Smith-Lemli-Opitz syndrome

Abstract

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.

Figure 1. Biochemical Pathways in SLOS

SLOS patients experience a broad range of biochemical consequences stemming from elevated 7-DHC and deficiency in cholesterol. As cholesterol is a precursor in the synthesis of steroid hormones, bile acids and oxysterols, these compounds may be deficient in SLOS patients. Conversely atypical sterols, oxysterols, steroid hormones and bile acids are formed from 7- and 8-DHC. Atypical bile acids appear to be formed in “acidic pathway” via 27-hydroxylation; formation of 27-hydroxylated 7- and 8-DHC (53) and conversion to 3β-hydroxycholestandienoic acids (49) has been demonstrated. *Can isomerize to form 8-DHC.

Figure 2

Part A: Typical facial features of Smith-Lemli-Opitz syndrome: microcephaly, bitemporal narrowing, ptosis, short nasal root, anteverted nares and micrognathia. Part B: Toe syndactyly in Smith-Lemli-Opitz syndrome. Part C: Smith-Lemli-Opitz syndrome with mild phenotype. These pictures were obtained and are reproduced with informed consent.

Figure 3

Diagram of the DHCR7 protein identifying the putative locations of the 9 transmembrane regions: TM1-9 (blue), the 3 Sterol Reductase motifs: SR1 (purple), SR2 (green) SRMS (red) and the Sterol Sensing domain