The goals of this project are to understand the pathophysiological processes underlying Smith-Lemli-Opitz syndrome (SLOS) and to investigate therapeutic interventions. SLOS is a human autosomal recessive multiple congenital anomaly/mental retardation syndrome characterized by facial dysmorphology, mental retardation with a characteristic behavioral phenotype, growth retardation, and variable structural anomalies of the heart, lungs, brain, gastrointestinal tract, limbs, genitalia and kidneys. SLOS also has a distinct behavioral phenotype which includes self-injurious and autistic features. Biochemically patients with SLOS have an inborn error of cholesterol biosynthesis. Specifically, they have a defect in the conversion of 7-dehydrocholesterol to cholesterol. Several clinical protocols have been initiated. We follow over 60 SLOS patients to determine the Natural History of SLOS on dietary cholesterol supplementation. As part of this protocol, we cloned the gene encoding the 7-dehydrocholesterol reductase, and subsequently identified mutations in this gene in our patients with Smith-Lemli-Opitz syndrome. Our laboratory continues to identify mutations in SLOS patients, and to determine residual enzymatic function in patient fibroblasts. This information is being used to establish genotype/enzymatic activity/phenotype correlations for this disorder. We are now working,in collaboration with multiple laboratories, to identify and characterize the biological activity of aberrant oxysterols, steroids, and neuroactive steroids. This protocol also serves as a screening protocol for other therapeutic trials. Parents frequently report improved behavior in SLOS children on dietary cholesterol supplementation. However, a blinded protocol studying the efficacy of dietary cholesterol therapy in ameliorating behavioral problems associated with SLOS has not been conducted. Thus, we designed and implemented a protocol to study the short-term efficacy of dietary cholesterol therapy to improve behavioral problems in forty SLOS children. Basic laboratory experiments using patient cells and our SLOS mouse model have suggested that simvastatin may be efficacious in improving the sterol abnormality in SLOS. Thus, we initiated a controlled, blinded cross-over protocol studying the safety and efficacy of simvastatin therapy in SLOS. Previously we have shown that SLOS fibroblasts have a secondary defect in intracellular cholesterol transport. As part of a Bench-to-Bedside proposal and in collaboration with the Platt laboratory, we have begun to study impaired cholesterol and glycosphingolipid transport in SLOS, and to investigate novel therapeutic interventions.

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