Retinal Degeneration and Cholesterol Deficiency

Smith-Lemli-Opitz syndrome is a recessive genetic disorder caused by mutations in the gene (. DHCR7) that encodes the enzyme sterol Delta7-reductase. Such mutations lead to inefficient conversion of 7-dehydrocholesterol to cholesterol. As a result, affected individuals exhibit abnormally low levels of cholesterol and excessive levels of 7-dehydrocholesterol in all bodily tissues and fluids, in addition to multiple dysmorphologies and cognitive and neurologic impairments, including visual deficits, failure to thrive, and premature death. A rat model of this hereditary disease has been developed, which exhibits progressive retinal degeneration and diminished scotopic and photopic visual function. Dietary cholesterol supplementation partially prevents the electrophysiologic visual deficits but not the histologic degeneration. Recent findings suggest that formation of oxysterol by-products derived from 7-dehydrocholesterol, rather than simply the lack of sufficient levels of cholesterol or abnormal levels of 7-dehydrocholesterol per se, may underlie some, if not many, of the observed pathologic features in the human disease as well as in the animal model. This suggests that blocking the formation of such oxysterols, for example, by suitable application of antioxidants, in combination with exogenous cholesterol administration, may provide an improved therapeutic intervention for this disease.