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

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/cognitive impairment syndrome characterized by the accumulation of 7-dehydrocholesterol (7DHC), a precursor sterol of cholesterol. Simvastatin, an HMG-CoA reductase inhibitor that crosses the blood-brain-barrier, has been proposed for treatment of SLOS based on in vitro and in vivo studies suggesting that simvastatin increases expression of hypomorphic DHCR7 alleles. METHODS: Safety and efficacy of simvastatin therapy in 23 mild to typical SLOS patients was evaluated in a randomized, double-blind, placebo-controlled trial. The cross-over trial consisted of two 12 month treatment phases separated by a 2 month wash-out period. RESULTS: No safety issues were identified in this study. Plasma dehydrocholesterol levels decreased significantly 8.9 ± 8.4% on placebo to 6.1 ± 5.5% on simvastatin (p<0.005) and we observed a trend toward decreased cerebral spinal fluid dehydrocholesterol levels. A significant improvement (p=0.017, paired t-test) was observed in the Aberrant Behavior Checklist-C Irritability when subjects were on simvastatin. CONCLUSIONS: This paper reports the first randomized, placebo-controlled trial designed to test the safety and efficacy of simvastatin therapy in SLOS. Simvastatin appears to be relatively safe in SLOS patients, improves the serum dehydrocholesterol/total sterol ratio, and significantly improves irritability symptoms in mild to classical SLOS patients