INVESTIGATION OF SIMVASTATIN THERAPY IN SMITH-LEMI-OPITZ SYNDROME

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。史密斯-莱姆利-奥普茨综合征(SLOS，RSH综合征，OMIM#270400)是一种由于先天性胆固醇生物合成错误而导致的常染色体隐性、多发性畸形、智力低下综合征。具体地说，这些患者由于3-β-羟基类固醇7-核糖核酸酶基因(DHCR7)的突变而缺乏3-β-羟基类固醇增量-7还原酶活性。这种酶的缺乏会损害7-脱氢胆固醇(7-DHC)在胆固醇生物合成的最后一步转化为胆固醇。SLOS的临床表现千差万别，表型谱广泛。在严重的情况下，SLOS是一种具有多种主要先天性异常的致命性疾病，在轻度病例中，SLOS合并轻微的身体污点与行为和学习障碍。根据临床研究，SLOS的发病率为1/10,000至1/60,000。分子研究表明，北美人群中最常见的SLOS突变等位基因的携带率约为1%。目前，治疗的基础是饮食中补充胆固醇。虽然已经注意到临床改善，但血清胆固醇水平很少恢复正常，血清7-DHC水平持续升高。由于升高的7-DHC水平可能有毒性作用，已提出使用HMG-CoA还原酶抑制剂治疗SLOS患者。辛伐他汀是一种抑制身体合成胆固醇能力的药物。因为IS在早期就阻碍了胆固醇的合成，它也阻碍了7-DHC的合成。在轻度到典型的SLOS儿童中，将7-DHC转化为胆固醇的蛋白质(酶)水平较低。我们怀疑辛伐他汀可能会增加这种酶的含量。如果发生这种情况，尽管这种酶的作用不会更好，但它的数量会更多。随着更多的酶的存在，更多的7-DHC可能会转化为胆固醇。尽管补充膳食胆固醇可改善临床症状，但血清胆固醇水平很少恢复正常，且血清7-DHC水平持续升高。这项临床研究方案的目标将是采用双盲、安慰剂对照交叉设计，测试辛伐他汀治疗作为补充胆固醇的轻度至经典SLOS患者的临床有效性和安全性。

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, RSH syndrome, OMIM #270400) is an autosomal recessive, multiple malformation, mental retardation syndrome due to an inborn error of cholesterol biosynthesis. Specifically, these patients have a deficiency of 3-beta-hydroxysterol delta-7 reductase activity due to mutation of the 3-beta-hydroxysterol 7-reuctase gene (DHCR7). This enzymatic deficiency impairs the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol in the last step of cholesterol biosynthesis. The clinical manifestations of SLOS are extremely variable and the phenotypic spectrum is broad. At the severe end of the spectrum SLOS is a lethal disorder with multiple major congenital anomalies, and in mild cases SLOS combines minor physical stigmata with behavioral and learning disabilities. Based on clinical studies, the incidence rate of SLOS is 1/10,000 to 1/60,000. Molecular studies have shown a carrier frequency of about 1% for the most common SLOS mutant allele in North American populations. Currently, therapy is based on dietary cholesterol supplementation. Although clinical improvement has been noted, serumcholesterol levels are rarely normalized and elevated serum 7-DHC levels persist. Because elevated 7-DHC levels may have toxic effects, treatment of SLOS patients with an HMG-CoA reductase inhibitor has been proposed. Simvastatin is a medication which inhibits the body's ability to synthesize cholesterol. Because is blocks cholesterol synthesis at an early step, it also blocks 7-DHC synthesis. In mild to typical SLOS children, the protein (enzyme) that converts 7-DHC to cholesterol works at a low level. We suspect that simvastatin may increase the amount of this enzyme. If this occurs, although the enzyme does ot work any better, there is more of it. With more enzyme present, more 7-DHC may be converted to cholesterol. Although clinical improvement has been noted with dietary cholesterol supplementation, serum cholesterol levels are rarely normalized and elevated serum 7-DHC levels persist. The goal of this clinicsl research protocol will be to test the clinical efficacy and safety of simvastatin therapy as an addition to cholesterol supplementation in mild to classical SLOS patients using a double-blind, placebo-controlled crossover design.