Defective Cholesterol Biosynthesis Associated with the Smith-Lemli-Opitz Syndrome

Abstract

The Smith-Lemli-Opitz syndrome (frequency, 1:20,000 to 1:40,000) is defined by a constellation of severe birth defects affecting most organ systems. Abnormalities frequently include profound mental retardation, severe failure to thrive, and a high infant-mortality rate. The syndrome has heretofore been diagnosed only from its clinical presentation. Using capillary-column gas chromatography-mass spectrometry, we measured the sterol composition of plasma, erythrocytes, lens, cultured fibroblasts, and feces from five children with the syndrome (three girls and two boys). Plasma cholesterol levels were abnormally low (8 to 101 mg per deciliter [0.20 to 2.60 mmol per liter]) in every patient, being well below the 5th percentile for age- and sex-matched controls. Concentrations of the cholesterol precursor 7-dehydrocholesterol (cholest-5,7-dien-3β-ol), which was not detectable in most of our controls, were elevated (11 to 31 mg per deciliter) more than 2000-fold above normal and were similar to the levels of cholesterol in all tissues from all patients. An isomeric dehydrocholesterol with a structure similar to that of 7-dehydrocholesterol was also detected. The combination of abnormally low plasma cholesterol levels and a high concentration of the cholesterol precursor 7-dehydrocholesterol points to a major block in cholesterol biosynthesis at the step in which the C-7(8) double bond of 7-dehydrocholesterol is reduced, forming cholesterol. The block may be sufficient to deprive an embryo or fetus of cholesterol and prevent normal development, whereas the incorporation of 7-dehydrocholesterol into all membranes may interfere with proper membrane function., The Smith-Lemli-Opitz syndrome 1 is an autosomal recessive disorder characterized by microcephaly, poor growth, easily recognized dysmorphic facies (anteverted nares, ptosis of eyelids, and micrognathia), limb abnormalities (especially syndactyly of the toes, polydactyly, and a high frequency of digital whorl ridges), genital disorders (cryptorchidism and hypospadias in affected boys), endocrine malfunction, cataracts, heart and kidney malformations, and mental retardation 1 – 5 . Its prevalence has been estimated to be 1 in 20,000, 6 with a probable carrier frequency of 1 to 2 percent, 5 and it may be the second most common autosomal recessive disorder in the North American white population, after cystic fibrosis… © 1994, Massachusetts Medical Society. All rights reserved.