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.

Keywords:

• cholesterol metabolism
• congenital malformation syndrome
• 7-dehydrocholesterol reductase
• inborn error of metabolism
• malformation syndrome
• Smith–Lemli–Opitz syndrome

Acknowledgment

JL Cross is co-supervised in her studies by Professor Frances Platt, University of Oxford, and is a recipient of a Wellcome Trust/NIH Studentship. FD Porter, CA Wassif and S Bianconi are supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Declaration of interest

This work has been sponsored by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (Grant number ZIA HD008825), with funds received by all authors. In addition, JC has received funding from a Wellcome Trust (Grant number 098257). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Notes

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