A Long-Term Study of Cholesterol Supplements for Smith-Lemli-Opitz Syndrome

Overview

Background: \- Smith-Lemli-Opitz syndrome (SLOS) is a genetic disorder that prevents the body from making enough cholesterol. People who have SLOS often need to take extra cholesterol, either in food or in supplements, for their bodies to work properly. Cholesterol is very important for the brain and nervous system. Therefore SLOS is highly related to autism, mental retardation, and other brain and nervous system disorders. Not much is known about how people with SLOS handle cholesterol and how taking extra cholesterol helps them. A long-term study of people with SLOS will help answer these and other questions. Objectives: \- To study the effects of a high-cholesterol diet on people with Smith-Lemli-Opitz syndrome. Eligibility: \- Individuals of any age who have Smith-Lemli-Opitz syndrome. Design: * Participants will have study visits up to two times in the first year and once a year every year after that. Each visit will last between 3 and 5 days. * Participants will be screened with a physical exam, medical history, and blood and urine tests. * Participants will provide regular blood, urine, stool, saliva, and skin cell samples for testing. * Participants will keep track of the foods they eat at home. During the study, they will eat a high-cholesterol diet at all times, except for the second study visit (3 to 6 months after the screening visit). That visit will involve a cholesterol-free diet for 4 weeks. * Participants will have special cholesterol tests with blood samples at different times during the study. * At different study visits, participants will have tests of mental and physical skills (including tests for autism). They will answer questions about their diet and food habits. They will also have hearing and eye tests, body and bone measurements, and imaging studies. Not all of the tests will be done at every study. * Participants will be allowed to leave the study at any time.

The purpose of this study is to learn as much as possible about Smith-Lemli-Opitz Syndrome (SLOS) by following a large group of individuals with SLOS over a period of time. We plan to measure cholesterol and other sterol levels, perform clinical observations, whole body testing and imaging studies (brain MRIs), to learn more about disease mechanisms and progression, variations in the clinical features among individuals with SLOS, and evaluate the effect of cholesterol supplementation in this condition. Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol synthesis, or production. It is caused by mutations in the DHCR7 gene which encodes for 7-dehydrocholesterol reductase, an enzyme necessary for the production of cholesterol in the body. Affected individuals exhibit multiple malformations and mental retardation. The features of SLOS are thought to be primarily related to cholesterol deficiency and accumulation of cholesterol precursors. However, the clinical phenotype is not well characterized, the biochemical pathogenesis is incompletely understood, and there is no proven therapy for this devastating condition. Thus our primary objective is to better define the clinical and biochemical phenotypes of the disease using a natural history study design. The study will contribute to creating a comprehensive SLOS patient registry, identify biomarkers that can be used for diagnostic testing, screening and outcome measures in future therapeutic trials. All patients with SLOS receive dietary cholesterol supplementation with the hope that cholesterol supplementation will improve the clinical manifestation of the disease. However, there is no evidence supporting a clinical benefit of cholesterol supplementation. Thus a secondary objective of the study is to determine if cholesterol intake correlates with changes in whole body cholesterol homeostasis and clinical end-points.