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.

Cholesterol: An evergreen molecule in biology

“…This is exemplified by a number of inherited disorders, such as the SmithLemli-Opitz syndrome (SLOS; see Fig. 2(c)), the molecular etiology of which lies in subtle defects in cholesterol biosynthesis [3,35,40,42]. SLOS is a congenital and developmental malformation syndrome associated with defective cholesterol biosynthesis.…”

7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

“…Altered DHCR7 activity led to increased 7DHC and reduced CHOL levels both in the serum and in the plasma membrane of fibroblasts and erythrocytes [16,61].The severity of the disease and life expectancy of the patients is mostly determined by initial serum CHOL level, while the ratio of 7DHC/CHOL has an additional prognostic value [5]. Oral cholesterol and simvastatin administration are used in the treatment of SLOS; however, retrospective studies did not confirm its effectiveness [12,19,24,58].…”

Suprasellar choristoma associated with congenital hydrocephalus, anophthalmia, cleft lip and palate, and clinodactly: a proposed variant of a unique new syndrome

“…Hypothalamic hamartomas similar to the choristoma found in the presented patient are often a component of several congenital syndromes involving midline malformations. Two of these, Pallister-Hall syndrome and Smith-Lemli-Opitz syndrome, also demonstrate cardiac, pulmonary, genitourinary, and multiple skeletal abnormalities [3] , [4] . The lack of these features in our patient implies that these processes are likely not the etiology of the malformations.…”