Clinical Information

Cholesterol plays an essential role in many cellular and developmental processes. In addition to its role as a membrane lipid, it is the precursor to numerous molecules that play important roles in cell growth and differentiation, protein glycosylation, and signaling pathways. The biosynthesis of cholesterol and its subsequent conversion to other essential compounds is complex, involving a number of intermediates and enzymes. Disorders that result from a deficiency of these enzymes lead to an accumulation of specific intermediates and inhibit the formation of important biomolecules. Clinical findings common to cholesterol biosynthesis disorders include congenital skeletal malformations, dysmorphic facial features, psychomotor retardation, and failure to thrive.

Smith-Lemli-Opitz syndrome (SLO) is an autosomal recessive disorder caused by mutations in the DHCR7 gene leading to a deficiency of the 7-dehydrocholesterol reductase enzyme. It is characterized biochemically by markedly increased plasma concentrations of 7-dehydrocholesterol (7-DHC) and 8-dehydrocholesterol (8-DHC) levels. Clinically, features can include microcephaly, growth retardation, developmental delay, dysmorphic facial features, cleft palate, limb abnormalities (especially 2-3 syndactyly of the toes and postaxial polydactyly), and heart and kidney malformations. However, the clinical spectrum ranges from mild to severe with some mildly affected individuals presenting with only 2 to 3 toe syndactyly and mild cognitive impairment. The reported incidence is between 1 in 10,000 and 1 in 60,000, but it may be more prevalent due to underdiagnosis of mildly affected individuals.

Other disorders of cholesterol biosynthesis, including desmosterolosis (desmosterol reductase deficiency) and sitosterolemia, may present with similar manifestations. These disorders can be detected biochemically by performing a quantitative profile of plasma sterols (STER / Sterols, Plasma).