Cerebrotendinous xanthomatosis

Douglas J Lanska MD FAAN MS MSPH (Dr. Lanska of the Great Lakes VA Healthcare System and the University of Wisconsin School of Medicine and Public Health has no relevant financial relationships to disclose.)
Originally released March 13, 1996; last updated June 17, 2016; expires June 17, 2019

This article includes discussion of cerebrotendinous xanthomatosis, cerebrotendinous cholesterosis, cerebral cholesterinosis, CTX, Van Bogaert-Scherer-Epstein syndrome, and 27-Hydroxylase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

This article reviews the clinical, biochemical, and molecular genetic characteristics of cerebrotendinous xanthomatosis. Cerebrotendinous xanthomatosis is an autosomal recessive disorder caused by mutations affecting the mitochondrial enzyme sterol 27-hydroxylase, with resulting cholestanol and cholesterol accumulation in virtually every tissue. There is variable clinical severity, with onset from infancy to adulthood. Typical clinical signs include early onset cataract, tendon xanthomas, and neurologic signs that include progressive adult onset dementia, psychiatric disturbances, and ataxia. Early treatment with chenodeoxycholic acid is beneficial.

Key points

 

• Cerebrotendinous xanthomatosis (MIM 213700) is caused by a deficiency of the mitochondrial enzyme sterol 27-hydroxylase.

 

• Sterol 27-hydroxylase (CYP27A1, NP_000775.1) is a key enzyme in the bile-acid-biosynthesis pathway.

 

• Cerebrotendinous xanthomatosis is a rare lipid-storage disease characterized by abnormal deposition of cholestanol and cholesterol in multiple tissues.

 

• Cerebrotendinous xanthomatosis is a treatable metabolic disease that requires early molecular diagnosis to prevent the dramatic, progressive, and unnecessary neurologic deterioration.

Historical note and terminology

Cerebrotendinous xanthomatosis was first described in 1937 by Van Bogaert and colleagues, who reported 2 cousins with a slowly progressive neurologic syndrome with cognitive and motor impairment and cataracts (Van Bogaert et al 1937). Tendon xanthomas were evident only in 1 patient at autopsy. The disease was described as a “cholestérinose généralisée.” Thirty years later, Menkes and colleagues identified the stored material as cholestanol, a metabolite of cholesterol present only in small amounts in controls (Menkes et al 1968). Since then, an increased serum cholestanol level has been a crucial diagnostic marker of the disease. In 1971, Salen reported that xanthomatosis was associated with defective bile acid pattern, with very low concentrations of chenodeoxycholic acid (CDCA) (Salen 1971). In 1974, Setoguchi described a defect in bile-acid biosynthesis, with incomplete oxidation of the C27-steroid side chain and with a greatly increased excretion of bile alcohols in bile, feces, and urine (Setoguchi et al 1974). In 1980, Oftebro and colleagues reported that a defect in the mitochondrial enzyme sterol 26-hydroxylase (currently designated 27-hydroxylase) is the cause of cerebrotendinous xanthomatosis (Oftebro et al 1980). These authors detected absent sterol 26-hydroxylase activity in a liver biopsy from a subject with cerebrotendinous xanthomatosis. Berginer and colleagues in 1984 reported encouraging results of long-term chenodeoxycholic acid treatment on metabolic and clinical alterations.

The human CYP27A1 gene was localized on the long arm of chromosome 2 (Cali and Russell 1991), and the first mutations were described (Cali et al 1991). The structure of the CYP27A1 gene has been established by Leitersdorf and colleagues (Leitersdorf et al 1993). To date, more than fifty different mutations within the CYP27A1 gene have been reported worldwide (Gallus et al 2006) (Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff).

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