STEROL METABOLISM & DIETARY CHOLESTEROL IN SLO SYNDROME

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In Smith-Lemli-Opitz Syndrome (SLOS) cholesterol levels in plasma and tissue are low, and concentrations of 7-dehyrdocholesterol and other sterols are high. These other sterols are pathologic and are not normally present. Patients with SLOS block the synthesis of cholesterol because of a deficiency in enzyme 7-dehydrocholesterol delta 7-reductase, and it is 7-dehydrocholesterol that converts to cholesterol in the last step of cholesterol synthesis. The principal investigator (PI) has proposed to feed dietary cholesterol from three different sources, egg yolk, crystalline cholesterol and butterfat to SLOS patients. Cholesterol absorption and synthesis will be determined in both very low cholesterol diets and high cholesterol diets. Using three different techniques, the PI will measure whole body cholesterol absorption and synthesis as well as bile acid synthesis in SLOS patients and in control subjects. The three different techniques include measuring cholesterol synthesis and absorption and bile acid synthesis by the sterol balance, determining cholesterol synthesis by measuring the incorporation of deuterated water into erythrocyte cholesterol, and determining sterol synthesis in SLOS patients and control subjects by measuring 24-hour urinary mevalonate excretion. The objective is to fully understand the effects that 7-dehydrocholesterol delta 7-reductase deficiency has on sterol metabolism in SLOS. Long-term dietary cholesterol supplementation feeding studies might produce more definitive results about the effect that 7-dehydrocholesterol delta 7-reductase deficiency has on sterol metabolism than have short-term supplementation feeding studies. Once the optimal dose and best source of dietary cholesterol (egg yolk, crystalline cholesterol or butterfat) is determined, the diets of SLOS patients will be supplemented for one year or longer. Biochemical parameters of these patients will be measured during this time. As a result of these feeding studies, therapies can be devised and applied to SLOS patients immediately following identification of their condition. It is the PI's plan to identify mutations in the 7-dehydrocholesterol delta 7-reductase gene in SLOS patients in order to establish a genotype-phenotype correlation based on dysmorphology and sterol synthesis. Developmental testing will be performed.