SC5D and Lathosterolosis

SC5D, encoding sterol C5-desaturase, is implicated in lathosterolosis, a disorder of cholesterol biosynthesis marked by congenital malformations, neurodevelopmental delay, and variable hepatic involvement. The clinical reports, spanning from early case descriptions to recent multi‐patient studies, consistently demonstrate that biallelic pathogenic variants in SC5D cause a biochemical block in the cholesterol synthesis pathway (PMID:12812989).

The genetic evidence supports autosomal recessive inheritance. Multiple independent case reports document homozygous or compound heterozygous mutations in SC5D. For example, one seminal study identified a homozygous variant c.137A>C (p.Tyr46Ser) in a patient with a severe phenotype, while additional studies reported recurrent and private mutations across different families (PMID:24142275, PMID:30097991).

Among the reported mutations, the variant c.137A>C (p.Tyr46Ser) stands out as a representative coding change, accurately fulfilling HGVS criteria with three‐letter amino acid codes. The spectrum of mutations also includes missense changes such as c.630C>A (p.Asp210Glu) and truncating alleles, emphasizing the loss of function underlying the disorder (PMID:33204591).

Functional studies, including knockout models, reinforce the role of SC5D in cholesterol biosynthesis. In Sc5d (–/–) mice, complete loss of enzyme activity results in elevated lathosterol levels, decreased cholesterol synthesis, and a gamut of congenital anomalies that correlate well with the human phenotype. These experimental observations provide moderate functional evidence that aligns with the genetic data (PMID:12812989).

No significant conflicting evidence has been reported; all clinical and functional assessments converge on a pathogenic mechanism resulting from SC5D deficiency. The consistency across multiple independent studies, improved biochemical assays, and animal model data highlights the reliability of this association for diagnostic purposes.

Key take‑home: Early molecular diagnosis of SC5D mutations enables timely recognition of lathosterolosis, thereby informing targeted management strategies for this inborn error of cholesterol metabolism.

References

• Human Molecular Genetics • 2003 • Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency PMID:12812989
• JIMD Reports • 2014 • Lathosterolosis: a disorder of cholesterol biosynthesis resembling Smith-Lemli-Opitz syndrome PMID:24142275
• JIMD Reports • 2019 • Lathosterolosis: A Relatively Mild Case with Cataracts and Learning Difficulties PMID:30097991
• JIMD Reports • 2020 • Successful treatment of lathosterolosis: A rare defect in cholesterol biosynthesis-A case report and review of literature PMID:33204591
• Journal of Pediatric Endocrinology & Metabolism • 2023 • Lathosterolosis: a rare cholesterol metabolism disorder with a wide range of clinical variability PMID:36607840

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