title: Cerebrotendinous xanthomatosis: an inborn error in bile acid synthesis with defined mutations but still a challenge.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institutet, Karolinska University Hospital Huddinge, S-14186 Huddinge, Sweden. ingemar.bjorkhem@karolinska.se
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.forename: Magnus
authors.initials: M
authors.lastname: Hansson
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics*; D004083:Cholestanol / Q000378:metabolism; D002783:Cholestenones / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D009154:Mutation; D019294:Xanthomatosis, Cerebrotendinous / Q000235:genetics*
chemical_list: D001647:Bile Acids and Salts; D002783:Cholestenones; C002656:7 alpha-hydroxy-4-cholesten-3-one; D004083:Cholestanol; D002790:Cholesterol 7-alpha-Hydroxylase; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse