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Abstract  Although cholesterol metabolism has been one of the most intensely studied metabolic pathways in humans, for many years the only known primary defect of the cholesterol biosynthetic pathway was mevalonic aciduria, a rare autosomal recessive deficiency of mevalonate kinase associated with developmental delays, craniofacial dysmorphism, and a variety of systemic and metabolic abnormalities (Chap. 93). However, in 1993, a second defect of cholesterol synthesis, a deficiency of 7-dehydrocholesterol reductase (DHCR7), was found to be the apparent cause of the RSH/Smith-Lemli-Opitz syndrome (SLOS), a relatively common autosomal-recessive multiple-malformation syndrome. Patients with both mild and severe forms of SLOS had markedly increased levels of 7-dehydrocholesterol (7DHC) and decreased levels of cholesterol. The finding 5 years later of disabling mutations in the DHCR7 gene in patients with SLOS confirmed SLOS as the second defect of cholesterol biosynthesis and the first affecting sterol metabolism per se.

Abstract  The discovery of the biochemical cause of SLOS and the subsequent redefinition of SLOS as an inborn error of cholesterol metabolism has led not only to successful treatment of affected patients, but also to the recognition of the important role of cholesterol in vertebrate embryogenesis. Moreover, the discovery at about the same time that cholesterol is directly involved in the hedgehog embryonic signaling pathway suggested an important link between embryogenesis and the abnormal metabolism in SLOS. No less important has been the recognition of the critical role that cholesterol plays in the expression of the abnormal behaviors that characterize SLOS.

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