Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital anomaly/mental retardation syndrome. Typical clinical features include a distinctive facial appearance, mental retardation, autistic behavior, hypotonia, failure to feed, poor growth, decreased life span, and variable structural anomalies of the heart, lungs, brain, gastrointestinal tract, limbs, genitalia and kidneys. The SLOS phenotypic spectrum is broad and variable. At the severe end of the spectrum SLOS is a lethal disorder with multiple major congenital anomalies; whereas, mild cases of SLOS present with a combination of minor physical stigmata, behavioral problems, and learning disabilities. SLOS is due to an inborn error of cholesterol biosynthesis. Biochemically, SLOS patients have a deficiency of 3beta-hydroxysterol delta(7)-reductase activity. 3beta-hydroxysterol delta-reductase is an NADPH dependent microsomal enzyme that catalyzes the reduction of the C7(8) double bond of 7-dehydrocholesterol (7-DHC) to yield cholesterol in the last step of cholesterol biosynthesis via the Kandutsch-Russel pathway. This inborn error of cholesterol biosynthesis results in elevated tissue and serum 7-DHC levels and typically decreased serum and tissue cholesterol levels. In 1998 we established that the deficiency in 3beta-hydroxysterol delta(7)-reductase activity is due to mutation of the 3beta-hydroxysterol delta(7)-reductase gene (DHCR7). Once the biochemical defect in SLOS was identified, dietary cholesterol supplementation was proposed and employed as a therapeutic approach. Although developmental malformations remain fixed, dietary cholesterol supplementation appears to improve the overall health of these patients, and initial results have shown that dietary cholesterol supplementation has had a positive impact on some of the behavioral manifestations of this disorder. Although our understanding of this disorder has advanced over the last few years, many questions remain concerning the effectiveness of cholesterol replacement therapy, the long term prognosis for individuals on dietary cholesterol supplementation, and the need for adjunctive measures in the clinical management of SLOS patients. We propose to answer some of these questions by continuing our longitudinal natural history/prognosis study on patients with SLOS.

The objectives of this study are as follows:

1. To establish the natural history, and thus prognoses, of a cohort of SLOS patients on dietary cholesterol supplementation.
2. To provide baseline information about SLOS patients on cholesterol supplementation in order to design and interpret future adjunctive therapies.
3. To function as a screening protocol to recruit patients into other therapeutic or investigative trials. This protocol provides for phenotypic evaluation, obtaining skin fibroblasts, initial laboratory testing, and genotyping which must be done prior to enrolling in the simvastatin protocol. This protocol also provides an alternative for patients who are excluded, or elect not to participate in our ongoing the simvastatin trial or a future therapeutic trial.
4. To maintain a large, diverse and well-characterized SLOS cohort to investigate new areas of clinical concern that arise.
5. To establish a genotype/phenotype correlation for SLOS, to continue to define the SLOS clinical spectrum and to determine other factors that may significantly influence a specific patient's phenotype.
6. To use in vitro studies of cholesterol metabolism in SLOS fibroblasts to further our understanding of the molecular, biochemical, and cellular processes that underlie the clinical problems encountered in SLOS.
7. To use modalities of magnetic resonance imaging (Quantitative MRS and Diffusion Tensor Imaging) and to correlate findings with both biochemical measures and neurocognitive testing.