Sterol balance in the Smith-Lemli-Opitz syndrome: reduction in whole body cholesterol synthesis and normal bile acid production

The Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/mental ret ardation syndrome caused by a deficiency of the enzyme 7-dehydrocholesterol Delta(7)-reductase. This enzyme converts 7-dehydrocholesterol (7-DHC) to c holesterol in the last step in cholesterol biosynthesis. The pathology of t his condition may result from two different factors: the deficiency of chol esterol itself and/or the accumulation of precursor sterols such as 7-DHC. Although cholesterol synthesis is defective in cultured SLOS cells, to date there has been no evidence of decreased whole body cholesterol synthesis i n SLOS and only incomplete information on the synthesis of 7-DHC and bile a cids. In this first report of the sterol balance in SLOS, we measured the s ynthesis of cholesterol, other sterols, and bile acids in eight SLOS subjec ts and six normal children. The diets were very low in cholesterol content and precisely controlled. Cholesterol synthesis in SLOS subjects was signif icantly reduced when compared with control subjects (8.6 vs, 19.6 mg/kg per day, respectively, P < 0.002). Cholesterol precursors 7-DHC, 8-DHC, and 19 -nor-cholestatrienol were synthesized in SLOS subjects (7-DHC synthesis was 1.66 +/- 1.15 mg/kp per day), but not in control subjects. Total sterol sy nthesis tvas also reduced in SLOS subjects (12 vs. 20 mg/kg per day, P < 0. 022). Bile acid synthesis in SLOS subjects (3.5 mg/kg per day) did not diff er significantly from control subjects (4.6 mg/kg per day) and was within t he range reported previously in normals. Normal primary and secondary bile acids were identified. This study provides direct evidence that whole body cholesterol synthesis is reduced iu patients with SLOS and that the synthes is of 7-DHC and other cholesterol precursors is profoundly increased. It is also the first reported measure of daily bile acid synthesis in SLOS and p rovides evidence that bile acid supplementation is not likely to be necessa ry for treatment. These sterol balance studies provide basic information ab out the biochemical defect in SLOS and strengthen the rationale for the use of dietary cholesterol in its treatment.-Steiner, R. D., L. M. Linck, D. P . Flavell, D. S. Lin, and W. E. Connor. Sterol balance in the Smith-Lemli-O pitz syndrome: reduction in whole body cholesterol synthesis and normal bil e acid production.