CEREBROTENDINOUS XANTHOMATOSIS - A FAMILY STUDY OF STEROL 27-HYDROXYLASE MUTATIONS AND PHARMACOTHERAPY

We examined the phenotypic characteristics, molecular genetics and opt imal pharmacological treatment of cerebrotendinous xanthomatosis (CTX) in an English family with combined hyperlipidaemia. The proband prese nted in adulthood with classical clinical characteristics of CTX, a gr eater than tenfold elevation in plasma cholestanol and combined hyperl ipidaemia. His brother also had typical features of CTX without the pr esence of dyslipidaemia. Genotyping revealed that the two brothers wer e compound heterozygotes for a novel missense mutation in exon 2 (R94Q ) and for a recently described nonsense mutation in exon 5, of the ste rol 27-hydroxylase gene (CYP27). Analysis of all available family memb ers revealed that hyperlipidaemia did not co-segregate with the presen ce of a CYP27 mutant allele. Trial of therapy showed that the lowest p lasma sterol and triglyceride concentrations and cholestanol:cholester ol ratio were achieved with the combination of chenodeoxycholic acid ( CDCA) 750 mg/day, a primary bile acid, and simvastatin 40mg/day, an in hibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase. CDCA alon e and simvastatin alone significantly lowered plasma cholestanol conce ntration, but the decrease was greater with the former. After 1 year t here was significant improvement in both cognitive and motor function with regression of tendon xanthomata on computerized tomography. We co nclude that CTX in this English pedigree is probably due to compound m utant alleles in CYP27, that combined hyperlipidaemia in this family i s unrelated to CTX, and that this complicated condition responds optim ally to the combination of CDCA and simvastatin.