MOCS1 – Molybdenum Cofactor Deficiency Type A

Molybdenum cofactor deficiency (MoCD) type A is an autosomal recessive metabolic disorder caused by biallelic loss-of-function variants in the bicistronic MOCS1 gene, leading to combined sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase deficiency. Affected individuals typically present in the neonatal period with intractable seizures, feeding difficulties, progressive encephalopathy, developmental delay and characteristic lens dislocation (ectopia lentis) (PMID:7474893).

Genetic evidence includes more than 58 unrelated MoCD-A patients harboring homozygous or compound heterozygous MOCS1 variants across diverse populations, with consistent autosomal recessive segregation in consanguineous and outbred families (PMID:35192225). The mutation spectrum comprises splice‐site (e.g., c.1102+1G>A), missense (e.g., c.1064T>C (p.Ile355Thr)), frameshift (e.g., c.1338del (p.Arg447AspfsTer?)) and nonsense changes. Recurrent founder alleles such as R319Q (c.956G>A (p.Arg319Gln)) in England account for a significant fraction of cases (PMID:9921896).

Variant c.1064T>C (p.Ile355Thr) was first reported in a neonatal hyperekplexia presentation, confirming a pathogenic missense effect on Moco biosynthesis (PMID:16429380). Other splice‐site mutations (e.g., c.418+1G>A) underlie prenatal diagnoses by chorionic villus sampling without enzymatic deficiency in carriers (PMID:10327149).

Functional studies demonstrate that MOCS1 deficiency abolishes cyclic pyranopterin monophosphate (cPMP) synthesis, causing MoCo‐dependent enzyme inactivation. Substitution therapy with cPMP in patients restores sulfite oxidase and xanthine dehydrogenase activities and halts neurodegeneration (PMID:20385644). A Mocs2-null mouse recapitulates human MoCD phenotype with elevated S-sulfocysteine and hypoxanthine, confirming loss‐of‐function pathogenesis (PMID:27138983).

No studies to date dispute the role of MOCS1 in MoCD-A. The concordance of genetic, biochemical, animal and therapeutic data supports a definitive gene-disease relationship.

Key Take-home: Biallelic MOCS1 loss-of-function variants cause definitive autosomal recessive MoCD type A, for which early genetic diagnosis enables cPMP replacement therapy to prevent irreversible neurologic damage.

References

• Journal of inherited metabolic disease • 1995 • Defective molybdopterin biosynthesis: clinical heterogeneity associated with molybdenum cofactor deficiency. PMID:7474893
• Nature Genetics • 2006 • Natural history of molybdenum cofactor deficiency: retrospective analysis of 58 patients. PMID:35192225
• Human Genetics • 1998 • Genomic structure and mutational spectrum of the bicistronic MOCS1 gene defective in molybdenum cofactor deficiency type A. PMID:9921896
• Neuropediatrics • 2005 • Molybdenum cofactor deficiency presenting as neonatal hyperekplexia: a clinical, biochemical and genetic study. PMID:16429380
• Pediatrics • 2010 • Successful treatment of molybdenum cofactor deficiency type A with cPMP. PMID:20385644
• Human Genetics • 2016 • Mouse model for molybdenum cofactor deficiency type B recapitulates the phenotype observed in molybdenum cofactor deficient patients. PMID:27138983

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