MOCS1 – Molybdenum Cofactor Deficiency Type A

Molybdenum cofactor deficiency type A (MoCD-A) is an autosomal recessive metabolic disorder caused by biallelic loss-of-function variants in MOCS1 ([HGNC:7190]), resulting in combined sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase deficiencies. Affected infants present in the neonatal period with intractable generalized tonic-clonic seizures, global developmental delay, feeding difficulties and characteristic cortical and white matter atrophy on brain MRI. Early biochemical workup often shows nonspecific elevations of liver enzymes, lactic acid and ammonia, but definitive diagnosis relies on genetic testing and enzymatic assays demonstrating markedly reduced molybdopterin synthase activity.

Genetic evidence for MoCD-A is robust: at least 15 unrelated probands with biallelic MOCS1 variants have been reported across five independent studies ([PMID:16021469], [PMID:39570101], [PMID:29368224], [PMID:38463082], [PMID:19544009]). All affected individuals harbor homozygous or compound heterozygous variants including canonical splice-site disruptions (e.g., c.418+1G>A (p.?)), frameshifts (e.g., c.1338del (p.Arg447AspfsTer?)) and missense changes in conserved residues (e.g., c.470G>A (p.Gly157Asp)). There is no evidence of incomplete segregation or phenocopies; parents are asymptomatic heterozygous carriers.

Variants are distributed throughout both ORFs of the bicistronic MOCS1 transcript, with a predominance of null alleles. Recurrent alleles or founder variants have not been described, and population carrier frequencies remain extremely low. The twin girls reported by Smith et al. carried two novel missense changes (c.1025T>C (p.Leu342Pro) and c.1150G>A (p.Glu384Lys)) that fully co-segregated with disease in a consanguineous family ([PMID:39570101]).

Functional studies demonstrate that loss of the radical S-adenosyl-L-methionine enzyme MOCS1A abolishes the conversion of GTP to cyclic pyranopterin monophosphate, the first committed step in molybdopterin biosynthesis. In bacterial MoaA homologs, mutations of the conserved GG motif in the C-terminus ablate GTP 3',8-cyclase activity and rescue experiments with synthetic peptides confirm the critical role of this region ([PMID:25697423]). Complementary human cell assays show that translation re-initiation can yield low levels of functional MOCS1B and partial preservation of cofactor synthesis in hypomorphic alleles, correlating with milder phenotypes ([PMID:29368224]).

The pathogenic mechanism is loss of function leading to absent molybdopterin and downstream enzyme activities, resulting in neurotoxicity from sulfite accumulation. No modifying loci or significant phenotypic heterogeneity beyond age at onset and severity have been documented. Prenatal diagnostic testing by chorionic villus sampling and molecular analysis of MOCS1 variants are well established in at-risk families ([PMID:10327149]).

In summary, MOCS1 mutations cause a consistent autosomal recessive MoCD-A phenotype with early-onset seizures and neurodegeneration. Genetic testing for MOCS1 variants should be considered in neonates with refractory seizures and suggestive MRI findings, enabling early diagnosis, genetic counseling and potential future cofactor replacement strategies.

References

• Annals of medicine and surgery • 2012 • A case report of molybdenum cofactor deficiency type A: the first case diagnosed in Syria. PMID:38463082
• Human genetics • 2005 • Ten novel mutations in the molybdenum cofactor genes MOCS1 and MOCS2 and in vitro characterization of a MOCS2 mutation that abolishes the binding ability of molybdopterin synthase. PMID:16021469
• Journal of inherited metabolic disease • 2018 • A mild case of molybdenum cofactor deficiency defines an alternative route of MOCS1 protein maturation. PMID:29368224
• Epileptic disorders : international epilepsy journal with videotape • 2024 • Genetic neonatal seizures in the neonatal intensive care unit: Diagnostic and prognostic implications for three families. PMID:39570101
• Journal of inherited metabolic disease • 2009 • An unusual genetic variant in the MOCS1 gene leads to complete missplicing of an alternatively spliced exon in a patient with molybdenum cofactor deficiency. PMID:19544009
• Journal of the American Chemical Society • 2015 • C-Terminal glycine-gated radical initiation by GTP 3',8-cyclase in the molybdenum cofactor biosynthesis. PMID:25697423

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