Smith-Lemli-Opitz Syndrome: A Longitudinal Clinical Study of Patients

Smith-Lemli-Opitz 综合征：患者的纵向临床研究

• 批准号: 8936529
• 负责人: Jean-Baptiste O Roullet
• 金额: $ 12万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8936529
• 关键词: 7-dehydrocholesterol; Adherence; Affect; Anisotropy; Biochemical; Biological Markers; Brain; Child; Cholesterol; Clinical; Clinical Research; Data; Development; Diagnosis; Diagnostic tests; Disease; Enteral; Enzymes; Evaluation; Exhibits; Family; Future; Genes; Goals; Health Personnel; Image; Individual; Intake; Intellectual functioning disability; Intervention; Lead; Learning; Magnetic Resonance Imaging; Measures; Modeling; Mutation; Natural History; Outcome Measure; Oxidoreductase; Participant; Pathogenesis; Patients; Plasma; Production; Research; Research Design; Research Personnel; Smith-Lemli-Opitz Syndrome; Sterols; Supplementation; Therapeutic Trials; Time; Treatment Efficacy; Variant; behavioral outcome; brain size; clinical phenotype; cohort; disease natural history; disease phenotype; isoprenoid; malformation; patient registry; screening

Project 1 PROJECT SUMMARY Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol synthesis caused by mutations in the DHCR7 gene which encodes for 7-dehydrocholesterol-delta7-reductase, an enzyme necessary for the production of cholesterol in the body. Affected individuals exhibit multiple malformations and intellectual disability. 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. The long-term goal of this study is to learn as much as possible about SLOS by following a cohort of patients with SLOS over time, and to build a comprehensive SLOS patient registry and identify biomarkers that can be used for diagnostic testing, screening and outcome measures in future therapeutic trials. Although most patients are treated with enteral cholesterol, there is no evidence that cholesterol supplementation is beneficial. The first aim of the study is thus to determine if cholesterol supplementation predicts changes in developmental and behavioral outcomes over time. The second aim of the study is to take advantage of this cohort of well-characterized patients to follow them over time and better define the clinical and biochemical phenotypes of the disease (biomarkers) using a natural history study design. To accomplish these aims, we plan to measure cholesterol and other sterol levels, perform clinical observations, measure changes in whole body cholesterol pool size as a result of enteral cholesterol supplementation, and conduct imaging studies (brain MRI) 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.

项目 1 项目概要 Smith-Lemli-Opitz 综合征 (SLOS) 是一种由 DHCR7 基因突变引起的胆固醇合成疾病，该基因编码 7-脱氢胆固醇-δ7-还原酶，这是体内产生胆固醇所必需的酶。受影响的个体表现出多种畸形和智力障碍。 SLOS 的特征被认为主要与胆固醇缺乏和胆固醇前体的积累有关。然而，临床表型尚未得到很好的表征，生化发病机制尚未完全了解，而且还没有针对这种破坏性疾病的有效治疗方法。 这项研究的长期目标是通过跟踪一组 SLOS 患者一段时间的情况来尽可能多地了解 SLOS，并建立全面的 SLOS 患者登记册并识别可用于诊断测试、筛查和结果的生物标志物未来治疗试验中的措施。尽管大多数患者接受肠内胆固醇治疗，但没有证据表明补充胆固醇是有益的。因此，该研究的首要目的是确定胆固醇补充剂是否可以预测发育和行为结果随时间的变化。该研究的第二个目标是利用这群特征明确的患者，对他们进行长期跟踪，并使用自然历史研究设计更好地定义疾病的临床和生化表型（生物标志物）。为了实现这些目标，我们计划测量胆固醇和其他甾醇水平，进行临床观察，测量肠内胆固醇补充导致的全身胆固醇库大小的变化，并进行成像研究（脑部 MRI）以了解更多关于疾病机制和SLOS 患者的进展、临床特征的变化，并评估补充胆固醇在这种情况下的效果。