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

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.Genet Med 19 3, 297-305.

Figure 1. Study design

Subjects were randomized to either placebo or simvastin in the first phase of this crossover trial. After 12 months in phase 1 and a 2-month washout period, subjects were switched to the alternative therapy for 12 months. One subject was excluded and 4 subjects were withdrawn.

Figure 2. Plasma sterol levels

Cholesterol and dehydrocholesterol (7DHC + 8DHC) levels were measured at baseline (B), washout (W, 14 mo) as well as at 1, 3, 6, 9 and 12 months in both the placebo and simvastatin treatment phase. Plasma cholesterol levels (A, B) and DHC (C, D) decreased significantly during the simvastatin phase compared to the placebo phase. The plasma DHC/Total Sterol ratio (E, F), which was the primary outcome measure of this study, also decreased significantly. Data expressed as mean ± SEM.

Figure 3. Cerebral spinal fluid sterol levels

Neither cholesterol (A) nor the DHC/Total Sterol ratio (B) were decreased in CSF from subjects when they were treated with simvastatin compared to when they were treated with placebo. A trend toward decreased DHC (C) levels was observed during simvastatin therapy compared to placebo. Data expressed as mean ± SEM.

Figure 4. Simvastin therapy reduces irritability in SLOS subjects

A) Comparison of ABC Irritability subscores from baseline (0 mo) and washout (14 mo). No significant differences were noted. B) Paired evaluation of data from the 14 subjects for whom we had data from both the placebo and simvastatin treatment arms demonstrated a significant improvement in the ABC-C Irritability subscale (p=0.017, paired t-test).