Oxysterols in the circulation of patients with the Smith-Lemli-Opitz syndrome: abnormal levels of 24S-and 27-hydroxycholesterol

Infants with the cholesterol synthesis defect Smith-Lemli-Opitz syndrome (S LO) have reduced activity of the enzyme 7-dehydrocholesterol-7-reductase an d accumulate 7-dehydrocholesterol, with the highest concentration in the br ain. As a result of the generally reduced content of cholesterol, plasma le vels of oxysterols would be expected to be reduced, 24S-hydroxycholesterol is almost exclusively formed in the brain, whereas 27-hydroxycholesterol is mainly formed from extrahepatic and extracerebral cholesterol, In accordan ce with the expectations, sterol-correlated plasma levels of 24S-hydroxycho lesterol were reduced in infants with SLO (by about 50%). In contrast, the sterol-correlated levels of 27-hydroxycholesterol in the circulation were m arkedly increased, No side-chain oxidized metabolites of 7-dehydrocholester ol were detected in the circulation, Recombinant human CYP27 had markedly l ower 27-hydroxylase activity toward 7-dehydrocholesterol than towards chole sterol. HEK293 cells expressing 24S-hydroxylase active toward cholesterol h ad no significant activity towards 7-dehydrocholesterol. The plasma levels of 3 beta ,7 alpha -dihydroxy-5-cholestenoic in the patients acid were redu ced, suggesting a generally reduced metabolism of 27-oxygenated steroids. I t is concluded that the accumulation of 7-dehydrocholesterol in the brains of patients with SLO reduces formation of 24S-hydroxycholesterol. The condi tion is associated with markedly increased circulating levels of 27-hydroxy cholesterol, most probably due to reduced metabolism of this oxysterol, We discuss the possibility that the circulating levels of 24S-hydroxycholester ol may be used as a marker for the severity of the disease.