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 language | English (US) |
|---|---|
| Pages (from-to) | 297-305 |
| Number of pages | 9 |
| Journal | Genetics in Medicine |
| Volume | 19 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2017 |
Fingerprint
Keywords
- Aberrant Behavior Checklist-Community
- DHCR7
- placebo-controlled trial
- randomized
- simvastatin
- Smith-Lemli-Opitz syndrome
ASJC Scopus subject areas
- Genetics(clinical)
Cite this
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 journal › Article
}
TY - JOUR
T1 - A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome
AU - Wassif, Christopher A.
AU - Kratz, Lisa
AU - Sparks, Susan E.
AU - Wheeler, Courtney
AU - Bianconi, Simona
AU - Gropman, Andrea
AU - Calis, Karim A.
AU - Kelley, Richard I.
AU - Tierney, Elaine
AU - Porter, Forbes D.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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.
AB - 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.
KW - Aberrant Behavior Checklist-Community
KW - DHCR7
KW - placebo-controlled trial
KW - randomized
KW - simvastatin
KW - Smith-Lemli-Opitz syndrome
UR - http://www.scopus.com/inward/record.url?scp=85014814093&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85014814093&partnerID=8YFLogxK
U2 - 10.1038/gim.2016.102
DO - 10.1038/gim.2016.102
M3 - Article
C2 - 27513191
AN - SCOPUS:85014814093
VL - 19
SP - 297
EP - 305
JO - Genetics in Medicine
JF - Genetics in Medicine
SN - 1098-3600
IS - 3
ER -