Biochemical and Phenotypical Aspects of Smith-Lemli-Opitz Syndrome and Related Disorders of Cholesterol Metabolism

Overview

Background: Smith-Lemli-Opitz Syndrome (SLOS) is a genetic disorder. It can cause birth defects and developmental delays. There is no cure for SLOS or other inherited diseases related to cholesterol production or storage. The data gained in this study may help researchers find ways to measure how well future treatments work. Objective: To learn more about SLOS and related disorders and how these diseases affect participants and relatives. Eligibility: People of any age who have or are suspected to have SLOS or another inherited disease related to cholesterol production or storage. Relatives are also needed. Design: Participants will be screened with a medical record review. Participants will have visits every 6 to 12 months. They will have a physical exam. They will fill out a survey about their medical and behavioral history. They may have an eye exam. They may have a neurodevelopmental assessment. They may have a hearing test. Their outer and middle ears may be examined. Their ability to speak, understand speech, eat, and swallow may be assessed. They may get X-rays while they chew and swallow. Their functional ability and needs for adaptive devices or braces may be assessed. They may have a lumbar puncture. Photographs may be taken of their face and body. Participants who cannot visit the NIH and relatives will have a virtual visit once a year. They will talk about their medical history and symptoms. They give blood, urine, and skin samples at a lab near their home. They will fill out a survey about their medical and behavioral history. Participation will last for several years.

Study Description: The objective of this study is to characterize the natural history of Smith-Lemli-Opitz Syndrome (SLOS) and related disorders (such as lathosterolosis, desmosterolosis, X-linked dominant chondrodysplasia punctata (CDPX2), CHILD syndrome, HEM dysplasia, and Antley-Bixler syndrome) by collecting both crosssectional and longitudinal data on individuals with these conditions. Our goal is to investigate genetic, biochemical, and clinical aspects of SLOS and related disorders in order to facilitate development and implementation of future therapeutic trials. This protocol consists of a main study and three sub-studies. The main study involves inperson evaluation of patients and carriers of SLOS and related disorders. The first sub-study includes collecting biorepository samples from patients and carriers of SLOS and related disorders. The second sub-study involves obtaining a telemedicine history and full review of systems for affected individuals with SLOS and related disorders. The third sub-study involves a survey of caregivers of deceased individuals with SLOS, which will address questions regarding the deceased individual s medical history and inform causes of death. All questions in the survey will be regarding the deceased individual s medical history, none of the questions will be about the caregivers. This protocol will also maintain a database of information collected over the past two decades at the NIH on SLOS trial participants. All individuals with SLOS, related disorders and carriers will be eligible for enrollment. Objectives: The primary objective of this study is to determine laboratory or clinical outcome measures that could be used in future therapeutic trials. The secondary objectives of these studies are to define comorbidities and mortality of the disease, investigate the causes of mortality, identify potential participants for future therapeutic trials and evaluate possible laboratory outcome measures and biomarkers in carriers and suspected carriers. Endpoints: Primary endpoints 1. Phenotypic characterization of individuals with SLOS and related inborn errors of cholesterol synthesis. Define and characterize disease related morbidity and mortality. 2. Establishing a biomaterial collection (Blood, urine, CSF, DNA/RNA and cell lines) corresponding to well-phenotyped individuals for biomarker discovery and characterization. Secondary endpoints: Phenotypic history as well as blood and urine biomarkers in individuals heterozygous for pathogenic DHCR7 variants or pathogenic variants in cholesterol synthetic genes. Additional outcomes include assessments of bone health.