DHCR24 – Desmosterolosis

Desmosterolosis is a rare autosomal recessive disorder of cholesterol biosynthesis caused by pathogenic variants in DHCR24 (PMID:12457401). Multiple independent case reports and multi‐patient studies have consistently identified biallelic mutations in DHCR24, with affected individuals presenting with a broad spectrum of congenital anomalies including agenesis or dysgenesis of the corpus callosum, distinct facial dysmorphism (e.g., downslanted palpebral fissures, micrognathia), musculoskeletal anomalies such as talipes equinovarus, and neurodevelopmental deficits such as global developmental delay (PMID:21671375, PMID:29175559).

Genetic evidence is robust with recurrent identification of distinct missense mutations, notably the variant c.571G>A (p.Glu191Lys), among others. Affected patients, including those from consanguineous backgrounds and compound heterozygous families, demonstrate a clear autosomal recessive inheritance pattern; segregation analysis across families further supports the pathogenicity of these variants (PMID:11519011, PMID:36538928).

Biochemical assays, heterologous expression studies in yeast, and in silico structural analyses have confirmed that these DHCR24 variants impair the enzyme’s ability to reduce desmosterol to cholesterol. These functional experiments consistently show elevated levels of desmosterol and reduced cholesterol synthesis, thereby recapitulating the clinical phenotype observed in patients (PMID:38239854, PMID:20568014).

Although phenotypic variability exists – with some patients also presenting features such as relative macrocephaly, hydrocephalus, and aortic valve stenosis – the convergence of genetic, segregation, and functional data firmly establishes the association between DHCR24 and desmosterolosis. Multiple studies have independently corroborated the role of DHCR24 in the cholesterol biosynthetic pathway and its disruption in affected individuals.

In summary, the combined genetic and experimental evidence unequivocally supports a strong association between DHCR24 and desmosterolosis. This association is vital for diagnostic decision‑making and has significant implications for clinical management and potential therapeutic interventions in cholesterol synthesis disorders.

Key Take‑home Message: DHCR24 mutations are a definitive cause of desmosterolosis, underlining their clinical utility in diagnostic screening and guiding the management of affected patients.

References

• American journal of medical genetics • 2002 • Desmosterolosis presenting with multiple congenital anomalies and profound developmental delay PMID:12457401
• American journal of medical genetics. Part A • 2011 • Desmosterolosis-phenotypic and molecular characterization of a third case and review of the literature PMID:21671375
• European journal of medical genetics • 2018 • Desmosterolosis presenting with multiple congenital anomalies PMID:29175559
• American journal of human genetics • 2001 • Mutations in the 3beta-hydroxysterol Delta24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis PMID:11519011
• Frontiers in genetics • 2023 • Exploiting in silico structural analysis to introduce emerging genotype-phenotype correlations in DHCR24-related sterol biosynthesis disorder: a case study PMID:38239854
• American journal of medical genetics. Part A • 2023 • First case of desmosterolosis diagnosed by prenatal whole exome sequencing PMID:36538928

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