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.

In order to test these hypotheses, children with SLOS and normal controls were admitted to the General Clinical Research Center for one week for metabolic studies. Dietary cholesterol intake was precisely controlled and stool collected daily for sterol balance studies. Subjects were studied on a cholesterol-free diet followed by a high cholesterol diet. For the high cholesterol diet, supplemental dietary cholesterol in the form of egg yolk(1-2 daily) was utilized. Whole body cholesterol and 7-DHC synthesis were calculated by the sterol balance technique. This technique allows precise calculation of sterol synthesis by measurement of neutral sterols and bile acids in stool by gas chromatography. Sterol synthesis equals excretion minus intake.

Total sterol synthesis in 7 SLOS subjects on a cholesterol-free diet was 13.1 ± 2.51 mg/kg/day (16.9 in controls). Cholesterol synthesis in 7 SLOS subjects on a cholesterol-free diet was 8.78 ± 2.70 mg/kg/day(16.9 in controls). Finally, 7-DHC synthesis in 7-SLOS subjects averaged 2.19± 1.43 mg/kg/day on a cholesterol free diet vs. 2.38 ± 1.85 in 5 SLOS subjects on a high cholesterol diet.

As expected, cholesterol synthesis in SLOS subjects is reduced compared to controls due to the block in cholesterol synthesis. Total sterol synthesis is not significantly different from controls and cholesterol supplementation does not inhibit synthesis of 7-DHC in SLOS subjects. If 7-DHC is toxic and contributes to the pathogenesis of SLOS, alternative strategies in addition to cholesterol supplementation will need to be employed in order to decrease its synthesis.