Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive condition with multiple malformations,
mental retardation, and growth failure, results from markedly reduced activity of the final
enzyme in the
cholesterol biosynthetic pathway,
7-dehydrocholesterol reductase (DHCR7). Clinical signs vary in severity, ranging from fetal loss to
holoprosencephaly with multiple malformations to isolated
syndactyly. The biochemical defect in SLOS is a deficiency of DHCR7, which results in an abnormally low
cholesterol level, and increased amounts of intermediates of
sterol biosynthesis. Animal models currently exist through the use of
cholesterol biosynthesis inhibitors, from which a great deal has been learned. Pregnant rats treated with inhibitors of DHCR7 yield pups that have abnormal
sterol profiles and
craniofacial abnormalities characteristic of severe SLOS. Biochemical testing of human patients can be performed using gas chromatography/mass spectroscopy (GC/MS) to analyze the
sterol content of tissues, amniotic fluid, or cell culture lysate. Numerous mutations have been identified in DHCR7 but seven individual mutations account for 67% of the total mutations reported in the literature. Clinical trials with SLOS are underway, with the goal of increasing the
cholesterol concentration in the plasma and tissues through the administration of
dietary cholesterol. Thus far, this approach has shown limited efficacy. Nevertheless, the recent identification of the biochemical and molecular genetic basis for SLOS is reason for optimism that the condition may one day yield to treatment.