CEREBROTENDINOUS XANTHOMATOSIS IN THE ISRAELI DRUZE - MOLECULAR-GENETICS AND PHENOTYPIC CHARACTERISTICS

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid-s torage disease caused by mutations in the sterol 27 hydroxylase gene ( CYP27). Clinically, a multitude of neurological, skeletal, and vascula r manifestations are usually present. Premature atherosclerosis has be en reported in CTX and may be related to the metabolic derangement cau sed by the deficiency of the enzyme. A CYP27 nonsense mutation created by the deletion of cytosine(376) has been identified in four Israeli Druze CTX patients residing in the same village. Molecular screening f or this mutation in families of two probands revealed a total of 10 ho mozygotes and 28 heterozygotes whose clinical and biochemical characte ristics are described. Overall, except for tendon xanthomas, most of t he clinical manifestations progress with age. The CYP27 mutation was a ssociated with modest differences in the levels of plasma total choles terol (TC) and LDL cholesterol (LDL-C). The distribution of plasma con centrations of TC and LDL-C in the CTX families was consistent with a polygenic model. A similar model that includes also the effects of the CYP27 genotypes was not better supported by the data. It may be concl uded that, in CTX, the presence of a CYP27 mutation does not significa ntly affect the plasma concentrations of lipids and lipoproteins. Ther efore, the reported increased prevalence of atherosclerosis in this di sease must be related to other factors.