CHOLESTEROL TREATMENT IN PATIENTS WITH THE SMITH-LEMLI-OPITZ SYNDROME (SLOS)

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 Smith-Lemli-Opitz综合征（SLOS）是一种复杂的遗传性疾病，与多种出生缺陷、畸形特征、生长障碍和智力迟钝相关。SLOS是由胆固醇生物合成最后一步的代谢错误引起的。酶7-脱氢胆固醇还原酶（7 DHCR）的异常产生/功能导致胆固醇缺乏，以及胆固醇前体7-和8-脱氢胆固醇（7-DHC和8-DHC）的异常积累。胆固醇缺乏和7-和8-DHC的积累都会破坏正常的胚胎发育，并干扰多器官系统的正常生理和生物功能。本研究的目的是评估胆固醇补充剂对这些异常的影响。特别是，在该方案中，密切关注SLOS患者的生长和发育、行为功能和视网膜功能。 此外，本方案有两个研究重点领域： 1)现在我们知道，SLOS谱系中非常轻微的患者可能患有自闭症。这部分SLOS患者是否会对胆固醇治疗产生反应并显示其自闭症特征的改善是一个非常感兴趣的领域，引入了潜在可治疗形式的自闭症的可能性。 2)在SLOS中观察到的代谢异常引起大鼠视网膜功能的严重破坏，并且在人类SLOS患者中已经报道了视网膜外观和功能的记录异常。这可能导致渐进性视力障碍。该方案是研究胆固醇治疗对SLOS人类患者视网膜功能影响的唯一研究中心。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Smith-Lemli-Opitz Syndrome (SLOS) is a complex genetic disorder, associated with multiple birth defects, dysmorphic features, growth failure and mental retardation. SLOS is caused by a metabolic error in the final step of cholesterol biosynthesis. Abnormal production/function of the enzyme 7-dehydrocholesterol reductase (7DHCR) leads to a deficiency of cholesterol, and abnormal accumulation of the cholesterol precursors, 7- and 8-dehydrocholesterol (7-DHC, and 8-DHC). Both cholesterol deficiency and accumulation of 7- and 8-DHC disrupt normal embryologic development, and interfere with the normal physiological and biological functioning of multiple organ systems. The purpose of this study is to evaluate the effects of cholesterol supplementation on these abnormalities. In particular, growth and development, behavioral function, and retinal function are closely followed in SLOS patients on this protocol. Additionally, there are two areas of research focus for this protocol: 1) It is now known that patients at the very mild end of the SLOS spectrum may present with autism. Whether this subset of SLOS patients will respond to cholesterol treatment and show improvement in their autistic features is an area of great interest, introducing the possibility of a potentially treatable form of autism. 2) The metabolic abnormalities seen in SLOS cause severe disruption of retinal function in the rat, and documented abnormalities in retinal appearance and function have been reported in human SLOS patients. This may lead to progressive visual impairment. This protocol is the only site studying the effects of cholesterol treatment on retinal function in human patients with SLOS.