Smith–Lemli–Opitz syndrome

Abstract

Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital malformation/intellectual disability syndrome, with clinical characteristics encompassing a wide spectrum and great variability. Elucidation of the biochemical and molecular genetic basis for the autosomal recessively inherited SLOS, specifically, understanding SLOS as a cholesterol deficiency syndrome caused by mutations 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. Still, 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 will surely be useful, especially models of brain cells. In vivo human studies are essential as well. There have only been limited natural history studies of SLOS to date. Biomarker development will be critical in facilitating clinical trials in this rare condition, since clinical phenotype may change over many years. Additional research in these and other areas is critical if we are to make headway towards ameloriating the effects of this devastating condition.

Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism

“…Interestingly, a recent study showed that cholesterol transfer mediated by NPC2 protein is inhibited by SM excess, indicating that sphingomyelinase participates in the complex machinery that regulates the secretion of free cholesterol from the lysosomal compartment ( 19 ). Therefore, the high oxysterol levels observed In SLOS patients, the defect of 7-dehydrocholesterol reductase causes a massive accumulation of 7-dehydrocholesterol (7-DHC) ( 22 ). The fi nding of increased 7-KC alone in SLOS patients can therefore be easily explained by conversion of excessive 7-DHC into 7-KC ( 23 ).…”

Novel Insight into Etiology, Diagnosis and Management of Primary Adrenal Insufficiency

“…anti-cortex adrenal antibodies and anti-21OH antibodies for autoimmune adrenalitis [8]) and metabolic tests (e.g. very long-chain fatty acids) for adrenoleukodystrophy or 7-dehydrocholesterol for Smith-Lemli Opitz disease [9,10], as well as markers of anticoagulation (APTT, Quick, D-dimers, anti-cardiolipin antibodies for adrenal infarction in the antiphospholipid syndrome [11]). In addition, adrenal imaging (CT or MRI) may be informative.…”

The Potential for Proteomics in Understanding Neurodevelopmental Disorders

“…SLOS symptoms improve rapidly (though incompletely) with cholesterol supplementation and children with ASD without SLOS have been identified with low total cholesterol [65]. Total or partial deficiency of Dhcr7 causes SLOS [69]. As mentioned, several developmental disorders are associated with SLOS, including incomplete myelination, and mental retardation [70] as well as autism [64][65][66][67].…”