Smith-Lemli-Opitz syndrome: A multiple malformation/mental retardation syndrome caused by defective cholesterol synthesis

Smith-Lemli-Opitz syndrome (SLOS) is a genetic condition characterized by dysmorphic facies, mental retardation and multiple malformations. A specific defect in cholesterol metabolism, 7-dehydrocholesterol-Δ⁷ reductase (DHCR7) deficiency due to mutation of the DHCR7 gene is the underlying cause of this syndrome. DHCR7 is a microsomal enzyme that catalyzes the conversion of 7-dehydrocholesterol (7DHC) to cholesterol. Hence, affected individuals exhibit low plasma cholesterol and high 7DHC levels. The phenotype most likely results from the combination of cholesterol deficiency and 7DHC accumulation. Diagnosis is based on clinical findings with confirmation by plasma sterol analysis. Prenatal diagnosis may be performed by sterol analysis of amniotic fluid/amniocytes or chorionic villi, or enzyme assay of chorionic villi. Maternal serum estriol and urine sterol analyses provide the opportunity for noninvasive prenatal diagnostic testing. Preliminary evidence from animal and human studies shows that dietary cholesterol supplementation may be beneficial for SLOS patients, but issues including prenatal onset of damage plus poor transport of cholesterol across the blood-brain barrier may limit treatment efficacy. The incidence of SLOS has been estimated to be one in 20,000 to one in 60,000 making it one of the most common autosomal recessive disorders. Recent studies suggest that the carrier frequency is much higher than the disease incidence would suggest.