MENTAL-RETARDATION AND CHOLESTEROL-SYNTHESIS IN THE BRAIN - THE SMITH-LEMLI-OPITZ-SYNDROME

The Smith-Lemli-Opitz syndrome is a debilitating and not uncommon birt h defect syndrome caused by a block in cholesterol biosynthesis at the step in which 7-dehydrocholesterol is converted to cholesterol. The p henotype is characterized by numerous dysmorphic facial and limb abnor malities and malformations of heart, lung, kidneys, digestive system a nd genitalia. Central and peripheral nervous system morphology and fun ction are abnormal, tonic disorders are common and all subjects are me ntally retarded. We have recently developed an animal model to study t issue function and experimental therapies in the syndrome by treating rats with BM 15.766, a chemical inhibitor of sterol C-7 reductase whic h mimics the biochemical defect in the syndrome. Brain, plasma and tis sue sterols were measured by gas-chromatography in postmortem samples from affected children and in rats fed BM 15.766 for 4 months with or without 2% cholesterol in the diet. The animals were then subjected to a classical conditioning of eyeblink response learning paradigm. Resu lts: In affected children, cholesterol accounted for only 4% of brain sterols but for 20% of plasma and tissue sterols. In rats, brain chole sterol concentrations declined 34% and 39%, respectively, in inhibitor alone and inhibitor plus cholesterol fed animals compared to controls . 7-dehydrocholesterol, which comprised 38% of brain sterols in inhibi tor fed animals declined to 23% (p<0.05) when cholesterol was added to the diet Animals fed the inhibitor alone could not learn the eyeblink response. But, feeding cholesterol together with the inhibitor restor ed learning to normal levels. The human brain and nervous system canno t develop and function properly when 7-dehydrocholesterol is substitut ed for cholesterol. In contrast, the rat brain can perform adequately when cholesterol biosynthesis is blocked as long as an exogenous suppl y of cholesterol is provided. (C) 1997, Medikal Press.