Smith-Lemli-Opitz syndrome: The first malformation syndrome associated with defective cholesterol synthesis

Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive condition with mu ltiple malformations, mental retardation, and growth failure, results from markedly reduced activity of the final enzyme in the cholesterol biosynthet ic pathway, 7-dehydrocholesterol reductase (DHCR7). Clinical signs vary in severity, ranging from fetal loss to holoprosencephaly with multiple malfor mations to isolated syndactyly. The biochemical defect in SLOS is a deficie ncy of DHCR7, which results in an abnormally low cholesterol level, and inc reased amounts of intermediates of sterol biosynthesis. Animal models curre ntly exist through the use of cholesterol biosynthesis inhibitors, from whi ch a great deal has been learned. Pregnant rats treated with inhibitors of DHCR7 yield pups that have abnormal sterol profiles and craniofacial abnorm alities characteristic of severe SLOS. Biochemical testing of human patient s can be performed using gas chromatography/mass spectroscopy (GC/MS) to an alyze the sterol content of tissues, amniotic fluid, or cell culture lysate . Numerous mutations have been identified in DHCR7 but seven individual mut ations account for 67% of the total mutations reported in the literature. C linical trials with SLOS are underway, with the goal of increasing the chol esterol concentration in the plasma and tissues through the administration of dietary cholesterol. Thus far, this approach has shown limited efficacy. Nevertheless, the recent identification of the biochemical and molecular g enetic basis for SLOS is reason for optimism that the condition may one day yield to treatment. (C) 2000 Academic Press.