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

项目1 Smith-Lemli-Opitz综合征（SLOS）是一种由DHCR 7基因突变引起的胆固醇合成障碍，该基因编码7-脱氢胆固醇-δ 7-还原酶，该酶是体内胆固醇产生所必需的酶。受影响的人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的积累有关。然而，临床表型没有得到很好的表征，生化发病机制也不完全清楚，并且对于这种毁灭性的疾病没有经过验证的治疗方法。 本研究的长期目标是通过随时间推移随访一组SLOS患者，尽可能多地了解SLOS，并建立一个全面的SLOS患者登记处，并确定可用于诊断测试的生物标志物，筛选和未来治疗试验的结果措施。虽然大多数患者接受肠内胆固醇治疗，但没有证据表明胆固醇补充剂有益。因此，这项研究的第一个目的是确定胆固醇补充剂是否可以预测随着时间的推移发育和行为结果的变化。该研究的第二个目的是利用这一具有良好特征的患者队列，随着时间的推移对其进行随访，并使用自然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固醇水平，进行临床观察，测量肠内胆固醇补充剂导致的全身胆固醇池大小的变化，并进行成像研究（脑MRI）以了解更多关于疾病机制和进展，SLOS患者临床特征的变化，并评估胆固醇补充剂在这种情况下的作用。

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.