Lack of Inhibition of 7-dehydrocholesterol Synthesis with Cholesterol Supplementation in Smith-Lemli-Opitz Syndrome † 737

Smith-Lemli-Opitz syndrome (SLOS) is an inherited multiple malformation and mental retardation syndrome. Characteristic features include microcephaly, dysmorphic features, limb defects, and other anomalies. SLOS is caused by deficiency of 7-dehydrocholesterol-D⁷-reductase, the final enzyme in the cholesterol synthetic pathway. Reduced plasma and tissue cholesterol as well as accumulation of cholesterol precursors such as 7-dehydrocholesterol(7-DHC) are hallmarks of this condition. It is unclear whether cholesterol deficiency or accumulation of potentially toxic cholesterol precursors or both are causative.

We and others have hypothesized that supplemental cholesterol may be therapeutic in SLOS. We also hypothesized that supplemental cholesterol might suppress synthesis of both cholesterol and 7-DHC in individuals with SLOS, via inhibition of HMG-CoA reductase.

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