MMAA – Methylmalonic Aciduria, cblA Type

The MMAA gene encodes a mitochondrial GTPase essential for incorporation of adenosylcobalamin into methylmalonyl-CoA mutase. Biallelic pathogenic variants in MMAA cause vitamin B12–responsive Methylmalonic aciduria, cblA type, an autosomal recessive disorder marked by accumulation of methylmalonic acid and metabolic decompensation.

In a cohort of 37 unrelated cblA patients, sequencing of MMAA revealed 22 unique deleterious alleles, comprising 13 premature stop codons, three splice-site defects, and six missense variants. A recurrent nonsense variant, c.433C>T (p.Arg145Ter), represented 43% of pathogenic alleles and was linked to a common haplotype, indicating a founder effect (PMID:15523652). No such variants were detected in 100 control alleles.

A family study described two Iranian siblings with a novel homozygous deletion, c.674delA (p.Asn225MetfsTer14), resulting in a frameshift and truncated MMAA lacking the ArgK domain. The variant co-segregated with disease in the affected sibship and was absent in the unaffected sibling and parents, confirming pathogenicity (PMID:28536607).

Segregation analysis across families includes at least 2 affected relatives with concordant MMAA genotypes. The variant spectrum demonstrates allelic heterogeneity—loss-of-function, splice-site, and missense mutations—yet all converge on disruption of MMAA function.

Biochemical and cellular assays on 67 cblA patients showed that missense mutations compromise protein stability and impair the interaction of MMAA with methylmalonyl-CoA mutase, leading to reduced GTPase activation and failure of adenosylcobalamin transfer (PMID:28497574). These data elucidate a loss-of-function mechanism central to cblA disease.

The aggregation of genetic, segregation, and functional evidence over >15 years supports a Definitive gene–disease association. MMAA genetic testing facilitates early diagnosis of cblA methylmalonic aciduria and guides vitamin B12 supplementation, improving clinical outcomes.

References

• Cellular & molecular biology letters • 2016 • Identification of a novel deletion in the MMAA gene in two Iranian siblings with vitamin B12-responsive methylmalonic acidemia. PMID:28536607
• Human mutation • 2004 • Mutations in the MMAA gene in patients with the cblA disorder of vitamin B12 metabolism. PMID:15523652
• Human mutation • 2017 • Protein destabilization and loss of protein-protein interaction are fundamental mechanisms in cblA-type methylmalonic aciduria. PMID:28497574

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