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

项目1项目总结 Smith-Lemli-Opitz综合征(SLOS)是一种由7-脱氢胆固醇-7-还原酶基因突变引起的胆固醇合成障碍，7-脱氢胆固醇-7-还原酶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残疾。SLOS的特征被认为主要与胆固醇缺乏和胆固醇前体积累有关。然而，临床表型尚不清楚，生化发病机制也不完全清楚，目前还没有针对这种毁灭性疾病的有效治疗方法。 这项研究的长期目标是通过跟踪SLOS患者的队列来尽可能多地了解SLOS，并建立一个全面的SLOS患者登记系统，并在未来的治疗试验中确定可用于诊断测试、筛查和结果衡量的生物标记物。虽然大多数患者接受肠道胆固醇治疗，但没有证据表明补充胆固醇是有益的。因此，这项研究的第一个目的是确定补充胆固醇是否可以预测随着时间的推移发育和行为结果的变化。这项研究的第二个目的是利用这一具有良好特征的患者队列来跟踪他们一段时间，并使用自然病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类固醇水平，进行临床观察，测量由于肠道补充胆固醇而导致的全身胆固醇池大小的变化，并进行成像研究(脑MRI)，以更多地了解SLOS患者的疾病机制和进展，临床特征的变化，并评估这种情况下补充胆固醇的效果。

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.