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A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome

Authors :
Karim A. Calis
Susan Sparks
Andrea L. Gropman
Courtney Wheeler
Elaine Tierney
Lisa E. Kratz
Richard I. Kelley
Christopher A. Wassif
Simona Bianconi
Forbes D. Porter
Source :
Genetics in medicine : official journal of the American College of Medical Genetics
Publication Year :
2017
Publisher :
Elsevier BV, 2017.

Abstract

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. Safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS were evaluated in a randomized, double-blind, placebo-controlled trial. The crossover trial consisted of two 12-month treatment phases separated by a 2-month washout period. 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. 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. Genet Med 19 3, 297–305.

Details

ISSN :
10983600
Volume :
19
Database :
OpenAIRE
Journal :
Genetics in Medicine
Accession number :
edsair.doi.dedup.....2521af9baf01dd4b9b141a36ad1e7d5e