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  • Updated 10.21.2020
  • Released 03.13.1996
  • Expires For CME 10.21.2023

Cerebrotendinous xanthomatosis

Introduction

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.

• Treatment with chenodeoxycholic acid may slow the progression of the disease and reverse symptoms in some patients.

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 (93). 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 (58). 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) (79). 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 (85). 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 (70). 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 (18), and the first mutations were described (17). The structure of the CYP27A1 gene has been established by Leitersdorf and colleagues (54). To date, more than fifty different mutations within the CYP27A1 gene have been reported worldwide (39) (Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff).

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