Exploring Recent Developments in the Manifestation, Diagnosis, and Treatment of Patients with Smith-Lemli-Opitz Syndrome: From Molecular Pathways to Clinical Innovations

Abstract

Smith-Lemli-Opitz syndrome (SLOS) is a rare, autosomal recessive genetic disorder caused by mutations in the DHCR7 gene, which encodes the enzyme responsible for the final step in cholesterol biosynthesis. Impaired enzyme function leads to cholesterol deficiency, affecting the development and function of the entire organism. The accumulation of cholesterol precursors enhances the formation of oxysterols, which are involved in the pathomechanism of neurological, ophthalmological, and vascular changes in patients. This review analyzes 53 studies published between 2020 and 2025 on the molecular mechanisms underlying the clinical features of SLOS, including cholesterol deficiency, oxysterol accumulation, and the latest diagnostic methods, including LC-MS/MS chromatography and biomarkers such as GFAP for monitoring disease progression. MRI is discussed as a supportive tool for neuroimaging, along with advances in prenatal diagnostics, such as the detection of cholesterol precursors in neonatal hair. Therapeutic options are also reviewed, with particular emphasis on cholesterol supplementation, cholic acid, and experimental treatments such as vitamin E supplementation, statin therapy, gene therapy, and liver transplantation. Current research indicates that expanding knowledge in this area not only improves patient prognosis but also provides hope for the development of effective therapies in the future.

Keywords: DHCR7; SLOS; Smith–Lemli–Opitz syndrome; cholesterol pathway.

Figure 1

Graphical representation of the five most frequently reported DHCR7 variants and their localization within the protein structure.

Figure 2

SLOS Severity Score. Types of SLOS phenotype according to SSS: mild (<20 points), typical (20–50 points), and severe (>50 points) [17,18,19] GI—gastrointestinal; MRI—magnetic resonance imaging; CNS—central nervous system.

Figure 3

The ranges of cholesterol levels in healthy children from birth to 12 years of age, by sex [22].

Figure 4

The metabolic bottleneck in Smith–Lemli–Opitz syndrome (SLOS). The deficiency of 7-dehydrocholesterol reductase (7-DHCR) leads to the accumulation of 7-dehydrocholesterol (7-DHC) and a reduction in cholesterol levels. Elevated levels of 7-DHC and its oxidized derivatives (oxysterols) contribute to neurotoxicity and premature neurogenesis. Cholesterol deficiency impairs multiple biological processes, including steroid and bile acid synthesis, 5-HT_1A receptor function, mTORC1 and insulin signaling, innate immune responses, and organ development. TLR4—Toll-like receptor 4; mTORC1—mammalian target of rapamycin complex 1; 5-HT_1A—serotonin 1A receptors.

Figure 5

Summary of the search and selection of studies related to SLOS.

Figure 6

Flowchart depicting the diagnostic pathway from clinical suspicion to confirmation of SLOS across prenatal and postnatal periods. 7-DHC—7-dehydrocholesterol; 8-DHC- 7-dehydrocholesterol; LC-MS/MS—liquid chromatography–tandem mass spectrometry; MRI—magnetic resonance imaging; CNS—central nervous system; CVS—chorionic villus sampling; IUGR—intrauterine growth restriction.