Cerebrotendinous xanthomatosis: a family study of sterol 27-hydroxylase mutations and pharmacotherapy.

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.