MARKEDLY INCREASED TISSUE CONCENTRATIONS OF 7-DEHYDROCHOLESTEROL COMBINED WITH LOW-LEVELS OF CHOLESTEROL ARE CHARACTERISTIC OF THE SMITH-LEMLI-OPITZ SYNDROME

The Smith-Lemli-Opitz syndrome is an autosomal recessive birth defect (frequency 1:20,000-1:40,000) that results in profound mental retardat ion, physical deformities, and failure to thrive. It is characterized biochemically by low plasma cholesterol and greatly elevated levels of two dehydrocholesterols, one of which is the cholesterol precursor 7- dehydrocholesterol. To determine whether the block in cholesterol bios ynthesis affects tissue sterols, we assayed several organs from two af fected individuals, a female who died at 27 hours and a 20-week male f etus. Cholesterol concentrations in abdominal wall, adrenal gland, and kidney from two or three unaffected fetuses, who served as controls, averaged 2.0, 1.5, and 1.4 mg/g wet weight, compared to 0.08, 0.44, an d 0.14, respectively, for the homozygous fetus. Cerebral cortex choles terol concentrations were 2.2 mg/g for two 20-22-week fetal controls b ut only 0.21 and 0.09 mg/g, respectively, for the homozygous child and fetus. Similarly, tissue cholesterol levels were abnormally low in th e homozygous child being less than 1 mg/g in liver, adipose, thymus, m uscle, and adrenal and 6.2 mg/dl in plasma. Dehydrocholesterols could not be detected by conventional means in any controls but were elevate d enough in tissues from affected individuals to make total sterol con centrations nearly normal. These results suggest that a defect in 3 be ta-hydroxysterol Delta(7)-reductase leads to both a profound lack of c holesterol and its replacement by dehydrocholesterols. Such a combinat ion may be lethal in the most severely affected individuals.