Clinical and biochemical features, molecular diagnosis and long-term management of a case of cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive sterol s torage disease characterised clinically by juvenile bilateral cataracts, pr ogressive neurological dysfunction, and formation of tendon xanthomata. We describe the clinical and biochemical features, molecular diagnosis and lon g-term management of the first reported Australasian case of CTX. Molecular analysis confirmed the diagnosis of CTX and demonstrated that the patient was homozygous for a G --> A transition in the splice donor site of intron 4 of the sterol 27-hydroxylase gene. Serum cholestanol concentrations were decreased with the HMG-CoA reductase inhibitor simvastatin alone and greate r reductions were achieved after the addition of the bile acid chenodeoxych olic acid; suggesting a synergistic effect of this combination. Despite ser um cholestanol concentrations remaining within the low-normal range, there has been no significant improvement in mental and physical abilities or in EEG abnormalities with 5 years of treatment. Metabolism of radiolabeled 7-k etocholesterol to aqueous soluble products was absent in CTX-derived macrop hages. Consistent wi th this finding, plasma 7 alpha -hydroxycholesterol, 7 beta -hydroxycholesterol, and 7-ketocholesterol concentrations were increa sed in the CTX subject compared with controls. (C) 2001 Elsevier Science B. V. All rights reserved.