Sterol and bile acid synthesis in Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome (SLO) is an autosomal recessive disorder with microcephaly and multiple malformations. Reduced cholesterol and elevated 7-dehydrocholesterol (7-DHC) in plasma and tissues are characteristic of SLO. The cause is reduced activity of the final enzyme in cholesterol synthesis, 7-DHC- Δ 7 reductase. We hypothesized reduced sterol and bile acid synthesis in SLO and that supplemental cholesterol may help by increasing plasma cholesterol and decreasing 7-DHC. We measured sterol and bile acid synthesis in SLO patients given very low and high cholesterol diets. We estimated cholesterol synthesis by mevalonate excretion. In 5 SLO patients, plasma cholesterol level was 60 mg/dl (132 mg/dl in controls) on very low cholesterol diets. Plasma cholesterol increased to 91 mg/dl in patients fed egg yolk; 7-DHC was unchanged from baseline, at 10.9±0.8 mg/dl. Under sterol balance conditions total sterol synthesis in 7 SLO patients was 13±4 mg/kg/d (control 17±7), cholesterol synthesis 8.8±2.7 mg/kg/d (control 17.9, p<0.05), 7-DHC synthesis 2.2 mg/kg/d. Bile acid synthesis was normal, 2.9±1.6 mg/kg/d vs. 2.6±2.1 mg/kg/d in controls. Baseline urine mevalonate excretion (low cholesterol diet) was 0.064±0.02 μmole/kg/d (0.060 in controls). It decreased to 0.040±0.02 μmole/kg/d (p<0.025) after egg yolk feeding. Thus, dietary cholesterol inhibited sterol synthesis in SLO patients. Finally, these data provide evidence for the treatment of this disorder.