QJM, Vol 89, Issue 1 55-63, Copyright © 1996 by Oxford University Press
GF Watts, WD Mitchell, JJ Bending, A Reshef and E Leitersdorf
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.
ORIGINAL PAPERS
Cerebrotendinous xanthomatosis: a family study of sterol 27-hydroxylase mutations and pharmacotherapy
University Department of Medicine, University of Western Australia, Perth.
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