Pathogenesis, Epidemiology, Diagnosis and Clinical Aspects of Smith-Lemli-Opitz Syndrome

Abstract

Introduction: Smith-Lemli-Opitz Syndrome (SLOS) is a malformation syndrome inherited in an autosomal recessive fashion. It is due to a metabolic defect in the conversion of 7-dehydrocholesterol to cholesterol, which leads to an accumulation of 7-dehydrocholesterol and frequently a deficiency of cholesterol. The syndrome is characterized by typical dysmorphic facial features, multiple malformations, and intellectual disability.

Areas covered: In this paper we provide an overview of the clinical phenotype and discuss how the manifestations of the syndrome vary depending on the age of the patients. We then explore the underlying biochemical defect and pathophysiological alterations that may contribute to the many disease manifestations. Subsequently we explore the epidemiology and succinctly discuss population genetics as they relate to SLOS. The next section presents the diagnostic possibilities. Thereafter, the treatment and management as is standard of care are presented.

Expert opinion: Even though the knowledge of the underlying molecular mutations and the biochemical alterations is being rapidly accumulated, there is currently no efficacious therapy addressing neurological dysfunction. We discuss the difficulty of treating this disorder, which manifests as a combination of a malformation syndrome and an inborn error of metabolism. A very important factor in developing new therapies is the need to rigorously establish efficacy in controlled trials.

Figure 1. SLOS craniofacial phenotype

Portrait and profile views of severe (1a, 1b), classical (1c, 1d), and mild disease (1e, 1f). Characteristic craniofacial features include microcephaly, bitemporal narrowing, midface hypoplasia, small upturned nose, ptosis, strabismus, a flat facial profile and micrognathia.

Figure 2. SLOS malformations

Limb anomalies include postaxial polydactyly of the hands (2a) or feet, a short posteriorly placed thumb (2a), and syndactyly of the 2^nd and 3^rd toe (2b). A bifid uvula (2c) is the mildest form of a midline cleft palate. Permission for the publication of photographs was obtained from guardians.

Figure 3

The ultimate step of cholesterol biosynthesis from 7-DHC to cholesterol including down-stream pathways that cholesterol and its precursors are utilized in.

Figure 4

Putative membrane structure of DHCR7 with location of mutations. Accompanying table (see supplemental materials Table 1) specifies the mutations and if they have been clinically identified or are predicted to be pathogenic utilizing PolyPhen-2 [115].