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

Christopher A. Wassif, Lisa Kratz, Susan E. Sparks, Courtney Wheeler, Simona Bianconi, Andrea Gropman, Karim A. Calis, Richard I. Kelley, Elaine Tierney, Forbes D. Porter

Research output: Contribution to journalArticle

Abstract

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, double-blind, 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.

Original languageEnglish (US)
Pages (from-to)297-305
Number of pages9
JournalGenetics in Medicine
Volume19
Issue number3
DOIs
StatePublished - Mar 1 2017
Externally publishedYes

Fingerprint

Smith-Lemli-Opitz Syndrome
Simvastatin
Placebos
Dehydrocholesterols
Safety
Sterols
Coenzyme A
Blood-Brain Barrier
Checklist
Cross-Over Studies
Cerebrospinal Fluid
Oxidoreductases
Randomized Controlled Trials
Alleles
Cholesterol
Serum
In Vitro Techniques

Keywords

  • Aberrant Behavior Checklist-Community
  • DHCR7
  • placebo-controlled trial
  • randomized
  • simvastatin
  • Smith-Lemli-Opitz syndrome

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Wassif, C. A., Kratz, L., Sparks, S. E., Wheeler, C., Bianconi, S., Gropman, A., ... Porter, F. D. (2017). A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome. Genetics in Medicine, 19(3), 297-305. DOI: 10.1038/gim.2016.102

A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome. / Wassif, Christopher A.; Kratz, Lisa; Sparks, Susan E.; Wheeler, Courtney; Bianconi, Simona; Gropman, Andrea; Calis, Karim A.; Kelley, Richard I.; Tierney, Elaine; Porter, Forbes D.

In: Genetics in Medicine, Vol. 19, No. 3, 01.03.2017, p. 297-305.

Research output: Contribution to journalArticle

Wassif, CA, Kratz, L, Sparks, SE, Wheeler, C, Bianconi, S, Gropman, A, Calis, KA, Kelley, RI, Tierney, E & Porter, FD 2017, 'A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome' Genetics in Medicine, vol 19, no. 3, pp. 297-305. DOI: 10.1038/gim.2016.102
Wassif CA, Kratz L, Sparks SE, Wheeler C, Bianconi S, Gropman A et al. A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome. Genetics in Medicine. 2017 Mar 1;19(3):297-305. Available from, DOI: 10.1038/gim.2016.102

Wassif, Christopher A.; Kratz, Lisa; Sparks, Susan E.; Wheeler, Courtney; Bianconi, Simona; Gropman, Andrea; Calis, Karim A.; Kelley, Richard I.; Tierney, Elaine; Porter, Forbes D. / A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome.

In: Genetics in Medicine, Vol. 19, No. 3, 01.03.2017, p. 297-305.

Research output: Contribution to journalArticle

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abstract = "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, double-blind, 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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