Background; The Smith-Lemli-Opitz Syndrome (frequency ca 1:20,000) is a major public health problem which is described by a constellation of severe birth defects, including profound mental retardation and severe failure to thrive heretofore diagnosed only from its characteristic facies and limb and organ defects. We have recently reported, for the first time, a major biochemical defect in the syndrome. In 28 children plasma cholesterol levels (4 to 132 mg/dl) are below the fifth percentile for age matched controls while concentrations (6 to 61 mg/dl) of the cholesterol precursor 7-dehydrocholesterol (cholest-5,7-dien-3beta-ol) are elevated 2500 to 6000- fold above normal. Although not detected in controls, 7-dehydrocholesterol is also found in high concentrations in all tissues as well as in cultured fibroblasts. Abnormally low plasma cholesterol concentrations combined with high levels of 7-dehydrocholesterol demonstrate major block in cholesterol biosynthesis at the step in which the C-7,8 double bond of 7- dehydrocholesterol is reduced to form cholesterol. This may be sufficient to cause cholesterol deprivation in the embryo and fetus and prevent its proper development while the incorporation of 7-dehydrocholesterol in cells is likely to interfere with proper membrane function. We have also affected a prenatal diagnosis in two women by detecting elevated 7- dehydrocholesterol in amniotic fluid. An isotope incorporation assay in fibroblasts suggest that a test for carriers might be possible. Planned Studies: Our goals are to further define the biochemical defect in the syndrome by measurements of tissue lipids, by carrying out in vitro measurements of appropriate enzymes in the cholesterol biosynthetic pathway (3beta-hydroxy-delta 5.7-steroid delta7--reductase and HMG-CoA reductase) in affected, carrier and control fibroblasts cultured under various conditions and to examine cellular function and membrane properties under conditions of reduced C-7 reductase activity. An animal model of the disease is being developed and has already been used to plan and test treatment strategies and to further study the biochemistry of the disease. Four children have been placed on controlled high cholesterol diets (replacement therapy). As a results, their plasma cholesterol levels appeared to increase and they seem to progress a little more rapidly. Finally a collaborative effort is being planned to purify the C-7 reductase enzyme, sequence it and clone the cDNA. Eventually, it is hoped that an efficient test for carriers will be developed.
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