INVESTIGATION OF SIMVASTATIN THERAPY IN SMITH-LEMI-OPITZ SYNDROME

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。Smith-Lemli-Opitz综合征（SLOS， RSH综合征，omim# 270400）是一种常染色体隐性遗传，多种畸形，智力低下综合征，由于先天的胆固醇生物合成错误。具体来说，这些患者由于3- β -羟基甾醇7-还原酶基因（DHCR7）突变而缺乏3- β -羟基甾醇δ -7还原酶活性。在胆固醇生物合成的最后一步，这种酶的缺乏损害了7-脱氢胆固醇（7-DHC）向胆固醇的转化。sls的临床表现多变，表型谱广泛。在严重的情况下，sls是一种致命的疾病，伴有多种主要的先天性异常，而在轻微的情况下，sls结合了轻微的身体污点和行为和学习障碍。根据临床研究，sls的发生率为1/10,000 ~ 1/60,000。分子研究表明，北美人群中最常见的sls突变等位基因的携带频率约为1%。目前，治疗是基于膳食胆固醇补充。虽然已注意到临床改善，但血清胆固醇水平很少正常化，血清7-DHC水平持续升高。由于7-DHC水平升高可能有毒性作用，已经提出用HMG-CoA还原酶抑制剂治疗sls患者。辛伐他汀是一种抑制人体合成胆固醇能力的药物。因为它在早期就阻断了胆固醇的合成，它也阻断了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数量。如果发生这种情况，尽管酶的作用不会更好，但会有更多的酶。有了更多的酶，更多的7-DHC可能转化为胆固醇。虽然补充膳食胆固醇可以改善临床，但血清胆固醇水平很少恢复正常，血清7-DHC水平持续升高。本临床研究方案的目的是通过双盲、安慰剂对照交叉设计，测试辛伐他汀治疗作为轻度至经典sls患者胆固醇补充的临床疗效和安全性。

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.