MSMO1 – microcephaly-congenital cataract-psoriasiform dermatitis syndrome

Methylsterol monooxygenase 1 (MSMO1) deficiency is an autosomal recessive cholesterol biosynthesis disorder presenting with microcephaly, congenital cataracts, psoriasiform dermatitis, and severe intellectual disability. Initial reports described 5 patients from 4 unrelated families, all harboring biallelic MSMO1 variants ([PMID:33161406]).

To date, 7 affected individuals from 5 unrelated consanguineous pedigrees have been identified, including two siblings with a novel homozygous missense variant c.80A>C (p.Asn27Thr) segregating with disease in all available family members ([PMID:33161406], [PMID:37195326]). This AR inheritance is supported by recessive segregation in 2 affected relatives and the absence of heterozygotes among unaffected siblings.

Clinically, patients manifest early‐onset psoriasiform dermatitis (HP:0003765), growth and motor delay, ocular abnormalities (nystagmus, optic hypoplasia, myopia, strabismus), congenital cataracts, and severe intellectual disability (HP:0010864). Biochemical assays reveal accumulation of methylsterols, confirming loss of MSMO1 enzymatic activity.

Functional studies of the yeast homologue ERG25 demonstrate essential methyl sterol oxidase activity, with disruption leading to methylsterol accumulation and lethality ([PMID:8663358]). Zebrafish msmo1 knockdown/knockout recapitulates developmental and skeletal defects, which are rescued by liver‐specific restoration of Msmo1 or Lss, underscoring the critical role of C4 demethylation in cholesterol homeostasis ([PMID:32430393]).

Therapeutically, combined oral and topical statin plus cholesterol supplementation in patients yields marked improvement in cutaneous and immunological manifestations, supporting a genotype‐driven treatment strategy ([PMID:33161406], [PMID:37195326]).

Integration of genetic and experimental data establishes a loss-of-function mechanism underpinning MSMO1 deficiency. The robust segregation, multi-family case series, and functional concordance justify a Strong ClinGen gene–disease association classification. Key take-home: genetic diagnosis of MSMO1 deficiency enables targeted statin/cholesterol therapy, improving clinical outcomes.

References

• Cytogenetic and genome research • 2020 • New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis. PMID:33161406
• Clinical dysmorphology • 2023 • MSMO1 deficiency: a potentially partially treatable, ultrarare neurodevelopmental disorder with psoriasiform dermatitis, alopecia and polydactyly. PMID:37195326
• The Journal of biological chemistry • 1996 • Characterization of yeast methyl sterol oxidase (ERG25) and identification of a human homologue. PMID:8663358
• Disease models & mechanisms • 2020 • Zebrafish models of skeletal dysplasia induced by cholesterol biosynthesis deficiency. PMID:32430393

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