Cholestanol cerebrotendinous xanthomatosis

CYP27A1 catalyzes the side chain oxidation (27-hydroxylation) in bile acid biosynthesis. Because bile acid synthesis is the only elimination pathway for cholesterol, mutations in the CYP27A1 gene lead to abnormal deposition of cholesterol and cholestanol in various tissues. This sterol storage disorder is known as cerebrotendinous xanthomatosis. CYP27B1 is the 1-alpha hydroxylase of vitamin D3 that converts it to the active vitamin form. The function of CYP27C1 is not yet known. 

Defective side-chain oxidation is found in patients affected by cerebrotendinous xanthomatosis (CTX), an autosomal recessive defect characterised by deficit of mitochondrial 27-hydroxylase. The CTX defect leads to an accumulation of cholestanol and cholesterol in most tissues, while serum concentrations of CA, as well as other BAs, are sensibly low. 

Nakamura, T., Matsuzawa, Y., Takemura, K., Knbo, M., Mikl, H., Tarui, S. Combined treatment with chenodeoxychohc acid and pravastatin improves plasma cholestanol levels associated with marked regression of tendon xanthomas in cerebrotendinous xanthomatosis. Metabolism 1991 40 741-746... 

Salen, G., Berginer, V.M., Shore, V., Horak, I., Horak, E., Tint, G.S., Shefer, S. Increased concentrations of cholestanol and apolipoprotein B in the cerebrospinal fluid of patients with cerebrotendinous xanthomatosis. New Engl. J. Med. 1987 316 1233-1238... 

Salen, G. (1971). Cholestanol deposition in cerebrotendinous xanthomatosis a possible mechanism. Ann. Intern. Med. 75 843-851. 

Menkes, J. H., Schimschok, J. R. and Swanson, P. D. (1968). Cerebrotendinous xanthomatosis The storage of cholestanol within the nervous system. Arch. Neurol. 19 47-53... 

Salen, G. and Grundy S. M. (1973). The metabolism of cholestanol, cholesterol, and bile acids in cerebrotendinous xanthomatosis. /. Clin. Invest. 52 2822-2835. 

A 17-year-old female, whose parents were first cousins, presents to a neurologist because of recurring seizures despite being on anticonvul-sive therapy. Nodules that appeared to be fatty deposits were present on her Achilles tendon and several of her joints. Plasma cholesterol concentrations were elevated, and an assay of plasma sterols indicated elevated cholestanol. Cultured skin fibroblasts did not contain any sterol 27-hydroxylase activity. A diagnosis of cerebrotendinous xanthomatosis, a genetic disease inherited in an autosomal fashion, was made. A deficiency in sterol 27-hydroxylase would lead to a decrease in the synthesis of which of the following compounds ... 

A stndy of the selectivity of sterol analogs as snbstrates indicates that more polar derivatives (e.g., cholesterol snUate) are better substrates [2572]. Sterols with a 3-oxo-A" stracture were found to be hydroj lated at higher rates than 3-ltydroxy-A analogs. The very high activity with the cholestanol precursor 4-cholesten-3-one may be of importance in the accnmnlation of cholestanol in patients with cerebrotendinous xanthomatosis disease. 

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