapeutic doses is unknown. Results of clinical trials of 1-5 years duration in older patient populations indicate high ocular safety. However, considering the slow life-long growth of the lens and its continuing need for cholesterol, longterm safety of the vastatins should perhaps be viewed in units of 10 or 20 years, particularly with younger patients. PMID: 8658343 [PubMed - indexed for MEDLINE] 262. Am J Ophthalmol. 1995 Nov;120(5):597-604. Ocular and systemic manifestations of cerebrotendinous xanthomatosis. Cruysberg JR, Wevers RA, van Engelen BG, Pinckers A, van Spreeken A, Tolboom JJ. Institute of Ophthalmology, University of Nijmegen, The Netherlands. PURPOSE: Cerebrotendinous xanthomatosis is a storage disease that usually leads to severe mental and neurologic deterioration before the diagnosis and start of treatment are established. We identified major ocular and systemic characteristics that may enable a diagnosis to be made earlier. METHODS: Ten patients (group 1) of the University Hospital Nijmegen, with a diagnosis of cerebrotendinous xanthomatosis, were re-examined for detailed ocular and major clinical manifestations. Meanwhile, we looked for similar but undiagnosed cases in patients (group 2) who visited the Institute of Ophthalmology during a 12-month period. RESULTS: A diagnosis of cerebrotendinous xanthomatosis had been made in the patients of group 1 at an average age of 40 years (range, 33 to 48 years). Subsequently, six new cases (group 2) were diagnosed in patients 7 to 37 years old (average age, 18 years). Bilateral cataract was the major ocular manifestation in all 16 patients. Small irregular corticonuclear opacities, anterior polar cataracts, and dense posterior subcapsular cataracts were diagnosed at various ages (mean, 18 years; range, 4 to 40 years). Four patients showed clinical signs of optic neuropathy, whereas retinal function was normal in all patients. Other major clinical signs included a history of chronic diarrhea (since childhood), mental deterioration (mean age, 23 years), neurologic deterioration (mean age, 31 years), and tendon xanthomas (mean age, 37 years). CONCLUSIONS: Appropriate biochemical investigations for cerebrotendinous xanthomatosis should be performed in patients with unexplained juvenile or early-onset adult cataracts, especially if these cataracts are associated with chronic diarrhea since infancy, mental retardation or deterioration, neurologic dysfunction, or xanthomas. PMID: 7485361 [PubMed - indexed for MEDLINE] 263. Steroids. 1995 Oct;60(10):709-12. Determination of the glucurono-conjugated position in bile alcohol glucuronides present in a patient with cerebrotendinous xanthomatosis. Kuramoto T, Suemura Y, Kihira K, Hiraoka T, Hoshita T. Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Japan. The determination of the glucurono-conjugated position in three bile alcohol glucuronides secreted in bile of a patient with cerebrotendinous xanthomatosis was carried out by a nuclear magnetic resonance study. The bile sample was extracted with ethanol and chromatographed on an ion-exchange column, a reverse-phase partition column and a silica gel column to isolate glucurono-conjugates of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol, 5 beta-cholestane-3 alpha, 7 alpha 12 alpha, 23-tetrol, and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23, 25-pentol. Proton and 13C nuclear magnetic resonance spectra of the two biliary bile alcohol glucuronides, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol glucuronide and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23, 25-pentol glucuronide were identical with those of the synthetic glucuronide 7 alpha, 12 alpha, 25-trihydroxy-5 beta-cholestane-3 alpha-O beta-D-glucopyranosyluronic acid and the isolated glucuronide 3 alpha, 7 alpha, 12 alpha, 25-tetrahydroxy-5 beta-cholestane-23-O-beta-D-glucopyranosyluronic acid from urine of a patient with cerebrotendinous xanthomatosis, respectively. Hence, the glucurono-conjugated positions of the biliary 25-tetrol glucuronide and the biliary 23,25-pentol glucuronide were C-3 and C-23, respectively. By comparison of the 13C chemical shift data with that of the unconjugated bile alcohol, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23-tetrol, the glucurono-conjugated position of the natural 23-tetrol glucuronide was determined to be C-23. Thus, the natural 23-tetrol glucuronide can be formulated as 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestane-23-O-beta-D-glucopyranosyluronic acid. PMID: 8539780 [PubMed - indexed for MEDLINE] 264. Eur J Nucl Med. 1995 Sep;22(9):1069-72. Gallium uptake in cerebrotendinous xanthomatosis. Okada J, Oonishi H, Tamada H, Kizaki T, Yasumi K, Matuo T. Department of Radiology, Narita Red Cross Hospital, Chiba-Ken, Japan. In a patient with cerebrotendinous xanthomatosis, a rare familial sterol storage disease, increased uptake of gallium-67 was observed in the tendon xanthomas. This is considered to have resulted from the tumour-like proliferation of histiocytic cells in the xanthomas. Abnormalities in the white matter of the cerebellum and the brain stem observed by X-ray computed tomography and magnetic resonance imaging were not detected by 67Ga scintigraphy, possibly due to the small size of the CNS lesions. PMID: 7588945 [PubMed - indexed for MEDLINE] 265. Rinsho Shinkeigaku. 1995 Jul;35(7):798-802. [A case of complicated form of hereditary spastic paraplegia associated with hypoplasia of the corpus callosum and cataracta]. [Article in Japanese] Tanaka M, Kobayashi Y, Sato M, Tsuji S. Department of Neurology, Brain Research Institute, Niigata University, Japan. Autosomal dominant, autosomal recessive and X-linked recessive varieties of spastic paraplegia have been recognized. Recently, Japanese patients with complicated form of autosomal recessive hereditary spastic paraplegia (HSP) associated with hypoplasia of the corpus callosum have been reported by Iwabuchi et al. We describe a patient with complicated HSP (Iwabuchi type) and cataracta. A 38-year-old man (his parents were a second cousin) was born uneventfully. His motor development was normal. Motor and mental dysfunctions were noticed during the lower classes of an elementary school. He could ride a bicycle at 18 years old but gradually developed galt disturbance and confined to wheelchair since 35 years. He was admitted to our hospital on February 25, 1994. A neurological examination showed mental retardation, dementia, cataracta, cerebellar ataxia, rigidity, spasticity, severe atrophy of the distal muscles of his extremities, paraparesis, hyperreflexia, positive Hoffmann reflexes and Babinski signs, pes cavus and hammer toes. Brain MRI showed thinning of corpus callosum. Clinical and laboratory findings did not support a diagnosis of metabolic disorders showing spastic paraparesis including adrenomyeloneuropathy, Globoid leukodystrophy, metachromatic leukodystrophy, cerebrotendinous xanthomatosis, Arginase deficiency. We considered that our patient was complicated form of HSP (Iwabuchi et al). However, cataract has not been found in Iwabuchi type of HSP. We discussed here other reports showing cataracta with spastic paraparesis. PMID: 8777806 [PubMed - indexed for MEDLINE] 266. J Hist Neurosci. 1995 Jun;4(2):127-31. Historical aspects of cerebrotendinous xanthomatosis (CTX). Berginer VM. Department of neurology, Ben Gurion University of the Negev, Beer-Sheva, Israel. PMID: 11619019 [PubMed - indexed for MEDLINE] 267. Rev Neurol. 1995 May-Jun;23(121):675-8. Cerebrotendinous xanthomatosis diagnosed after traumatic subdural haematoma. Arpa J, Sánchez C, Vega A, Cruz-Martínez A, Ferrer T, López-Pajares R, Muñoz J, Barreiro P. Servicio de Neurologia, Hospital La Paz, Madrid. We report the case of a 34-year old man, who, after presenting with subacute traumatic subdural haematoma, was diagnosed as CTX. He presented a ten year history of progressive deterioration of cognitive functions, unsteadiness of gait and surgery for bilateral cataracts at age 21. Cholestanol level in serum was 120.7 mmol/liter, and cholestanol/cholesterol ratio 2.52%. Bile alcohols in urine were 23, 25-pentol: 2.2665 mg/mmol creatinine, 24, 25-pentol: 1.3226 mg/mmol creatinine, and 27-nor-24, 25-pentol: 0.7363 mg/mmol creatinine. Electrophysiological study was consistent with a mixed demyelinating and axonal neuropathy. The assessment of autonomic nervous system (ANS) showed a postganglionic cholinergic failure accompanying somatic peripheral neuropathy. Brain-stem auditory evoked potentials (BAEPs) demonstrated markedly low amplitude and poorly defined waves, and almost symmetrical peak V and I to V interpeak latency (IPL) slight delays. Two nodular, bilateral, symmetrical lesions, strongly suggestive of calcifications, in the cerebellar white matter on CT and MRI were noted. On T2-weighted images diffuse high signal lesions were found in the cerebellar white matter, and multiple, hyperintense cerebral foci of demyelination or gliosis. MRI study of the Achilles tendon showed neither enlargement of the tendon, nor areas of lipid deposits. After ten months of treatment with chenodeoxycholic acid (CDCA) (750 mg/d) the clinical course was unaffected and the neurophysiological measures, CT and MRI remained unchanged. PMID: 8597991 [PubMed - indexed for MEDLINE] 268. J Neurol Sci. 1995 Apr;129(2):106-8. Mitochondrial enzyme deficiency in cerebrotendinous xanthomatosis. Dotti MT, Manneschi L, Federico A. Istituto di Scienze Neurologiche, Policlinico Le Scotte, U.O. Malattie Neurometaboliche, Università di Siena, Italy. We report reduced respiratory chain enzyme activity in isolated muscle mitochondria and high levels of serum and CSF pyruvate and lactate in a case of cerebrotendinous xanthomatosis. These findings raise the question of the pathogenetic role of mitochondrial dysfunction in this syndrome. PMID: 7608723 [PubMed - indexed for MEDLINE] 269. Clin Radiol. 1995 Feb;50(2):117-9. Cerebrotendinous xanthomatosis in two sisters: case reports and MR imaging. Chakraverty S, Griffiths PD, Walls TJ, McAllister VL. Department of Neuroradiology, Newcastle General Hospital, Newcastle upon Tyne. Cerebrotendinous xanthomatosis is a rare inherited disorder of bile acid metabolism producing xanthomata and severe, progressive neurological deficits. In spite of the rarity of the condition it is important because it is treatable: the neurological deterioration can be halted and in some cases reversed. PMID: 7867261 [PubMed - indexed for MEDLINE] 270. Hum Genet. 1995 Feb;95(2):238-40. Premature termination codon at the sterol 27-hydroxylase gene causes cerebrotendinous xanthomatosis in a French family. Segev H, Reshef A, Clavey V, Delbart C, Routier G, Leitersdorf E. Division of Medicine, Hadassah University Hospital, Jerusalem, Israel. Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid-storage disease caused by mutations in the sterol 27-hydroxylase gene (CYP27). So far several mutations causing CTX have been identified and characterized. A new mutation creating an insertion of cytosine at position 6 in the cDNA, which is expected to result in a frameshift and a premature termination codon at codon 179, has been identified in a French family. The mutation creates a new site for the restriction endonuclease HaeIII. PMID: 7860076 [PubMed - indexed for MEDLINE] 271. Australas Radiol. 1995 Feb;39(1):61-5. Magnetic resonance imaging of cerebrotendinous xanthomatosis. Tai KS, Brockwell J, Chan FL, Janus ED, Lam KS. Department of Diagnostic Radiology, Queen Mary Hospital, Hong Kong. Cerebrotendinous xanthomatosis is a rare familial sterol storage disease with accumulation of cholestanol and cholesterol particularly in xanthomas, bile and brain. Magnetic resonance imaging is a useful modality for imaging the affected tissues. It contributes to the evaluation and management of the disease. PMID: 7695531 [PubMed - indexed for MEDLINE] 272. Ryoikibetsu Shokogun Shirizu. 1995;(8):362-6. [Congenital disorders of the bile acid metabolism (3 beta-hydroxy-delta 5-steroid dehydrogenase/isomerase deficiency, delta 4-3-oxosteroid 5 beta-reductase deficiency, cerebrotendinous xanthomatosis, and peroxisomal disorders]. [Article in Japanese] Kondo KH, Maeda Y, Setoguchi T. First Department of Surgery, Miyazaki Medical College. PMID: 8581653 [PubMed - indexed for MEDLINE] 273. Eur Neurol. 1995;35(1):55-7. Nephrolithiasis and nephrocalcinosis in cerebrotendinous xanthomatosis: report of three siblings. Chang WN, Cheng YF. Department of Neurology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan. We report the existence of nephrocalcinosis (NC) and/or nephrolithiasis (NL) in three siblings with cerebrotendinous xanthomatosis (CTX). Incomplete renal tubular acidosis (RTA) type 1 is also found in these three siblings after the evaluation of renal acidification function. Although the association of RTA with NC and/or NL is well known, they are rarely reported in CTX patients. PMID: 7737249 [PubMed - indexed for MEDLINE] 274. Acta Neuropathol. 1995;90(2):213-20. The neuropathology of cerebrotendinous xanthomatosis revisited: a case report and review of the literature. Soffer D, Benharroch D, Berginer V. Department of Pathology (Neuropathology), Hadassah Medical Center, Jerusalem, Israel. Cerebrotendinous xanthomatosis (CTX), a rare autosomal-recessive lipid storage disease, has been well characterized clinically and biochemically, and recently also from the molecular biological aspect. However, only a very few publications deal with its neuropathology, and views on its pathogenesis vary. Based on a recently examined case, we propose that central-peripheral distal axonopathy is the major pathogenetic mechanism of nervous system injury in CTX. The latter is characterized by white matter pathology, typically in form of long tract involvement with the more distal parts of the tract more severely affected. Most severely affected are the cerebellar white matter, the optic pathways and the long tracts of the brain stem and spinal cord, particularly the pyramidal tracts, although there is hardly a CNS region which does not display some form of pathology. Lesions are characterized by loss of myelinated fibers and accumulation of lipid products in form of foamy macrophages, clear oil-red-O-positive spaces and crystalline clefts, accompanied by gliosis, occasional axonal spheroids, and in the cerebellum--the most severely affected structure--also by multi-nucleated foreign body giant cells. Demyelination is not seen, and ultrastructurally myelin sheaths are normally structured. Signs of axonal degeneration are also present in the spinal roots. We hypothesize that the basic enzymatic defect in CTX leads to accumulation of metabolites in the brain which may be neurotoxic and may impair the metabolic apparatus of neurons with resultant axonopathy and subsequent nonspecific lipid deposition in the injured tracts. PMID: 7484100 [PubMed - indexed for MEDLINE] 275. Am J Hum Genet. 1994 Nov;55(5):907-15. Cerebrotendinous xanthomatosis in the Israeli Druze: molecular genetics and phenotypic characteristics. Leitersdorf E, Safadi R, Meiner V, Reshef A, Björkhem I, Friedlander Y, Morkos S, Berginer VM. Division of Medicine, Hadassah University Hospital, Jerusalem, Israel. Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid-storage disease caused by mutations in the sterol 27 hydroxylase gene (CYP27). Clinically, a multitude of neurological, skeletal, and vascular manifestations are usually present. Premature atherosclerosis has been reported in CTX and may be related to the metabolic derangement caused by the deficiency of the enzyme. A CYP27 nonsense mutation created by the deletion of cytosine376 has been identified in four Israeli Druze CTX patients residing in the same village. Molecular screening for this mutation in families of two probands revealed a total of 10 homozygotes and 28 heterozygotes whose clinical and biochemical characteristics are described. Overall, except for tendon xanthomas, most of the clinical manifestations progress with age. The CYP27 mutation was associated with modest differences in the levels of plasma total cholesterol (TC) and LDL cholesterol (LDL-C). The distribution of plasma concentrations of TC and LDL-C in the CTX families was consistent with a polygenic model. A similar model that includes also the effects of the CYP27 genotypes was not better supported by the data. It may be concluded that, in CTX, the presence of a CYP27 mutation does not significantly affect the plasma concentrations of lipids and lipoproteins. Therefore, the reported increased prevalence of atherosclerosis in this disease must be related to other factors. PMCID: PMC1918342 PMID: 7977352 [PubMed - indexed for MEDLINE] 276. Neurology. 1994 Nov;44(11):2218. Treatment of cerebrotendinous xanthomatosis. Federico A, Dotti MT. Comment on Neurology. 1991 Mar;41(3):434-6. PMID: 7970001 [PubMed - indexed for MEDLINE] 277. J Lipid Res. 1994 Oct;35(10):1795-800. Bile acid synthesis in HepG2 cells: effect of cyclosporin. Levy J, Budai K, Javitt NB. Division of Hepatic Diseases, New York University Medical Center, NY 10016. The hypothesis that cyclosporin specifically affects the pathway of bile acid synthesis that begins with 27-hydroxylation of cholesterol was evaluated in HepG2 cells, which synthesize chenodeoxycholic acid and cholic acid from endogenous 7 alpha-hydroxycholesterol. At a concentration in the medium of 8.3 microM cyclosporin, the proportion of cholic acid increased from 29 +/- 7% to 44 +/- 6% (P < 0.001) with no major change in total bile acid production. Chenodeoxycholic acid synthesis was enhanced by the addition of either 7 alpha-hydroxycholesterol or 5 beta-cholestane-3 alpha,7 alpha-diol to the medium and cholic acid synthesis was enhanced by the addition of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol to the medium. Cyclosporin significantly inhibited only enhanced chenodeoxycholic acid synthesis, indicating a selective interference in mitochondrial side chain oxidation of less polar intermediates in bile acid synthesis derived from either initial 7 alpha- or initial 27-hydroxylation of cholesterol. The increase in the proportion of cholic acid that occurs in the presence of cyclosporin mimics that occurring in genetically determined sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis). Cyclosporin is useful for dissecting the subcellular pathways of bile acid synthesis. PMID: 7852856 [PubMed - indexed for MEDLINE] 278. AJNR Am J Neuroradiol. 1994 Oct;15(9):1721-6. Cerebrotendinous xanthomatosis (van Bogaert-Scherer-Epstein disease): CT and MR findings. Dotti MT, Federico A, Signorini E, Caputo N, Venturi C, Filosomi G, Guazzi GC. Istituto di Scienze Neurologiche, Università di Siena, Italy. PURPOSE: To describe the CT and MR findings in the brain and spinal cord of patients with cerebrotendinous xanthomatosis and to seek possible correlations between clinical, biochemical (cholestanol levels), and neuroimaging findings. METHODS: Ten patients with well-defined clinical and biochemical diagnoses of cerebrotendinous xanthomatosis were examined. Brain CT was performed in eight cases. In all patients MR was obtained using spin-echo and gradient-echo sequences. In eight patients spine MR was also performed. RESULTS: Neuroradiologic findings included diffuse cerebral and cerebellar atrophy. In half the cases, atrophy of the brain stem and corpus callosum was also found. In the majority of patients cerebellar bilateral focal lesions and mild white matter signal alterations were present. Spinal cord MR did not show signal abnormalities or atrophy. CONCLUSIONS: We found cranial alterations in patients with severe neurologic impairment, but there was no correlation with cholestanol plasma levels. No spinal cord abnormalities were present. PMID: 7847220 [PubMed - indexed for MEDLINE] 279. Tanpakushitsu Kakusan Koso. 1994 Sep;39(12):2102-12. [A paradigm to elucidate a congenital disease, cerebrotendinous xanthomatosis]. [Article in Japanese] Okuda K, Setoguchi T. Department of Surgery I, Miyazaki Medical College, Japan. PMID: 7938607 [PubMed - indexed for MEDLINE] 280. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8592-6. Atherosclerosis and sterol 27-hydroxylase: evidence for a role of this enzyme in elimination of cholesterol from human macrophages. Björkhem I, Andersson O, Diczfalusy U, Sevastik B, Xiu RJ, Duan C, Lund E. Department of Medical Nutrition, Karolinska Institute, Huddinge University Hospital, Sweden. 27-Hydroxycholesterol was found in surprisingly high amounts in atherosclerotic human femoral arteries. When human macrophages were cultured in a medium containing serum, there was a significant transfer of 27-hydroxy-cholesterol and 3 beta-hydroxy-5-cholestenoic acid from the cells into the medium. Sterol 27-hydroxylase (EC 1.14.13.15) is likely to be responsible for formation of the two products as shown by use of immunoblotting, a specific inhibitor, and the 18O-labeling technique. Sterol 27-hydroxylase has the unusual ability to hydroxylate the same methyl group three times to give a carboxylic acid; thus, 3 beta-hydroxy-5-cholestenoic acid is likely to be a direct product of the enzyme. The production of these steroids increased after addition of cholesterol to the culture medium. By using deuterium-labeled cholesterol, it was ascertained that most of the oxidized products were formed from exogenous cholesterol taken up by the cells. 27-Hydroxycholesterol and 3 beta-hydroxy-5-cholestenoic acid are present in the circulation and are efficiently converted into bile acids in human liver. It is suggested that conversion of cholesterol into 27-hydroxycholesterol and 3 beta-hydroxy-5-cholestenoic acid represents a general defence mechanism for macrophages and possibly also other peripheral cells exposed to cholesterol. Absence of this defence mechanism may contribute to the premature atherosclerosis known to occur in patients with sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis). PMCID: PMC44652 PMID: 8078928 [PubMed - indexed for MEDLINE] 281. Metabolism. 1994 Aug;43(8):1018-22. Comparative effects of lovastatin and chenodeoxycholic acid on plasma cholestanol levels and abnormal bile acid metabolism in cerebrotendinous xanthomatosis. Salen G, Batta AK, Tint GS, Shefer S. Veterans Administration Medical Center, East Orange, NJ. We investigated the effect of the hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin and the primary bile acid chenodeoxycholic acid (CDCA) on plasma sterol and bile alcohol concentrations and the excretion of bile alcohols in urine in a 38-year-old homozygote with cerebrotendinous xanthomatosis (CTX). Untreated, plasma cholesterol concentrations were less than normal (171 +/- 5 v 185 +/- 3 mg/dL, P < .05) while plasma cholestanol levels were more than 20 times higher than the control mean (2.26 +/- 0.17 v 0.1 +/- 0.1 mg/dL, P < .0001). Plasma and urinary bile alcohol concentrations were markedly increased (12.6 +/- 0.6 and 154 micrograms/mL, respectively, v trace amounts in controls), with the ratio of 5 beta-cholestane-3 alpha,7 alpha,12 alpha, 25-tetrol to 5 beta-cholestane, 3 alpha,7 alpha,12 alpha,23 (22 and 24),25-pentols being 1.6 in plasma and reversed to 0.15 in urine. Treatment with lovastatin (40 mg/d) reduced plasma cholesterol concentrations 13%, but failed to decrease plasma cholestanol or bile alcohol levels. Abundant amounts of bile alcohols continued to be excreted in urine. In contrast, CDCA (750 mg/d) inhibited abnormal bile acid synthesis, as evidence by a 17-fold decrease in total bile alcohol levels in plasma and a 29-fold decrease in urine and the virtual elimination of cholic acid and deoxycholic acid from the bile. Plasma cholestanol concentrations also decreased 85%, but cholesterol levels increased 14%. The combination of CDCA with lovastatin did not improve plasma cholestanol or bile alcohol concentrations compared with CDCA treatment alone.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 8052141 [PubMed - indexed for MEDLINE] 282. J Neurol Sci. 1994 Aug;125(1):22-8. Treatment of cerebrotendinous xanthomatosis: effects of chenodeoxycholic acid, pravastatin, and combined use. Kuriyama M, Tokimura Y, Fujiyama J, Utatsu Y, Osame M. Third Department of Internal Medicine, Kagoshima University School of Medicine, Japan. Treatments by oral administration of chenodeoxycholic acid (CDCA) alone, 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitor (pravastatin) alone, and combination of the two drugs were attempted for 7 patients with cerebrotendinous xanthomatosis (CTX). CDCA treatment at a dose of 300 mg/day reduced serum cholestanol (67.3% reduction), lathosterol (50.8%), campesterol (61.7%) and sitosterol (12.7%). However, the sera of the patients changed to be "atherogenic"; total cholesterol, triglyceride and low-density lipoprotein (LDL)-cholesterol were increased, while high-density lipoprotein (HDL)-cholesterol was decreased. Contrarily, pravastatin at a dose of 10 mg/day improved the sera of the patients to be markedly "anti-atherogenic", but the reductions of cholestanol (30.4%), lathosterol (44.0%), campesterol (22.9%) and sitosterol (9.6%) were inadequate. Combined treatment with CDCA and pravastatin showed good overlapping of the effects of each drug alone. The sera of the patients were apparently more "anti-atherogenic" than those after CDCA treatment. Serum cholestanol concentration was still 2.7 times higher than in controls, but the serum lathosterol level was within the normal range, indicating that the enhancement of overall cholesterol synthesis in the patients was sufficiently suppressed. Plant sterol levels were also within the normal range. The combination of CDCA and pravastatin was a good treatment for CTX, based on the improvement of serum lipoprotein metabolism, the suppression of cholesterol synthesis, and reductions of cholestanol and plant sterol levels. In all of 7 patients, the progression of disease was arrested, but dramatic effects on clinical manifestations, xanthoma, and electrophysiological findings could not be found after the treatment of these drugs. PMID: 7964884 [PubMed - indexed for MEDLINE] 283. J Lipid Res. 1994 Jun;35(6):1031-9. Identification of new mutations in sterol 27-hydroxylase gene in Japanese patients with cerebrotendinous xanthomatosis (CTX). Kim KS, Kubota S, Kuriyama M, Fujiyama J, Björkhem I, Eggertsen G, Seyama Y. Department of Physiological Chemistry and Nutrition, Faculty of Medicine, University of Tokyo, Japan. Cerebrotendinous xanthomatosis (CTX) is a hereditary sterol storage disease associated with accumulation of cholesterol and cholestanol in various tissues, especially tendons and neural tissues. The biochemical defect that causes CTX is a deficiency of the mitochondrial sterol 27-hydroxylase which oxidizes the side chain of cholesterol in connection with formation of bile acids. Japan has a relatively high prevalence of CTX and more cases of the disease are found here than in any other country. In the present study two new different point mutations are described in the heme-ligand binding domain of the sterol 27-hydroxylase gene in three Japanese CTX patients and one CTX heterozygote. Two of the homozygotes as well as the heterozygote subject have a single base substitution of A for G at codon 441 [CGG (Arg) to CAG (Gln)]. Another homozygote has a transition of C to T at codon 441 [CGG (Arg) to TGG (Trp)]. These two different mutations result in two restriction fragment length polymorphisms (RFLPs) for the enzymes StuI or HpaII. We also assayed sterol 27-hydroxylase activity using skin fibroblasts derived from three CTX patients, one CTX heterozygote, and normal subjects. While two of the homozygous subjects have undetectable levels of the enzyme activity, one homozygous subject and one heterozygous subject have decreased levels of the enzyme activity, about 1.4% and 10% of normal, respectively. The results suggest that the newly identified point mutations in the sterol 27-hydroxylase gene could account for the sterol 27-hydroxylase deficiency in the Japanese CTX patients. PMID: 7915755 [PubMed - indexed for MEDLINE] 284. J Assoc Physicians India. 1994 Jun;42(6):491-2. Cerebrotendinous xanthomatosis. Nair KR, Jose J, Kunju M, Iype M. Medical College, Thiruvanthapuram, Kerala. PMID: 7702660 [PubMed - indexed for MEDLINE] 285. Biol Pharm Bull. 1994 May;17(5):721-3. Biochemical studies of inherited diseases related to abnormal cholesterol metabolism. I. High-performance liquid chromatographic analysis of bile alcohol glucuronides in cerebrotendinous xanthomatosis. Ohshima A, Kuramoto T, Hoshita T. Department of Surgery 1, Kyushu University School of Medicine, Fukuoka, Japan. We developed a rapid and simple quantitative method for measuring bile alcohol glucuronides in serum involving high-performance liquid chromatography without group separation and hydrolysis. The assay of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol 3-glucuronide, the major bile alcohol component in serum from cerebrotendinous xanthomatosis patients, with the present method was useful for the diagnosis of cerebrotendinous xanthomatosis. PMID: 7920441 [PubMed - indexed for MEDLINE] 286. J Biochem. 1994 Apr;115(4):655-8. Determination of the glucurono-conjugated position in bile alcohol glucuronides excreted in urine of a patient with cerebrotendinous xanthomatosis by a nuclear magnetic resonance study. Kuramoto T, Fukuda K, Ohshima A, Kihira K, Hoshita T. Institute of Pharmaceutical Science, Hiroshima University School of Medicine. This paper describes the determination of the glucurono-conjugated position in two bile alcohol glucuronides excreted in urine of a patient with cerebrotendinous xanthomatosis by a nuclear magnetic resonance study. The urine sample was extracted with reversed-phase resin, and chromatographed on a reversed-phase partition column and a silica gel column to isolate glucurono-conjugates of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23,25- pentol. Proton and carbon-13 nuclear magnetic resonance spectra of the natural tetrol glucuronide were identical with those of the chemically synthesized tetrol glucuronide, 7 alpha, 12 alpha, 25-trihydroxy-5 beta-cholestane-3 alpha-O-beta-D- glucopyranosyluronic acid. Hence, the glucurono-conjugated position of the natural tetrol glucuronide was determined to be the C-3 position. By comparison of the 13C chemical shift data with that of the unconjugated pentol, 5 beta-cholestane-3 alpha, 7 alpha, 23,25-pentol, the glucurono-conjugated position of the natural pentol glucuronide was determined to be C-23. Thus the natural pentol glucuronide can be formulated as 3 alpha, 7 alpha, 12 alpha, 25- tetrahydroxy-5 beta-cholestane-23-O-beta-D-glucopyranosyluronic acid. The difference in the glucurono-conjugated position between the 25-tetrol glucuronide and the 23,25-pentol glucuronide indicates that the former is not the biosynthetic precursor of the latter. PMID: 8089079 [PubMed - indexed for MEDLINE] 287. Curr Opin Lipidol. 1994 Apr;5(2):138-42. Cerebrotendinous xanthomatosis. Leitersdorf E, Meiner V. Division of Medicine, Hadassah University Hospital, Jerusalem, Israel. Cerebrotendinous xanthomatosis is an autosomal recessive lipid-storage disease caused by mutations in the sterol 27-hydroxylase (CYP27) gene. Recent cloning and characterization of CYP27 enables further analysis and understanding of the pathophysiology of this multisystem disease. Molecular diagnosis provides means for the identification of heterozygotes and pre-symptomatic detection of affected individuals. PMID: 8044416 [PubMed - indexed for MEDLINE] 288. J Lipid Res. 1994 Apr;35(4):663-8. A point mutation in the bile acid biosynthetic enzyme sterol 27-hydroxylase in a family with cerebrotendinous xanthomatosis. Nakashima N, Sakai Y, Sakai H, Yanase T, Haji M, Umeda F, Koga S, Hoshita T, Nawata H. Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan. Cerebrotendinous xanthomatosis (CTX) is a rare familial disorder characterized by progressive neurological dysfunction, atherosclerosis, and xanthomas with sterol storage in the nervous system, vessels, and tendons. Increased serum cholestanol, derived from intermediates of cholesterol catabolism, may possibly be a major cause of the disease. An examination was made of the cDNA encoding cytochrome P450 sterol 27-hydroxylase (CYP27) in hepatic mitochondria, considered a defective enzyme inducing CTX, in a Japanese housewife afflicted with CTX and her family. The proposita and one of her brothers, who also had CTX symptoms and hypercholestanolemia, were found to be homozygotic, carrying a point mutation in the CYP27 gene at Arg104 (CGG) to Trp104 (TGG). The mutant position has a 100% conserved positive charge in all known vertebrate cytochrome P450s and even in bacterial cytochrome P450cam. The mother of the proposita and another brother were both free of CTX symptoms and were heterozygotic for the mutation, although their plasma cholesterol increased moderately. An increase in plasma cholestanol alone would, thus, not appear to be a direct cause of sterol storage in CTX, while CTX is strongly suggested to be caused by defects in both alleles of the CYP27 gene. PMID: 8006521 [PubMed - indexed for MEDLINE] 289. J Neurol Sci. 1994 Mar;122(1):102-8. Magnetic resonance imaging in cerebrotendinous xanthomatosis: a prospective clinical and neuroradiological study. Berginer VM, Berginer J, Korczyn AD, Tadmor R. Department of Neurology, Soroka Medical Center, Beer-Sheva, Israel. We describe MRI findings in 13 persons with typical clinical, EEG, CT and biochemical features of cerebrotendinous xanthomatosis (CTX). MRI showed brain (13/13) and cerebellar (12/13) atrophy and diffuse white matter hypodensity (4/13) presumably reflecting sterol infiltration with demyelination. Focal lesions were rare (2/13). Mass effect, edema or enhancement were not observed. Treatment with chenodeoxycholic acid (CDCA) 750 mg/day orally improved neurological and biochemical abnormalities. MRI appears to be of little value in following improvement after treatment has begun. Otherwise, the MRI studies are very sensitive and useful in diagnosing early incomplete forms of CTX. PMID: 8195796 [PubMed - indexed for MEDLINE] 290. J Lipid Res. 1994 Mar;35(3):478-83. Molecular genetics of cerebrotendinous xanthomatosis in Jews of north African origin. Reshef A, Meiner V, Berginer VM, Leitersdorf E. Division of Medicine, Hadassah University Hospital, Jerusalem, Israel. Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive sterol storage disease characterized by the accumulation of a bile alcohol, cholestanol, in diverse tissues. The disorder is manifested by extensive nervous system involvement, juvenile cataracts, tendon xanthomas, and premature atherosclerosis and is caused by sterol 27-hydroxylase (EC 1.14.13.15) mutations. Recently, two mutations were shown to cause CTX in four Jewish families of Moroccan origin. An additional mutant allele, found in a Jewish family of Algerian origin is characterized here. Sequence analysis revealed a C to T transition at cDNA position 1037 which predicted a threonine to methionine substitution at residue 306 (designated T306M). It is highly suggestive, but not definitive, that this transition is the mutation causing CTX in this family. A search for additional cases from Jewish families of North African extraction identified five new families including 10 cases. The three sterol 27-hydroxylase gene mutations account for all 10 CTX families and their presence may suggest the existence of positive selective forces that lead to an increased prevalence of this relatively rare disease in Jews from North Africa. PMID: 8014582 [PubMed - indexed for MEDLINE] 291. J Lipid Res. 1994 Mar;35(3):361-72. Liver mitochondrial P450 involved in cholesterol catabolism and vitamin D activation. Okuda KI. Department of Surgery I, Miyazaki Medical College, Japan. The isolation, purification, and cloning of the mitochondrial P450 enzyme catalyzing not only the 27-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha-diol and cholestane-3 alpha, 7 alpha, 12 alpha-triol, but also the 25-hydroxylation of vitamin D3 are reviewed. The sterol hydroxylase was shown to be present on the mitochondrial inner membrane-matrix, to be inactivated by carbon monoxide, and to be activated by 450 nm radiation, establishing its membership in the P450 class. Characterization of the reaction product indicated that hydroxylation occurred on the 27 methyl group; the enzyme also mediated 25-hydroxylation of vitamin D3. Cloning of the enzyme confirmed that it was of mitochondrial origin and that it catalyzed both sterol and vitamin D hydroxylation. Enzymatic activity was deficient in fibroblasts from patients with cerebrotendinous xanthomatosis. Genetic analysis of patients with cerebrotendinous xanthomatosis has shown several genetic defects: 1) two different point mutations in which arginine codons were replaced by cysteine codons; 2) deletion of thymidine in exon 4; and 3) a guanosine to adenosine substitution at the 3' splice acceptor site of intron 4 of the gene. The mitochondrial 27-hydroxylase is a key enzyme in bile acid biosynthesis and can be distinguished from microsomal hydroxylases that also catalyze hydroxylation of the side chain of cholesterol and intermediates in bile acid biosynthesis. In the rat, a microsomal enzyme catalyzes 26-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol, but the importance of this pathway in bile acid biosynthesis is unclear. PMID: 8014573 [PubMed - indexed for MEDLINE] 292. J Formos Med Assoc. 1994 Mar;93(3):256-9. Treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid in three siblings. Chang WN, Kuriyama M, Chee EC. Department of Neurology, Chang Gung Memorial Hospital, Kaohsiung, Hsien, Taiwan, R.O.C. We investigated the therapeutic effect of chenodeoxycholic acid (750 mg/day) in three siblings with cerebrotendinous xanthomatosis. All three siblings had characteristic clinical manifestations, abnormal findings of magnetic resonance imaging and electroencephalogram, and high serum levels of cholestanol, cholesterol precursor (lathosterol), and plant sterols (campesterol, sitosterol). After treatment for one year, the serum levels of these sterols were decreased and some neurologic improvements in the pyramidal tract signs and cerebellar signs were noted. The electroencephalographic findings were markedly changed and normalized. However, mental defects and sensorimotor polyneuropathy still remained. No changes of neuroradiologic features could be detected. A longer period of treatment is required to estimate the overall effects of chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis. PMID: 7920069 [PubMed - indexed for MEDLINE] 293. Neurology. 1994 Feb;44(2):288-90. Cerebrotendinous xanthomatosis: molecular diagnosis enables presymptomatic detection of a treatable disease. Meiner V, Meiner Z, Reshef A, Björkhem I, Leitersdorf E. Division of Medicine, Hadassah University Hospital, Jerusalem, Israel. We report an early molecular diagnosis of cerebrotendinous xanthomatosis (CTX) in a Jewish Moroccan family with two affected siblings. The proband displayed characteristic manifestations of the disease, whereas a younger brother, homozygous for the mutant allele, was asymptomatic. Clinical studies in the younger patient disclosed mild cognitive impairment, peripheral neuropathy, and abnormal EEG. Elevated plasma cholestanol levels were evident in both affected patients, with documented normal levels in the molecularly diagnosed heterozygous family members. Molecular characterization of affected CTX families provides early diagnosis and treatment of homozygotes in the presymptomatic state as well as identification of heterozygotes, which is crucial for genetic counseling and for prenatal diagnosis. PMID: 8309576 [PubMed - indexed for MEDLINE] 294. J Neurol Sci. 1994 Feb;121(2):229-32. LDL-apheresis cannot be recommended for treatment of cerebrotendinous xanthomatosis. Berginer VM, Salen G. Comment on J Neurol Sci. 1993 Feb;114(2):227-30. PMID: 8158220 [PubMed - indexed for MEDLINE] 295. Am J Med Sci. 1994 Jan;307(1):54-63. Chenodeoxycholate: the bile acid. The drug. a review. Broughton G 2nd. Department of Surgery, William Beaumont Army Medical Center, El Paso, Texas. Chenodeoxycholate (3 alpha, 7 alpha-dihydroxy-5 beta-cholanic acid) is a primary bile acid directly synthesized from cholesterol. It is an amphipathic molecule, possessing both a hydrophobic side and a polar hydrophilic side, giving it the ability to solubilize lipids in a water environment. Bile acids are necessary for the absorption of fats and fat soluble vitamins. Chenodeoxycholate inhibits the rate-limiting step of cholesterol synthesis, the formation of hydroxymethyl-glutaryl-coenzyme A. It was first reported to be useful in the dissolution of cholesterol gallstones in 1972. Today, chenodeoxycholate has other medicinal uses and is used for the management of cerebrotendinous xanthomatosis, hypertriglyceremia, congenital liver diseases, rheumatoid arthritis, and constipation. This article details some finer points of chenodeoxycholate biochemistry and physiology and discusses in some detail the current and past clinical uses of chenodeoxycholate. This is not an exhaustive discussion on gallstone dissolution therapies, but an overview of some of the lesser-known uses for this drug. PMID: 8291509 [PubMed - indexed for MEDLINE] 296. Hum Mol Genet. 1994 Jan;3(1):193-4. Premature termination codon at the sterol 27-hydroxylase gene causes cerebrotendinous xanthomatosis in an Afrikaner family. Meiner V, Marais DA, Reshef A, Björkhem I, Leitersdorf E. Division of Medicine, Hadassah University Hospital, Jerusalem, Israel. PMID: 8162025 [PubMed - indexed for MEDLINE] 297. Scand J Gastroenterol Suppl. 1994;204:68-72. Inborn errors of metabolism with consequences for bile acid biosynthesis. A minireview. Björkhem I. Unit for Clinical Chemistry, Karolinska Institute, Huddinge Hospital, Sweden. Five inborn errors with consequences for bile acid biosynthesis have been described: 7-dehydrocholesterol 7-reductase deficiency, 3 beta-hydroxysteroid delta 5-oxidoreductase/isomerase deficiency, 3-oxo-delta 4-steroid 5 beta-reductase deficiency, sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis), and peroxisomal disease(s) with absence of peroxisomes. Diagnosis and treatment of these very rare disorders are discussed. Bile acid therapy is important in most of these disorders and in the case of 3 beta-hydroxysteroid delta 5-oxidoreductase/isomerase deficiency and 3-oxo-delta 4-steroid 5 beta-reductase deficiency such therapy may save the life of the affected cholestatic infant. In the case of sterol 27-hydroxylase deficiency, early treatment with chenodeoxycholic acid may prevent the development of progressive neurological dysfunction, dementia, and ataxia. In the latter three cases early diagnosis and treatment is of utmost importance. PMID: 7824882 [PubMed - indexed for MEDLINE] 298. Metabolism. 1993 Nov;42(11):1497-8. Osteoporosis and increased bone fractures in cerebrotendinous xanthomatosis. Kuriyama M, Fujiyama J, Kubota R, Nakagawa M, Osame M. Comment on Metabolism. 1993 Jan;42(1):69-74. PMID: 8231848 [PubMed - indexed for MEDLINE] 299. Presse Med. 1993 Oct 16;22(31):1460. [Early coronary atheroma. A little known complication of cerebrotendinous xanthomatosis]. [Article in French] Kerleau JM, Lefebvre H, Houdent C, Wolf LM. PMID: 8265531 [PubMed - indexed for MEDLINE] 300. Neurologia. 1993 Oct;8(8):268-70. [Magnetic resonance of the brain and Achilles tendon in cerebrotendinous xanthomatosis]. [Article in Spanish] Pardo J, Prieto JM, Rodríguez JR, Vadillo J, Dapena MD, Noya M. Servicio de Neurología, Hospital General de Galicia Clínico-Universitario, Santiago de Compostela. We report a 31 year old patient with cerebrotendinous xanthomatosis who presented with dementia, tendinous xanthomas, cataracts, pyramidal involvement, cerebellar ataxia and peripheral neuropathy. Cerebral CT scan demonstrated diffuse hypodensity in the white matter in both cerebellar hemispheres while MR detected additional focal alterations in both frontal lobes. MR study of the Achilles tendon showed a diffuse enlargement of the tendon with multiple areas of hypersignals in T1 and T2 demonstrative of the lipid deposits, interpossed between the isosignal zones that may correspond to the inflammatory reaction secondary to the accumulation of cholesterol and cholestanol. PMID: 8240840 [PubMed - indexed for MEDLINE] 301. Tijdschr Kindergeneeskd. 1993 Aug;61(4):125-34. [Inborn errors of bile acid metabolism]. [Article in Dutch] Stellaard F, Wolthers BG. Researchlaboratorium, afd. Kindergeneeskunde, Academisch Ziekenhuis Groningen. A review on inherited diseases caused by defects in the synthesis of bile acids is presented. In the first part the biochemical synthesis of bile acids from cholesterol, taking place in the liver, is described. Three consecutive events can be discerned: 1. modifications in the skeleton of cholesterol, 2. oxidation of the last carbon atom of the cholesterol side chain, 3. further oxidation of the side chain leading to shortening with three carbon atoms; this last step takes place in liver peroxisomes. In the second part a description of inborn errors (enzyme deficiencies) is given, which can occur in each of the above mentioned three steps, leading to serious aberrations. As a result abnormal metabolites, i.e. bile acids or sterols, are present in serum or urine, which can be detected using advanced analytical techniques like gas chromatography or mass spectrometry, leading to diagnosis. In contrast to defects in the first or third step in bile acid synthesis, giving rise to disorders already shortly after birth, symptoms of the disease cerebrotendinous xanthomatosis, caused by a defect in the second step, are only noticeable several years after birth. A number of these diseases can be treated successfully, but for peroxisomal defects no useful therapy exists. PMID: 8122223 [PubMed - indexed for MEDLINE] 302. J Clin Invest. 1993 Jun;91(6):2488-96. Frameshift and splice-junction mutations in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis in Jews or Moroccan origin. Leitersdorf E, Reshef A, Meiner V, Levitzki R, Schwartz SP, Dann EJ, Berkman N, Cali JJ, Klapholz L, Berginer VM. Department of Medicine, Hadassah University Hospital, Jerusalem, Israel. The sterol 27-hydroxylase (EC 1.14.13.15) catalyzes steps in the oxidation of sterol intermediates that form bile acids. Mutations in this gene give rise to the autosomal recessive disease cerebrotendinous xanthomatosis (CTX). CTX is characterized by tendon xanthomas, cataracts, a multitude of neurological manifestations, and premature atherosclerosis. A relatively high prevalence of the disease has been noted in Jews originating from Morocco. The major objectives of the present investigation were to determine the gene structure and characterize the common mutant alleles that cause CTX in Moroccan Jews. The gene contains nine exons and eight introns and encompasses at least 18.6 kb of DNA. The putative promoter region is rich in guanidine and cytosine residues and contains potential binding sites for the transcription factor Sp1 and the liver transcription factor, LF-B1. Blotting analysis revealed that the mutant alleles do not produce any detectable sterol 27-hydroxylase mRNA. No major gene rearrangements were found and single-strand conformational polymorphism followed by sequence analysis identified two underlying mutations: deletion of thymidine in exon 4 and a guanosine to adenosine substitution at the 3' splice acceptor site of intron 4 of the gene. The molecular characterization of CTX in Jews of Moroccan origin provides a definitive diagnosis of this treatable disease. PMCID: PMC443309 PMID: 8514861 [PubMed - indexed for MEDLINE] 303. Rev Med Brux. 1993 Apr;14(4):110-5. [Congenital deficiencies in bile acid synthesis: from diagnosis to treatment]. [Article in French] Vanderpas J. Service de Biologie Clinique, Hôpital Ambroise Paré, Mons. Bile acids represent the principal excretion pathway of cholesterol. Their synthesis involves hydroxylations of the sterol nucleus and shortening of the lateral chain transforming an highly insoluble and immiscible molecule in an hydrophilic and detergent one. Congenital defect of one of the enzymes of bile acid synthesis (26-alpha-hydroxylase) constitutes the etiology of cerebrotendinous xanthomatosis, associating degenerative disease of the central nervous system, cutaneous xanthomas and cataract; the degenerative process may be stopped by a substitutive therapy with chenodeoxycholic acid. In another syndrome characterised by a lack of peroxisomes (Zellweger disease and associated syndromes), some bile acid metabolites accumulate due to the enzymatic block. Some cases of malabsorption due to a congenital defect of bile sterol synthesis are reported; such a case was jointly investigated in Brussels and Groningen. PMID: 8502858 [PubMed - indexed for MEDLINE] 304. J Neurol Sci. 1993 Mar;115(1):67-70. Cerebrotendinous xanthomatosis: pathophysiological study on bone metabolism. Federico A, Dotti MT, Loré F, Nuti R. Istituto di Scienze Neurologiche, Università di Siena, Italy. A condition of osteopenia in some cerebrotendinous xanthomatosis (CTX) patients led us to investigate bone metabolism in 8 patients belonging to 5 families. Serum calcium, phosphate and vitamin D metabolites were in the normal range; a reduction in total body density and impairment of intestinal radiocalcium absorption were found in the majority of our patients. PMID: 8468594 [PubMed - indexed for MEDLINE] 305. Carbohydr Res. 1993 Feb 24;240:133-42. Bile alcohol glucuronides: regioselective O-glucuronidation of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol and 24-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol. Dayal B, Salen G, Padia J, Shefer S, Tint GS, Sasso G, Williams TH. Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark 07103. A facile and regiocontrolled procedure for the preparation of 5-beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol-3-O-beta-D-glucuronide and its corresponding C-26 analogue is described. The method involves direct coupling of bile alcohols, namely, 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol and 24-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol to methyl (tetra-O-acetyl-beta-D-glucopyranuronate) in the presence of a Lewis acid, tin(IV) chloride, in dichloromethane. The resulting anomeric pairs of 1,2-trans- and 1,2-cis-glucuronides of tetrols were resolved by analytical and preparative thin-layer chromatography, and their identities were established by high-resolution 1H NMR spectroscopy and by chemical-ionization and fast-atom-bombardment mass spectrometry. The method described has a practical advantage over the traditional two-step synthesis involving bromides as it is more efficient and uses inexpensive and less toxic materials. It is suggested that these compounds will be useful for studying permeability of the blood-brain barrier in cerebrotendinous xanthomatosis (CTX). PMID: 8458007 [PubMed - indexed for MEDLINE] 306. Klin Monbl Augenheilkd. 1993 Feb;202(2):89-93. [Treatable diseases of the nervous system with cataract formation]. [Article in German] Baumgartner RW, Waespe W. Neurologische Klinik, Universitätsspital, Zürich, Schweiz. The detection of a cataract in combination with a neurological deficit may provide the physician with important diagnostic help. But a minority of underlying diseases (angiokeratoma corporis diffusum, cerebrotendinous xanthomatosis, diabetes mellitus, galactosemia, hypocalcemia, Refsum's disease, Wilson's disease; Charles Bonnet syndrome; relapsing Perichondritis; adverse effects of medication and intoxications) can be treated causally. Therefore they are summed up and discussed in this paper. PMID: 8487473 [PubMed - indexed for MEDLINE] 307. J Neurol Sci. 1993 Feb;114(2):227-30. Treatment of cerebrotendinous xanthomatosis with low-density lipoprotein (LDL)-apheresis. Mimura Y, Kuriyama M, Tokimura Y, Fujiyama J, Osame M, Takesako K, Tanaka N. Third Department of Internal Medicine Kagoshima University School of Medicine, Japan. Comment in J Neurol Sci. 1994 Feb;121(2):229-32. We studied the effects of LDL-apheresis on the biochemical and clinical abnormalities of 5 patients with cerebrotendinous xanthomatosis (CTX). Levels of both cholestanol and cholesterol decreased to approximately 60% of those of pretreatment after one perfusion and gradually returned to their initial levels within 2 weeks. Improvement of clinical manifestations and regression of Achilles tendon xanthomas were detected after several perfusions, though dramatic changes could not be recognized. EEG abnormalities were improved immediately after LDL-apheresis in one patient. We conclude that LDL-apheresis may affect the serum cholestanol level and clinical manifestations in patients with CTX. PMID: 8445406 [PubMed - indexed for MEDLINE] 308. Metabolism. 1993 Jan;42(1):69-74. Osteoporosis and increased bone fractures in cerebrotendinous xanthomatosis. Berginer VM, Shany S, Alkalay D, Berginer J, Dekel S, Salen G, Tint GS, Gazit D. Soroka Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Comment in Metabolism. 1993 Nov;42(11):1497-8. Significant osteoporosis determined by skeleton radiography and bone densitometry was found in 15 patients with cerebrotendinous xanthomatosis (CTX) whose mean age was 31 +/- 11 years. In three CTX patients, bone biopsies confirmed osteoporosis. Nine patients also sustained bone fractures following minimal trauma. Serum 25-hydroxyvitamin D ([25-OHD] 14.6 +/- 6.6 ng/mL v [normal] 30.4 +/- 8.0 ng/mL; P < .001) and 24,25-dihydroxyvitamin D ([24,25(OH)2D] 1.2 +/- 0.4 ng/mL v [normal] 2.7 +/- 0.8 ng/mL; P < .001) levels were low. Serum concentrations of 1,25(OH)2D, calcium, inorganic phosphorus, alkaline phosphatase, parathyroid hormone, and calcitonin were normal. Patients showed classic manifestations of CTX, including dementia, pyramidal and cerebellar insufficiency, peripheral neuropathy, cataracts, and tendon xanthomas associated with elevated serum cholestanol concentrations. These results demonstrate that extensive osteoporosis and increased risk of bone fractures are components of this inherited disease. PMID: 8446051 [PubMed - indexed for MEDLINE] 309. J Formos Med Assoc. 1992 Dec;91(12):1190-4. Cerebrotendinous xanthomatosis in three siblings from a Taiwanese family. Chang WN, Kuriyama M, Lui CC, Jeng SF, Chen WJ, Chee EC. Department of Neurology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan, R.O.C. We present and discuss the clinical and biochemical findings of three siblings with cerebrotendinous xanthomatosis, which has not been previously reported in Taiwan. Clinical features consisted of tendinous xanthomas, cataracts, mental defects, pyramidal signs, cerebellar ataxia, peripheral neuropathy and renal stones. Biochemical findings included normal serum cholesterol levels, high serum cholestanol levels and elevated serum cholestanol to cholesterol ratios. The serum levels of cholesterol precursor (lathosterol) and plant sterols (campesterol, sitosterol) were also elevated. PMID: 1363642 [PubMed - indexed for MEDLINE] 310. J Neurol Sci. 1992 Oct;112(1-2):139-46. Somatosensory and motor evoked potentials in the assessment of cerebrotendinous xanthomatosis before and after treatment with chenodeoxycholic acid: a preliminary study. Restuccia D, Di Lazzaro V, Servidei S, Colosimo C, Tonali P. Department of Neurology, Catholic University, Rome, Italy. We studied two unrelated patients with cerebrotendinous xanthomatosis, in whom clinical examination revealed central nervous system long tract involvement. Brain and spinal cord magnetic resonance imaging showed no signs supporting the involvement of the long pathways. Somatosensory and motor evoked potentials demonstrated central sensory and motor conduction abnormalities, which suggested distal degeneration of longer fibers, rather than scattered focal lesions in the CNS. In one of the patients the neurophysiological study was repeated 6 and 12 months after the beginning of treatment with chenodeoxycholic acid, showing a progressive improvement. Therefore, our data suggest that central motor and sensory conduction studies may be useful in the assessment of the disease and in monitoring treatment. PMID: 1469424 [PubMed - indexed for MEDLINE] 311. Ital J Neurol Sci. 1992 Sep;13(6):511-5. Cerebrotendinous xanthomatosis. Case report. Bacchi O, Stefanucci S, Brustenghi PL, Pagliacci A, Bellanti GM. Unità Organica di Neurologia-Foligno. PMID: 1330974 [PubMed - indexed for MEDLINE] 312. Rinsho Shinkeigaku. 1992 May;32(5):488-93. [Cerebrotendinous xanthomatosis--a case of brain MRI abnormality and osteoporosis]. [Article in Japanese] Kubota R, Nakagawa M, Nakamura A, Kuriyama M, Osame M. Department of Neurology, National Okinawa Hospital. A 37-year-old male with cerebrotendinous xanthomatosis showed brain abnormal MRI findings and osteoporosis. His parents had no similar symptoms. He had mental retardation since childhood. Swelling of Achilles tendons was noticed at age 28, and gait disturbance appeared at age 34. Physical examination revealed bilateral cataracts and swelling of Achilles tendons. Neurologically, he showed mental retardation, cerebellar ataxia and spastic tetraparesis. Cerebrotendinous xanthomatosis was diagnosed by marked elevations of serum cholestanol level (24.3 micrograms/ml) and cholestanol/cholesterol ratio (1.81%) as well as characteristic clinical manifestations. On brain MRI study, T2-weighted sequence showed bilateral focal lesions with high intensity signal in the globus pallidus and cerebellar white matter adjacent to the dentate nucleus, and T1-weighted sequence showed low to iso-intensity signal in the same regions. These findings suggested demyelination rather than xanthoma or lipid infiltration. Radiological examination showed mild osteoporosis of lumbar bone. However, serum levels of vitamin D3 and calcitonin were within normal range, and renal function was normal. Osteoporosis in this patient possibly resulted from disuse bone atrophy for several years. The combination therapy of oral administration of chenodeoxycholic acid and HMG-CoA reductase inhibitor (pravastatin), and LDL apheresis slightly improved EEG abnormality and gait disturbance, but not brain MRI abnormality. PMID: 1333927 [PubMed - indexed for MEDLINE] 313. Arch Neurol. 1992 May;49(5):469-75. Evoked potentials in cerebrotendinous xanthomatosis and effect induced by chenodeoxycholic acid. Mondelli M, Rossi A, Scarpini C, Dotti MT, Federico A. Institute of Neurological Sciences, Medical School, University of Siena, Italy. Evoked potentials are reported in 10 patients with cerebrotendinous xanthomatosis, eight of whom had peripheral neuropathy. Four subjects showed delayed N13 to N20 interpeak latencies for arm somatosensory evoked potentials, and five showed moderately prolonged I to III and I to V interpeak latencies of brain-stem auditory evoked potentials. Six of seven patients showed marked delay and desynchronization of visual evoked potentials. All five patients undergoing transcutaneous magnetic stimulation of the motor cortex presented greatly delayed central motor conduction time, especially of the lower limbs. After treatment with chenodiol (750 mg/d for at least 2 years), there was a significant improvement in nerve conduction velocities, N13 to N20 interpeak latencies, and visual evoked potential latencies. Brain-stem auditory evoked potentials remained unchanged. PMID: 1316120 [PubMed - indexed for MEDLINE] 314. Steroids. 1992 Jan;57(1):32-6. Radioimmunoassay of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol 3-glucuronide in serum of patients with cerebrotendinous xanthomatosis. Une M, Kataoka J, Nakata Y, Hoshita T. Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Japan. A rapid, convenient, and specific radioimmunoassay for 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol has been developed. Specific antiserum was obtained from rabbits immunized by the bile alcohol-bovine serum albumin conjugate, which was coupled by an (O-carboxymethyl)oxime bridge at the C-3 position. The assay produces values for serum concentrations of bile alcohol glucuronides in patients with cerebrotendinous xanthomatosis. PMID: 1585391 [PubMed - indexed for MEDLINE] 315. Neuroradiology. 1992;34(4):308-12. Cerebrotendinous xanthomatosis: cranial CT and MRI studies in eight patients. Hokezu Y, Kuriyama M, Kubota R, Nakagawa M, Fujiyama J, Osame M. Third Department of Internal Medicine, Kagoshima University School of Medicine, Japan. We report the findings on cranial computed tomography (CT) and magnetic resonance imaging (MRI) and their correlation with the clinical manifestations, disease severity and biochemical abnormalities in eight patients with cerebrotendinous xanthomatosis. CT revealed cerebral atrophy in seven cases, cerebellar atrophy in four and focal low density lesions in the cerebral white matter in two. T2-weighted MRI showed high signal lesions in the cerebral white matter, focal in four cases and diffuse in one, and in the globus pallidus in three patients, two of whom also had lesions in the cerebellar white matter. While severely affected patients showed variable CT and MRI abnormalities, our cases did not show the dramatic findings expected from the neurological manifestations. Diffuse lesions in the cerebral and cerebellar white matter have been emphasized in previous reports, but in our study the focal lesions in the cerebral white matter were also present; the globus pallidus was frequently involved. PMID: 1528440 [PubMed - indexed for MEDLINE] 316. Rev Neurol (Paris). 1992;148(8-9):541-5. [Cerebrotendinous xanthomatosis. 2 cases with magnetic resonance imaging]. [Article in French] Rogelet P, Gérard JM, Michotte A, Masingue M, Destée A. Service de Clinique Neurologique A, CHU Lille. A 40-year-old woman presented with bilateral juvenile cataract, tendinous xanthomas, intellectual deterioration, spastic tetraparesis, proprioceptive deficit and parkinsonian syndrome. A younger sister's clinical picture differed by the absence of xanthomas and the presence of a cerebellar syndrome. The diagnosis of cerebrotendinous xanthomatosis was confirmed by a high concentration of plasma cholestanol and by urinary chromatography. Magnetic resonance imaging displayed some abnormalities in the hemispheric and cerebellar white matter. Under chenodesoxycholic therapy the biological abnormalities decreased while the clinical disturbances were unchanged. PMID: 1494725 [PubMed - indexed for MEDLINE] 317. J Inherit Metab Dis. 1992;15(3):374-6. Paediatric cerebrotendinous xanthomatosis. Wevers RA, Cruysberg JR, Van Heijst AF, Janssen-Zijlstra FS, Renier WO, Van Engelen BG, Tolboom JJ. Institute of Neurology, University Hospital Nijmegen, The Netherlands. PMID: 1405473 [PubMed - indexed for MEDLINE] 318. Zh Nevropatol Psikhiatr Im S S Korsakova. 1992;92(4):13-22. [Cerebrotendinous xanthomatosis]. [Article in Russian] Berginer VM. Cerebrotendinous xanthomatosis (CTX) is a rare familial lipid storage disease caused by defective bile acid synthesis. As a result, cholestanol, a derivative of cholesterol, is accumulated by virtually every tissue, predominantly by the nervous system, xanthomas and bile. Clinically, progressive neurologic dysfunction, tendon xanthomas, cataracts, osteoporosis and atherosclerosis are commonly found. Replacement therapy with chenodeoxycholic acid (750 mg/day), a primary bile acid, which is almost absent from the bile in CTX, reduces elevated cholestanol synthesis and concentrations and improves neurologic function in this disease. PMID: 1333699 [PubMed - indexed for MEDLINE] 319. Clin Neurol Neurosurg. 1992;94 Suppl:S165-7. Cerebrotendinous xanthomatosis. van Hellenberg Hubar JL, Joosten EM, Wevers RA. Department of Neurology and Clinical Neurophysiology, University Hospital, Leiden, The Netherlands. Cerebrotendinous xanthomatosis (CTX) is a familial sterol storage disease based on an inborn error of metabolism involving bile acid synthesis. Predominant clinical features are a chronic progressive neurological syndrome, mental deterioration, bilateral cataract and xanthomas. The presence of xanthomas usually leads to the diagnosis, and the reverse is probably also true: without xanthomas the diagnosis will often not be made. CTX may therefore be less rare than commonly thought, and the incidence of xanthomas in CTX may be overestimated. Four cases without xanthomas among the presenting symptoms are described, and the relevance of xanthomas in CTX is discussed. PMID: 1320501 [PubMed - indexed for MEDLINE] 320. J Neurol Neurosurg Psychiatry. 1992 Jan;55(1):52-5. Electrophysiological studies in cerebrotendinous xanthomatosis. Tokimura Y, Kuriyama M, Arimura K, Fujiyama J, Osame M. Third Department of Internal Medicine, Kagoshima University School of Medicine, Japan. Seven patients with cerebrotendinous xanthomatosis (CTX) were studied by electrophysiological techniques. The percentages of abnormalities detected in nerve conduction studies and electroencephalograms were 28.6% (two patients) and 100%, respectively. All patients showed prolonged central conduction times in short latency somatosensory evoked potentials (SSEPs) by tibial nerve stimulation but normal SSEPs by median nerve stimulation. Brain stem auditory evoked potentials and visual evoked potentials were abnormal in three (42.9%) and four patients (57.1%), respectively. These electrophysiological parameters were correlated with the ratio of serum cholestanol to cholesterol concentration. The results of SSEPs suggest that the polyneuropathy in CTX is caused by distal axonopathy affecting longer axons before shorter axons (central-peripheral distal axonopathy). PMCID: PMC488934 PMID: 1312580 [PubMed - indexed for MEDLINE] 321. Am J Ophthalmol. 1991 Nov 15;112(5):606-7. Juvenile cataract associated with chronic diarrhea in pediatric cerebrotendinous xanthomatosis. Cruysberg JR, Wevers RA, Tolboom JJ. PMID: 1951610 [PubMed - indexed for MEDLINE] 322. Ann Neurol. 1991 Nov;30(5):734-5. Muscle mitochondrial changes in cerebrotendinous xanthomatosis. Federico A, Dotti MT, Volpi N. PMID: 1763899 [PubMed - indexed for MEDLINE] 323. Epilepsia. 1991 Sep-Oct;32(5):657-61. Epileptic seizure as a presenting symptom of cerebrotendinous xanthomatosis. Arlazoroff A, Roitberg B, Werber E, Shidlo R, Berginer VM. Department of Neurology, Assaf Harofeh Medical Center, Zerifin, Israel. Cerebrotendinous xanthomatosis (CTX) is a rare hereditary disease characterized by xanthomata of tendons, osteoporosis, cataracts, cerebellar ataxia, spastic paresis, and dementia. Though electroencephalographic (EEG) abnormalities are frequent in CTX, epileptic seizures have not been recognized as a major feature. A CTX patient is reported who presented with a generalized epileptic seizure and was evaluated with EEG and neuropsychological testing. Epilepsy should be considered a feature of CTX, and CTX considered as a possible, though rare, cause of symptomatic seizures. PMID: 1915172 [PubMed - indexed for MEDLINE] 324. Steroids. 1991 Sep;56(9):464-8. Identification of (23S)-5 alpha-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol in urine of patients with cerebrotendinous xanthomatosis. Kihira K, Fukuda K, Kuramoto T, Kuriyama M, Fujiyama J, Osame M, Hoshita T. Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Japan. This paper describes the identification of a new bile alcohol possessing the 5 alpha-cholestane structure that was found in the urine of patients with cerebrotendinous xanthomatosis. The urine samples were extracted with reversed-phase resin, treated with beta-glucuronidase, and separated on silica gel and reversed-phase column chromatography. The new bile alcohol isolated was the second component of the urinary bile alcohols and was identified as (23S)-5 alpha-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol by means of gas-liquid chromatography/mass spectrometry and nuclear magnetic resonance spectroscopic studies. PMID: 1805458 [PubMed - indexed for MEDLINE] 325. Clin Chim Acta. 1991 Aug 15;200(1):1-11. Atherogenic risk factors in cerebrotendinous xanthomatosis. Fujiyama J, Kuriyama M, Arima S, Shibata Y, Nagata K, Takenaga S, Tanaka H, Osame M. Third Department of Internal Medicine, Kagoshima University School of Medicine, Japan. In a study of coronary artery disease in patients with cerebrotendinous xanthomatosis (CTX), we documented the presence or absence of atherogenic risk factors and performed detailed analyses of serum lipid and lipoprotein profiles. Four of the seven patients examined had coronary arterial narrowing and/or obstruction, but multiple atherogenic risk factors were not found in any of these patients. Total cholesterol (T.ch) levels and low density lipoprotein-cholesterol (LDL-ch) levels were lower, and high density lipoprotein2-cholesterol (HDL2-ch) levels were higher in CTX patients than in controls. Triglyceride and very low density lipoprotein (VLDL) levels were significantly lower in the former. Indices correlating with the risk of atherosclerosis, such as the atherogenic index, and the ratios of apolipoprotein B/apolipoprotein AI, HDL2-ch/LDL-ch, HDL2-ch/HDL3-ch, indicated that CTX serum was, in fact, 'anti-atherogenic'. However, coronary artery disease is frequently seen in patients with CTX. This discrepancy suggests the existence of a unique mechanism by which atherosclerosis is induced in patients with CTX. We discuss a mechanism of disturbed lipoprotein metabolism which might be responsible for the deposition of sterols in the tissues of patients with CTX. PMID: 1934506 [PubMed - indexed for MEDLINE] 326. Metabolism. 1991 Jul;40(7):741-6. Combined treatment with chenodeoxycholic acid and pravastatin improves plasma cholestanol levels associated with marked regression of tendon xanthomas in cerebrotendinous xanthomatosis. Nakamura T, Matsuzawa Y, Takemura K, Kubo M, Miki H, Tarui S. Second Department of Internal Medicine, Osaka University Medical School, Japan. We studied the effect of chenodeoxycholic acid (CDCA) and a competitive HMG-CoA reductase inhibitor, pravastatin, on clinical symptoms and sterol metabolism in a 36-year-old Japanese man with cerebrotendinous xanthomatosis (CTX). He had marked tendon xanthomas and mild dementia, with obvious electroencephalographic (EEG) abnormalities. He was treated for 2 years with CDCA alone (0.6 g/d) and then for a further year with the combination of pravastatin (10 mg/d) and CDCA (0.6 g/d). For the following year, he was given pravastatin alone, and then was returned to combined treatment again. The plasma cholestanol level before treatment was 3.12 mg/dL, which was 20 times above the control level. After CDCA alone, the plasma cholestanol was reduced to 1.96 mg/dL, and this was further reduced to 0.92 mg/dL by combination therapy with CDCA and pravastatin. However, after the discontinuation of CDCA, his cholestanol levels returned to the pretreatment levels despite the continuing of pravastatin treatment. When the combination therapy was restarted, his cholestanol level was once again markedly reduced. His clinical symptoms showed a close association with the plasma cholestanol level; the xanthomas regressed remarkably and the mental retardation improved in association with normalization of EEG findings during treatment with CDCA alone or in combination with pravastatin. However, during treatment with pravastatin alone, his tendon xanthomas enlarged again and slow waves reappeared on the EEG. Because inhibition of cholesterol synthesis by treatment with the HMG-CoA reductase inhibitor alone was not effective in causing a reduction of cholestanol, the increase in plasma cholestanol levels in CTX may not have been solely due to increased cholesterol synthesis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 1908036 [PubMed - indexed for MEDLINE] 327. Schweiz Med Wochenschr. 1991 Jun 8;121(23):858-64. [Cerebrotendinous xanthomatosis]. [Article in German] Baumgartner RW, Hauser V, Grob P, Waespe W. Neurologische Klinik und Medizinische Poliklinik, Universitätsspital Zürich. Cerebrotendinous xanthomatosis (CTX) is a rare lipid storage disorder due to an autosomal-recessive inherited defect of the hepatic mitochondrial steroid 26-hydroxylase. The resultant reduced biosynthesis of cholic and especially chenodeoxycholic acid and the increased production and accumulation of cholestanol and cholesterol in most tissues is described and pathogenetic aspects as well as typical pathological findings are discussed. In the light of three personal observations the clinical symptoms and the results of auxiliary investigations are discussed and compared with the literature. The suspected diagnosis of CTX may be confirmed by demonstration of a pathologically elevated concentration of cholestanol or biliary alcohols in serum and urine respectively. The chronically progressive neurologic deficit can be halted or is in some cases partially reversible by treatment with chenodeoxycholic acid. Therefore, early diagnosis is mandatory and CTX should be considered in every patient presenting with intellectual impairment, spastic-ataxic signs, juvenile cataracts and tendon xanthomas. PMID: 1857943 [PubMed - indexed for MEDLINE] 328. Rinsho Shinkeigaku. 1991 Jun;31(6):677-9. [A case of cerebrotendinous xanthomatosis with spastic paraparesis, epilepsy, and bradykinesia]. [Article in Japanese] Kondo R, Wakamatsu N, Ishikawa A, Yuasa T, Miyatake T. Department of Neurology, Niigata University. A 26-year-old female developed mental deterioration, general convulsion, cataract and spastic gait in order since her entrance into elementary school. A diagnosis of cerebrotendinous xanthomatosis (CTX) was made because of hypercholestanolemia. At the time of admission, cataract, a mild thickening of Achilles tendons, mental deterioration, spastic paraparesis, truncal ataxia, and bradykinesia were noted. Bilateral slowing of 2 to 7 Hz was recorded in EEG, and brain CT and MRI revealed mild cerebellar atrophy. HVA and 5-HIAA levels in CSF were low. Oral administration of chenodeoxycholic acid, 300 mg per day, resulted in improvement of bradykinesia and EEG abnormality, increase of HVA and 5-HIAA levels in CSF, and decrease of serum cholesterol level in two weeks. Bradykinesia observed in the present case is a rare clinical finding of CTX, and the improvement of bradykinesia soon after the treatment with chenodeoxycholic acid has not been reported yet. This case is important for elucidating the mechanism of neurological disorders in CTX. PMID: 1934787 [PubMed - indexed for MEDLINE] 329. Clin Chim Acta. 1991 May 31;199(1):83-9. Stable isotope dilution assay for 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol in human serum using [26,27-D6] labeled internal standards; a highly accurate approach to the serological diagnosis of cerebrotendinous xanthomatosis. Kosaka D, Hiraoka T, Kohoda T, Kajiyama G, Yamauchi T, Kihira K, Kuramoto T, Hoshita T. First Department of Internal Medicine, Hiroshima University School of Medicine, Japan. PMID: 1934504 [PubMed - indexed for MEDLINE] 330. J Biol Chem. 1991 Apr 25;266(12):7779-83. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. Cali JJ, Hsieh CL, Francke U, Russell DW. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235. The sterol storage disorder cerebrotendinous xanthomatosis (CTX) is characterized by abnormal deposition of cholesterol and cholestanol in multiple tissues. Deposition in the central nervous system leads to neurological dysfunction marked by dementia, spinal cord paresis, and cerebellar ataxia. Deposition in other tissues causes tendon xanthomas, premature atherosclerosis, and cataracts. In two unrelated patients with CTX, we have identified different point mutations in the gene (CYP27) encoding sterol 27-hydroxylase, a key enzyme in the bile acid biosynthesis pathway. Transfection of mutant cDNAs into cultured cells results in the synthesis of immunoreactive sterol 27-hydroxylase protein with greatly diminished enzyme activity. We have localized the CYP27 gene to the q33-qter interval of human chromosome 2, and to mouse chromosome 1, in agreement with the autosomal recessive inheritance pattern of CTX. These findings underscore the essential role played by sterols in the central nervous system and suggest that mutations in other sterol metabolizing enzymes may contribute to diseases with neurological manifestations. PMID: 2019602 [PubMed - indexed for MEDLINE] 331. J Neurol Sci. 1991 Apr;102(2):225-32. Cerebrotendinous xanthomatosis: clinical and biochemical evaluation of eight patients and review of the literature. Kuriyama M, Fujiyama J, Yoshidome H, Takenaga S, Matsumuro K, Kasama T, Fukuda K, Kuramoto T, Hoshita T, Seyama Y, et al. Third Department of Internal Medicine, Kagoshima University School of Medicine, Japan. We present the clinical and laboratory findings of 8 patients with cerebrotendinous xanthomatosis. The clinical features consisted of a combination of bilateral Achilles tendon xanthomas, cataracts, low intelligence, pyramidal signs, cerebellar signs, convulsions, peripheral neuropathy, foot deformity, cardiovascular disease or atherosclerosis, EEG abnormality, and increased CSF protein. Increased cholesterol was present in the serum, CSF and red cell membrane of all 8 patients. The bile of one patient with late age onset of the disease showed an attenuated production of bile acids and bile alcohols. Three of the 7 had obstruction and/or marked narrowing of the coronary arteries. Data on 136 patients reported throughout the world are reviewed. PMID: 2072121 [PubMed - indexed for MEDLINE] 332. Rinsho Shinkeigaku. 1991 Apr;31(4):402-6. [Hypothyroidism with increased serum levels of cholestanol and bile alcohol--analogous symptoms to cerebrotendinous xanthomatosis]. [Article in Japanese] Idouji K, Kuriyama M, Fujiyama J, Osame M, Hoshita T. Third Department of Internal Medicine, Kagoshima University School of Medicine. We reported a 53-year-old woman with hypothyroidism due to ectopic thyroid gland. She showed intellectual impairment, bilateral pyramidal tract sings, slight cerebellar signs, and degenerative changes of brain white matter on CT and MRI, which were similar to symptoms and signs in cerebrotendinous xanthomatosis (CTX). We found increases of serum cholestanol in the patient and additional 3 patients with hypothyroidism. Total bile alcohol was also increased in the serum of the patients. We speculate that hypothyroidism and CTX might have a similar pathophysiological background on the development of neurological complications and atherosclerosis. PMID: 1914325 [PubMed - indexed for MEDLINE] 333. J Lipid Res. 1991 Apr;32(4):603-12. Use of determinations of 7-lathosterol (5 alpha-cholest-7-en-3 beta-ol) and other cholesterol precursors in serum in the study and treatment of disturbances of sterol metabolism, particularly cerebrotendinous xanthomatosis. Wolthers BG, Walrecht HT, van der Molen JC, Nagel GT, Van Doormaal JJ, Wijnandts PN. Central Laboratory for Clinical Chemistry, University Hospital, Groningen, The Netherlands. The sterol composition of sera from patients with cerebrotendinous xanthomatosis (CTX) was investigated by gas chromatographic analysis of saponified extracts, using a polar (CP Wax 52CB) and an apolar (CP Sil 5CB) capillary column. Apart from already known sterols, the presence of increased amounts of 8-lathosterol (5 alpha-cholest-8(9)-en-3 beta-ol) and significant amounts of 8-dehydrocholesterol (cholesta-5,8-dien-3 beta-ol) were noticed. The latter compound has not been detected previously in human serum and possibly represents a hitherto unknown cholesterol precursor. The apparently elevated levels of delta 8-sterols in CTX serum suggests partial inhibition of migration of the 8,9 double bond to the 7,8 position in this condition. The concentration of 7-lathosterol, an indicator of cholesterol production rate, is also highly elevated in CTX serum and quickly returns to normal values after oral bile acid therapy. Determinations of serum lathosterol are not only useful in the follow-up of therapy of CTX patients, but also in the follow-up of hypercholesterolemic patients treated with either HMG-CoA reductase inhibitors or bile acid sequestrants. PMID: 1856606 [PubMed - indexed for MEDLINE] 334. Neurology. 1991 Mar;41(3):434-6. Cerebrotendinous xanthomatosis: treatments with simvastatin, lovastatin, and chenodeoxycholic acid in 3 siblings. Peynet J, Laurent A, De Liege P, Lecoz P, Gambert P, Legrand A, Mikol J, Warnet A. Laboratoire de Biochimie, Hospital Lariboisière, Paris. Comment in Neurology. 1994 Nov;44(11):2218. We report 3 sisters treated for cerebrotendinous xanthomatosis. We treated one, with a severe neurologic form of the illness, with chenodeoxycholic acid, then lovastatin and simvastatin. These drugs had different efficacy and tolerance, but induced no clinical improvement. Her sisters, without neurologic symptoms, received chenodeoxycholic acid, which normalized the cholestanol level. Optimal treatment of this illness must begin before there is significant clinical symptomatology. PMID: 2006015 [PubMed - indexed for MEDLINE] 335. Jpn J Med. 1991 Mar-Apr;30(2):189-92. Parkinsonism in cerebrotendinous xanthomatosis. Fujiyama J, Kuriyama M, Yoshidome H, Suehara M, Eiraku N, Kashio N, Osame M. Third Department of Internal Medicine, Kagoshima University School of Medicine, Japan. This report describes a case of cerebrotendinous xanthomatosis (CTX) accompanied by clinical manifestations of parkinsonism, including oily and masked face, marked akinesia, muscle rigidity and resting hand tremor. Magnetic resonance imaging (MRI) of the brain showed high intensity areas on T2 weighted imaging, and slightly low intensity areas on T1 weighted imaging in the right globus pallidus and the left putamen. Cerebral cortical atrophy with slight ventricular dilatation and cerebellar atrophy were present as well. This is a case report of CTX which manifested parkinsonism. Parkinsonism may not be a coincidental manifestation in CTX, but rather represent a symptom of the same underlying diathesis. PMID: 1865593 [PubMed - indexed for MEDLINE] 336. J Lipid Res. 1991 Feb;32(2):223-9. High levels of plant sterols and cholesterol precursors in cerebrotendinous xanthomatosis. Kuriyama M, Fujiyama J, Kasama T, Osame M. Third Department of Internal Medicine, Kagoshima University School of Medicine, Japan. We measured the cholestanol, cholesterol precursor (lathosterol), and plant sterol (campesterol and sitosterol) concentrations of serum and bile in 11 patients with cerebrotendinous xanthomatosis. The mean values of serum cholestanol, lathosterol, campesterol, and sitosterol were, respectively, 8.4-, 2.5-, 2.7-, and 1.4-times higher in the patients than in normal control subjects (n = 26). Cholestanol (6.7-fold) and campesterol (3.7-fold) levels in bile (n = 4) were also elevated in the patients. There was no significant difference of serum sterol levels between patients with coronary artery disease and those without it. Chenodeoxycholic acid treatment for periods ranging from 6 months to 3 years and 4 months lowered serum lathosterol (57.7% reduction) and campesterol (57.8%) levels in parallel with cholestanol (70.8%) level, but the sitosterol level (19.7%) decreased less. Thus, increased levels of cholesterol precursor (lathosterol), plant sterols (campesterol and sitosterol), and cholestanol were found in the serum and bile in cerebrotendinous xanthomatosis. Chenodeoxycholic acid treatment effectively reduced the levels of these sterols, except for sitosterol. PMID: 2066659 [PubMed - indexed for MEDLINE] 337. Skeletal Radiol. 1991;20(2):99-102. Computed tomography of tendinous xanthomata in cerebrotendinous xanthomatosis. Hertzanu Y, Berginer J, Berginer VM. Department of Radiology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Tendinous xanthomata with maximum expression on Achilles tendons are a characteristic feature of cerebrotendinous xanthomatosis, a rare autosomal recessive lipid storage disease. Twenty patients are under review; three of them, at different stages of the disease, underwent computed tomographic (CT) examination. CT demonstrates with a high degree of accuracy the increased size of the tendon and its heterogeneous structure resulting from cholesterol and cholestanol crystal deposits. PMID: 2020870 [PubMed - indexed for MEDLINE] 338. Dev Neurosci. 1991;13(4-5):371-6. Cerebrotendinous xanthomatosis as a multisystem disease mimicking premature ageing. Dotti MT, Salen G, Federico A. Istituto di Scienze Neurologiche, Università di Siena, Italy. The authors report the clinical findings in 10 Italian cases of cerebrotendinous xanthomatosis (CTX). In addition to the classical neurological manifestations, the presence of psychiatric symptoms and osteopenia is stressed. Chronic treatment with chenodeoxycholic acid resulted in decreased plasma cholestanol levels and improvement of some central and peripheral neurophysiological parameters including EEG, VEP, SEP and conduction velocities. Due to the presence of cataracts, ischemic heart disease, premature atherosclerosis, mental deterioration and osteoporosis, usually found in old age, CTX can be considered a useful model of premature ageing. PMID: 1817044 [PubMed - indexed for MEDLINE] 339. Dev Neurosci. 1991;13(4-5):363-70. Biochemical abnormalities in cerebrotendinous xanthomatosis. Salen G, Shefer S, Berginer V. UMD-New Jersey Medical School, Newark. Cerebrotendinous xanthomatosis (CTX) is a rare recessive inherited lipid storage disease that was first described by Van Bogaert. Although the principal clinical presentation affects the nervous system with dementia, spinal cord paresis, cerebellar ataxia and peripheral neuropathy, the liver is is the organ where the major biochemical abnormalities are expressed. The following sections deal with the pathogenesis and treatment of the biochemical problems in CTX. PMID: 1817043 [PubMed - indexed for MEDLINE] 340. J Inherit Metab Dis. 1991;14(4):478-96. Inborn errors of bile acid metabolism. Clayton PT. Department of Child Health, Institute of Child Health, London, UK. Cholesterol is converted to cholic acid and chenodeoxycholic acid by a series of reactions involving modifications to the steroid nucleus and oxidation of the side chain. These reactions can be affected by a number of inborn errors of metabolism. When this happens unusual bile acids or bile alcohols are synthesized; these can be identified using gas chromatography-mass spectrometry and fast atom bombardment mass spectrometry techniques. Two defects affecting the modifications to the steroid nucleus have been described; both present with cholestatic liver disease of neonatal onset. The better characterized of the two--3 beta-hydroxy-delta 5-C27-steroid dehydrogenase deficiency--leads to excretion of 3 beta-7 alpha-dihydroxy-5-cholenoic acid and 3 beta,7 alpha,12 alpha-trihydroxy-5-cholenoic acid in the urine. The liver disease improves dramatically on treatment with chenodeoxycholic acid. Deficient activity of 3-oxo-delta 4-steroid 5 beta-reductase is thought to be the cause of familial liver disease in some infants who excrete 7 alpha-hydroxy-3-oxo-4-cholenoic acid and 7 alpha,12 alpha-dihydroxy-3-oxo-4-cholenoic acid in the urine. However, diagnosis of this disorder is problematical; a similar pattern of metabolite excretion can occur as a result of liver damage caused by viruses or inborn errors of pathways unrelated to bile acid synthesis. Defective side chain oxidation in patients with cerebrotendinous xanthomatosis (CTX) leads to synthesis of bile alcohols such as 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol. Patients with CTX do not have cholestatic liver disease. Their major problems (neurological disease, atherosclerosis and xanthomata) are caused by accumulation of cholestanol and cholesterol in the tissues. Bile acid precursors are probably diverted into synthesis of cholestanol. Chenodeoxycholic acid suppresses the production of abnormal metabolites from cholesterol (by inhibition of cholesterol 7 alpha-hydroxylase) and leads to improvement in the neurological disease. Defective side chain oxidation also occurs in peroxisomal disorders but this time it leads to accumulation of C27 bile acids such as 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid (trihydroxycoprostanic acid, THCA). This compound is readily detected in the bile and plasma of patients with defects of peroxisome biogenesis. In patients with defects of a single peroxisomal beta-oxidation enzyme (the 3-hydroxyacyl-CoA component of the bifunctional protein or the thiolase), the major C27 bile acid in bile may be 3 alpha,7 alpha,12 alpha,24-tetrahydroxy-5 beta-cholestanoic acid (varanic acid).(ABSTRACT TRUNCATED AT 400 WORDS) PMID: 1749214 [PubMed - indexed for MEDLINE] 341. Rev Neurol (Paris). 1991;147(5):385-8. [Peripheral neuropathy in a sporadic case of cerebrotendinous xanthomatosis]. [Article in French] Ben Hamida M, Chabbi N, Ben Hamida C, Mhiri C, Kallel R. Institut National de Neurologie, Tunis, Tunisie. The authors report the case of a 22-year old man presenting with cerebrotendinous xanthomatosis who developed peripheral neuropathy. Nerve biopsy showed evidence of demyelination and remyelination, suggesting axonal degeneration. The neurological symptoms improved after treatment with chenodesoxycholic acid. PMID: 1649488 [PubMed - indexed for MEDLINE] 342. Clin Chim Acta. 1990 Dec 14;193(3):113-8. Reduction of urinary bile alcohol excretion and serum cholestanol in patients with cerebrotendinous xanthomatosis after oral administration of deoxycholic acid. Wolthers BG, van der Molen JC, Walrecht H, Hesselmans LF. Central Laboratory for Clinical Chemistry, University Hospital, Groningen, The Netherlands. Deoxycholic acid and chenodeoxycholic acid were administered alternately to four patients with cerebrotendinous xanthomatosis. During this oral therapy serum cholestanol and urinary bile alcohols were determined. Both showed a marked decrease after the start of the two different therapies. It can be concluded that not only chenodeoxycholic acid but also deoxycholic acid is able to suppress endogenous human bile acid synthesis, which is in accordance with other experiments describing the effect of feeding of various bile acids on endogenous bile acid synthesis. PMID: 2282689 [PubMed - indexed for MEDLINE] 343. Med J Malaysia. 1990 Dec;45(4):275-80. Cerebrotendinous xanthomatosis with cholestanolaemia--involvement of five individuals in a Malay family. Othman NH, Rahman SA. Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan. Cerebrotendinous xanthomatosis (CTX), a rare inherited lipid storage disease is due to a defect in bile acid metabolism. Involvement of five members of a family is presented. The clinical features, laboratory and pathologic findings are discussed. Tendinous and tuberous xanthomatosis, bilateral cataracts, cerebral impairment and raised serum cholestanol are the salient features. We believe this is the first report of CTX in Malaysia. PMID: 2152046 [PubMed - indexed for MEDLINE] 344. Br J Ophthalmol. 1990 Oct;74(10):629-30. A case of cerebrotendinous xanthomatosis. II: The sterol content of a cataractous lens. McKenna P, Morgan SJ, Bosanquet RC, Laker MF. Department of Clinical Biochemistry, Royal Victoria Infirmary, Newcastle upon Tyne. The cholestanol content of a cataractous lens nucleus from a patient with cerebrotendinous xanthomatosis (CTX) was quantified by gas chromatography-mass spectrometry and found to be 0.27 micrograms per mg freeze-dried lens tissue. The cholestanol-cholesterol ratio of 1.7% in the lens nucleus was similar to that in the serum of the CTX patient. The cholestanol content and cholestanol-cholesterol ratio in the CTX lens were approximately four-fold and six-fold greater respectively than the mean levels found in three senile cataractous lens nuclei analysed simultaneously for comparative purposes. PMCID: PMC1042235 PMID: 2285688 [PubMed - indexed for MEDLINE] 345. J Lipid Res. 1990 Oct;31(10):1895-902. Identification of short side chain bile acids in urine of patients with cerebrotendinous xanthomatosis. Kuramoto T, Furukawa Y, Nishina T, Sugimoto T, Mahara R, Tohma M, Kihira K, Hoshita T. Institute of Pharaceutical Sciences, Hiroshima University School of Medicine, Japan. Urine from patients with cerebrotendinous xanthomatosis (CTX) was found to contain a number of minor bile acids along with three major bile acids, 7-epicholic acid, norcholic acid, and cholic acid. The following minor bile acids were identified by combined gas-liquid chromatography-mass spectrometry: 7-ketobisnordeoxycholic acid; 12-ketobisnorchenodeoxycholic acid; 7-ketonordeoxycholic acid; 12-ketochenodeoxycholic acid; 7-ketodeoxycholic acid; 12-ketochendeoxycholic acid; bisnorcholic acid; allonorcholic acid; allocholic acid; 1 beta-hydroxybisnorcholic acid; 1 beta-hydroxynorcholic acid; 1 beta-hydroxycholic acid; 2 beta-hydroxybisnorcholic acid; 2 beta-hydroxy-norcholic acid; 2 beta-hydroxycholic acid. The presence of C22 and C23 bile acids in urine of the CTX patients suggests that bile alcohols having a hydroxyl group at C22 or C23 in the side chain may be further degraded to these bile acids. PMID: 2079611 [PubMed - indexed for MEDLINE] 346. Rinsho Shinkeigaku. 1990 Sep;30(9):978-84. [Parkinsonism associated with cerebrotendinous xanthomatosis]. [Article in Japanese] Shibata N, Moroo I, Hayashi M. Department of Neurology, Kofu City Hospital. Two sibling cases of cerebrotendinous xanthomatosis with parkinsonism were reported. One was a woman of 39 years old, and another was her sister of 36 years old. In both cases, febrile convulsion appeared on 1.5 year old, and mental deterioration, ataxic -spastic gait, cataract and swelling of Achilles tendons developed in order since entrance into elementary school. Five years ago, while they were in hospital at the first time, they were diagnosed as cerebrotendinous xanthomatosis by mental disturbance, cerebellar ataxia, pyramidal tract sign, histologically xanthomatous granuloma of Achilles tendons and hypercholestanolemia and family history of autosomal recessive trait. After the second admission, parkinsonism was noticed in addition to those findings above. Parkinsonism consisted of the following: Resting tremor of parkinsonian type, mild muscle rigidity of forearm and intrinsic-plus hand were observed in the elder sister, and generalized severe rigidity and bradykinesia in the younger sister. In both cases, brain CT showed the pontocerebellar atrophy, and the bilateral low density area in corona radiata, posterior portion of internal capsule, cerebral peduncle, tegmentum of midbrain and deep matter of cerebellum. Brain MRI also showed abnormal intensity in the same regions as on the brain CT. Administration of anti-parkinsonian drugs was challenged for the parkinsonism. Oral L-dopa test (500 mg) moderately improved parkinsonism in both cases. Therapy of diphenylpyraline hydrochloride (10 mg/day) entirely inhibited parkinsonian tremor and mild rigidity in the elder sister but was less effective for severe rigidity in the younger sister than administration of L-dopa.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 2265509 [PubMed - indexed for MEDLINE] 347. J Lipid Res. 1990 Sep;31(9):1527-33. 26-Hydroxycholesterol: synthesis, metabolism, and biologic activities. Javitt NB. Division of Hepatic Diseases, New York University Medical Center, NY 10016. Cholest-5-ene-3 beta,26-diol (26-hydroxycholesterol) is synthesized by a mitochondrial P-450 enzyme that appears to be widely distributed in tissues. Together with other C-27 steroid intermediates it is transported to the liver and metabolized to bile acids. Although 26-hydroxycholesterol is transported in plasma lipoproteins mostly as the fatty acid ester, neither its assembly and orientation within lipoproteins nor its mechanism of transport across the sinusoidal liver membrane is known. Cell culture studies indicate that 26-hydroxycholesterol can inhibit both cholesterol synthesis and low density lipoprotein (LDL) receptor activity. Inhibition of DNA synthesis also occurs and may not be related to the reduction in HMG-CoA reductase activity. The relationship of these in vitro activities to the physiologic role(s) of 26-hydroxycholesterol remains to be clarified. A clue to its biologic role is the knowledge that markedly decreased 26-hydroxylase activity appears to be the molecular basis of cerebrotendinous xanthomatosis, an inborn error of metabolism characterized by a significant decrease in 26-hydroxycholesterol and bile acid synthesis and an increase in cholesterol synthesis. PMID: 2246606 [PubMed - indexed for MEDLINE] 348. J Neurol. 1990 Jun;237(3):216-9. Cerebrotendinous xanthomatosis: clinical, electrophysiological and nerve biopsy findings, and response to treatment with chenodeoxycholic acid. Donaghy M, King RH, McKeran RO, Schwartz MS, Thomas PK. Department of Neurological Science, Royal Free Hospital School of Medicine, London, UK. A 30-year-old patient with cerebrotendinous xanthomatosis was studied over a 6-year period. The clinical manifestations were cataracts, intellectual deterioration, ataxia, palatal and pharyngeal myoclonus, corticospinal tract damage and an electrophysiologically demonstrated sensorimotor peripheral neuropathy. Peripheral motor and sensory nerve conduction velocity was slowed. Sural nerve biopsy revealed reduced densities of both myelinated and unmyelinated axons and teased fibres showed evidence of axonal regeneration and some remyelination. The loss of myelinated nerve fibres particularly affected those of larger diameter, thus contributing to the slowing of nerve conduction. Chenodeoxycholic acid treatment for two separate periods of 10 and 6 months each increased nerve conduction velocity. This electrophysiological improvement was not matched by detectable clinical neurological improvement. PMID: 2196342 [PubMed - indexed for MEDLINE] 349. Klin Monbl Augenheilkd. 1990 May;196(5):407-10. [Zonular juvenile cataract and cerebrotendinous xanthomatosis]. [Article in French] Farpour H. The present paper describes two cases, with the same type of zonular cataract associated with the rare disease of cerebrotendinous xanthomatosis. The disease is characterized by lipopexia in the Achilles' tendons, neurologic symptoms and low IQ. The mode of inheritance is autosomal recessive. The physiopathology and biochemistry of the disease are discussed with reference to recent publications. PMID: 2114502 [PubMed - indexed for MEDLINE] 350. J Dermatol. 1990 Feb;17(2):115-9. Cerebrotendinous xanthomatosis. Hwang SY, Lee KH, Ahn JI. Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea. A case report on a 23-year-old female patient with cerebrotendinous xanthomatosis (CTX) is presented. From 8 years of age, the patient clinically showed multiple xanthoma masses on both knees, both heels, and the nasal bridge, juvenile cataracts, multiple abnormal neurologic dysfunctions, and dementia. The level of cholestanol in urine, serum, and xanthoma mass tissues was increased, as determined by capillary gas chromatography. PMID: 2329221 [PubMed - indexed for MEDLINE] 351. Rinsho Shinkeigaku. 1990 Feb;30(2):207-9. [A case of cerebrotendinous xanthomatosis with convulsive seizures]. [Article in Japanese] Matsumuro K, Takahashi K, Matsumoto H, Okatsu Y, Kuriyama M. Department of Neurology, Okatsu Hospital, Kagoshima. A 35 year-old male was admitted to our hospital because of convulsive seizures. His parents are first cousins. No other members of his family have similar symptoms. He showed mental retardation since childhood. At age 14, he had generalized convulsive seizures that were intractable. Bilateral cataracts were found and extracted at age 18. He noticed bilateral swellings at Achilles tendons at around 25 years of age. Physical examination revealed bilateral swellings of Achilles tendons. Neurologically, he showed poor intellectual ability, hyperreflexia with positive Babinski's sign and cerebellar ataxia. Marked elevations of cholestanol level (53.84 micrograms/ml; normal: 2.71 +/- 0.81, n = 17) and cholestanol/cholesterol ratio (2.20%; normal: 0.16 +/- 0.05, n = 17) were detected in serum. EEG showed abnormal background activities with bursts of high voltage slow theta activities. MRI study showed high intensity lesions in globus pallidus and multiple lesions in white matter with long spin echo sequence. Oral administration of chenodeoxycholic acid improved EEG findings, serum cholestanol level and convulsive seizures. However, the MRI abnormalities remained unchanged, which suggested irreversible brain damage. We reviewed the previous reports of 144 cases of CTX. Fourteen cases had convulsive seizures. We stress that CTX is one the causes of symptomatic epilepsy. PMID: 2190743 [PubMed - indexed for MEDLINE] 352. Steroids. 1990 Feb;55(2):74-8. Use of positive ion fast atom bombardment mass spectrometry for rapid identification of a bile alcohol glucuronide isolated from cerebrotendinous xanthomatosis patients. Dayal B, Salen G, Tint GS, Shefer S, Benz SW. Department of Medicine, UMDNJ-New Jersey Medical School, Newark. The identification of a major biliary and plasma bile alcohol glucuronide, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol-3-0-beta-D-glucuronide, present in cerebrotendinous xanthomatosis (CTX) patients, was investigated by positive ion fast atom bombardment mass spectrometry (FAB-MS). The spectrum was characterized by abundant ions formed by attachment of a proton, [M + H]+, or of alkali ions, [M + Na]+ and [M + 39K]+, to the glucuronide salt. These ions allowed an unambiguous deduction of the molecular weight of the sample. It is suggested that FAB-MS could be used in the rapid diagnosis of CTX. PMID: 2183402 [PubMed - indexed for MEDLINE] 353. J Neurol Neurosurg Psychiatry. 1990 Feb;53(2):166-7. Magnetic resonance imaging of the brain and spinal cord in cerebrotendinous xanthomatosis. Bencze KS, Vande Polder DR, Prockop LD. Department of Neurology, College of Medicine, University of South Florida, Tampa. This reports a 40 year old man with cerebrotendinous xanthomatosis who had bilateral cataracts, enlarged Achilles tendons, progressive dementia, gait disturbance and peripheral neuropathy. Electroencephalography, electromyography, and magnetic resonance imaging (MRI) of the brain and spine were performed. Magnetic resonance imaging revealed cerebral, cerebellar and cervical cord atrophy and white matter involvement in the cerebrum and cerebellum correlating well with the clinical findings. To date there has been one previous report of MRI of the brain in cerebrotendinous xanthomatosis and none of the spinal cord. PMCID: PMC487959 PMID: 2107278 [PubMed - indexed for MEDLINE] 354. J Neurol Neurosurg Psychiatry. 1990 Jan;53(1):76-8. Cerebrotendinous xanthomatosis: clinical and MRI study (a case report). Fiorelli M, Di Piero V, Bastianello S, Bozzao L, Federico A. Dipartimento di Scienze Neurologiche, Università degli Studi di Roma La Sapienza, Italy. We report a patient with cerebrotendinous xanthomatosis (CTX) presenting with dementia, spastic tetraparesis and an unreported akinetic-rigid syndrome. Computed tomography (CT) showed only cerebellar abnormalities while magnetic resonance imaging (MRI) detected additional pallidal and mesencephalic focal alterations. MRI findings, but not CT, correlated with the clinical picture. PMCID: PMC1014102 PMID: 2303834 [PubMed - indexed for MEDLINE] 355. J Rheumatol. 1989 Dec;16(12):1611-2. Joint hypermobility in patients with cerebrotendinous xanthomatosis. Sukenik S, Horowitz J, Berginer VM. PMID: 2625697 [PubMed - indexed for MEDLINE] 356. J Neurol Sci. 1989 Dec;94(1-3):101-5. Type IIa hyperlipoproteinemia masquerading as cerebrotendinous xanthomatosis. Ijichi S, Ijichi N, Niina K, Kuriyama M, Izumo S, Nakamura F, Osame M. Division of Internal Medicine, Kagoshima Municipal Hospital, Japan. We describe an adult patient with type IIa hyperlipoproteinemia, presenting with Achilles tendon xanthomas, cataracts, dementia, ataxia, pyramidal tract signs, and peripheral neuropathy, which are commonly seen in cerebrotendinous xanthomatosis (CTX). However, the diagnosis of CTX was excluded on the basis of the cholestanol level and the normal cholestanol/cholesterol ratio in his serum and tendon. The pathomechanism for some of the clinical manifestations in type IIa hyperlipoproteinemia and CTX might be caused by a common biochemical disturbance. PMID: 2614461 [PubMed - indexed for MEDLINE] 357. Br J Ophthalmol. 1989 Dec;73(12):1011-4. Case of cerebrotendinous xanthomatosis. I: Unusual ophthalmic features. Morgan SJ, McKenna P, Bosanquet RC. Department of Ophthalmology, Newcastle General Hospital. A case of cerebrotendinous xanthomatosis is reported. In addition to the classical ophthalmic and systemic features the patient presented with unilateral proptosis. This feature has never previously been reported. The results of investigations are described and illustrated. PMCID: PMC1041958 PMID: 2611184 [PubMed - indexed for MEDLINE] 358. J Clin Invest. 1989 Dec;84(6):1713-21. The reactivity of desmosterol and other shellfish- and xanthomatosis-associated sterols in the macrophage sterol esterification reaction. Tabas I, Feinmark SJ, Beatini N. Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032. The acyl-CoA: cholesterol acyl transferase (ACAT) reaction in macrophages is a critical step in atherosclerotic foam cell formation, but little is known about the reaction's sterol substrate specificity. In this report we examine the macrophage ACAT reactivity of the shellfish sterol, desmosterol, and other sterols found in man because of shellfish ingestion or in association with the foam cell diseases sitosterolemia and cerebrotendinous xanthomatosis (CTX). We first show that the J774 macrophage, a foam cell model with a hyperactive ACAT pathway, synthesizes desmosterol instead of cholesterol and that both endogenous and exogenous desmosterol are substrates and stimulators of the ACAT reaction in these cells. When exogenous desmosterol was added to human monocyte-derived macrophages, ACAT was stimulated 29- and 4-fold compared with control and cholesterol-treated cells, respectively. Steryl ester mass accumulation in desmosterol-treated human macrophages was 10-fold greater than in control cells and 3-fold greater than in cholesterol-treated cells. Another shellfish sterol, 24-methylene cholesterol, also stimulated ACAT in human macrophages, but most of the xanthomatosis-related sterols did not stimulate ACAT. These data suggest that: (a) the shellfish sterols desmosterol and 24-methylene cholesterol may be atherogenic; and (b) the excessive foam cell formation seen in sitosterolemia and CTX cannot be explained by ACAT hyperreactivity of their associated sterols. PMCID: PMC304047 PMID: 2592557 [PubMed - indexed for MEDLINE] 359. Am J Cardiol. 1989 Sep 15;64(10):680-2. Macroreentrant ventricular tachycardia and coronary artery disease in cerebrotendinous xanthomatosis. Chen PS, Fleck RP, Calisi CM, Kozina JA, Feld GK. Department of Medicine, Veterans Administration Medical Center, San Diego, California. PMID: 2782260 [PubMed - indexed for MEDLINE] 360. Nervenarzt. 1989 Jul;60(7):444-7. [Cerebrotendinous xanthomatosis: description of 2 cases and differential diagnosis in relation to encephalomyelitis disseminata]. [Article in German] Diedrich U, Ropte S. Neurologische Klinik, Georg-August-Universität Göttingen. PMID: 2761665 [PubMed - indexed for MEDLINE] 361. J Lipid Res. 1989 May;30(5):633-40. Chenodeoxycholic acid normalizes elevated lipoprotein secretion and catabolism in cerebrotendinous xanthomatosis. Tint GS, Ginsberg H, Salen G, Le NA, Shefer S. Department of Medicine, VA Medical Center, East Orange, NJ 07019. Cerebrotendinous xanthomatosis (CTX) is a rare inherited lipid storage disease caused by a defect in bile acid synthesis in which cholesterol and its product cholestanol are deposited in neurological and vascular tissue. Therapy with chenodeoxycholic acid but not with the 7 beta-epimeric ursodeoxycholic acid is usually successful. In an untreated patient, total and low density lipoprotein (LDL) cholesterol were found to be low (134 +/- 11 and 78 +/- 8 mg/dl, respectively). The production rate (PR) and fractional catabolic rate (FCR) of very low density (VLDL) apolipoprotein B (apoB) were, however, both markedly increased (34.7 mg/kg per day and 13.7 pools/day, respectively vs. 15.1 +/- 5.0 mg/kg per day and 6.2 +/- 3.8 pools/day in controls) while the PR and FCR of LDL apoB were moderately elevated (16.3 mg/kg per day and 0.65 pools/day, respectively vs. 12.9 +/- 1.2 mg/kg per day and 0.52 +/- 0.10 pools/day in controls). After 1 month of 750 mg/day of chenodeoxycholic acid, the FCR and PR of both VLDL and LDL apoB became normal while total plasma cholesterol increased significantly to 145 +/- 18 mg/dl. In a second patient who had been receiving 750 mg/day of chenodeoxycholic acid for 6 months lipoprotein kinetics were normal. These parameters did not change when the subject was switched to 750 mg/day ursodeoxycholic acid. We postulate that cholesterol biosynthesis in CTX is derepressed by a diminished hepatic pool of chenodeoxycholic acid and that the elevated secretion of apoB is a response to the increased rate of cholesterol production. PMID: 2760539 [PubMed - indexed for MEDLINE] 362. Rinsho Shinkeigaku. 1989 Feb;29(2):196-201. [Effect of LDL-apheresis on a case of Cerebrotendinous Xanthomatosis]. [Article in Japanese] Fukuo Y, Hayama N, Hara K, Terashi A, Seta K. Cerebrotendinous Xanthomatosis (CTX) is a rare familial disease characterized by tendon-xanthomas, cataracts, progressive cerebellar ataxia, dementia and an elevation of serum cholestanol with normal levels of cholesterol. Although the pathogenesis of CTX is not fully understood, increment of cholestanol is suggested one of the major metabolic derangements of the disease. Recently, the LDL-apheresis has been developed as a new therapeutical equipment in the field of hyperlipidemia and been widely used to reduce the levels of LDL-cholesterol by selective LDL adsorption. From the point of view that cholestanol is involved mainly in LDL-cholesterol (1.019 less than d less than 1.063), we used this LDL-apheresis in the aim of reducing the cholestanol in 58 years old woman with typical sign and symptoms of CTX. The levels of serum cholestanol and cholesterol before the treatment with LDL-apheresis, were 10.7 micrograms/ml and 175 mg/dl respectively. Also the ratio of cholestanol/cholesterol indicated 0.63. By the first procedure of apheresis, the level of cholestanol was markedly decreased to 5.2 micrograms/ml (50%). Several LDL-apheresis treatments were carried out once a month. During 5 months treatments, neurological deterioration was arrested, dementia which included disorientation and recent-memory loss, cleaned a little. Although the xanthomas did not decrease in size, this patients was better oriented to person, place, time and was able to speak rationally, 2nd her cerebellar dysfunction revealed improvement. From our new experiments-we believe that the LDL-apheresis offers the strong hope of preventing the progress on cerebrotendinous xanthomatosis. PMID: 2752648 [PubMed - indexed for MEDLINE] 363. Neurol Clin. 1989 Feb;7(1):55-74. Cerebrotendinous xanthomatosis. Berginer VM, Salen G, Shefer S. Department of Neurology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Cerebrotendinous xanthomatosis is a rare familial lipid storage that is caused by a defect in bile acid synthesis. As a result, large amounts of cholestanol, the 5 alpha-dihydro derivative of cholesterol, accumulate in virtually every tissue, with extra large deposits in the nervous system, xanthomas, and bile. Clinically, progressive neurologic dysfunction, tendon xanthomas, cataracts, and atherosclerosis are commonly found. Because chenodeoxycholic acid, a primary bile acid, is almost devoid from the bile, replacement therapy (750 mg per day) suppresses abnormal bile acid synthesis, reduces elevated cholestanol synthesis and plasma concentrations, and improves neurologic function in this disease. PMID: 2493565 [PubMed - indexed for MEDLINE] 364. Ann Med Interne (Paris). 1989;140(6):525-7. [Cerebrotendinous xanthomatosis. Apropos of a case using magnetic resonance study of the brain and nerve biopsy]. [Article in French] Amiel H, Gherardi R, Kanaan HY, Buisson J, Genthon R, Zinszner J, Giroux C, Delaporte P, Salama J. PMID: 2624369 [PubMed - indexed for MEDLINE] 365. Virchows Arch B Cell Pathol Incl Mol Pathol. 1989;57(6):367-74. Membranocystic lesion in the brain in cerebrotendinous xanthomatosis. Histochemical and ultrastructural study with evidence of its ceroid nature. Elleder M, Michalec C, Jirásek A, Khun K, Havlová M, Ranný M. 1st Department of Pathology, Faculty of Medicine, Charles University, Prague, Czechoslovakia. A case is described of cerebrotendinous xanthomatosis with purely neurological manifestations. Cholestanol deposition in both affected and unaffected brain regions was markedly increased, reaching 18.5-20.8% of the sterol fraction. The unilateral lesions localized in the basal ganglia and cerebellar white matter featured perivascular accumulation of foam cells containing apolar lipid and ceroid. Necrosis with lipid-rich debris was a frequent finding often accompanied by prominent collagen deposition. Within these lesions there were numerous refractile thick membranes which, according to lipid histochemical techniques, could be qualified as ceroid-type lipopigment. It is suggested that the ceroid membranes arise extracellularly directly from the lipid-rich debris. Ultrastructurally, they were composed of convolutes of highly organized trilaminar membranes about 15 nm thick similar to those seen in intracellular ceroid granules. The membranes were embedded in an amorphous substance of low or medium density and were identical in their general appearance, stainability and fine structure to the membranocystic lesion in Nasu-Hakola disease and to the extracellular ceroid in atherosclerotic plaques. PMID: 2575300 [PubMed - indexed for MEDLINE] 366. Adv Exp Med Biol. 1989;266:191-206; discussion 207. So-called membranocystic lesion (MCL)--a new variant of ceroid type lipopigment. Elleder M. 1st Department of Pathology, Charles University, School of Medicine, Prague, Czechoslovakia. Structures very close morphologically to the so-called membranocystic formations of the Nasu-Hakola's disease and identical in histochemical properties with them were found in several other metabolically unrelated conditions such as cerebrotendinous xanthomatosis (perivascularly in the brain) and in human atheromatous plaques. This with some other literary data points to unspecific nature of the membranocystic lesion (MCL) which also has been resisting satisfactory classification in terms of pathobiochemistry. Evidence is presented suggesting the MCL is lipopigment in nature. This is based on its lipid histochemical properties dominated by prominent autofluorescence and marked sudanophilia resistant to lipid extraction procedures. Ultrastructural pattern of the MCL was membranous, being dominated by mostly individual trilaminar membranes about 15 nm thick which could be also occasionally identified in various intralysosomal ceroid type lipopigments. It is supposed that the MCL lipopigment is formed mainly extracellularly from the lipid rich debris. PMID: 2486151 [PubMed - indexed for MEDLINE] 367. Arteriosclerosis. 1989 Jan-Feb;9(1 Suppl):I164-8. Studies on inborn errors of metabolism in Norway. Norum KR. School of Medicine, University of Oslo, Norway. Some 50 years ago, Müller described hypercholesterolemia, xanthomas, and coronary heart disease as symptoms of a genetic disorder. In the 1930s, other important discoveries concerning inborn errors of metabolism were made in Norway. Følling described phenylketonuria, and Refsum examined his first patients with heredopathia atactica polyneuritiformis (phytanic acid storage disease). Several other inborn errors of metabolism have been discovered in Norway: familial lecithin-cholesterol acyltransferase deficiency, methylmalonic acidemia, beta-methylcrotonyl-coenzyme A carboxylase deficiency, pyroglutamic aciduria, and N-acetyl aspartic aciduria. Metabolic and biochemical studies in these patients have revealed new and important metabolic pathways. Studies on patients with inborn errors not first described in Norway have also given important information on key enzymes in metabolic pathways. Thus, studies on patients with cerebrotendinous xanthomatosis and those with Zellweger's syndrome have revealed the normal metabolic route for conversion of cholesterol to bile acids. The discoveries and the clinical and biochemical research in former days were mostly good examples of serendipity combined with excellent clinical alertness. In more recent years, several of the discoveries have resulted from systematic biochemical screening of urine, plasma, or other body fluids from patients with unusual clinical syndromes. PMID: 2463828 [PubMed - indexed for MEDLINE] 368. Harefuah. 1988 Nov 1;115(9):224-6. [Cerebrotendinous xanthomatosis in a Druze family]. [Article in Hebrew] Ben Dror G, Geller A, Berginer V, Manelis J. PMID: 3229672 [PubMed - indexed for MEDLINE] 369. J Chromatogr. 1988 Oct 28;452:543-7. Potential application of thin-layer chromatography and thin-layer chromatography with flame ionization detection of cholestanol in the diagnosis of cerebrotendinous xanthomatosis. Michalec C, Ranný M. Laboratory of Protein Metabolism, Charles University Medical Faculty, Prague, Czechoslovakia. PMID: 3243858 [PubMed - indexed for MEDLINE] 370. Mayo Clin Proc. 1988 Oct;63(10):1012-21. Cyclosporine, low-density lipoprotein, and cholesterol. de Groen PC. Division of Gastroenterology, Mayo Clinic, Rochester, MN 55905. Lipoproteins are known to be able to transport a variety of drugs. This report suggests that low-density lipoprotein not only functions as an important carrier of cyclosporine in plasma but also facilitates transport of cyclosporine across the cell membrane by means of the low-density lipoprotein receptor. Such a mechanism would explain (1) the similar tissue distribution of cyclosporine and the low-density lipoprotein receptor, (2) the increase in immunosuppression and toxicity with low total serum cholesterol levels, and (3) the relative absence of immunosuppression and toxicity with high levels of cyclosporine in the blood in patients with hypertriglyceridemia. In addition to receptor-mediated uptake, a disturbance of the blood-brain barrier is suggested as an explanation of the high frequency of cyclosporine-induced central nervous system toxicity after liver transplantation. Cyclosporine-induced inhibition of the mitochondrial steroid 26-hydroxylase, an enzyme involved in the formation of bile acids from cholesterol and deficient in patients with cerebrotendinous xanthomatosis, may cause or contribute to the observed central nervous system toxicity. It also may explain the similar clinical features of cyclosporine-induced central nervous system toxicity and cerebrotendinous xanthomatosis. PMID: 3172850 [PubMed - indexed for MEDLINE] 371. Am J Med Genet. 1988 Sep;31(1):11-6. Pregnancy in women with cerebrotendinous xanthomatosis (CTX): high risk condition for fetus and newborn infant? Berginer VM, Carmi R, Salen G. Department of Neurology, Soroka University Hospital, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Cerebrotendinous xanthomatosis (CTX), is one of the few autosomal recessive progressive storage diseases allowing affected individuals to reproduce. We investigated 38 CTX patients and most of their families. The possibility of a high risk situation for the fetus and/or the apparently healthy newborn infant born to CTX mothers and female carriers of the gene is discussed for genetic counseling purposes and in view of available treatment. PMID: 3223491 [PubMed - indexed for MEDLINE] 372. Scand J Clin Lab Invest. 1988 Sep;48(5):425-9. Reduced C27-steroid 26-hydroxylase activity in heterozygotes for cerebrotendinous xanthomatosis. Skrede S, Björkhem I, Kvittingen EA, East C, Grundy S, Skrede S. Institute of Clinical Biochemistry, University of Oslo, Rikshospitalet, Norway. C27-steroid 26-hydroxylase activity in fibroblasts from two heterozygotes for CTX was determined, using an optimized enzyme assay. With 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol, 5 beta-cholestane-3 alpha,7 alpha-diol, 7 alpha-hydroxy-4-cholestane-3-one or 7 alpha-hydroxycholesterol as substrates, the activities were about 50% of those of control cells. The Km for the substrates was not increased in the CTX heterozygotes. These findings support that deficiency of the C27-steroid 26-hydroxylase is the primary enzymatic defect in CTX. PMID: 3206189 [PubMed - indexed for MEDLINE] 373. J Neurol Neurosurg Psychiatry. 1988 Aug;51(8):1069-74. Central motor and sensory conduction in adrenoleukomyeloneuropathy, cerebrotendinous xanthomatosis, HTLV-1-associated myelopathy and tabes dorsalis. Ugawa Y, Kohara N, Shimpo T, Mannen T. Department of Neurology, School of Medicine, University of Tokyo, Japan. Central motor and sensory conduction was studied by percutaneous electrical stimulation of brain and spinal cord and by somatosensory evoked potential techniques respectively, in patients with adrenoleukomyeloneuropathy, cerebrotendinous xanthomatosis, human T-cell lymphotropic virus-1-associated myelopathy and tabes dorsalis. The results were all consistent with clinical and neuropathological findings in these disorders. Conductions in the corticospinal tract and posterior column could be evaluated separately with these two techniques. Percutaneous electrical stimulation technique would be useful for investigating conduction in the corticospinal tract in patients with spinal cord disorders. PMCID: PMC1033116 PMID: 2851031 [PubMed - indexed for MEDLINE] 374. S Afr Med J. 1988 Jul 16;74(2):79-80. Cerebrotendinous xanthomatosis. A case report. Shamley DJ, Heckmann JM, Mendelsohn D, Saffer SD. Department of Neurology, Baragwanath Hospital, Johannesburg. Cerebrotendinous xanthomatosis is a rare hereditary disease, which manifests with tendinous xanthomas, cataracts, dementia and nervous system involvement. The first southern African black patient with this disorder is reported and biochemical abnormalities and treatment are briefly discussed. PMID: 3399978 [PubMed - indexed for MEDLINE] 375. Rinsho Shinkeigaku. 1988 Jul;28(7):819-27. [Central sensory and motor conduction in adrenoleukodystrophy (ALD), cerebrotendinous xanthomatosis (CTX), HTLV-1-associated myelopathy (HAM) and tabes dorsalis]. [Article in Japanese] Ugawa Y, Kohara N, Shimpo T, Mannen T. PMID: 3233856 [PubMed - indexed for MEDLINE] 376. Clin Chim Acta. 1988 May 31;174(2):197-205. Plasma and biliary cholestanol related to steroid metabolism in familial hypercholesterolemia patients with and without ileal exclusion. Koivisto PV, Miettinen TA. Second Department of Medicine, University of Helsinki, Finland. Plasma cholestanol is increased in cerebrotendinous xanthomatosis and in sitosterolemia with xanthomatosis. We measured plasma and biliary cholestanol in heterozygous familial hypercholesterolemia patients with (n = 10) and without (n = 12) ileal exclusion. In the unoperated patients plasma cholestanol concentration (12.9 mumol/l) and content (1.2 mmol/mol cholesterol) were slightly higher than in the nonhypercholesterolemic control subjects studied by us. Ileal exclusion had lowered plasma cholestanol concentration but only in proportion to the lowering of plasma cholesterol concentration, and plasma cholestanol content (mmol/mol cholesterol) was similar in the operated and unoperated subjects. Plasma and biliary cholestanol contents were positively associated. In the unoperated patients the fractional cholesterol absorption and plasma plant sterols, also reflecting sterol absorption, were positively correlated with plasma cholestanol content. Our study suggests, that plasma cholestanol is slightly elevated in familial hypercholesterolemia and that, in addition to plasma lipoprotein level, sterol absorption is important in the regulation of plasma cholestanol level. Ileal exclusion decreases plasma cholestanol in proportion to the decrement in the plasma cholesterol concentration. PMID: 3133140 [PubMed - indexed for MEDLINE] 377. Am J Cardiol. 1988 May 1;61(13):1150-2. Aneurysmal coronary artery disease in cerebrotendinous xanthomatosis. Potkin BN, Hoeg JM, Connor WE, Salen G, Quyyumi AA, Brush JE Jr, Roberts WC, Brewer HB Jr. Molecular Disease Branche, National Heart, Lung, and Blood Institute, Bethesda, Maryland. PMID: 3364377 [PubMed - indexed for MEDLINE] 378. Tanpakushitsu Kakusan Koso. 1988 Apr;33(5):794-7. [Cerebrotendinous xanthomatosis and phytosterolemia]. [Article in Japanese] Nakamura T, Matsuzawa Y. PMID: 3152095 [PubMed - indexed for MEDLINE] 379. Clin Chim Acta. 1988 Mar 31;173(1):57-80. Clinical biochemistry of peroxisomal disorders. Kaiser E, Kramar R. Institut für Medizinische Chemie der Universität Wien, Vienna, Austria. Peroxisomes have been shown to participate in a variety of pathological processes. Peroxisomal anomalities are central features of Zellweger's cerebro-hepato-renal syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease and several other genetic metabolic disorders (pseudo-Zellweger syndrome, Leber congenital amaurosis, cerebrotendinous xanthomatosis, rhizomelic chondrodysplasia punctata). In disorders with general loss of peroxisomal functions (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease) an accumulation of very long-chain fatty acids and pathological bile acids are found. Patients have a defective synthesis of plasmalogens and show increased excretion of dicarboxylic acids of medium chain length and of pipecolic acid in the urine. These anomalities which are due to the lack of peroxisomal enzymes, supply the basis for clinical laboratory tests. The study of these peroxisomal disorders has presented valuable information on the normal function of peroxisomes. PMID: 3289796 [PubMed - indexed for MEDLINE] 380. Am J Psychiatry. 1988 Mar;145(3):354-7. Psychiatric disorders in patients with cerebrotendinous xanthomatosis. Berginer VM, Foster NL, Sadowsky M, Townsend JA 3rd, Siegel GJ, Salen G. Department of Neurology, Soroka Medical Center, Beer-Sheva, Israel. Cerebrotendinous xanthomatosis is a familial recessive disorder. Patients with the disorder present with tendon xanthomas, juvenile cataracts, dementia, and pyramidal and cerebellar abnormalities but have normal plasma cholesterol. High plasma cholestanol concentrations and abnormal bile acid metabolism are specific for this disease. The authors describe four patients with cerebrotendinous xanthomatosis and prominent psychiatric symptoms. In three of these patients appropriate diagnosis and treatment were delayed for years because the presence of cerebrotendinous xanthomatosis was not recognized. Early recognition of this potentially lethal disease is important because both the psychiatric and neurological symptoms respond to treatment with chenodeoxycholic acid. PMID: 3344851 [PubMed - indexed for MEDLINE] 381. J Biochem. 1988 Feb;103(2):375-9. Effect of cholestanol feeding on sterol concentrations in the serum, liver, and cerebellum of mice. Byun DS, Kasama T, Shimizu T, Yorifuji H, Seyama Y. Department of Physiological Chemistry and Nutrition, Faculty of Medicine, University of Tokyo. In order to elucidate the mechanism of xanthoma formation in cerebrotendinous xanthomatosis, mice were fed for 32 weeks with a diet rich in 5 alpha-cholestan-3 beta-ol (cholestanol) (1%, w/w). The concentrations of sterols in the serum, liver, and cerebellum were determined using high performance liquid chromatography. In the cholestanol-fed mice, the cholestanol concentrations in the serum and liver reached maxima in the first 2 to 4 weeks; the levels were about 30- to 100-fold higher than in the control diet mice. The cholestanol concentrations declined thereafter, finally to 50-60% of the maxima. Cholesterol concentrations were slightly lower in the cholestanol-fed mice throughout the experiments than in the control diet mice. On the other hand, the levels of cholestanol in the cerebellum increased almost linearly in parallel to the feeding time, and no decline was observed. These results suggest that the capacity of the liver to remove or degrade cholestanol was increased by long-term intake of this compound, whereas the cerebellum had no such feed-back regulation. Histological examinations using an electron microscope revealed the enlargement of lysosomal granules in the liver of the cholestanol-fed mice. PMID: 3372493 [PubMed - indexed for MEDLINE] 382. J Lipid Res. 1988 Feb;29(2):157-64. Hepatic 7 alpha-dehydroxylation of bile acid intermediates, and its significance for the pathogenesis of cerebrotendinous xanthomatosis. Skrede S, Buchmann MS, Björkhem I. Institute of Clinical Biochemistry, Rikshospitalet, University of Oslo, Norway. The bile acid precursor 7 alpha-hydroxy-4-cholesten-3-one was found to be enzymatically dehydroxylated at a slow rate by liver tissues from the rat, human, and guinea pig. The rat liver enzyme is localized in the microsomal fraction, has a pH optimum of about 8.5, an apparent Km of 0.03-0.04 mM, and a Vmax of 10-15 nmoles.mg protein-1.hr-1. The product from 7 alpha-hydroxy-4-cholesten-3-one was identified as cholesta-4,6-dien-3-one by its chromatographic properties and by mass spectrometry. The reaction proceeded both in air and N2, and pyridine nucleotides were not required as cofactors. In addition to the enzymatic reaction, there was a significant nonenzymatic dehydroxylation of 7 alpha-hydroxy-4-cholesten-3-one, in particular at high pH and with high concentrations of protein. No 7 alpha-dehydroxylation occurred with various 7 alpha-hydroxylated 3 beta-hydroxy-delta 5-steroids. We have previously shown that at least part of the accumulation of cholestanol in cerebrotendinous xanthomatosis (CTX) is due to accelerated 7 alpha-dehydroxylation of bile acid intermediate(s), which are further converted into cholestanol. The capacity to dehydroxylate 7 alpha-hydroxy-4-cholesten-3-one was found to be about the same in homogenates of liver biopsies from two patients with CTX as in preparations from control subjects. It is suggested that increased levels of substrate (7 alpha-hydroxy-4-cholesten-3-one) in the liver, rather than increased amounts of 7 alpha-dehydroxylase is the explanation for the accelerated 7 alpha-dehydroxylation in CTX that leads to increased biosynthesis of cholestanol. PMID: 3367085 [PubMed - indexed for MEDLINE] 383. Acta Univ Carol Med (Praha). 1988;34(1-2):111-6. Increased serum cholestanol in patients with cerebrotendinous xanthomatosis (CTX): chromatographic study. Michalec C. PMID: 3152022 [PubMed - indexed for MEDLINE] 384. J Inherit Metab Dis. 1988;11(1):56-75. Cerebrotendinous xanthomatosis: a review of biochemical findings of the patient population in The Netherlands. Koopman BJ, Wolthers BG, van der Molen JC, van der Slik W, Waterreus RJ, van Spreeken A. Central Laboratory for Clinical Chemistry, University Hospital, Groningen, The Netherlands. This study gives a review of the results obtained from biochemical investigations of 20 patients in The Netherlands suffering from cerebrotendinous xanthomatosis, an inborn error of metabolism in bile acid synthesis. Diagnosis can best be established by determining the excretion of urinary bile alcohols, in particular 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha,23,25-pentol, in urine by means of capillary gas chromatography. Measurement of serum cholestanol levels or serum cholestanol/cholesterol ratios, commonly used for establishing cerebrotendinous xanthomatosis, are not reliable. The effectiveness of the different therapies, i.e. administration of bile acids, can be evaluated by monitoring the urinary excretion of bile alcohols. From such investigations it was concluded that cholic acid especially, but also chenodeoxycholic acid are the therapies of choice for the treatment of cerebrotendinous xanthomatosis. All patients, until now diagnosed in The Netherlands were not discovered before the third or fourth decade of life because the characteristic signs only then become manifest clearly. Unfortunately, because sterol storage is almost irreversible, therapy only results in minor improvements of the patient's condition. Therefore early detection of the presence of cerebrotendinous xanthomatosis is desirable so that treatment can start before extensive storage of sterols is a fact. We developed some laboratory assays with the purpose of early detection. One consists of the detection of cerebrotendinous xanthomatosis carriers by subjecting them to oral cholestyramine administration and monitoring the urinary excretion of the bile alcohol 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol before and after treatment. Secondly, a relatively simple screening test for cerebrotendinous xanthomatosis was developed based on an enzymatic assay of 7 alpha-hydroxylated steroids in urine. After suitable modification this assay in principle allows the screening of large populations for the existence of cerebrotendinous xanthomatosis and thus to detect the disease at an earlier stage of life. PMID: 3128689 [PubMed - indexed for MEDLINE] 385. Ann Med Interne (Paris). 1988;139(6):395-402. [Van Bogaert's cerebrotendinous xanthomatosis. A study of 3 cases]. [Article in French] Laurent A, Dairou F, Luc G, Truffert J, Lapresle J, de Gennes JL. Centre Hospitalier de Bicêtre, Service de Neurologie, Le Kremlin Bicêtre. The authors report three observations of cerebro-tendinous xanthomatosis (CTX). The three patients presented tendinous xanthoma and cataract. The neurologic disorders were different in each case. The first one, a 43 years old woman suffered from dementia, ataxia and pseudobulbar palsy: CT scan showed cerebellar hypodense lesions. After the apparition of bulbar signs ans cachexia she died at 45. The second patient, a 39 years old man had an ataxia and mild psychiatric disorders. He was stabilized with a treatment of chenodesoxycholic acid. The third one, a 49 years old women suffered only from tendinous xanthoma, cataract, and had no neurological disorder. His plasmatic cholestanol level was high. CTX is a recessive deficit of the hepatic 26 hydroxylase with deposits of abnormal metabolites in tendons, crystalline lenses and central nervous system. Reviewing the 44 observations of CTX in the literature, the authors define the genetical, clinical, biochemical and therapeutical aspects of CTX, and underline the necessity of a early diagnosis with cholestanol dosage, before the apparition of neurological disorders and the short terminal phase. CTX is a rare but fortunately treatable neurolipidosis. PMID: 3066249 [PubMed - indexed for MEDLINE] 386. J Neurol Sci. 1987 Dec;82(1-3):89-99. Polyneuropathy with lipid deposits in Schwann cells and axonal degeneration in cerebrotendinous xanthomatosis. Voiculescu V, Alexianu M, Popescu-Tismana G, Pastia M, Petrovici A, Dan A. Institute of Neurology and Psychiatry, Institute Cantacuzino, Bucharest, Romania. The present paper is a histological, histochemical and electron microscopic study of biopsied specimens from both right and left Achilles tendon, sural nerve and gastrocnemius muscle in a case of peripheral neuropathy with decreased sensory conduction velocity within a cerebrotendinous xanthomatosis confirmed biochemically in a 29-year-old woman. The tendon specimens contained large deposits of complex, non-homogeneous lipids, distributed intra- and extracellularly. The right sural nerve specimen showed a very severe neuropathy with massive diffuse myelinated fiber loss, presence of foamy macrophages and lipid droplets in Schwann cells. Segmental de- and remyelination was noted in 17% of the teased myelinated fibers. No onion bulbs were observed. Two years later, the left sural nerve specimen revealed a mild diffuse myelinated fiber loss, a more active segmental de- and remyelination (23%) without onion bulbs, and an active regeneration. Lipid storage aspects were absent. The gastrocnemius muscle specimens exhibited slight alterations of neurogenic origin. The pathogenesis of this neuropathy is discussed. PMID: 2831311 [PubMed - indexed for MEDLINE] 387. Biochim Biophys Acta. 1987 Nov 21;922(2):111-7. Metabolism of the cholestanol precursor cholesta-4,6-dien-3-one in different tissues. Buchmann MS, Björkhem I, Skrede S. Institute of Clinical Biochemistry, Rikshospitalet, University of Oslo, Norway. Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease where the basic defect is a lack of the mitochondrial C27-steroid 26-hydroxylase involved in bile acid synthesis (EC 1.14.13.15). Cholestanol and cholesterol accumulate in all tissues. At least part of the accumulation of cholestanol is due to a 7 alpha-dehydroxylation of early bile acid intermediates. Cholesta-4,6-dien-3-one, a proposed intermediate in this pathway, is found in increased concentrations in serum of the patients. This study shows that cholesta-4,6-dien-3-one may be metabolized to 4-cholesten-3-one and cholestanol by liver, adrenals and brain. No conversion was found in intestinal mucosa or in kidneys. The capacity to convert cholesta-4,6-dien-3-one into 4-cholesten-3-one and cholestanol varied in different tissues as well as in different species. The results are discussed in relation to the cholestanol accumulation in CTX. PMID: 3676336 [PubMed - indexed for MEDLINE] 388. Scand J Clin Lab Invest. 1987 Nov;47(7):701-4. Normal activity of C27-steroid 26-hydroxylase in cultured sitosterolaemia fibroblasts. Boberg KM, Björkhem I, Skrede S. Institute of Clinical Biochemistry, University of Oslo, Rikshospitalet, Norway. The primary defect in sitosterolaemia is unknown. In some patients excretion of bile alcohols is increased, and it has been suggested that the defect is located to some step in the biosynthesis of bile acids. The activity of C27-steroid 26-hydroxylase was measured in cultured skin fibroblasts from a sitosterolaemic patient. The same assay was used as before in demonstrating deficiency of this enzyme activity in cerebrotendinous xanthomatosis (CTX), a disease in which high excretion of bile alcohols is typical. The substrate, 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol, was 26-hydroxylated to the same extent in the patient cells as in those of healthy controls. Thus, the sitosterolaemia cells have a normal activity of this enzyme. PMID: 3685870 [PubMed - indexed for MEDLINE] 389. J Lipid Res. 1987 Aug;28(8):1006-12. Increased plasma bile alcohol glucuronides in patients with cerebrotendinous xanthomatosis: effect of chenodeoxycholic acid. Batta AK, Salen G, Shefer S, Tint GS, Batta M. Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103. Large quantities of C27 bile alcohols hydroxylated at C-25 are excreted in the bile and urine of patients with cerebrotendinous xanthomatosis, a lipid storage disease that results from defective bile acid synthesis. The presence of both biliary and urinary bile alcohols reflects impaired bile acid synthesis. After treatment of samples with beta-glucuronidase, plasma bile alcohols were quantitated by gas-liquid chromatography-mass spectrometry. 5 beta-Cholestane-3 alpha,7 alpha,12 alpha,25-tetrol (334 micrograms/dl) was found to be the major bile alcohol, followed by 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23R,25-pentol (65 micrograms/dl), and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24(R and S),25-pentols (62.5 micrograms/dl and 64.5 micrograms/dl, respectively) in the plasma of these patients. When compared to biliary and urinary bile alcohol excretions, the plasma pattern resembled bile where 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol glucuronide predominated. In contrast, urinary bile alcohols were composed chiefly of 5 beta-cholestanepentol glucuronides with only small amounts of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol glucuronide. Treatment with chenodeoxycholic acid, which suppresses abnormal bile acid synthesis in these patients, reduced plasma bile alcohol concentrations dramatically. These results show that large quantities of bile alcohol glucuronides, particularly 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrolglucuronide, circulate in plasma of patients with cerebrotendinous xanthomatosis. The plasma bile alcohols closely resemble biliary bile alcohols which indicates their hepatic origin. The large quantities of polyhydroxylated bile alcohols in the urine may suggest their formation, at least in part, from 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol by renal hydroxylating mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 3668385 [PubMed - indexed for MEDLINE] 390. J Chromatogr. 1987 Jul 29;400:241-6. Quantitative analysis of sterols in serum by high-performance liquid chromatography. Application to the biochemical diagnosis of cerebrotendinous xanthomatosis. Kasama T, Byun DS, Seyama Y. Department of Physiological Chemistry and Nutrition, Faculty of Medicine, University of Tokyo, Japan. A method for the simultaneous determination of 5 alpha-cholestan-3 beta-ol and cholesterol in serum by high-performance liquid chromatography was developed. After addition of internal standard (5 beta-cholestan-3 alpha-ol) and saponification with ethanolic potassium hydroxide, the sterols were converted into their benzoyl derivatives, which were subjected to reversed-phase liquid chromatography with ultraviolet detection at 228 nm. Only 0.1 ml of serum was needed to give a reproducible result. This method has been used for the biochemical diagnosis of cerebrotendinous xanthomatosis, a hereditary disorder of cholesterol metabolism. PMID: 3667750 [PubMed - indexed for MEDLINE] 391. Rinsho Shinkeigaku. 1987 Jul;27(7):873-6. [A case of familial type IIa hyperlipoproteinemia with the clinical features similar to cerebrotendinous xanthomatosis]. [Article in Japanese] Imasato M, Uozumi T, Tsuji S, Murai Y, Nakajima Y. PMID: 3665278 [PubMed - indexed for MEDLINE] 392. Neurology. 1987 Jun;37(6):1091-2. Cerebrotendinous xanthomatosis: more on diagnosis and treatment. Waterreus RJ, Koopman BJ. PMID: 3587638 [PubMed - indexed for MEDLINE] 393. N Engl J Med. 1987 May 14;316(20):1233-8. Increased concentrations of cholestanol and apolipoprotein B in the cerebrospinal fluid of patients with cerebrotendinous xanthomatosis. Effect of chenodeoxycholic acid. Salen G, Berginer V, Shore V, Horak I, Horak E, Tint GS, Shefer S. We investigated the effect of chenodeoxycholic acid on cerebrospinal fluid sterol and protein composition in six patients with cerebrotendinous xanthomatosis, a progressive neurologic disease, and in 11 control subjects. In the cerebrospinal fluid from the controls, the mean (+/- SD) levels of cholesterol and cholestanol were 400 +/- 300 and 4 +/- 7 micrograms per deciliter, respectively. The levels were almost 1.5 and 20 times higher in cerebrospinal fluid from untreated patients with cerebrotendinous xanthomatosis. Cholestanol levels were also markedly elevated in the plasma of untreated patients, but their plasma cholesterol levels (215 +/- 61 mg per deciliter) were not different from control values. Treatment with chenodeoxycholic acid reduced cerebrospinal fluid cholesterol by 34 percent and cholestanol threefold. Plasma cholestanol levels also decreased sharply. Normal cerebrospinal fluid contained small quantities of albumin, apolipoproteins, and lecithin:cholesterol acyltransferase. In cerebrospinal fluid from untreated patients with cerebrotendinous xanthomatosis, immunoreactive apolipoprotein B or apolipoprotein B fragment was increased about 100-fold and albumin about 3.5-fold; apolipoprotein AI, apolipoprotein D, and lecithin:cholesterol acyltransferase were 1.5 to 3 times more concentrated. Apolipoprotein AIV and apolipoprotein E concentrations were comparable to those in controls, and apolipoprotein AII was considerably decreased. During treatment, the concentrations of albumin and apolipoproteins AI and B declined. These results suggest that increased cerebrospinal fluid sterols are derived from plasma lipoproteins by means of a defective blood-brain barrier in patients with cerebrotendinous xanthomatosis. Therapy with chenodeoxycholic acid reestablished selective permeability of the blood-brain barrier and normalized the concentrations of sterol and apolipoprotein in the cerebrospinal fluid. PMID: 3106810 [PubMed - indexed for MEDLINE] 394. J Chromatogr. 1987 Apr 24;416(1):1-13. Determination of some hydroxycholesterols in human serum samples. Koopman BJ, van der Molen JC, Wolthers BG, Vanderpas JB. The simultaneous determination of some hydroxycholesterols in human serum samples is described. The procedure is based on hydrolysis and extraction of these compounds in serum samples, followed by removal of especially cholesterol (making use of reversed-phase high-performance liquid chromatography) and derivatization of the purified compounds to their trimethylsilyl ethers and subsequent gas chromatography using flame ionization detection. Serum levels of 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol and 26-hydroxycholesterol were determined in several groups of patients: normals, untreated patients suffering from cerebrotendinous xanthomatosis, patients suffering from cerebrotendinous xanthomatosis and treated with either chenodeoxycholic acid or cholic acid in an effective dose, patients suffering from cerebro-hepato-renal syndrome, patients suffering from hypercholesterolemia and treated with cholestyramine for prolonged periods and one patient presumed to be suffering from an inborn error of metabolism in bile acid synthesis. It can be concluded that the 7 alpha-hydroxycholesterol concentration in serum is a good parameter for establishing disorders involving the metabolic conversion of 7 alpha-hydroxycholesterol towards bile acids. In addition, 26-hydroxycholesterol levels in patients suffering from cerebrotendinous xanthomatosis are beyond detectable limits, even during treatment with bile acids in an effective dose, whereas in all other conditions this compound is substantially present. PMID: 3597624 [PubMed - indexed for MEDLINE] 395. Metabolism. 1987 Mar;36(3):270-6. Low-density lipoprotein metabolism in cerebrotendinous xanthomatosis. Ballantyne CM, Vega GL, East C, Richards G, Grundy SM. Cerebrotendinous xanthomatosis (CTX) is a rare disorder characterized by a defect in conversion of cholesterol into bile acids, increased plasma levels of cholestanol, and accumulations of sterols in tendons, brain, and coronary arteries. Despite the presence of tendon xanthomas, patients with CTX frequently have low levels of plasma cholesterol and low density lipoproteins (LDL). The mechanisms for a low LDL are not understood. The present study, therefore, was carried out to examine the metabolism of LDL in a 58-year-old black man with CTX. This particular patient had an LDL-cholesterol in the mid-normal range (149 +/- 6 mg/dL). Nonetheless, his fractional catabolic rate (FCR) for LDL-apolipoprotein (apo-LDL) was 0.45 pools/d, which was increased compared to 15 aged-matched men (FCR, 0.30 +/- 0.01 pools/d). His production rate for apo-LDL (18.5 mg/kg-d) also was increased compared to those of middle-aged men (13.5 +/- 2.5 mg/kg-d). Since the underlying defect in CTX can be reversed by administration of chenodeoxycholic acid (chenodiol), the patient was treated with chenodiol (250 mg 4X daily), and measurements of LDL kinetics were repeated. During chenodiol therapy, his LDL-cholesterol concentration rose significantly to 165 +/- 12 mg/dL; his FCR for apo-LDL fell to 0.29 pools/d; and his production rate of apo-LDL declined to 14.4 mg/kg-d. We postulate that chenodiol suppressed the excessive synthesis of cholesterol and bile acids, which had two effects. It curtailed both the overproduction of LDL and the excessive synthesis of LDL receptors, the latter being responsible for the high FCR of apo-LDL in the untreated state. PMID: 3821507 [PubMed - indexed for MEDLINE] 396. Hepatology. 1987 Mar-Apr;7(2):266-71. Accumulation of 7 alpha-hydroxy-4-cholesten-3-one and cholesta-4,6-dien-3-one in patients with cerebrotendinous xanthomatosis: effect of treatment with chenodeoxycholic acid. Björkhem I, Skrede S, Buchmann MS, East C, Grundy S. Evidence was recently presented that an essential part of the accumulation of cholestanol in patients with cerebrotendinous xanthomatosis is due to acceleration of a novel pathway, involving 7 alpha-hydroxylated intermediates in bile acid biosynthesis as precursors (J. Clin. Invest. 1985; 75:448-456). Such intermediates accumulate in patients with cerebrotendinous xanthomatosis due to lack of the mitochondrial 26-hydroxylase involved in the major pathway for bile acid biosynthesis. The new pathway may involve the following steps: 7 alpha-hydroxycholesterol----7 alpha-hydroxy-4-cholesten-3-one----cholesta-4,6- dien-3-one----4-cholesten-3-one----cholestanol. Accurate methods have been developed for assay of 7 alpha-hydroxy-4-cholesten-3-one and cholesta-4,6-dien-3-one in serum, based on isotope dilution-mass spectrometry. The serum levels of 7 alpha-hydroxy-4-cholesten-3-one as well as those of cholesta-4,6-dien-3-one were found to be markedly elevated in the three patients with cerebrotendinous xanthomatosis. Treatment of two of the patients with chenodeoxycholic acid reduced the serum levels of the two steroids by more than 80%. The concentration of cholestanol was reduced by 72% in one patient and by 48% in the other. The possibility is discussed that accumulation of cholestanol in patients with cerebrotendinous xanthomatosis is secondary to accumulation of 7 alpha-hydroxy-4-cholesten-3-one and cholesta-4,6-dien-3-one. PMID: 3557306 [PubMed - indexed for MEDLINE] 397. Biochim Biophys Acta. 1987 Feb 14;917(2):238-46. Abnormal urinary bile acids in a patient suffering from cerebrotendinous xanthomatosis during oral administration of ursodeoxycholic acid. Koopman BJ, Wolthers BG, van der Molen JC, Nagel GT, Kruizinga W. The urinary bile acid profile, obtained by capillary gas chromatography, of a patient suffering from cerebrotendinous xanthomatosis and treated with ursodeoxycholic acid demonstrated, besides the occurrence of 23-norcholic acid and (23R)-hydroxycholic acid (as a consequence of this disease), six additional unknown bile acids and three known bile acids, viz. ursodeoxycholic acid, hyocholic acid and omega-muricholic acid. The structure of two of the unknown bile acids were elucidated and proven by organic syntheses. These were 23-norursodeoxycholic acid and 3 beta-ursodeoxycholic acid. The structures of three bile acids were tentatively elucidated as being 1 beta-hydroxyursodeoxycholic acid, 21-hydroxyursodeoxycholic acid and 22-hydroxyursodeoxycholic acid, and the possibility that the structure of the remaining bile acid is that of 5-hydroxyursodeoxycholic acid is discussed. Two of these bile acids (1 beta-hydroxyursodeoxycholic acid and 5-hydroxyursodeoxycholic acid) also occurred in urine of a healthy individual during oral ursodeoxycholic acid treatment, whereas 23-norcholic acid, 23-norursodeoxycholic acid, (23R)-hydroxycholic acid, 21-hydroxyursodeoxycholic acid and 22-hydroxyursodeoxycholic acid were only present in urine of the patient suffering from cerebrotendinous xanthomatosis. The metabolism of ursodeoxycholic acid, both in the normal state and in the cerebrotendinous xanthomatosis, is discussed. PMID: 3801500 [PubMed - indexed for MEDLINE] 398. J Pediatr Gastroenterol Nutr. 1987 Jan-Feb;6(1):33-41. Malabsorption of liposoluble vitamins in a child with bile acid deficiency. Vanderpas JB, Koopman BJ, Cadranel S, Vandenbergen C, Rickaert F, Quenon M, Wolthers BG, Brauherz G, Vertongen F, Tondeur M. A male born to first cousins presented at 12 months with hypocalcemic convulsions, rickets, epistaxis due to vitamin K deficiency, and extremely low serum levels of beta-carotene and vitamin A. Liver function was altered moderately (glutamic-oxaloacetic transaminase, 55 U/L; glutamic-pyruvic transaminase, 37 U/L; lactate dehydrogenase, 255 U/L; alkaline phosphatase, 437 U/L). To correct the deficiencies, 8,000 IU vitamin D/day, 10,000 IU vitamin A/day, and intramuscular administration of vitamin K1 were required. At 9 years, he presented signs of neuromuscular affection, and the serum vitamin E level (measured for the first time) was extremely low. Classic lipid malabsorption syndromes (abetalipoproteinemia, chronic cholestasis, mucoviscidosis, coeliac disease, Whipple's disease) were excluded by appropriate examinations. Composition of duodenal bile acids was characterized by undetectable levels of cholic acid metabolites, and only chenodeoxycholic acid metabolites were present. Serum total bile acid concentration was normal, with an atypical low cholic acid/chenodeoxycholic acid ratio and abnormal presence of 3 beta-OH-delta 5-cholenic acid and 6-OH-bile acids. Urinary bile acid composition was also characterized by elevated 6-OH-bile acids. Known enzymopathies of the bile acid synthetic pathway were excluded (cerebrotendinous xanthomatosis, cerebro-hepato-renal syndrome of Zellweger, coprostanic acidemia). Bile acid pool sizes were determined by using stable isotopes: cholic acid pool size [2.90 (N, 32 +/- 16) microM/kg] and chenodeoxycholic acid pool size [10.8 (N, 32.6 +/- 9.9) microM/kg] were extremely low; fractional turnover rates of both bile acids were in a normal range.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 3794931 [PubMed - indexed for MEDLINE] 399. Clin Neurol Neurosurg. 1987;89(3):169-75. Cerebrotendinous xanthomatosis (CTX): a clinical survey of the patient population in The Netherlands. Waterreus RJ, Koopman BJ, Wolthers BG, Oosterhuis HJ. Department of Neurology, University Hospital, Groningen, The Netherlands. The clinical features and additional investigations of 20 Dutch patients suffering from cerebrotendinous xanthomatosis (CTX), an inborn error of metabolism in bile acid synthesis, are described. The onset was in the second or third decade. The clinical picture at the time of examination consisted of a combination of two or more of the following signs: cataract, xanthoma of a tendon, mental deterioration, pyramidal tract signs, cerebellar signs and epilepsy. Mental retardation was reported in patients. CT-scanning showed cerebellar hypodensity in 8 out of 16 patients but this feature did not correlate well with cerebellar signs. The EEG was abnormal in all but one patient. Treatment with chenodeoxycholic acid resulted in a normalization of EEG and biochemical abnormalities but not of the clinical signs. Cholic acid was equally effective but had much less side effects. The importance of a diagnosis in early life is stressed as well as the examination of clinically unaffected heterozygous relatives. PMID: 3665290 [PubMed - indexed for MEDLINE] 400. Skeletal Radiol. 1987;16(4):346-9. Case report 427: Cerebrotendinous xanthomatosis. Burnstein M, Buckwalter KA, Martel W, McClatchey KD, Quint D. PMID: 3616675 [PubMed - indexed for MEDLINE] 401. Clin Chem. 1987 Jan;33(1):142-3. Screening for cerebrotendinous xanthomatosis by using an enzymatic assay for 7 alpha-hydroxylated steroids in urine. Koopman BJ, Van der Molen JC, Wolthers BG, Waterreus RJ. We used a commercial enzymatic kit for measuring 7 alpha-hydroxylated bile acids to screen urines from normal subjects, liver-transplant recipients, and patients with various liver diseases, cerebro-hepato-renal syndrome, or cerebrotendinous xanthomatosis (CTX). Because of their high concentrations of 7 alpha-hydroxylated compounds excreted, the CTX patients were clearly distinguished from all other groups except for a slight overlap with the patients with cerebro-hepato-renal syndrome and liver-transplant recipients. Gas chromatography for bile alcohols completed the differential diagnosis. PMID: 3542288 [PubMed - indexed for MEDLINE] 402. Lipids. 1986 Dec;21(12):738-43. Effects of cholestanol feeding and cholestyramine treatment on the tissue sterols in the rabbit. Buchmann MS, Clausen OP. Rabbits were fed diets enriched with cholestanol or cholesterol (3.5 g/wk) for 4-12 weeks. During cholestanol feeding, the concentration of cholestanol in blood serum, liver, heart and aorta increased 15-30 times. In serum and liver, the concentration of cholesterol also increased. Cholestanol-fed rabbits developed inflammatory changes in the liver, with proliferation of small bile ducts. Liver tests were only slightly abnormal. Morphological atherosclerosis of the aorta was only occasionally seen in rabbits receiving cholestanol for eight weeks or less. During cholesterol feeding, the amounts of cholesterol in different tissues increased dramatically, most in the aorta. Morphological atherosclerosis in the aorta was found in all rabbits fed cholesterol-enriched diets for more than four weeks. Brain cholestanol was doubled in rabbits fed cholestanol for eight weeks, whereas brain sterols did not change significantly during cholesterol feeding. After an additional regression period with cholestyramine for eight weeks, the increased content of cholestanol in the brain was unchanged in cholestanol-fed rabbits. These observations are discussed in relation to the cholestanolosis of the brain that develops in the rare inherited human disease cerebrotendinous xanthomatosis. PMID: 3821387 [PubMed - indexed for MEDLINE] 403. J Lipid Res. 1986 Dec;27(12):1328-32. Configuration at C-25 in 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25,26-pentol excreted by patients with cerebrotendinous xanthomatosis: circular dichroism and 13C-NMR studies. Dayal B, Salen G, Toome V, Tint GS. The configuration at C-25 in 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha,25,26-pentol isolated from the bile and feces of patients with cerebrotendinous xanthomtosis (CTX) was determined from the lanthanide-induced circular dichroism (CD) Cotton effects and 13C-NMR measurements. Under anhydrous conditions, CD spectra of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha,25,26-pentol in the presence of Eu(fod)3 exhibited a large induced negative Cotton effect at 320 nm. On the basis of the empirical rule (primary-tertiary-alpha-diols) in which R compounds have positive Cotton effects and S compounds have negative Cotton effects at 320 nm, it was concluded that 25,26-pentol has the 1,2,glycol structure with C-25 having the S-configuration. This assignment was based upon comparison with model compounds, 25(R and S),26-dihydroxy cholesterols and 25(R and S),26-dihydroxy cholecalciferols whose single-crystal X-ray structure and 13C-NMR studies have been performed. It is suggested that these data may be helpful to clarify the stereospecificity of the hydroxylation of the terminal methyl group of the cholesterol side chain in CTX. PMID: 3559396 [PubMed - indexed for MEDLINE] 404. Clin Chim Acta. 1986 Nov 15;160(3):255-63. Quantitative analysis of the mitochondrial cytochrome P-450-linked monooxygenase system: NADPH-hepatoredoxin reductase, hepatoredoxin, and cytochrome P-450s27 in livers of patients with cerebrotendinous xanthomatosis. Miki H, Takeuchi H, Yamada A, Nishioka M, Matsuzawa Y, Hamamoto I, Hiwatashi A, Ichikawa Y. We studied the mitochondrial cytochrome P-450-linked monooxygenase system in livers of two patients with cerebrotendinous xanthomatosis (CTX). The three components of this system, which catalyzes steroid 27-hydroxylation, NADPH-hepatoredoxin reductase, hepatoredoxin, and cytochrome P-450s27, were stained on a nitrocellulose sheet with antibodies against NADPH-adrenodoxin reductase, adrenodoxin, and cytochrome P-450scc, respectively, from bovine adrenocortical mitochondria. The concentrations of hepatoredoxin in the patients were not significantly different from a control, but the level of NADPH-hepatoredoxin reductase was three times that of the control. Cytochrome P-450s27 was not detected in the patients, but it was present (22.8 pmol/mg of protein) in the control liver. This implies that a defect of mitochondrial cytochrome P-450s27 prevents steroid 27-hydroxylation of hepatic mitochondria in patients with CTX. PMID: 3791635 [PubMed - indexed for MEDLINE] 405. Arch Dermatol. 1986 Nov;122(11):1269-72. Capillary gas chromatography of urine samples in diagnosing cerebrotendinous xanthomatosis. Bouwes Bavinck JN, Vermeer BJ, Gevers Leuven JA, Koopman BJ, Wolthers BG. A patient is described with many clinical features of cerebrotendinous xanthomatosis (CTX), but with only slightly elevated cholestanol/cholesterol concentration ratios in serum and xanthomatous tissue. However, with capillary gas chromatographic determinations of urinary bile acids and bile alcohols we demonstrated the typical biochemical abnormalities as seen in CTX patients. This article emphasizes the value of urinary capillary gas chromatography as a specific test to establish the diagnosis of CTX and to monitor the biochemical effectivity of the different treatment regimens. PMID: 3777973 [PubMed - indexed for MEDLINE] 406. J Lipid Res. 1986 Nov;27(11):1154-62. Identification of unconjugated bile acids in human bile. Matoba N, Une M, Hoshita T. Unconjugated bile acids in the bile of healthy and diseased humans were determined qualitatively and quantitatively by means of gas-liquid chromatography and gas-liquid chromatography-mass spectrometry, after their isolation by ion-exchange chromatography. In a healthy person and three patients with cholelithiasis, unconjugated bile acids comprised 0.1-0.4% of total biliary bile acids. The bile acid composition of the unconjugated fraction was quite different from that of the glycine- or taurine-conjugate fraction, in that it contained a relatively large proportion of unusual bile acids including C23 and C27 bile acids. In two patients with cerebrotendinous xanthomatosis, C22 and C23 bile acids were the major constituents of the biliary unconjugated bile acids, and comprised about 0.8% of total bile acids; no detectable amounts of C27 bile acids were found in their bile. The analysis of biliary unconjugated bile acids may be useful for the diagnosis of metabolic diseases concerning bile acids, particularly the accumulation or disappearance of unusual bile acids. PMID: 3559381 [PubMed - indexed for MEDLINE] 407. Biochim Biophys Acta. 1986 Oct 1;883(3):585-92. Increased (23R)-hydroxylase activity in patients suffering from cerebrotendinous xanthomatosis, resulting in (23R)-hydroxylation of bile acids. Koopman BJ, Wolthers BG, Van der Molen JC, Nagel GT, Rutgers H, Strijtveen B, Kaptein B. Patients suffering from cerebrotendinous xanthomatosis, an inborn error of metabolism in bile acid synthesis, excrete excessive amounts of 23-hydroxylated bile alcohols, 23-norcholic acid and 23-hydroxycholic acid into urine. In this study the configuration of this excreted 23-hydroxycholic acid was established as (23R)-hydroxycholic acid. Urine samples of two treated patients, receiving chenodeoxycholic acid, were investigated to see whether this administered bile acid was partly converted into 23-hydroxychenodeoxycholic acid. One patient was treated with ursodeoxycholic acid for 1 month and subsequently with chenodeoxycholic acid, and the urinary excretion of both (23R)-hydroxychenodeoxycholic acid and (23R)-hydroxyursodeoxycholic acid were followed. Indeed, all three patients excreted (23R)-hydroxylated chenodeoxycholic acid during oral treatment with chenodeoxycholic acid, and the patient treated with ursodeoxycholic acid excreted (23R)-hydroxylated ursodeoxycholic acid. During treatment with chenodeoxycholic acid the excretion of (23R)-hydroxychenodeoxycholic acid increases at first and later on decreases markedly. These findings suggest increased (23R)-hydroxylase activity in patients suffering from cerebrotendinous xanthomatosis, acting both on endogenously synthesized bile alcohols and on exogenously administered bile acids; during continuation of chenodeoxycholic acid treatment in an effective dose (750 mg/day) this enzyme activity gradually disappears. PMID: 3756224 [PubMed - indexed for MEDLINE] 408. J Clin Invest. 1986 Sep;78(3):729-35. Demonstration of 26-hydroxylation of C27-steroids in human skin fibroblasts, and a deficiency of this activity in cerebrotendinous xanthomatosis. Skrede S, Björkhem I, Kvittingen EA, Buchmann MS, Lie SO, East C, Grundy S. 26-Hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol and other C27-steroids was demonstrated in cultured skin fibroblasts from healthy individuals. Activities in skin fibroblasts were approximately 5-10% of those previously found in human liver homogenates, and were inhibited by CO. The apparent Km was lowest for 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol (1.3 mumol/liter) and highest for 5-cholestene-3 beta, 7 alpha-diol (12 mumol/liter). The rate of 26-hydroxylation was highest with 7 alpha-hydroxy-4-cholesten-3-one. These characteristics are similar to those of hepatic mitochondrial C27-steroid 26-hydroxylase. In skin fibroblasts from three patients with cerebrotendinous xanthomatosis (CTX), 26-hydroxylation of C27-steroids proceeded at a rate of only 0.2-2.5% of healthy controls. No accumulation of endogenous 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol could be demonstrated in these cells, and the lowered formation of radioactive, 26-hydroxylated products could not be explained by dilution of the labeled exogenous substrate. The present results add strong evidence to the concept that the primary metabolic defect in CTX is a deficiency of C27-steroid 26-hydroxylase. PMCID: PMC423662 PMID: 3745434 [PubMed - indexed for MEDLINE] 409. Clin Chim Acta. 1986 Jul 30;158(2):179-85. Detection of carriers of cerebrotendinous xanthomatosis. Koopman BJ, Waterreus RJ, Van den Brekel HW, Wolthers BG. Patients suffering from cerebrotendinous xanthomatosis (an autosomal recessive inborn error of metabolism) can easily be distinguished from patients not suffering from this disease, as the first excrete large amounts of the bile alcohol, 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol, in urine, whereas the second do not. In order to find out, whether carriers of cerebrotendinous xanthomatosis can be detected in a biochemical way, we compared known carriers with controls. The urinary excretions of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol of both groups were practically absent and no selection of carriers with cerebrotendinous xanthomatosis could be made on that basis. When, however, carriers and non-carriers were subjected to cholestyramine treatment, by which endogenous bile acid synthesis was stimulated, the urinary excretion of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol in the carrier rose considerably, whereas this excretion remained essentially the same in the non-carriers. This test can be of value in the genetic counseling of carriers with cerebrotendinous xanthomatosis and helpful in the detection of newborn patients with cerebrotendinous xanthomatosis. PMID: 3742821 [PubMed - indexed for MEDLINE] 410. Steroids. 1986 Jul-Aug;48(1-2):109-19. Bile acid profiles in bile, urine, and feces of a patient with cerebrotendinous xanthomatosis. Kihira K, Shimazu K, Kuwabara M, Yoshii M, Takeuchi H, Nakano I, Ozawa S, Onuki M, Hatta Y, Hoshita T. Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Japan. Bile acid profiles of bile, urine, and feces obtained from a patient with cerebrotendinous xanthomatosis on the same day have been analyzed by gas-liquid chromatography-mass spectrometry after fractionation into groups by mode of conjugation by an ion-exchange chromatography. The predominant biliary bile acid was cholic acid conjugated with glycine and taurine. Lesser amounts of the amino acid conjugates of chenodeoxycholic acid, ursodeoxycholic acid, 7-ketodeoxycholic acid, allocholic acid, and deoxycholic acid, and of unconjugated norcholic acid and allonorcholic acid were also present in the bile. The major fecal bile acid was 7-epicholic acid. Relatively large amounts of bile acids were excreted in the urine. Unconjugated 7-epicholic acid, norcholic acid, allonorcholic acid, and cholic acid predominated. The bile acid profiles of the patient were different from those of normal subjects and should be useful for the diagnosis. PMID: 3660436 [PubMed - indexed for MEDLINE] 411. Ann Neurol. 1986 Jul;20(1):89-91. Chronic demyelinating peripheral neuropathy in cerebrotendinous xanthomatosis. Argov Z, Soffer D, Eisenberg S, Zimmerman Y. Three siblings with chemically proved cerebrotendinous xanthomatosis presented with typical neurological manifestations of dementia and spinocerebellar disorder. Electrodiagnostic tests revealed demyelinating neuropathy in all three. Sural nerve biopsies showed loss of myelinated large fibers, marked Schwann cell proliferation, and onion bulb formation. Teased-fiber preparations confirmed the occurrence of segmental demyelination and remyelination. We suggest that demyelinating neuropathy is part of the neurological spectrum of cerebrotendinous xanthomatosis and should be considered in the differential diagnosis of a recessively inherited motor and sensory neuropathy. PMID: 3017187 [PubMed - indexed for MEDLINE] 412. J Biochem. 1986 Mar;99(3):771-5. Biochemical diagnosis of cerebrotendinous xanthomatosis using reversed phase thin layer chromatography. Kasama T, Seyama Y. We developed a simple quantitative procedure for cholestanol in serum involving reversed phase thin layer chromatography. This procedure was satisfactory with regard to the linearity of the calibration curve in the range of 100 ng to 1,000 ng, recovery and reproducibility. Only 100 microliter of serum was needed for determination of the cholestanol concentration. Prior to thin layer chromatography, cholesterol was converted to alpha- and beta-epoxides with m-chloroperbenzoic acid, which were clearly distinguishable from cholestanol on TLC. Detection of sterols was performed by spraying with phosphomolybdic acid solution. Quantification of cholestanol was carried out with a TLC scanning densitometer. When serum cholestanol in cerebrotendinous xanthomatosis (CTX) patients was quantified by TLC, GC-MS, and GC, the correlation among the three methods was found to be approximately 1:1:1. It was found that the present method was useful for the primary diagnostic screening of CTX because of its simplicity and because many samples could be analyzed at one time. PMID: 3086296 [PubMed - indexed for MEDLINE] 413. J Biochem. 1986 Feb;99(2):477-83. Bile alcohol profiles in bile, urine, and feces of a patient with cerebrotendinous xanthomatosis. Shimazu K, Kuwabara M, Yoshii M, Kihira K, Takeuchi H, Nakano I, Ozawa S, Onuki M, Hatta Y, Hoshita T. Bile alcohols in bile, urine, and feces of a patient with cerebrotendinous xanthomatosis have been analyzed by a combination of capillary gas-liquid chromatography and mass spectrometry after fractionation into groups according to mode of conjugation. The presence of at least 18 bile alcohols, which were excreted mainly as glucurono-conjugates in bile and urine, and as unconjugated forms in feces, was demonstrated. The following bile alcohols were identified with certainty by direct comparison with reference compounds: 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol; (23R)-5 beta-cholestane-3 alpha,7 alpha,12 alpha,23-tetrol; 5 alpha- and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24-tetrols; 5 alpha- and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrols; 27-nor-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,25-pentol; (22R)-5 beta-cholestane-3 alpha,7 alpha,12 alpha,22,25-pentol; (23R)- and (23S)-5 beta-cholestane-3 alpha,7 alpha, 12 alpha,23,25-pentols; 3 alpha,12 alpha,25-trihydroxy-5 beta-cholestane-7-one; (24R)- and (24S)-5 beta-cholestane-3 alpha,7 alpha,12 alpha,24,25-pentols; 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25,26-pentol. Although the bile alcohol profile in urine was quite different from those in bile and feces, the determination of urinary bile alcohols as well as of biliary and fecal bile alcohols could be used for diagnosis of cerebrotendinous xanthomatosis. PMID: 3700361 [PubMed - indexed for MEDLINE] 414. Neurology. 1986 Jan;36(1):124-6. Magnetic resonance imaging in cerebrotendinous xanthomatosis. Swanson PD, Cromwell LD. In a patient with cerebrotendinous xanthomatosis, magnetic resonance imaging (MRI) revealed findings of demyelination in the cerebral white matter, which was also hypodense on CT. The MRI abnormality seemed to be clinically significant in this patient with progressive dementia and abnormal gait. PMID: 3941768 [PubMed - indexed for MEDLINE] 415. Clin Invest Med. 1986;9(2):94-9. Tendon xanthomas associated with cholestanolosis and hyperapobetalipoproteinemia. Lussier-Cacan S, Cantin M, Roy CC, Sniderman AD, Nestruck AC, Davignon J. Large Achilles tendon xanthomas of the type found in severe familial hypercholesterolemia were the first manifestation of cholestanolosis (cerebrotendinous xanthomatosis) in our patient, an otherwise asymptomatic normolipidemic 21-year-old woman. Extensive laboratory investigation disclosed the presence of hyperapobetalipoproteinemia which did not resolve with the administration of probucol. Immunofluorescent studies revealed marked accumulation of apolipoprotein B in a xanthoma excised from the tricipital area. This was in contrast to the spotty and weak fluorescence observed in a tuberous xanthoma, from the same anatomical area and histologically otherwise identical, obtained from a patient with heterozygous familial hypercholesterolemia. Hyperapobetalipoproteinemia has been reported before in association with sitosterolemia but not with cholestanolosis. We suggest that cholestanol, like sitosterol, may interfere with the normal uptake and degradation of low-density lipoproteins by peripheral cells. PMID: 3731582 [PubMed - indexed for MEDLINE] 416. Scand J Clin Lab Invest Suppl. 1986;184:41-6. On the mechanism of biosynthesis of cholestanol from 7 alpha-hydroxycholesterol. Buchmann MS, Björkhem I, Lund AM, Skrede S. In a patient with cerebrotendinous xanthomatosis (CTX), a small part of i.v. administered [7 beta-3H]-7 alpha-hydroxycholesterol was converted into cholestanol. Traces of 3H were also found in plasma cholesterol, but its specific radioactivity was only about 1% of that of cholestanol. When [7 beta-3H]-7 alpha-hydroxycholesterol was given orally to rabbits, significant amounts of 3H were found in cholestanol in different organs. Much less 3H was found in cholesterol. Our results support the conclusion that the pathway from 7 alpha-hydroxycholesterol to cholestanol does not involve cholesterol, but 7 alpha-hydroxy-4-cholesten-3-one and cholesta-4,6-dien-3-one as intermediates. PMID: 3109015 [PubMed - indexed for MEDLINE] 417. Scand J Gastroenterol. 1985 Dec;20(10):1262-6. Studies of the mechanism of the increased biosynthesis of cholestanol in cerebrotendinous xanthomatosis. The activity of delta 5-3 beta-hydroxysteroid dehydrogenase. Buchmann MS, Björkhem I, Fausa O, Skrede S. It was recently proposed that the increased biosynthesis of cholestanol in cerebrotendinous xanthomatosis (CTX) is due to increased activity of the delta 5-3 beta-hydroxysteroid dehydrogenase involved in bile acid biosynthesis, causing increased conversion of cholesterol into cholestanol through 4-cholesten-3-one. Our attempts to confirm this hypothesis have failed. Liver biopsy specimens from two patients with CTX did not have any increased capacity to catalyze conversion of 7 alpha-hydroxycholesterol into 7 alpha-hydroxy-4-cholesten-3-one. Further, we did not find any changes in the activity of liver microsomal delta 5-3 beta-hydroxysteroid dehydrogenase after feeding rabbits with cholestanol or cholesterol. The findings are discussed in relation to our hypothesis that the accelerated biosynthesis of cholestanol in CTX is due to an increased conversion of early bile acid intermediates into cholestanol. PMID: 3868019 [PubMed - indexed for MEDLINE] 418. Clin Chim Acta. 1985 Oct 31;152(1-2):115-22. Bile acid therapies applied to patients suffering from cerebrotendinous xanthomatosis. Koopman BJ, Wolthers BG, van der Molen JC, Waterreus RJ. Patients suffering from cerebrotendinous xanthomatosis, an inborn error of metabolism in bile acid synthesis, were given oral treatment with chenodeoxycholic acid, ursodeoxycholic acid, cholic acid and taurocholic acid. The effectiveness of the different therapies was evaluated by measuring the urinary excretion of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol, which should decrease, when the administered bile acid is able to suppress endogenous bile acid synthesis. From the results it is concluded that chenodeoxycholic acid and cholic acid activate the bile acid negative feedback mechanism, contrary to ursodeoxycholic acid and taurine conjugated cholic acid. Either cholic acid or chenodeoxycholic acid are the therapies of choice for the treatment of cerebrotendinous xanthomatosis. For various reasons the use of cholic acid is especially recommended. PMID: 4053393 [PubMed - indexed for MEDLINE] 419. Ann Neurol. 1985 Oct;18(4):517-8. Treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. Pedley TA, Emerson RG, Warner CL, Rowland LP, Salen G. We describe a patient with cerebrotendinous xanthomatosis who was treated for one year with chenodeoxycholic acid. Modest clinical improvement was accompanied by marked improvement in visual and brainstem auditory evoked potentials. Improved central nervous system function coincided with return of plasma and cerebrospinal fluid cholestanol levels to normal. PMID: 4073846 [PubMed - indexed for MEDLINE] 420. Arch Neurol. 1985 Oct;42(10):1008-10. Peripheral neuropathy in cerebrotendinous xanthomatosis. Katz DA, Scheinberg L, Horoupian DS, Salen G. We performed a sural nerve biopsy in a patient with cerebrotendinous xanthomatosis (CTX) because of electrophysiologic evidence of peripheral neuropathy. The sections showed a striking loss of myelinated axons, the distribution of which suggested a compressive and/or ischemic process. Biochemical analysis disclosed large amounts of cholestanol, a cholesterol derivative that characteristically accumulates in CTX. However, the biochemical abnormality was not associated with any obvious structural alterations in the myelin lamellae or with abnormal storage material in Schwann's cells. PMID: 2994606 [PubMed - indexed for MEDLINE] 421. Scand J Clin Lab Invest. 1985 Sep;45(5):443-6. Fast atom bombardment mass spectrometry in the diagnosis of cerebrotendinous xanthomatosis. Egestad B, Pettersson P, Skrede S, Sjövall J. Urine from a patient with cerebrotendinous xanthomatosis (CTX) was extracted with a Sep-Pak C18 cartridge and the extract was analysed by fast atom bombardment mass spectrometry. The spectra indicated the presence of glucuronidated bile alcohols with four to seven hydroxyl groups. The method is simple and rapid and is suggested as an aid in the diagnosis of CTX with possible application to prenatal diagnosis. PMID: 4035280 [PubMed - indexed for MEDLINE] 422. N Engl J Med. 1985 Aug 15;313(7):455. Cerebrotendinous xanthomatosis. Barron JL. PMID: 4022076 [PubMed - indexed for MEDLINE] 423. J Clin Invest. 1985 Aug;76(2):744-51. Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26. Salen G, Shefer S, Tint GS, Nicolau G, Dayal B, Batta AK. To examine the defect in side-chain oxidation during the formation of bile acids in cerebrotendinous xanthomatosis, we measured in vitro hepatic microsomal hydroxylations at C-12 and C-25 and mitochondrial hydroxylation at C-26 and related them to the pool size and synthesis rates of cholic acid and chenodeoxycholic acid as determined by the isotope dilution technique. Hepatic microsomes and mitochondria were prepared from seven subjects with cerebrotendinous xanthomatosis and five controls. Primary bile acid synthesis was markedly reduced in cerebrotendinous xanthomatosis as follows: cholic acid, 133 +/- 30 vs. 260 +/- 60 mg/d in controls; and chenodeoxycholic acid, 22 +/- 10 vs. 150 +/- 30 mg/d in controls. As postulated for chenodeoxycholic acid synthesis, mitochondrial 26-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha-diol was present in all specimens and was 30-fold more active than the corresponding microsomal 25-hydroxylation. However, mean mitochondrial 26-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha-diol was less active in cerebrotendinous xanthomatosis than in controls: 59 +/- 17 compared with 126 +/- 21 pmol/mg protein per min. As for cholic acid synthesis, microsomal 25-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol was substantially higher in cerebrotendinous xanthomatosis and control preparations (620 +/- 103 and 515 +/- 64 pmol/mg protein per min, respectively) than the corresponding control mitochondrial 26-hydroxylation of the same substrate (165 +/- 25 pmol/mg protein per min). Moreover in cerebrotendinous xanthomatosis, mitochondrial 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol-26-hydroxylase activity was one-seventh as great as in controls. Hepatic microsomal 12 alpha-hydroxylation, which may be rate-controlling for the cholic acid pathway, was three times more active in cerebrotendinous xanthomatosis than in controls: 1,600 vs. 500 pmol/mg protein per min. These results demonstrate severely depressed primary bile acid synthesis in cerebrotendinous xanthomatosis with a reduction in chenodeoxycholic acid formation and pool size disproportionately greater than that for cholic acid. The deficiency of chenodeoxycholic acid can be accounted for by hyperactive microsomal 12 alpha-hydroxylation that diverts precursors into the cholic acid pathway combined with decreased side-chain oxidation (mitochondrial 26-hydroxylation). However, side-chain oxidation in cholic acid biosynthesis may be initiated via microsomal 25-hydroxylation of 5beta-cholestane-3alpha,7alpha,12alpha-triol was substantially lower in control and cerebrotendinous xanthomatosis liver. Thus, separate mechanisms may exist for the cleavage of the cholesterol side chain in cholic acid and chenodeoxycholic acid biosynthesis. PMCID: PMC423892 PMID: 4031069 [PubMed - indexed for MEDLINE] 424. Pediatr Dermatol. 1985 Jul;2(4):294-6. Cerebrotendinous xanthomatosis is treatable. White SW. Cerebrotendinous xanthomatosis is a recessively inherited disorder of bile acid metabolism. Cataracts and tendinous xanthomas begin during adolescence. Results of routine tests of plasma lipids are normal. Therapy with chenodeoxycholic acid may reduce the production of cholestanol and thus slow the course of the disease. PMID: 3925446 [PubMed - indexed for MEDLINE] 425. J Lipid Res. 1985 Jun;26(6):690-8. Effect of chenodeoxycholic acid on biliary and urinary bile acids and bile alcohols in cerebrotendinous xanthomatosis; monitoring by high performance liquid chromatography. Batta AK, Shefer S, Batta M, Salen G. Biliary and urinary bile alcohol and bile acid composition has been determined by high performance liquid chromatography in patients with cerebrotendinous xanthomatosis before and after treatment with chenodeoxycholic acid. Most of the bile acids and bile alcohols in the bile and urine were separated in less than 30 min using a radial pack C18 muBondapak 5 micron particle size column with a mobile phase of acetonitrile-water-methanol-acetic acid 70:70:20:1 (v/v/v/v) at a flow rate of 2 ml/min, and a refractive index detector. Before treatment, cholic acid (49%) and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol (27%) were the major biliary bile acid and bile alcohol, respectively, but were not detected in the urine of five patients. 5 beta-Cholestane-pentols were, instead, the major urinary bile alcohols with 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23 xi, 25-pentol (56%) predominating. Whereas 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24S,25-pentol was not detected in the bile, it was isolated in the urine of all patients (27%). The only urinary bile acid isolated by high performance liquid chromatography was nor-cholic acid. After 1 month of treatment with chenodeoxycholic acid, 0.75 g/day, chenodeoxycholic acid became the major bile acid in the bile of all patients (71%) along with its metabolite, ursodeoxycholic acid (21%). Cholic acid and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25-tetrol were drastically reduced and were only 3% each. The excretion of 5 beta-cholestane-pentols in the urine was also drastically reduced from 130 mg/day to 15 mg/day. PMID: 4031647 [PubMed - indexed for MEDLINE] 426. J Clin Invest. 1985 Feb;75(2):448-55. A novel pathway for biosynthesis of cholestanol with 7 alpha-hydroxylated C27-steroids as intermediates, and its importance for the accumulation of cholestanol in cerebrotendinous xanthomatosis. Skrede S, Björkhem I, Buchmann MS, Hopen G, Fausa O. A mixture of 7 alpha-3H- and 4-14C-labeled cholesterol was administered intravenously to rats. Cholestanol with 20-30% lower ratio between 3H and 14C than in cholesterol could be isolated from different organs. In a healthy human control, cholestanol isolated from feces had a 3H/14C ratio which was 28% lower than in administered cholesterol. Cholesterol and coprostanol reisolated in these experiments had the same ratio between 3H and 14C as in the precursor. A previously unknown pathway for formation of cholestanol, involving 7 alpha-hydroxylated intermediates, may explain these results. Under normal conditions, this pathway is responsible for at most 30% of the cholestanol synthesized from cholesterol. Intravenous administration of the 7 alpha-3H- and 4-14C-labeled cholesterol to a patient with cerebrotendinous xanthomatosis (CTX) resulted in formation of cholestanol which had 70-75% lower 3H/14C ratio. It is concluded that the novel pathway involving 7 alpha-hydroxylated intermediates is accelerated in patients with CTX. This acceleration may contribute essentially to the accumulation of cholestanol, which is a predominant feature of this disease. 7 alpha-Hydroxycholesterol and 7 alpha-hydroxy-4-cholesten-3-one might be intermediates in the novel pathway to cholestanol. After intravenous administration of 7 beta-3H-labeled 7 alpha-hydroxycholesterol in a patient with CTX, significant amounts of 3H were incorporated into plasma and fecal cholestanol. Only small amounts of 7 alpha-hydroxycholesterol and 7 alpha-hydroxy-4-cholesten-3-one are excreted into the intestine, and we therefore conclude that the 7 alpha-dehydroxylation step mainly occurs in the liver. In CTX, the synthesis of cholestanol may be accelerated because the concentrations of 7 alpha-hydroxylated bile acid intermediates in the liver are increased. A possible mechanism for the conversion of a minor fraction of 7 alpha-hydroxycholesterol into cholestanol is suggested. PMCID: PMC423517 PMID: 3919058 [PubMed - indexed for MEDLINE] 427. Scand J Clin Lab Invest Suppl. 1985;177:15-21. A novel route for the biosynthesis of cholestanol, and its significance for the pathogenesis of cerebrotendinous xanthomatosis. Skrede S, Bjørkhem I. The main symptoms in cerebrotendinous xanthomatosis (CTX) are caused by increased synthesis of cholestanol (5 alpha-cholestan-3 beta-ol) and depositions of this steroid in brain and xanthomas. Previously, we have shown a deficiency in CTX of the mitochondrial C27-steroid 26-hydroxylase essential for normal degradation of the cholesterol side chain. Because of this defect, different 7 alpha-hydroxylated substrates for the 26-hydroxylase accumulate in the liver - among these 7 alpha-hydroxy-4-cholesten-3-one. The possibility that such accumulated 7 alpha-hydroxylated bile acid precursors can be converted into cholestanol was studied by administration of labelled 7 alpha-hydroxy-cholesterol to bile fistula rats and to a patient with CTX. Label was incorporated into cholestanol in the rats as well as in the CTX-patient. The quantitative significance of this 7 alpha-hydroxylation/dehydroxylation route for the biosynthesis of cholestanol was examined by administering a mixture of 7 alpha-3H and 4-14C-labeled cholesterol to rats, rabbits and a human volunteer. In all species, about 25% of 3H was lost during the conversion of cholesterol to cholestanol. In a patient with CTX, the flow through the 7 alpha-hydroxylation/dehydroxylation route was greatly increased, since 75% of 3H present in the precursor (cholesterol) had been removed in cholestanol isolated from bile, serum and faeces. Experiments with germfree rats and bile fistula rats indicate that the 7 alpha-dehydroxylation mainly occurs in the liver. The microsomal fraction of rat liver was found to 7 alpha-dehydroxylate 7 alpha-hydroxy-4-cholesten-3-one at a slow rate.(ABSTRACT TRUNCATED AT 250 WORDS) PMID: 3865344 [PubMed - indexed for MEDLINE] 428. N Engl J Med. 1984 Dec 27;311(26):1694-5. Cerebrotendinous xanthomatosis. Grundy SM. PMID: 6504107 [PubMed - indexed for MEDLINE] 429. N Engl J Med. 1984 Dec 27;311(26):1649-52. Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid. Berginer VM, Salen G, Shefer S. We studied the effect of chenodeoxycholic acid in 17 patients with cerebrotendinous xanthomatosis. Before treatment, all subjects were symptomatic, with Achilles tendon xanthomas (in 15 of 17), cataracts (in 12 of 17), dementia (in 13 of 17), pyramidal-tract signs (in all 17), cerebellar dysfunction (in 13 of 17), mild peripheral neuropathy (in 7 of 17), electroencephalographic abnormalities (in 10 of 13), and abnormal cerebral computerized axial tomographic scans (in 10 of 12). After at least one year of chenodeoxycholic acid treatment (750 mg per day), dementia cleared in 10 subjects, and pyramidal and cerebellar signs disappeared in 5 and improved in another 8. Peripheral neuropathy was no longer detected in six. The electroencephalogram became normal in five and showed fewer abnormalities in another three subjects. Cerebral computerized axial tomographic scans improved in seven patients; the changes included the disappearance of a cerebellar xanthoma in one case. Concomitantly, mean plasma cholestanol levels declined threefold, and abnormal bile acid synthesis was suppressed. We conclude that long-term therapy with chenodeoxycholic acid may correct the biochemical abnormalities and arrest and possibly reverse the progression of cerebrotendinous xanthomatosis. PMID: 6504105 [PubMed - indexed for MEDLINE] 430. Hawaii Med J. 1984 Dec;43(12):472-3, 477-8. Cerebrotendinous xanthomatosis in Hawaii--a therapeutic failure. Hinman RC. PMID: 6519979 [PubMed - indexed for MEDLINE] 431. J Clin Invest. 1984 Nov;74(5):1773-81. Comparative effects of cholestanol and cholesterol on hepatic sterol and bile acid metabolism in the rat. Shefer S, Hauser S, Salen G, Zaki FG, Bullock J, Salgado E, Shevitz J. Large amounts of cholestanol, the 5 alpha-dihydro derivative of cholesterol are found in tissues of patients with the rare inherited sterol storage disease cerebrotendinous xanthomatosis. Although small amounts of cholestanol are present in virtually every tissue of normal man, little is known about its metabolism and effect on cholesterol and bile acid formation. The purpose of this study is to investigate the absorption and metabolism of cholestanol and its early effects on hepatic morphology and on the rate-limiting enzymes of cholesterol and bile acid biosynthesis. After 2 wk on a diet supplemented with 2% cholestanol, total liver sterol content increased by 48% (3.26 vs. 2.20 mg/g), and resulted in a significant rise in hepatic cholestanol concentration to 1.4 mg/g. However, cholestanol was less efficiently absorbed from the intestine than cholesterol and interfered with cholesterol absorption. Furthermore, hepatic hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase activity rose 2.6-fold (from 150.3 to 397.0 pmol/mg per min) during cholestanol feeding, and was associated with a marked proliferation of the smooth endoplasmic reticulum of the centrilobular areas. In addition, significant amounts of allocholic acid (16%) and allochenodeoxycholic acid (5%) were formed from cholestanol and excreted in the bile. These results show that cholestanol is absorbed from the intestine, interferes with cholesterol absorption, and is deposited in the liver. However, in contrast to cholesterol, cholestanol feeding was associated with a marked elevation of HMG-CoA reductase activity. Thus, despite structural similarity between cholesterol and its 5 alpha-saturated derivative, cholestanol does not exert feedback inhibition on hepatic cholesterol biosynthesis. PMCID: PMC425357 PMID: 6501569 [PubMed - indexed for MEDLINE] 432. Clin Chim Acta. 1984 Sep 15;142(1):103-11. Capillary gas chromatographic determinations of urinary bile acids and bile alcohols in CTX patients proving the ineffectivity of ursodeoxycholic acid treatment. Koopman BJ, Wolthers BG, van der Molen JC, Nagel GT, Waterreus RJ, Oosterhuis HJ. Urine samples and serum samples of a patient with cerebrotendinous xanthomatosis (CTX) were investigated by means of capillary gas chromatography, both before and during oral treatment with ursodeoxycholic acid (UDCA), and the results compared with those obtained during chenodeoxycholic acid (CDCA) therapy. The predominantly excreted bile alcohol, 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol and two abnormal bile acids, i.e. 23-norcholic acid and 23-hydroxycholic acid were determined. In addition, the serum cholestanol/cholesterol ratio was determined. Whereas previous experiments demonstrated that the urinary excretion of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol and the abnormal bile acids decreased within a few weeks during CDCA therapy, the present study shows that their urinary excretions remain essentially the same during UDCA treatment. In contrast to the decrease in the serum cholestanol/cholesterol ratio during CDCA therapy, this ratio remains essentially the same during UDCA therapy. It is therefore concluded that, in contrast to CDCA therapy, UDCA treatment is not effective in the treatment of CTX. PMID: 6478619 [PubMed - indexed for MEDLINE] 433. Ned Tijdschr Geneeskd. 1984 Aug 25;128(34):1604-7. [Timely treatment of cerebrotendinous xanthomatosis, a hereditary disorder of cholesterol metabolism]. [Article in Dutch] Waterreus RJ, de Jager AE, Koopman BJ, Wolthers BG, Suurmeyer AJ. PMID: 6483031 [PubMed - indexed for MEDLINE] 434. Gastroenterology. 1984 Aug;87(2):276-83. Transformation of 4-cholesten-3-one and 7 alpha-hydroxy-4-cholesten-3-one into cholestanol and bile acids in cerebrotendinous xanthomatosis. Salen G, Shefer S, Tint GS. In order to determine whether cholestanol and bile acids are derived from the same precursor, key intermediates of both biosynthetic pathways beyond cholesterol were administered intravenously to a patient with cerebrotendinous xanthomatosis and to a control subject. After pulse-labeling with [4-14C]4-cholesten-3-one and [G-3H]7 alpha-hydroxy-4-cholesten-3-one, cholestanol, cholesterol, and the two primary bile acids, cholic acid and chenodeoxycholic acid were isolated from specimens of bile. Each compound was purified by thin-layer chromatography and conclusively identified by gas-liquid chromatography-mass spectrometry. In other studies, the in vitro formation of 4-cholesten-3-one from cholesterol was measured in hepatic microsomal fractions prepared from a subject with cerebrotendinous xanthomatosis and from 3 control individuals. In all subjects, cholic acid and chenodeoxycholic acid were labeled with tritium, but neither cholesterol nor cholestanol contained this isotope. In contrast, 14C was detected in the cholestanol fraction with trace amounts in chenodeoxycholic acid, cholic acid, and cholesterol. Hepatic microsomes prepared from liver biopsy specimens obtained from a subject with cerebrotendinous xanthomatosis produced three times more 4-cholesten-3-one than the controls. The results indicate that 4-cholesten-3-one was converted primarily into cholestanol and 7 alpha-hydroxy-4-cholesten-3-one into cholic acid and chenodeoxycholic acid. Neither ketonic steroid was transformed into cholesterol. The increased production of cholestanol in cerebrotendinous xanthomatosis may be accounted for by enhanced hepatic formation of 4-cholesten-3-one. 7 alpha-Hydroxy-4-cholesten-3-one is a precursor of bile acids, but not of cholestanol. PMID: 6735073 [PubMed - indexed for MEDLINE] 435. J Lipid Res. 1984 Aug;25(8):871-5. Absolute configuration at carbon 23 of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol excreted by patients with cerebrotendinous xanthomatosis. Kihira K, Kubota A, Hoshita T. Absolute configuration at C-23 of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol, one of the bile alcohols isolated from the patients with cerebrotendinous xanthomatosis, was unequivocally determined as 23S by conversion of a key intermediate, (23S)-5 beta-cholest-25-ene-3 alpha,7 alpha,12 alpha,23-tetrol to either the bile alcohol of known absolute configuration, (23R)-5 beta-cholestane-3 alpha,7 alpha,12 alpha,23-tetrol, or the naturally occurring 23,25-pentol. PMID: 6491531 [PubMed - indexed for MEDLINE] 436. Nihon Rinsho. 1984 Jul;42(7):1664-70. [Cerebrotendinous xanthomatosis and bile acids]. [Article in Japanese] Hoshita T. PMID: 6492409 [PubMed - indexed for MEDLINE] 437. Clin Chim Acta. 1984 Mar 13;137(3):305-15. Capillary gas chromatographic determination of cholestanol/cholesterol ratio in biological fluids. Its potential usefulness for the follow-up of some liver diseases and its lack of specificity in diagnosing CTX (cerebrotendinous xanthomatosis). Koopman BJ, van der Molen JC, Wolthers BG, de Jager AE, Waterreus RJ, Gips CH. The concentration ratios of cholestanol/cholesterol in biological materials (serum, cerebrospinal fluid and tendon biopsy) were determined using a capillary gas chromatographic method. The method was validated by gas chromatography-mass spectrometry. The ratio was determined in several groups of patients: (a) patients with cerebrotendinous xanthomatosis (in serum, cerebrospinal fluid and tendon biopsy), before and during chenodeoxycholic acid therapy, (b) patients receiving cholestyramine therapy (in serum), (c) patients suffering from various liver diseases (in serum) and (d) one patient before and after liver transplantation (in serum). It can be concluded that the cholestanol/cholesterol concentration ratio is a potentially useful parameter for monitoring liver diseases but is not specific for establishing the diagnosis of cerebrotendinous xanthomatosis. PMID: 6421514 [PubMed - indexed for MEDLINE] 438. Acta Neuropathol. 1984;64(3):259-64. Neuroaxonal pathology of central and peripheral nervous systems in cerebrotendinous xanthomatosis (CTX). Pop PH, Joosten E, van Spreeken A, Gabreëls-Festen A, Jaspar H, ter Laak H, Vos A. We studied three siblings and one unrelated patient with cerebrotendinous xanthomatosis (CTX). Of two unrelated patients, we examined biopsies of sural nerve, soleus muscle, and achilles tendon. We also performed neurophysiologic investigations. Another patient died, and a postmortem examination of both brain and spinal cord was made. It was concluded that both the central and the peripheral nervous system were involved in CTX, but the peripheral system only to a slight degree, and that the pathology was predominantly neuroaxonal rather than demyelinating in character. PMID: 6496040 [PubMed - indexed for MEDLINE] 439. Rinsho Shinkeigaku. 1984 Jan;24(1):38-44. [Two cases of familial cerebrotendinous xanthomatosis--intrahepatic enzyme assay and therapeutic trial with chenodeoxycholic acid]. [Article in Japanese] Orimo S, Kobayashi T, Furukawa T, Tsukagoshi H, Kano I. PMID: 6467736 [PubMed - indexed for MEDLINE] 440. Steroids. 1983 Oct;42(4):441-8. Identification of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25, 26-pentol in cerebrotendinous xanthomatosis. Dayal B, Tint GS, Greeley DN, Williams TH, Salen G. An unrecognized pentahydroxy bile alcohol has been isolated from the bile and feces of patients with cerebrotendinous xanthomatosis (CTX). Its structure, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 25, 26-pentol has been deduced by spectroscopic methods and confirmed by comparison with a synthetic analog. PMID: 6679948 [PubMed - indexed for MEDLINE] 441. Biochim Biophys Acta. 1983 Sep 20;753(2):220-6. Isolation of 5 alpha-cholestane-3 beta, 7 alpha-diol from bile of patients with cerebrotendinous xanthomatosis. Inefficiency of this steroid as a precursor to cholestanol. Björkhem I, Buchmann MS, Skrede S. Cerebrotendinous xanthomatosis is a rare, inherited disease characterized by defective bile acid biosynthesis as well as by accumulation of cholesterol and cholestanol. The mechanism behind the accumulation of cholestanol is unknown. Using combined gas chromatography-mass spectrometry, 5 alpha-cholestane-3 beta, 7 alpha-diol could be identified as a minor component in bile from two such patients. There were no significant amounts of this steroid in bile from control subjects. Most probably, the 5 alpha-cholestan-3 beta, 7 alpha-diol found is formed from 7 alpha-hydroxy-4-cholesten-3-one in the liver. 7 alpha-Hydroxy-1-cholesten-3-one, being a normal intermediate in bile acid biosynthesis, is known to accumulate in the liver and bile of patients with cerebrotendinous xanthomatosis, due to a defect of the mitochondrial 26-hydroxylase. The possibility was tested that (7 beta-3H)-labeled 5 alpha-cholestane-3 beta, 7 alpha-diol could be converted into cholestanol by a direct 7 alpha-dehydroxylation in the intestine. This conversion did not occur in rabbits, however, regardless of whether the labelled steroid was administered orally or intracoecally. It is concluded that 5 alpha-cholestane-3 beta, 7 alpha-diol is of little or no importance as a precursor to cholestanol in rabbits. Most probably, this is also the case in patients with cerebrotendinous xanthomatosis. PMID: 6412759 [PubMed - indexed for MEDLINE] 442. J Nerv Ment Dis. 1983 Sep;171(9):568-71. Depression in a patient with dementia secondary to cerebrotendinous xanthomatosis. Shapiro S. The occurrence of depression in a patient with pre-existing dementia, associated with a rare neurological disorder, is described. Cerebrotendinous xanthomatosis is a genetically transmitted disease that is associated with deposition of cholestanol in the central nervous system and Achilles tendons. A focus on the often unusual presentation of combined major depression and dementia is offered as well as the interaction of genetic disorders and psychiatric symptoms. The diagnostic and treatment approach to these patients is discussed in regard to this reported case. Also, there is a review of the importance of recognition of early signs and symptoms of both depression in demented patients and evidences of presenile dementia because the prospects of treatability and reversibility should be a prime consideration for these disorders. This case report illustrates the potential for effectiveness of psychiatric interventions for patients with neurological and genetic disorders. PMID: 6886686 [PubMed - indexed for MEDLINE] 443. Acta Pathol Jpn. 1983 Sep;33(5):959-77. Lipid storage disease: Part I. Ultrastructure of xanthoma cells in various xanthomatous diseases. Takahashi K, Naito M. The fundamental ultrastructure of lipid storage in the xanthoma cells of various xanthomatous diseases, including familial hyperlipoproteinemia type IIa, III, and V, cerebrotendinous xanthomatosis, Wolman's disease, Tangier disease, Hand-Schüller-Christian disease, and normolipidemic cutaneous xanthomatosis, revealed lipid vacuoles, either membrane-bound or with no single unit membrane, cholesterol crystals, multivesicular or multilocular lipid bodies, myelin-like bodies, and ceroid granules (residual bodies). According to the presence or absence of such a single unit membrane and enzyme cytochemical demonstration of acid phosphatase activity, these lipid storage inclusions were largely classified into lysosomal and non-lysosomal ones; the former included membrane-bound lipid vacuoles, cholesterol crystals, multivesicular or multilocular lipid bodies, myelin-like bodies, and ceroid granules and the latter was lipid vacuoles with no limiting membrane. The ultrastructural relationship on formation of these lysosomal and non-lysosomal lipid storage inclusions and pathogenesis of the lipid storage in the xanthoma cells of the disorders were presented. As for the origin of the xanthoma cells, the majority of them were considered to be derived from macrophages in many of the disease; however, transformation of fibroblasts into xanthoma cells was confirmed in xanthomatous diseases, such as Hand-Schüller-Christian disease. PMID: 6650173 [PubMed - indexed for MEDLINE] 444. Br Med J (Clin Res Ed). 1983 Jul 2;287(6384):21-2. Cerebrotendinous xanthomatosis: biochemical response to inhibition of cholesterol synthesis. Lewis B, Mitchell WD, Marenah CB, Cortese C, Reynolds EH, Shakir R. PMCID: PMC1548166 PMID: 6407679 [PubMed - indexed for MEDLINE] 445. Clin Chim Acta. 1983 Jun 30;131(1-2):53-65. Diagnosis of cerebrotendinous xanthomatosis (CTX) and effect of chenodeoxycholic acid therapy by analysis of urine using capillary gas chromatography. Wolthers BG, Volmer M, van der Molen J, Koopman BJ, de Jager AE, Waterreus RJ. By means of capillary gas chromatography urine samples of patients with cerebrotendinous xanthomatosis (CTX) were investigated before and during treatment by oral administration of chenodeoxycholic acid. The occurrence of various conjugated bile alcohols, presumably glucuronides, was demonstrated, the major compound being 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23 xi, 25-pentol. In the bile acid fraction norcholic acid and hydroxycholic acid were shown to be present in considerable amounts. In this way the presence of CTX can be demonstrated conclusively. After chenodeoxycholic acid therapy the excretion of both abnormal bile acids as well as of bile alcohols rapidly decreased within a few weeks, showing the effectiveness of the treatment. By early discovery and subsequent therapy it may be possible to prevent the onset of the detrimental symptoms such as mental deficiency, caused by the accumulation of cholestanol and cholesterol in CTX patients. PMID: 6883710 [PubMed - indexed for MEDLINE] 446. Acta Neurol Scand. 1983 May;67(5):305-11. Cerebrotendinous xanthomatosis: clinical and laboratory study of 2 cases. Canelas HM, Quintão EC, Scaff M, Vasconcelos KS, Brotto MW. Cerebrotendinous xanthomatosis is an unusual disease, clinically characterized by dementia, cataracts, progressive cerebellar ataxia, pyramidal signs, and multiple xanthomas of tendons and other tissues. It was first described in 1937, and in 1968 the storage of cholesterol and cholestanol in the tissues was demonstrated. About 30 cases have been reported. The authors of the present communication report 2 cases in siblings with parental consanguinity. They showed mental impairment and cataract, and multiple xanthomas; in 1 case, pyramidal signs were detected in the 4 limbs associated with a rise of the vibration sense thresholds in the feet. The diagnosis was confirmed in both cases by greatly increased cholestanol levels in the blood serum, bile and in a tendon xanthoma. Cholesterol concentrations in the blood serum and bile were normal although increased in the xanthoma. One case had a gallstone. Computerized tomography showed hyperdense nodules in the cerebellar hemispheres of one patient, and a calcified parietal nodule in his sister. The etiopathogenesis of the disease is discussed. Treatment with ursodeoxycholic acid is in course in both patients. PMID: 6410671 [PubMed - indexed for MEDLINE] 447. Tissue Antigens. 1983 Mar;21(3):233-7. Study of a family with Cerebrotendinous Xanthomatosis. No HLA linkage, but an informative recombination between HLA-B and Bf. Brautbar C, Yehuda O, Eisenberg S, Cohen N, Amar A, Sharon R, Fried K, Aghasi M, Cohen T. A large family with three children affected with the autosomal recessive disease of Cerebrotendinous Xanthomatosis (CTX) was studied for class I (HLA-A,B,C) and class II antigens (HLA-DR,D,SB), properdin factor B and glyoxalase. The extensive typing revealed an informative cross-over between HLA-B and Bf, indicating that Bf is located centromeric to the HLA-B locus and segregated in this family with HLA-D/DR. The parents in this family were first cousins and their parents were also first cousins. Three of their four haplotypes share B14, BfS, DR1, Dx and SB4 and may be identical by descent. The three affected children carried among them all four parental haplotypes, indicating that close linkage of the CTX locus to HLA is unlikely. PMID: 6574616 [PubMed - indexed for MEDLINE] 448. J Clin Invest. 1983 Jan;71(1):142-8. Role of the 26-hydroxylase in the biosynthesis of bile acids in the normal state and in cerebrotendinous xanthomatosis. An in vivo study. Björkhem I, Fausa O, Hopen G, Oftebro H, Pedersen JI, Skrede S. On the basis of different in vitro studies, we have previously suggested that the basic metabolic defect in the rare inherited disease cerebrotendinous xanthomatosis (CTX) is a lack of a hepatic mitochondrial C27-steroid 26-hydroxylase, involved in the normal biosynthesis of bile acids (1980. J. Clin. Invest. 65: 1418-1430; 1981. J. Lipid Res. 22: 191-200; 22: 632-640). In the present work, this hypothesis was tested in vivo. One patient with CTX and two control subjects received intravenously a mixture of [4-14C]7 alpha-hydroxy-4-cholesten-3-one and [6 beta-3H]7 alpha,26-dihydroxy-4-cholesten-3-one, steroids believed to be important precursors of chenodeoxycholic acid. The ratio between 14C and 3H in cholic acid and chenodeoxycholic acid isolated from bile of the CTX-patient was approximately 1/40 and 1/60 of those of the control subjects, respectively. Another patient with CTX and one control subject received a mixture of [4-14C]5 beta-cholestane-3 alpha,7 alpha-diol and [1,2-3H]5 beta-cholestane-3 alpha,7 alpha,26-triol, both possible precursors to chenodeoxycholic acid. In this case the 14C/3H ratio in cholic acid and chenodeoxycholic acid from the patient with CTX was 1/10 and 1/15, respectively, compared with that of the control subject. The most likely explanation for these findings is that very little of the 14C-precursors, i.e. without a 26-hydroxyl group, can be converted into cholic acid and chenodeoxycholic acid because of a defect of the 26-hydroxylase step. The results obtained are in accord with our previous findings in vitro. The results further underline the importance of the 26-hydroxylase pathway in the normal biosynthesis of cholic acid and chenodeoxycholic acid in man. PMCID: PMC436846 PMID: 6848555 [PubMed - indexed for MEDLINE] 449. Chem Pharm Bull (Tokyo). 1982 Aug;30(8):3040-1. Configuration at C-23 in 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23-tetrol excreted by patients with cerebrotendinous xanthomatosis. Kihira K, Ohira S, Kuramoto M, Kuramoto J, Nakayama M, Hoshita T. PMID: 7139840 [PubMed - indexed for MEDLINE] 450. J Biol Chem. 1982 Jul 25;257(14):8363-7. Biosynthesis of cholestanol from intestinal 7 alpha-hydroxy-4-cholesten-3-one. Skrede S, Björkhem I. Using isotope dilution-mass spectrometry, it was shown that human bile contains significant amount of 7 alpha-hydroxy-4-cholesten-3-one, an intermediate in the major pathway for bile acid biosynthesis. In bile from 14 healthy subjects, the concentration was 0.14 +/- 0.01 micrograms/ml (mean +/- S.E.). Four bile samples collected from two patients with cerebrotendinous xanthomatosis contained considerably higher amounts of this steroid, 0.47-1.32 micrograms/ml. After oral administration of [4-14C]7 alpha-hydroxy-4-cholesten-3-one to rabbits, 14C-labeled cholestanol could be isolated from the intestinal wall, liver, and blood after 24 h. The label incorporated into the intestinal wall was about 10% of that obtained with [4-14C]cholesta-4,6-dien-3-one or [4-14C]4-cholesten-3-one as precursors. Labeled cholesta-4,6-dien-3-one and 4-cholesten-3-one could be isolated from the intestinal contents 12 h after feeding [4-14C]7 alpha-hydroxy-4-cholesten-3-one to rabbits. It is proposed that cholesta-4,6-dien-3-one and 4-cholesten-3-one are formed from 7 alpha-hydroxy-4-cholesten-3-one by the same mechanism as that involved in 7 alpha-dehydroxylation of primary bile acids. We suggest that biliary 7 alpha-hydroxy-4-cholesten-3-one may be a physiological precursor to cholestanol. The possibility is discussed that part of the increased formation of cholestanol in patients with cerebrotendinous xanthomatosis is due to excess biliary 7 alpha-hydroxy-4-cholesten-3-one or some metabolite of this steroid. PMID: 7045120 [PubMed - indexed for MEDLINE] 451. Jpn J Med. 1982 Jul;21(3):210-5. A case of cerebrotendinous xanthomatosis: effects of ursodeoxycholic acid administration on serum bile acids and cholestanol. Kimura S, Beppu T, Kugai N, Koide Y, Fujita T, Iida K, Yamashita N, Yamashita K, Seyama Y. Cerebrotendinous xanthomatosis (CTX) is a rare familiar disease characterized by tendon xanthomas, cataracts, cerebellar ataxia, dementia and an elevated serum cholestanol level. In this paper, a 50-year-old man with typical signs and symptoms of CTX is described. Serum cholestanol and chelesterol concentrations were 17.9-28.6 micrograms/ml and 109-153 mg/dl, respectively. The determination of non-sulfated bile acid concentration in the serum assayed by mass fragmentography disclosed an abnormal profile. The concentration of cholic acid (0.30-0.52 microgram/ml) was higher than normal, while those of chenodeoxycholic acid, ursodeoxycholic acid, deoxycholic acid and lithocholic acid were extremely low or undetectable. Administration of ursodeoxycholic acid (300 mg per day, orally) for 2 weeks resulted in a marked reduction of serum cholic acid concentration. However, serum cholestanol levels remained unchanged. PMID: 7143816 [PubMed - indexed for MEDLINE] 452. J Lipid Res. 1982 May;23(4):627-30. Cerebrotendinous xanthomatosis: reduced serum 26-hydroxycholesterol. Javitt NB, Kok E, Cohen B, Burstein S. Serum 26-hydroxycholesterol was quantitated by isotope dilution-mass spectrometry in normal individuals and in patients with cerebrotendinous xanthomatosis. In the normal individuals, the concentration of 26-hydroxycholesterol in serum ranged from 4.3 to 13.0 microgram/100 ml. In five patients with CTX, 26-hydroxycholesterol in serum ranged from 0 to 0.6 microgram/100 ml. The findings can be explained by reduced or absent mitochondrial C27 steroid 26-hydroxylase activity. The method is useful for detection of CTX and perhaps other disturbances of sterol and bite acid metabolism. PMID: 7097127 [PubMed - indexed for MEDLINE] 453. J Lipid Res. 1982 May;23(4):597-603. Biosynthesis of cholesterol, lanosterol, and delta 7-cholestenol, but not cholestanol, in cultured fibroblasts from normal individuals and patients with cerebrotendinous xanthomatosis. Tint GS, Salen G. The cholesterol and cholestanol biosynthetic pathways and the control of cholesterolgenesis were investigated in skin fibroblasts, from patients with cerebrotendinous xanthomatosis (CTX) and from normal subjects, growth in a lipoprotein deficient (d less than 1.25 g/ml) medium. [3H]Acetate was added to the culture medium and its incorporation into sterols was assayed by both argentation and reversed-phase thin-layer chromatography (TLC). The labeling patterns were similar in both CTX and control cells with 3H being found, in order of increasing activity, in lanosterol, delta 7-cholestenol, and cholesterol. No 3H-labeled material at all, however, could be detected in the TLC mobility region corresponding to cholestanol. The ratio of cholestanol to cholesterol in the low density lipoprotein (LDL) subfraction from the plasma of individuals with CTX ranged from 1.4 to 5.3%, which is equal to or slightly greater than the ratio in whole plasma. Approximately 65-70% of the total plasma and LDL cholestanol and cholesterol were esterified. Since CTX-LDL, added to incubates of normal cells and normal LDL added to CTX fibroblasts suppressed HMG-CoA reductase activity and stimulated cholesterol esterification equally, and since 125-I-labeled control LDL was degraded with normal kinetics from the surface of CTX fibroblasts, both CTX-LDL and CTX fibroblasts LDL membrane receptors appear to be biologically normal. These results suggest that 1) cholesterol is synthesized in cultured CTX and control fibroblasts via delta 7-cholestenol, a C-24,25 saturated intermediate; 2) cholestanol is not synthesized in the skin of CTX patients but is transported there from the liver via the plasma LDL; and 3) CTX is not a disease associated with a defect of peripheral tissue LDL receptors. PMID: 7097124 [PubMed - indexed for MEDLINE] 454. Am J Med Sci. 1982 May-Jun;283(3):147-52. Cerebrotendinous xanthomatosis: A cause of cataracts and tendon xanthoma. Swartz M, Burman KD, Salen G. Patients with cerebrotendinous xanthomatosis may present with adolescent-onset cataracts and tendon xanthomas, and can have progressive neurological, myocardial, pulmonary, and endocrine dysfunction leading to death. The disease is inherited as an autosomal recessive and results in increasing deposition of cholesterol and cholestanol in vital organ systems; the primary biochemical abnormality is a block in bile acid synthesis which is manifested by a diminished pool of chenodeoxycholic acid. Replacement therapy with chenodeoxycholic acid may reduce cholesterol and cholestanol production. PMID: 6805326 [PubMed - indexed for MEDLINE] 455. Clin Electroencephalogr. 1982 Apr;13(2):89-96. EEG in cerebrotendinous xanthomatosis (CTX). Berginer VM, Radwan H, Korczyn AD, Kott E, Salen G, Shefer S. PMID: 7094358 [PubMed - indexed for MEDLINE] 456. Nouv Presse Med. 1982 Mar 6;11(11):855-7. [Cerebrotendinous xanthomatosis: long-term treatment with chenodesoxycholic acid (author's transl)]. [Article in French] Wolf LM, Houdent C, Laudat MH, Brasseur G, Balacheff O, Uzac L. A case of cerebrotendinous xanthomatosis without hyperlipidaemia but with tendinous scanthomatosis, subtle neurological disorders and endocrine cataract is reported. Accumulation of cholestanol, a cholesterol derivative, was detected by mass fragmentography. The plasma cholestanol : cholesterol ratio was 30 times higher than normally. Treatment with chenodesoxycholic acid during 26 months brought about neurological improvement, stabilization of the cataract and xanthomatosis and return to normal of plasma cholestanol levels. PMID: 7070978 [PubMed - indexed for MEDLINE] 457. Clin Chim Acta. 1982 Feb 5;118(2-3):167-75. Serum bile acid profiles in cerebrotendinous xanthomatosis. Beppu T, Seyama Y, Kasama T, Serizawa S, Yamakawa T. Non-sulfated bile acid concentrations in sera of 10 cases of cerebrotendinous xanthomatosis (CTX) were determined by mass fragmentography. Total bile acid (TBA) in serum was 0.492 +/- 0.436 microgram/ml (mean +/- SD) which was significantly lower than that (1.481 +/- 0.571) in healthy control sera. Cholic acid was 0.342 +/- 0.291 microgram/ml and was the dominant bile acid, which constituted 69.5% of TBA in serum. Chenodeoxycholic acid was 0.111 +/- 0.133 microgram/ml being a minor component in CTX sera, although it was the major bile acid in healthy control sera. Other bile acids such as deoxycholic acid, lithocholic acid and ursodeoxycholic acid were scarcely detected. Subnormal TBA level and deranged bile acid composition in CTX sera may reflect the defect of bile acid biosynthesis in CTX patients. Determination of serum bile acid may be useful in the diagnosis of CTX. PMID: 7055978 [PubMed - indexed for MEDLINE] 458. J Inherit Metab Dis. 1982;5(2):91-3. Cerebrotendinous xanthomatosis: a defect in cellular sterol biosynthetic control. Barron JL, Maxwell JU, Rutherfoord GS. A mentally retarded woman with tendon xanthomata and normal serum cholesterol concentration was found to have raised cholestanol concentrations in the serum and in a xanthoma. This confirmed the diagnosis of cerebrotendinous xanthomatosis (CBX). No specific lipoprotein fraction was found to transport cholestanol. For the first time cultured fibroblasts from a patient with CBX were found to accumulate cholestanol. PMID: 6820431 [PubMed - indexed for MEDLINE] 459. J Clin Invest. 1981 Nov;68(5):1295-304. Abnormal high density lipoproteins in cerebrotendinous xanthomatosis. Shore V, Salen G, Cheng FW, Forte T, Shefer S, Tint GS, Lindgren FT. The plasma lipoprotein profiles and high density lipoproteins (HDL) were characterized in patients with the genetic disease cerebrotendinous xanthomatosis (CTX). Abnormalities in the HDL may contribute to their increased atherogenesis and excessive deposits of tissue sterols in the presence of low or low-normal concentrations of plasma cholesterol (165 +/- 25 mg/dl) and low density lipoproteins (LDL). The mean HDL-cholesterol concentration in the CTX plasmas was 14.5 +/- 3.2 mg/dl, about one-third the normal value. The low HDL-cholesterol reflects a low concentration and an abnormal lipid composition of the plasma HDL. Relative to normal HDL, the cholesteryl esters are low, free cholesterol and phospholipids essentially normal, and triglycerides increased. The ratio of apoprotein (apo) to total cholesterol in the HDL of CTX was two to three times greater than normal. In the CTX HDL, the ratio of apoAI to apoAII was high, the proportion of apoC low, and a normally minor form of apoAI increased relative to other forms. The HDL in electron micrographs appeared normal morphologically and in particle size. The abnormalities in lipoprotein distribution profile and composition of the plasma HDL result from metabolic defects that are not understood but may be linked to the genetic defect in bile acid synthesis in CTX. As a consequence, it is probable that the normal functions of the HDL, possibly including modulation of LDL-cholesterol uptake and the removal of excess cholesterol from peripheral tissues, are perturbed significantly in this disease. PMCID: PMC370925 PMID: 7298854 [PubMed - indexed for MEDLINE] 460. Neurology. 1981 Nov;31(11):1463-5. Computed tomography in cerebrotendinous xanthomatosis. Berginer VM, Berginer J, Salen G, Shefer S, Zimmerman RD. In nine patients with cerebrotendinous xanthomatosis (CTX), computed tomography (CT) demonstrated diffuse white matter hypodensity above and below the tentorium. This was attributed to sterol infiltration with secondary demyelination. In one patient, a focal right cerebellar hypodense lesion reflected a true xanthoma. These findings suggest that the neurologic symptoms, no matter how longstanding, result from metabolic encephalopathy rather than irreversible destruction of brain tissue by xanthomas. PMID: 7198194 [PubMed - indexed for MEDLINE] 461. J Am Acad Dermatol. 1981 Sep;5(3):290-6. Normolipemic tendon and tuberous xanthomas. Fleischmajer R, Tint GS, Bennett HD. Tendon and skin xanthomas have been found in association with familial hypercholesterolemia, broad beta disease, beta sitosterolemia, and cerebrotendinous xanthomatosis. We are reporting a patient with tendon and tuberous xanthomas accompanied by normal plasma lipids. In addition, the plasma and xanthoma concentration of cholestanol was normal, while beta sitosterol was absent. These data rule out the disorders listed and suggest that this patient's disorder may represent a new normolipemic xanthomatosis. PMID: 7263974 [PubMed - indexed for MEDLINE] 462. Am J Med. 1981 Aug;71(2):313-9. A unique patient with coexisting cerebrotendinous xanthomatosis and beta-sitosterolemia. Wang C, Lin HJ, Chan TK, Salen G, Chan WC, Tse TF. An adult Chinese man presented with tendinous and tuberous xanthomatosis and severe atheromatous changes in the coronary arteries. In addition, he had chronic hemolytic anemia, with spherostomatocytic erythrocytes. Cerebrotendinous xanthomatosis was diagnosed on the basis of increased cholestanol levels in his plasma, red cells and xanthoma, changes in bile acid composition due to the defective synthesis of chenodeoxycholic acid. Coexisting beta-sitosterolemia was confirmed by the finding of large amounts of the plant sterols such as beta-sitosterol and campesterol. This is the first report of these two rare lipid storage disorders in the same patient. PMID: 7258222 [PubMed - indexed for MEDLINE] 463. J Biochem. 1981 Jul;90(1):17-21. Simplified determination of cholestanol in serum by gas-liquid chromatography: biochemical diagnosis of cerebrotendinous xanthomatosis. Serizawa S, Seyama Y, Otsuka H, Kasama T, Yamakawa T. Cholestanol (5 alpha-cholestan-3 beta-ol) in human serum was determined by gas-liquid chromatography after removal by epoxidation of cholesterol which is present in amounts about 400 times those of cholestanol and disturbs the accurate determination of minor sterols in serum. Epicholestanol (5 alpha-cholestan-3 alpha-ol) was used as an internal standard. By this method the cholestanol content in sera of 7 patients with cerebrotendinous xanthomatosis was determined. The cholestanol levels in those sera were significantly higher than those of normal subjects and the present method proved to be useful in a biochemical diagnosis of cerebrotendinous xanthomatosis. PMID: 7287675 [PubMed - indexed for MEDLINE] 464. J Lipid Res. 1981 May;22(4):632-40. Cerebrotendinous xanthomatosis: defective liver mitochondrial hydroxylation of chenodeoxycholic acid precursors. Oftebro H, Björkhem I, Størmer FC, Pedersen JI. Oxidation of the side chain of 5 beta-cholestane-3 alpha, 7 alpha-diol, 7 alpha-hydroxy-4-cholesten-3-one, and 5-cholestene-3 beta, 7 alpha-diol has been studied in subcellular fractions of liver from a patient with cerebrotendinous xanthomatosis (CTX) and a control subject. All intermediates were efficiently 26-hydroxylated and further converted to the corresponding 26-carboxylated derivatives by the mitochondrial fraction of normal human liver. No such conversion was observed with the mitochondria from the liver of the CTX patient and the control subject. 12 alpha-Hydroxylation of the patient and the control subject. 12 alpha-Hydroxylation of the substrates was very efficient with the microsomal fractions from both subjects. Bases on these and previous findings (Oftebro, H., I. Björkhem, S. Skrede, A. Schreiner, and J. I. Pedersen. 1980. J. Clin. Invest. 65: 1481-1430), it i concluded that the metabolic defect in CTX is a complete lack of mitochondrial C27-steroid 26-hydroxylase. In CTX the precursors of chenodeoxycholic acid are first attacked by the microsomal 12 alpha-hydroxylase and subsequently by the microsomal 25-hydroxylase as an alternate route to cholic acid formation. This explains the increased ratio of cholic acid to chenodeoxycholic acid observed in the bile of these patients. In the normal liver the formation of both cholic acid and chenodeoxycholic acid involves a mitochondrial 26-hydroxylation. PMID: 6792308 [PubMed - indexed for MEDLINE] 465. J Lipid Res. 1981 Feb;22(2):191-200. Assay of intermediates in bile acid biosynthesis using isotope dilution--mass spectrometry: hepatic levels in the normal state and in cerebrotendinous xanthomatosis. Björkhem I, Oftebro H, Skrede S, Pedersen JI. The synthesis of 2H4-labeled 5 beta-cholestane-3 alpha, 7 alpha-diol, 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol, 7 alpha-hydroxy-4-cholesten-3-one, and 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one is described. A mixture of these compounds, together with 2H3-labeled 5-cholestene-3 beta, 7 alpha-diol, was added to extracts of different subcellular fractions of liver. After purification by high performance liquid chromatography and conversion into trimethylsilyl ethers, the amounts of different endogenous unlabeled steroids were determined by selected ion monitoring. In normal liver, the concentration of 5-cholestene-3 beta, 7 alpha-diol (about 0.1-0.2 microgram/ml protein) was higher than the concentration of the other steroids (about 0.01-0.05 microgram/mg protein). The concentration of the different steroids was highest in the microsomal fraction of the liver homogenate. In a liver sample from a patient with cerebrotendinous xanthomatosis (CTX), the amounts of the 12 alpha-hydroxylated steroids were considerably higher than in the normal liver. The levels of 7 alpha-hydroxy-4-cholesten-3-one and 5 beta-cholestane-3 alpha, 7 alpha-diol were similar or only slightly higher than in the liver of the control patients. The concentration of 5-cholestene-3 beta, 7 alpha-diol was very high in the mitochondrial fraction of the CTX-liver. The findings are in accordance with the previous demonstration that the basic metabolic defect in CTX is a lack of the mitochondrial 26-hydroxylase. The results are further compatible with the contention that 7 alpha,26-dihydroxy-4-cholesten-3-one is an important intermediate in the normal bile acid biosynthesis. PMID: 7017048 [PubMed - indexed for MEDLINE] 466. Am J Med Genet. 1981;10(2):151-7. Genetics of cerebrotendinous xanthomatosis (CTX): an autosomal recessive trait with high gene frequency in Sephardim of Moroccan origin. Berginer VM, Abeliovich D. We described 6 patients (from 3 families) affected with cerebrotendinous xanthomatosis (CTX). All are Sephardic Jews of Moroccan extraction. In view of the small number of CTX patients diagnosed in the world (a total of 50 including our 6 patients), we are probably dealing with an ethnic subgroup with a high CTX gene frequency, which we have estimated to be 1/108. Since there are differences in expression in this disease, we recommend cholestanol study in cases of undiagnosed cataract or tendinous xanthomas in childhood or early adolescence. The diagnosis in CTX is important not only for genetic counseling, but also in veiw of possible treatment. PMID: 7315872 [PubMed - indexed for MEDLINE] 467. Pathol Res Pract. 1980 Dec;170(1-3):192-201. Liver in cerebrotendinous xanthomatosis (CTX)--a histochemical and EM study of four cases. Boehme DH, Sobel HJ, Marquet E, Salen G. VA Medical Center, East Orange, New Jersey 07019, USA. Cerebrotendinous xanthomatosis (CTX) is a rare inherited lipid storage disease. The primary biochemical defect in CTX is a block in hepatic bile acid synthesis with consequent accumulation of two bile pentols in the liver. Hence specimens of liver from four affecteds were examined by light and electron microscopy. These revealed perisinusoidal fibrosis, bile canalicular alterations and hepatocellular alterations including the appearance of fat droplets, proliferation of the smooth endoplasmic reticulum, accumulation of lipofuscin-like pigment, foci of cytoplasmic degeneration, proliferation of microbodies and prominent mitochondrial changes. In one untreated patient crystalloid cores were noted in the microbodies. These disappeared on therapy. PMID: 18788163 [PubMed - indexed for MEDLINE] 468. J Lipid Res. 1980 Nov;21(8):1015-21. Occurrence of bile alcohol glucuronides in bile of patients with cerebrotendinous xanthomatosis. Hoshita T, Yasuhara M, Une M, Kibe A, Itoga E, Kito S, Kuramoto T. Using thin-layer chromatography, bile alcohol glucuronides were found with taurine- and glycine-conjugated bile acids in the bile of four patients with cerebrotendinous xanthomatosis. The concentration of the bile alcohol glucuronides was 1.7-5.2 times higher than that of the conjugated bile acids. Detectable amounts of unconjugated bile alcohols were not found in the bile of these patients. The bile alcohol glucuronides were isolated from the bile of one of the patients by means of preparative thin-layer chromatography. Treatment with beta-glucuronidase of the bile alcohol glucuronides liberated glucuronic acid and a mixture of bile alcohols. More than 90% of the liberated bile alcohols was 5 beta-cholestane-3 alpha, 7 alpha, 25-tetrol, and lesser amounts of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23-tetrol, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24-tetrol, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23, 25-pentol, and 5 beta-cholestane-3 alpha,-7 alpha, 12 alpha, 24 alpha, 25-pentol were also obtained. The bile alcohol glucuronides were not oxidized by the treatment with 3 alpha-hydroxysteroid dehydrogenase, indicating that the glucuronide moiety was at 3 alpha-hydroxyl position of the bile alcohols. Comparison of the mass spectra of the acetylated and methylated derivatives of the natural glucuronides and the synthetic 7 alpha, 12 alpha, 25-triacetoxy-5 beta-cholestan-3 alpha-O-(methyl 2,3,4-tri-O-acetyl-beta-D-glucopyranosyluronate) also indicated that the bile alcohol glucuronides consisted of mainly 5 beta - cholestane - 3 alpha, 7 alpha, 12 alpha, 25 - tetrol - glucuronide. PMID: 7462799 [PubMed - indexed for MEDLINE] 469. J Clin Invest. 1980 Jun;65(6):1418-30. Cerebrotendinous xanthomatosis: a defect in mitochondrial 26-hydroxylation required for normal biosynthesis of cholic acid. Oftebro H, Björkhem I, Skrede S, Schreiner A, Pederson JI. Oxidation of side chain of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol was studied in a patient with cerebrotendinous xanthomatosis (CTX) and in control subjects, using various subcellular fractions of liver homogenate and a method based on isotope dilution-mass spectrometry. In the control, 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol was converted into 5 beta-cholestane-3 alpha,7 alpha,12 alpha,26-tetrol and 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid by the mitochondrial fraction, and into 5 beta-cholestane-3 alpha,7 alpha,12 alpha,-25-tetrol by the microsomal fraction. In the CTX patient, liver mitochondria were completely devoid of 26-hydroxylase activity. The same mitochondrial fraction catalyzed 25-hydroxylation of vitamin D3. The microsomal fraction of liver of the subject with CTX contained more than 50-fold the normal amount of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol. The basic metabolid defect in CTX appears to be a lack of the mitochondrial 26-hydroxylase. The excretion in the bile of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24 alpha,25-pentol observed in CTX patients may be secondary to the accumulation of the major substrate for the 26-hydroxylase, i. e., 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol, and exposure of this substrate to the normally less active microsomal 25-and 24-hydroxylases. It is concluded that the major pathway in the biosynthesis of cholic acid in human liver involves a mitochondrial C27-steroid 26-hydroxylation. PMCID: PMC371480 PMID: 7410549 [PubMed - indexed for MEDLINE] 470. Steroids. 1980 Apr;35(4):439-44. A facile synthesis of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol. Dayal B, Bagan E, Speck J, Salen G. A convenient procedure for the synthesis of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol via a modified homologation sequence of the intermediate 3 alpha,7 alpha,12 alpha-triformyloxy-24-oxo-25-diazo-25-homo-5 beta-cholane involving a homogeneous medium is described. This involves treating the intermediate alpha-diazoketone in methanol with a solution of silver benzoate in triethylamine. Grignard reaction of the resulting triformyloxy methyl homocholate yielded 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol. Large amounts of this bile alcohol were needed to further investigate the defect of cholic acid biosynthesis in patients with cerebrotendinous xanthomatosis (CTX). PMID: 7376230 [PubMed - indexed for MEDLINE] 471. Physiol Chem Phys. 1980;12(2):153-65. A new unified theory: C-C-2W is the chemical cause of all so-called cholesterol and cholestanol lipidoses. Boldrini P. The water-insoluble cholesterol-cholestanol-water adduct C-C-2W, chemical and physical cause of atherosclerosis and gallstones, has now been found in tendinous xanthoma as well; C-C-2W, and not cholestanol, is the initial compound deposited in hereditary CTX (cerebrotendinous xanthomatosis). From these and other findings it is theorized that what have been termed cholesterol or cholestanol lipidoses should instead be characterized as C-C-2W lipidoses. More than 1 mg of cholestanol . H2O present in the body causes crystallizaion of C-C-2W . This happens when the steroid meets cholesterol . H2O in sufficient concentration to reach a solubility product of 10(-7) mg/ml. In this light the literature can be interpreted to indicate that C-C-2W exerts negative effects on liver, intima tissue, eyes, lungs, and other parts of the body. Those effects include inflammation, cell necrosis, destruction of cell membranes, abnormal growth and, perhaps, neoplastic activity. Up to 200 g of C-C-2W in the body may be tolerated if evenly spread but not if localized in one or two areas only; e.g., the brain or the cardiovascular system. It is estimated that about 1000 g of C-C-2W, even if spread, are beyond the limit of human tolerance. PMID: 6776547 [PubMed - indexed for MEDLINE] 472. Gastroenterology. 1979 Nov;77(5):1068-73. Transformation of chenodeoxycholic acid and ursodeoxycholic acid by human intestinal bacteria. Fedorowski T, Salen G, Tint GS, Mosbach E. Feces from normal subjects and patients with cerebrotendinous xanthomatosis were incubated anaerobically with labeled chenodeoxycholic acid and ursodeoxycholine acid for known periods, and the bile acids formed were analyzed by TLC and scintillation counting. In the normal subjects, 80% of the chenodeoxycholic acid and 41% of the ursodeoxycholic acid were 7-dehydroxylated to lithocholic acid during 2 hr of incubation. In contrast, the fecal flora of the CTX patients transformed only 5% of chenodeoxycholic acid and less than 1% of ursodeoxycholic acid to lithocholic acid during the same time period. In several subjects (normals and CTX), the intestinal flora converted chenodeoxycholic acid to ursodeoxycholic acid without the accumulation of the hypothetical intermediate 7-ketolithocholic acid (3 alpha-hydroxy-7-keto-5 beta-cholanoic acid). These results indicate that the fecal bacterial flora is capable of 7-dehydroxylating chenodeoxycholic acid and ursodeoxycholic acid to yield lithocholic acid. Apparently the enzymes involved are relatively stereospecific since the 7 beta-hydroxy group of ursodeoxycholic acid was removed more slowly than the 7 alpha-hydroxy group of chenodeoxycholic acid. PMID: 488633 [PubMed - indexed for MEDLINE] 473. Neurology. 1979 Jun;29(6):880-1. Peripheral neuropathy in cerebrotendinous xanthomatosis. Kuritzky A, Berginer VM, Korczyn AD. Four patients with cerebrotendinous xanthomatosis (CTX) underwent electrophysiologic investigations, which demonstrated impairment in the functioning of the peripheral nerves in all four cases. The changes consisted of slow motor and sensory conduction. The changes were most marked in the older subjects, in whom the disease was more advanced, and who also had clinical manifestations of mild peripheral neuropathy. We conclude that the peripheral nerves are damaged in CTX. PMID: 221858 [PubMed - indexed for MEDLINE] 474. Steroids. 1979 Mar;33(3):327-38. Configurational assignment of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23, 25-pentol excreted by patients with cerebrotendinous xanthomatosis (a circular dichroism study). Dayal B, Tint GS, Shefer S, Salen G. The absolute configuration of the C27 pentahydroxy bile alcohol present in bile and feces of two patients with cerebrotendinous xanthomatosis (CTX) was determined by circular dichroism (CD) spectroscopy. Under anhydrous conditions CD spectra of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23, 25-pentol in the presence of Eu (fod) 3[tris (1, 1, 1, 2, 2, 3, 3-hepta fluoro-7, 7-dimethyl-octane-4, 6-dionato) europium (III)] exhibited a large induced split Cotton effect at ca. 310 nm. From the induced circular dichroism of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23, 25-pentol with Eu(fod) 3 it was concluded that the CTX bile alcohol has the 1, 3 glycol structure with carbon 23 having the R configuration. This information will be useful in elucidating a structural mechanism for the conversion of 5 beta-cholestranepentols into bile acids in man and rat. PMID: 442127 [PubMed - indexed for MEDLINE] 475. Acta Neuropathol. 1979 Jan 12;45(1):43-5. De- and remyelination and onion bulb in cerebrotendinous xanthomatosis. Ohnishi A, Yamashita Y, Goto I, Kuroiwa Y, Murakami S, Ikeda M. In a case of cerebrotendinous xanthomatosis (CTX), confirmed biochemically and histologically quantitative histological studies of the biopsies sural nerve revealed significantly higher incidence of de- and remyelination and onion bulb than in controls. The density of total myelinated fibers fell within the range of controls, although the density of large myelinated fibers seemed to be slightly decreased. It was suggested that the preferential involvement of the myelin sheath and Schwann cell may exist in CTX. PMID: 760364 [PubMed - indexed for MEDLINE] 476. J Clin Invest. 1979 Jan;63(1):38-44. Cholic acid biosynthesis: the enzymatic defect in cerebrotendinous xanthomatosis. Salen G, Shefer S, Cheng FW, Dayal B, Batta AK, Tint GS. Cholic acid biosynthesis is defective in individuals with cerebrotendinous xanthomatosis (CTX) and is associated with the excretion of 5beta-cholestane-3alpha,7alpha, 12alpha,25-tetrol, an intermediate in the 25-hydroxylation pathway of cholic acid in CTX. To define the enzymatic defect in CTX, two suspected precursors of cholic acid, namely 5beta-[7beta-(3)H]cholestane-3alpha,7alpha, 12alpha-triol and 5beta-[24-(14)C]cholestane-3alpha,7alpha, 12alpha,24S,25-pentol were examined by both in vivo and in vitro experiments. A third precursor, 5beta-[7beta-(3)H]-cholestane-3alpha,7alpha, 12alpha,25-tetrol, was compared with them in vitro. In the in vivo experiments, each one of the labeled precursors was administered intravenously to two CTX and two control subjects. In the controls, 5beta-[7beta-(3)H]cholestane-3alpha,7alpha, 12alpha-triol as well as 5beta-[24-(14)C]-cholestane-3alpha,7alpha, 12alpha,24S,25-pentol were rapidly converted to labeled cholic acid. Maximum specific activity values were reached within 1 d after pulse labeling, followed by exponential decay of the cholic acid specific activity curves. In contrast, these two precursors differed widely when administered to two CTX patients. While 5beta-[24-(14)C]cholestane-3alpha,7alpha, 12alpha,24S,25-pentol was rapidly converted to [24-(14)C]cholic acid and yielded identical decay curves with those obtained in the control subjects, maximum specific activity values in [7beta-(3)H]cholic acid were much lower and peaked only on the second day after the injection of 5beta-[7beta-(3)H]cholestane-3alpha,7alpha, 12alpha-triol. Furthermore, an appreciable amount of (3)H label was present in the 5beta-cholestane-3alpha,7alpha, 12alpha,25-tetrol isolated from the bile of the subjects with CTX. In the in vitro experiments, three enzymes on the 25-hydroxylation pathway of cholic acid were examined in both control and CTX subjects. The rate of the 25-hydroxylation of 5beta-cholestane-3alpha,7alpha, 12alpha-triol in CTX patients was comparable to that in the controls. Similarly, the transformation of 5beta-cholestane-3alpha,7alpha, 12alpha,24S,25-pentol to cholic acid, catalyzed by soluble enzymes, proceeded at approximately equal rates in CTX and in control individuals. On the other hand, the rate of 5beta-cholestane-3alpha,7alpha, 12alpha,24S,25-pentol formation was about four times greater in the control subjects than in the CTX patients.The results of the in vivo as well as the in vitro experiments suggest that the site of the enzymatic defect in CTX is at the 24S-hydroxylation of 5beta-cholestane-3alpha,7alpha, 12alpha,25-tetrol. The relative deficiency of this hydroxylase in CTX patients, accompanied by the accumulation of its substrate in bile and feces, probably accounts for the subnormal production of bile acids in CTX patients. PMCID: PMC371915 PMID: 762246 [PubMed - indexed for MEDLINE] 477. J Lipid Res. 1979 Jan;20(1):22-30. Metabolism of potential precursors of chenodeoxycholic acid in cerebrotendinous xanthomatosis (CTX). Salen G, Shefer S, Mosbach EH, Hauser S, Cohen BI, Nicolau G. In patients with cerebrotendinous xanthomatosis (CTX), diminished cholic acid production is associated with incomplete oxidation of the cholesterol side chain and the excretion of C(25)-hydroxy bile alcohols. The aims of this investigation were 1) to provide quantitative information on the pool size and production rate of chenodeoxycholic acid by the isotope dilution technique; and 2) to investigate the possible existence of a block in chenodeoxycholic acid synthesis and explain the absence of chenodeoxycholic acid precursors in CTX. After the injection of [24-(14)C]chenodeoxycholic acid, measurements of chenodeoxycholic acid pool size and production rate in a CTX subject were, respectively, 1/20 and 1/6 as great as controls. Further, three potential precursors of chenodeoxycholic acid, namely [G-(3)H]7alpha-hydroxy-4-cholesten-3-one, [G-(3)H]5beta-cholestane-3alpha,7alpha,25-triol, and [G-(3)H]5beta-cholestane-3alpha,7alpha,26-triol, were administered to the CTX and control subjects and the specific activity curves of [G-(3)H]cholic acid and [G-(3)H]chenodeoxycholic acid were constructed and compared. In the control subjects, the two bile acids decayed exponentially, but in the CTX patient maximum specific activities were abnormally delayed, indicating the hindered transformation of precursor into bile acid. These results show that chenodeoxycholic acid synthesis is small in CTX and that the conversion of 7alpha-hydroxy-4-cholesten-3-one, 5beta-cholestane-3alpha,7alpha,25-triol, and 5beta-cholestane-3alpha,7alpha,26-triol to both chenodeoxycholic acid and cholic acid were similarly impaired. PMID: 438653 [PubMed - indexed for MEDLINE] 478. Rinsho Shinkeigaku. 1978 Jun;18(6):312-20. [Cerebrotendinous xanthomatosis with hyperthyroidism (author's transl)]. [Article in Japanese] Murakami S, Yamashita Y, Goto I, Kuroiwa Y, Ohnishi A. PMID: 699435 [PubMed - indexed for MEDLINE] 479. Nihon Rinsho. 1978 May;Suppl:1698-9. [Cerebrotendinous xanthomatosis]. [Article in Japanese] Kito S. PMID: 691484 [PubMed - indexed for MEDLINE] 480. Steroids. 1978 Mar;31(3):333-45. Identifications of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23 beta-tetrol, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24 alpha-tetrol, and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24 beta-tetrol in cerebrotendinous xanthomatosis. Yasuhara M, Kuramoto T, Hoshita T, Itoga E, Kito S. The bile alcohols present in the feces of a patient with cerebrotendinous xanthomatosis were studied. Three bile alcohols which are different from any known natural bile alcohol were isolated as minor components of the fecal bile alcohol fraction. The structures of these compounds were established as 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 23 beta-tetrol, 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24 alpha-tetrol, and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha, 24 beta-tetrol by comparison with synthetic samples. PMID: 663972 [PubMed - indexed for MEDLINE] 481. J Lipid Res. 1978 Feb;19(2):187-90. Absolute configuration of pentahydroxy bile alcohols excreted by patients with cerebrotendinous xanthomatosis: a circular dichroism study. Dayal B, Salen G, Tint GS, Toome V, Shefer S, Mosbach EH. The absolute configurations of the C27 pentahydroxy bile alcohols present in bile and feces of two patients with cerebrotendinous xanthomatosis (CTX) were determined by circular dichroism (CD) spectroscopy. The CD spectra of 5beta-cholestane-3alpha,7alpha,12alpha,24alpha,25-pentol in the presence of Eu(fod)3 [tris(1,1,1,2,2,3,3-heptafluoro-7,7-dimethyloctane-4,6-dionato) europium (III)] exhibited a negative Cotton effect and was assigned to 24R absolute configuration. Conversely, 5beta-cholestane-3alpha,7alpha,12alpha,24beta,25-pentol showed a strong positive Cotton effect and was assigned the 24S configuration. These assignments were based upon comparison with a model compound, 5-cholestene-3beta,24(R),25-triol, whose single-crystal X-ray structure has been determined. The importance of these data is to establish a structural mechanism for the conversion of 5beta-cholestane-3alpha,7alpha,12alpha,24S,25-pentol rather than 5beta-cholestane-3alpha,7alpha,12alpha,24R,25-pentol into cholic acid in man as well as in animals. PMID: 632682 [PubMed - indexed for MEDLINE] 482. Gastroenterology. 1978 Jan;74(1):82-9. Intrahepatic pigment and crystal forms in patients with cerebrotendinous xanthomatosis (CTX). Salen G, Zaki FG, Sabesin S, Boehme D, Shefer S, Mosbach EH. Liver specimens from two patients with cerebrotendinous xanthomatosis revealed intracellular inclusions that appeared either as amorphous pigment or in a crystalloid form. The pigment was usually found in assoication with the smooth endoplasmic reticulum and occasionally free floating in the cytosol. The chemical nature of these inclusions has not yet been determined. However, the accumulation of such material may indicate the presence of nonmetabolizable bile alcohols resulting from a defect in bile acid synthesis. PMID: 618433 [PubMed - indexed for MEDLINE] 483. Metabolism. 1977 Jul;26(7):721-9. Evidence for the early reduction of the 24,25 double bond in the conversion of lanosterol to cholesterol in cerebrotendinous xanthomatosis. Tint GS, Salen G. The metabolism of lanosterol and 24,25-dihydrolanosterol (DL) was examined in a patient with cerebrotendinous xanthomatosis after intravenous pulse labeling with a mixture of DL-2-14C and 3S,4S,3R,4R-(4-3H)mevalonate. Sterols were isolated from the feces and purified by silver nitrate thin-layer chromatography, and their identities were confirmed by gas-liquid chromatography and mass spectrometry. Their specific activities were then determined and plotted as a function of time. These isotope ratio measurements and specific activity decay curves were consistent with 24,25-dihydrolanosterol and delta7-cholestenol being intermediates in the synthesis of cholesterol from mevalonate and lanosterol, and they suggested that reduction of the lanosterol side chain may occur as an early step in the synthesis of cholesterol. These results are in contrast to the results reported after the administration of triparanol, a delta24-reductase inhibitor. PMID: 865281 [PubMed - indexed for MEDLINE] 484. Harefuah. 1977 Jun 15;92(12):537-40. [Cerebrotendinous xanthomatosis (author's transl)]. [Article in Hebrew] Barginer V, Korczyn AD, Mayersdorf A. PMID: 885399 [PubMed - indexed for MEDLINE] 485. Acta Ophthalmol (Copenh). 1977 Apr;55(2):201-7. The ultrastructure of lens and iris in cerebrotendinous xanthomatosis. Seland JH, Slagsvold JE. The lens and an iris biopsy from a patient with cerebrotendinous xanthomatosis has been examined in the electron microscope. Subepithelial electron-lucent areas were demonstrated. The iris was normal. The lens changes were thought to be due to deposition of the specific cholesterol breakdown product inherent to this disease. PMID: 577091 [PubMed - indexed for MEDLINE] 486. Clin Neurol Neurosurg. 1977;79(4):253-72. Cerebrotendinous cholestanolosis in relation to other cerebral xanthomatoses. de Jong JG, van Gent CM, Delleman JW. A synopsis is given of 37 reported patients with cerebrotendinous xanthomatosis; divided in 11 possible, but not proven cases of C.T.Ch (cerebrotendinous cholestanolosis), and 26 proven cases. An increased content of cholestanol in serum or tissue, was used as the main criterion. The ophthalmological and neurological signs are tabulated. Attention is drawn to the fact that cholestanol is not mentioned in the extensive literature on related diseases with possible cerebrospinal xanthomas, such as eosinophilic granulomatosis and hyperlipoproteinemia. The importance of a possible role of cholestanol in these diseases is stressed. A hypothetical form of cerebrotendinous cholesterolosis is discussed. A family with a sibship of parents and twelve children, three of which showed C.T.Ch is described. The development of the clinical picture confirmed the variable expression of the autosomal recessive disease. Two patients showed disturbances of steroid metabolism. A first contribution to the search for linkage with the H.L.A. system is presented. Cholestanol over cholesterol ratio, appeared to be independent of the type of lipoprotein. In search for therapy we found in patients with hyperlipoproteinemia type II A, that cholestyramine alone gave dangerously high blood levels of cholestanol; in combined treatment of cholestyramine with clofibrate cholestanol, levels were comparable to those of the controls. The possibilities of therapy are discussed. PMID: 200389 [PubMed - indexed for MEDLINE] 487. J Biochem. 1976 Aug;80(2):223-8. Quantitative determination of cholestanol in plasma with mass fragmentography. Biochemical diagnosis of cerebrotendinous xanthomatosis. Seyama Y, Ichikawa K, Yamakawa T. A simple, sensitive, and accurate method for determination of cholestanol in plasma is described. In this method a fixed amount of cholestane is added to 1 ml of plasma as an internal standard and steroids are saponified and extracted with n-hexane. The amounts of cholestanol and cholesterol are determined by mass fragmentography by monitoring the intensities of m/e 306, m/e 329, and m/e 372 fragment ions. The relative standard deviation of results for cholestanol was about 6.3%. The cholestanol concentrations in the plasma, erythrocyte stroma, and plasma lipoproteins of three patients with cerebrotendinous xanthomatosis were determined by this method. PMID: 794060 [PubMed - indexed for MEDLINE] 488. Steroids. 1976 May;27(5):657-64. Identification of (23S)-5beta-cholestane-3alpha, 7alpha, 12alpha, 23, 25-pentol in cerebrotendinous xanthomatosis. Hoshita T, Yasuhara M, Kihira K, Kuramoto T. The synthesis of (23R)- and (23S)-5beta-cholestane-3alpha, 7alpha, 12alpha, 23, 25-pentols is described. Norcholyl aldehyde was converted into the cholestanepentols by a Reformatsky reaction with ethyl bromoacetate followed by a Grignard reaction with methylmagnesium iodide. One of the synthetic pentols, the 23S epimer was identical with a bile alcohol isolated from patients with cerebrotendinous xanthomatosis. PMID: 941184 [PubMed - indexed for MEDLINE] 489. J Clin Invest. 1976 Apr;57(4):897-903. A 25-hydroxylation pathway of cholic acid biosynthesis in man and rat. Shefer S, Cheng FW, Dayal B, Hauser S, Tint GS, Salen G, Mosbach EH. This paper describes a pathway of cholic acid synthesis, in man and in the rat, which involves 25-hydroxylated intermediates and is catalyzed by microsomal and soluble enzymes. The subcellular localization, stereospecificity, and other properties of the enzymes involved were studied with liver fractions of normolipidemic subjects, cerebrotendinous xanthomatosis patients, and rats. 5beta-Cholestane-3alpha,7alpha,12alpha,25-tetrol was converted to 5beta-cholestane-3alpha,7alpha,12alpha,24beta,25-pentol by the microsomal fraction in the presence of NADPH and O2. 5beta-Cholestane-3alpha,7alpha,12alpha,24alpha,25-pentol, 5beta-cholestane-3alpha,7alpha,12alpha,-23xi,25-pentol, and 5beta-cholestane-3alpha,7alpha,12alpha,25,26-pentol were also formed. In the presence of NAD, 5beta-cholestane-3alpha,7alpha,12alpha,24beta,25-pentol, but not the other 5beta-cholestanepentols formed, was converted to cholic acid by soluble enzymes in good yield. These experiments demonstrate the existence of a pathway for side-chain degradation in cholic acid synthesis which does not involve hydroxylation at C-26 or the participation of mitochondria. PMCID: PMC436733 PMID: 181403 [PubMed - indexed for MEDLINE] 490. Arch Ophthalmol. 1976 Jan;94(1):148-50. Cerebrotendinous xanthomatosis. Kearns WP, Wood WS. A case of presumed cerebrotendinous xanthomatosis is described. The association of cataracts with central nervous system signs and tendon xanthoma is noted. Deposition of cholestanol appears to be the primary lesion in this disease. PMID: 1247403 [PubMed - indexed for MEDLINE] 491. Biochem Med. 1975 Sep;14(1):57-74. Chenodeoxycholic acid inhibits increased cholesterol and cholestanol synthesis in patients with cerebrotendinous xanthomatosis. Salen G, Meriwether TW, Nicolau G. PMID: 1212241 [PubMed - indexed for MEDLINE] 492. J Lipid Res. 1975 Jul;16(4):280-6. Identification of pentahydroxy bile alcohols in cerebrotendinous xanthomatosis: characterization of 5beta-cholestane-3alpha, 7alpha, 12alpha, 24xi, 25-pentol and 5beta-cholestane-3alpha, 7alpha, 12alpha, 23xi, 25-pentol. Shefer S, Dayal B, Tint GS, Salen G, Mosbach EH. This paper describes studies dealing with the nature of the C27 pentahydroxy bile alcohols present in the bile and feces of two patients with cerebrotendinous xanthomatosis (CTX). The presence of a bile alcohol having the structure 5beta-cholestane-3alpha,7alpha,12alpha,24alpha,25-pentol was confirmed by separation of the two 24-hydroxy epimers of 5beta-cholestane-3alpha,7alpha,12alpha,24,25-pentol and characterization of the dpimers by gas-liquid chromatography and infrared and mass spectrometry. Tentative assignment of the 24alpha and 24beta configuration was made on the basis of molecular rotation differences. A second major bile alcohol excreted by the CTX subjects was 5beta-cholestane-3alpha,7alpha,12alpha,23xi,25-pentol. Its structure was determined by infrared spectrometry, proton magnetic resonance spectrometry, and mass spectrometry because a reference compound was not available. PMID: 1141769 [PubMed - indexed for MEDLINE] 493. J Clin Invest. 1975 Jul;56(1):226-31. Bile alcohol metabolism in man. Conversion of 5beta-cholestane-3alpha, 7alpha,12alpha, 25-tetrol to cholic acid. Salen G, Shefer S, Setoguchi T, Mosbach EH. To study the role of C25-HYDROXY BILE ALCOHOLS AS PRECURSORS OF CHOlic acid, [G-3-H]5beta-cholestane-3alpha,7alpha12alpha,25-tetrol was administered intravenously to two subjects with cerebrotendinous xanthomatosis (CTX) and two normal individuals. One day after pulse labeling, radioactivity was present in the cholic acid isolated from the bile and feces of the subjects with CTX and the bile of the normal individuals. In the two normal subjects, the sp act decay curves of [G-3-H]-cholic acid were exponential, and no traces of [G-3-H]-5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol were detected. In contrast, appreciable quantities of labeled 5beta-cholestane-3alpha,-7aopha,12alpha,25-tetrol were present in the bile and feces of the CTX subjects. The sp act vs. time curves of fecal [G-3-H]5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol and [G-3-H]-cholic acid showed a precursor-product relationship. Although these results suggest that 5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol may be a precursor of cholic acid in man, the possibility that C26-hydroxy intermediates represent the normal pathway can not be excluded. PMCID: PMC436573 PMID: 1141434 [PubMed - indexed for MEDLINE] 494. Acta Neurol Scand. 1975 May;51(5):405-16. Cerebrotendinous xanthomatosis (cholestanolosis). Investigations on two sisters and their family. Schreiner A, Hopen G, Skrede S. Two sisters, aged 38 and 32, suffering from cerebrotendinous xanthomatosis are described. The most important clinical findings were xanthomas, central nervous affection with motor and mental dysfunction, EEG changes and juvenile cataract. The diagnosis was established by the demonstration of increased amounts of cholestanol in serum. Both sisters had amenorrhea, and their excretion of dehydroepiandrosterone in the urine was increased. In the elder sister, the levels of urinary 17-keto steroids, androsterone and estradiol were also increased. Other unusual features of the disease in the elder sister were hyper-prebeta-lipoproteinemia and serum cholesterol in the higher normal range. PMID: 1130172 [PubMed - indexed for MEDLINE] 495. Arch Neurol. 1975 Apr;32(4):223-5. Familial cerebrotendinous xanthomatosis. Report of a new family and review of the literature. Farpour H, Mahloudji M. Cerebrotendinous xanthomatosis occurred in a new family. This is a rare familial disorder characterized by juvenile cataracts, enlargement of tendons, low intelligence, and a variable neurological syndrome with cerebellar ataxia as the most prominent feature. The mode of inheritance is autosomal recessive. The basic defect remains obscure, but recent investigations have shown an excess of cholestanol in the tissues and serum of affected persons, which forms the basis of diagnosis. PMID: 1124985 [PubMed - indexed for MEDLINE] 496. J Can Assoc Radiol. 1974 Dec;25(4):282-6. Cerebrotendinous xanthomatosis. Pastershank SP, Yip S, Sodhi HS. PMID: 4443363 [PubMed - indexed for MEDLINE] 497. J Lipid Res. 1974 May;15(3):256-62. Transformation of 5 alpha-cholest-7-en-3 beta-ol to cholesterol and cholestanol in cerebrotendinous xanthomatosis. Tint GS, Salen G. The metabolism of Delta(7)-cholestenol, cholesterol, and cholestanol was examined in a patient with cerebrotendinous xanthomatosis after intravenous pulse-labeling with a mixture of dl-[2-(14)C]mevalonate and stereospecific 3S,4S,3R,4R-[4-(3)H]mevalonate. Silver nitrate and reversed-phase thin-layer chromatography were used to purify the sterols isolated from the feces, and their identities were confirmed by gas-liquid chromatography-mass spectrometry. The specific activities were determined and plotted as a function of time. Isotope ratio measurements and specific activity decay curves showed that sterol synthesis proceeded in the following sequence: mevalonate, squalene, lanosterol, Delta(7)-cholestenol, cholesterol, cholestanol. Labeled cholesterol precursors might be advantageously used to measure changes in cholesterol synthesis because they appear to equilibrate rapidly and have very short turnover times. PMID: 4827915 [PubMed - indexed for MEDLINE] 498. J Clin Invest. 1974 May;53(5):1393-401. A biochemical abnormality in cerebrotendinous xanthomatosis. Impairment of bile acid biosynthesis associated with incomplete degradation of the cholesterol side chain. Setoguchi T, Salen G, Tint GS, Mosbach EH. Bile acid production in cerebrotendinous xanthomatosis (CTX) is subnormal, yet the activity of cholesterol 7alpha-hydroxylase, the rate-determining enzyme of bile acid synthesis, is elevated. To explain this discrepancy, bile acid precursors were sought in bile and feces of three CTX subjects. Over 10% of the total sterols excreted in bile and feces consisted of compounds more polar than cholesterol. Chromatographic analysis of the polar fractions in conjunction with gasliquid chromatography (GLC)-mass spectrometry indicated two major constituents, 5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol and 5beta-cholestane-3alpha,7alpha,12alpha,24xi,25-pentol. After i.v. injection of [4-(14)C]cholesterol both bile alcohols were radioactive proving that they were derived from cholesterol. The accumulation of alcohols hydroxylated at C-25 and C-24,25 suggests that decreased bile acid synthesis in CTX results from impaired oxidation of the cholesterol side chain. This finding and the virtual absence of intermediates hydroxylated at C-26 indicate that current views of the major pathway of bile acid synthesis may require revision. PMCID: PMC302628 PMID: 4825231 [PubMed - indexed for MEDLINE] 499. Scand J Clin Lab Invest. 1974 Apr;33(2):97-100. Plasma esterification of cholestanol, normally and in cerebrotendinous xanthomatosis. Skrede S, Stokke KT. PMID: 4853665 [PubMed - indexed for MEDLINE] 500. Rinsho Shinkeigaku. 1974 Mar;14(3):306-10. [Case of cerebrotendinous xanthomatosis]. [Article in Japanese] Iwabuchi S, Tsuya Y, Hagihara T, Yoshikura N, Kitagawa T. PMID: 4472665 [PubMed - indexed for MEDLINE] 501. J Clin Invest. 1974 Feb;53(2):612-21. Increased formation of ursodeoxycholic acid in patients treated with chenodeoxycholic acid. Salen G, Tint GS, Eliav B, Deering N, Mosbach EH. Division of Gastroenterology, Manhattan Veterans Administration Hospital, New York, USA. The formation of ursodeoxycholic acid, the 7 beta-hydroxy epimer of chenodeoxycholic acid, was investigated in three subjects with cerebrotendinous xanthomatosis and in four subjects with gallstones. Total biliary bile acid composition was analyzed by gas-liquid chromatography before and after 4 months of treatment with 0.75 g/day of chenodeoxycholic acid. Individual bile acids were identified by mass spectrometry. Before treatment, bile from cerebrotendinous xanthomatosis (CTX) subjects contained cholic acid, 85%; chenodeoxycholic acid, 7%; deoxycholic acid, 3%; allocholic acid, 3%; and unidentified steroids, 2%; while bile from gallstone subjects contained cholic acid, 45%; chenodeoxycholic acid, 43%; deoxycholic acid, 11%, and lithocholic acid, 1%. In all subjects, 4 months of chenodeoxycholic acid therapy increased the proportion of this bile acid to approximately 80% and decreased cholic acid to 3% of the total biliary bile acids, the remaining 17% of bile acids were identified as ursodeoxycholic acid. After the intravenous injection of [3H]chenodeoxycholic acid, the specific activity of biliary ursodeoxycholic acid exceeded the specific activity of chenodeoxycholic acid, and the resulting specific activity decay curves suggested precursor-product relationships. When [3H]7-ketolithocholic acid was administrated to another patient treated with chenodeoxycholic acid, radioactivity was detected in both the ursodeoxycholic acid and chenodeoxycholic acid fractions. These results indicate that substantial amounts of ursodeoxycholic acid are formed in patients treated with chenodeoxycholic acid. The ursodeoxycholic acid was synthesized from chenodeoxycholic acid presumably via 7-ketolithocholic acid. PMCID: PMC301505 PMID: 11344576 [PubMed - indexed for MEDLINE] 502. J Clin Invest. 1973 Nov;52(11):2822-35. The metabolism of cholestanol, cholesterol, and bile acids in cerebrotendinous xanthomatosis. Salen G, Grundy SM. The metabolism of cholesterol and its 5-dihydro derivative, cholestanol, was investigated by means of sterol balance and isotope kinetic techniques in 3 subjects with cerebrotendinous xanthomatosis (CTX) and 11 other individuals. All subjects were hospitalized on a metabolic ward and were fed diets practically free of cholesterol and cholestanol. After the intravenous administration of [1,2-(3)H]cholestanol, the radioactive sterol was transported and esterified in plasma lipoproteins in an identical manner to cholesterol. In these short-term experiments, the specific activity-time curves of plasma cholestanol conformed to two-pool models in both the CTX and control groups. However, cholestanol plasma concentrations, total body miscible pools, and daily synthesis rates were two to five times greater in the CTX than control individuals. The short-term specific activity decay curves of plasma [4-(14)C]cholesterol also conformed to two-pool models in both groups. However, in the CTX subjects the decay was more rapid, and daily cholesterol synthesis was nearly double that of the control subjects. Plasma concentrations and the sizes of the rapidly turning over pool of exchangeable cholesterol were apparently small in the CTX subjects, and these measurements did not correlate with the large cholesterol deposits found in tendon and tuberous xanthomas. Despite active cholesterol synthesis, bile acid formation was subnormal in the CTX subjects. However, bile acid sequestration was accompanied by a rise in plasma cholestanol levels and greatly augmented fecal cholestanol outputs. In contrast, the administration of clofibrate lowered plasma cholesterol levels 50% and presumably reduced synthesis in the CTX subjects. Plasma cholesterol concentrations and fecal steroid excretion did not change significantly during this therapy. These findings indicate that the excessive tissue deposits of cholesterol and cholestanol that characterize CTX were associated with hyperactive neutral sterol synthesis. The demonstration of subnormal bile acid formation suggests that defective bile acid synthesis may predispose to the neutral sterol abnormalities. PMCID: PMC302550 PMID: 4355999 [PubMed - indexed for MEDLINE] 503. Br Med J. 1972 Feb 5;1(5796):353-4. Cerebrotendinous xanthomatosis. Truswell AS, Pfister PJ. PMCID: PMC1787294 PMID: 5008664 [PubMed - indexed for MEDLINE] 504. J Clin Invest. 1972 Jan;51(1):134-40. Biosynthesis of 5 -cholestan-3 -ol in cerebrotendinous xanthomatosis. Salen G, Polito A. Cerebrotendinous Xanthomatosis is a rare, inherited disease characterized by an extraordinary accumulation of cholestanol in all tissues, xanthomatous deposits in the brain, lungs, and Achilles tendons, premature atherosclerosis, and low plasma cholesterol concentrations. In two patients with the disease, the biosynthesis of cholestanol was examined by different techniques. After cholesterol-4-(14)C was injected intravenously into one patient, cholestanol and cholesterol isolated from the bile on 3 different days over the ensuing week contained significant radioactivity. The specific radioactivity-time curves for cholesterol-(14)C and cholestanol-(14)C suggested a precursor product relationship and provided additional evidence for the transformation of cholesterol into cholestanol. The second patient received intravenously a mixture of mevalonate-2-(14)C and stereospecifically labeled mevalonate-3R,4R-(3)H. Again cholesterol and cholestanol were isolated from the bile, and the (3)H/(14)C ratio in both sterols was almost the same. This experiment again demonstrated that the biosynthetic path of cholestanol proceeded through cholesterol and not directly from earlier 5alpha-H-saturated precursors. These two independent lines of evidence indicate that the extraordinary deposition of cholestanol in Cerebrotendinous Xanthomatosis arises from cholesterol presumably through the accentuation of the normal biosynthetic pathway. PMCID: PMC332938 PMID: 4550120 [PubMed - indexed for MEDLINE] 505. Ann Intern Med. 1971 Dec;75(6):843-51. Cholestanol deposition in cerebrotendinous xanthomatosis. A possible mechanism. Salen G. PMID: 5134895 [PubMed - indexed for MEDLINE] 506. J Neurochem. 1971 Mar;18(3):403-13. Subcellular distribution of cerebral cholestanol in cerebrotendinous xanthomatosis. Stahl WL, Sumi SM, Swanson PD. PMID: 5559251 [PubMed - indexed for MEDLINE] 507. Trans Am Neurol Assoc. 1971;96:241-4. Cerebrotendinous xanthomatosis: in vivo labeling of cerebral sterols and sterol esters. Gardner-Medwin D, Kishimoto Y, Derby BM, Moser HW. PMID: 5159092 [PubMed - indexed for MEDLINE] 508. Arch Neurol. 1969 Dec;21(6):603-10. Cholestanolosis (cerebrotendinous xanthomatosis). A follow-up study on the original family. Philippart M, Van Bogaert L. PMID: 5355255 [PubMed - indexed for MEDLINE] 509. Trans Am Neurol Assoc. 1969;94:322-4. Cerebrotendinous xanthomatosis: a generalized disorder of cholestanol metabolism. Philippart M, van Bogaert L. PMID: 5374477 [PubMed - indexed for MEDLINE] 510. Arch Neurol. 1968 Jul;19(1):47-53. Cerebrotendinous xanthomatosis. The storage of cholestanol within the nervous system. Menkes JH, Schimschock JR, Swanson PD. PMID: 5676919 [PubMed - indexed for MEDLINE] 511. Arch Neurol. 1968 Jun;18(6):688-98. Cerebrotendinous xanthomatosis. Clinical and pathological studies. Schimschock JR, Alvord EC Jr, Swanson PD. PMID: 5652996 [PubMed - indexed for MEDLINE] 512. N Engl J Med. 1968 Apr 11;278(15):857. Cerebrotendinous xanthomatosis. Harris WR Jr. PMID: 5642511 [PubMed - indexed for MEDLINE] 513. N Engl J Med. 1968 Apr 11;278(15):857. Cerebrotendinous xanthomatosis. Swanson PD. PMID: 4868195 [PubMed - indexed for MEDLINE] 514. Trans Am Neurol Assoc. 1968;93:66-9. Cholestanol storage in the nervous system of two patients with cerebrotendinous xanthomatosis. Menkes JH, Philippart M. PMID: 5711054 [PubMed - indexed for MEDLINE] 515. Trans Am Neurol Assoc. 1968;93:64-5. Cerebrotendinous xanthomatosis. Schimschock JR, Alvord EC Jr, Swanson PD. PMID: 5711053 [PubMed - indexed for MEDLINE]