期刊
GENETICS IN MEDICINE
卷 19, 期 3, 页码 297-305出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/gim.2016.102
关键词
Aberrant Behavior Checklist-Community; DHCR7; randomized, placebo-controlled trial; simvastatin; Smith-Lemli-Opitz syndrome
资金
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Autism Speaks
- Johns Hopkins Institute for Clinical and Translational Research (ICTR)
- National Center for Advancing Translational Sciences (NCATS) - National Institutes of Health (NIH) [UL1 TR 001079]
- NIH Roadmap for Medical Research
Background: Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/cognitive impairment syndrome characterized by the accumulation of 7-dehydrocholesterol, a precursor sterol of cholesterol. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor that crosses the blood-brain barrier, has been proposed for the treatment of SLOS based on in vitro and in vivo studies suggesting that simvastatin increases the expression of hypomorphic DHCR7 alleles. Methods: Safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS were evaluated in a randomized, doubleblind, placebo-controlled trial. The crossover trial consisted of two 12-month treatment phases separated by a 2-month washout period. Results: No safety issues were identified in this study. Plasma dehydrocholesterol concentrations decreased significantly: 8.9 +/- 8.4% on placebo to 6.1 +/- 5.5% on simvastatin (P < 0.005); we observed a trend toward decreased cerebrospinal fluid dehydrocholesterol-concentrations. A significant improvement (P = 0.017, paired t-test) was observed on the irritability subscale of the Aberrant Behavior Checklist-C when subjects were taking simvastatin. Conclusion: This article reports what is, to our knowledge, the first randomized, placebo-controlled trial designed to test the safety and efficacy of simvastatin therapy in SLOS. Simvastatin seems to be-relatively safe in patients with SLOS, improves the serum-dehydrocholesterol-to-total sterol ratio, and significantly improves irritability symptoms in patients with mild to classic SLOS.
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