Smith–Lemli–Opitz syndrome (SLOS) is an autosomal recessive, multiple
congenital malformation and intellectual disability syndrome, with clinical
characteristics that encompass a wide spectrum and great variability. Elucidation of the
biochemical and genetic basis for SLOS, specifically understanding SLOS as a cholesterol
deficiency syndrome caused by mutation in DHCR7, opened up enormous
possibilities for therapeutic intervention. When cholesterol was discovered to be the
activator of sonic hedgehog, cholesterol deficiency with inactivation of this
developmental patterning gene was thought to be the cause of SLOS malformations, yet this
explanation is overly simplistic. Despite these important research breakthroughs, there is
no proven treatment for SLOS. Better animal models are needed to allow potential treatment
testing and the study of disease pathophysiology, which is incompletely understood.
Creation of human cellular models, especially models of brain cells, would be useful, and
in vivo human studies are also essential. Biomarker development will be crucial in
facilitating clinical trials in this rare condition, because the clinical phenotype can
change over many years. Additional research in these and other areas is critical if we are
to make headway towards ameliorating the effects of this devastating condition.