MMAB – cblB-type methylmalonic aciduria

Methylmalonic aciduria cblB type is an autosomal recessive disorder caused by biallelic variants in MMAB encoding mitochondrial ATP:cob(I)alamin adenosyltransferase. Affected individuals present in infancy with metabolic decompensation, elevated methylmalonic acid, and mitochondrial dysfunction due to impaired adenosylcobalamin synthesis and methylmalonyl-CoA mutase activity.

Genetic evidence includes 35 cblB patients with 19 distinct MMAB mutations (PMID:16410054) and 97 individuals harboring bi-allelic variants across 33 recurrent and 16 novel alleles (PMID:34796408). Segregation in at least six affected siblings across three families supports autosomal recessive inheritance (two siblings in an iPSC study [PMID:29660608]; two sibling pairs in a mitochondrial study [PMID:24813872]).

The variant spectrum comprises missense, nonsense, splice-site, and frameshift changes, with pathogenic alleles clustering in exon 7. Notable examples include c.287T>C (p.Ile96Thr) and recurrent founder variants p.Arg186Trp and p.Arg191Trp, none detected in controls (PMID:16410054; PMID:34796408).

Functional assays reveal that destabilizing missense mutations and truncating variants abolish ATR stability and enzymatic activity, increase reactive oxygen species, impair mitochondrial respiration, and recapitulate patient fibroblast phenotypes (PMID:24813872; PMID:20556797). Pharmacological chaperones restore stability and activity of the p.Ile96Thr mutant in vitro and in mouse liver and brain, confirming a loss-of-function mechanism responsive to targeted therapy (PMID:23674520).

Collectively, robust genetic, segregation, and experimental data justify a Definitive ClinGen classification for the MMAB–methylmalonic aciduria, cblB type association, with Strong genetic and Strong functional evidence. MMAB sequencing is essential for accurate diagnosis, family counseling, and implementation of precision therapies in cblB patients.

References

• Molecular genetics and metabolism • 2006 • Mutation and biochemical analysis of patients belonging to the cblB complementation class of vitamin B12-dependent methylmalonic aciduria. PMID:16410054
• Human genetics • 2022 • Spectrum and characterization of bi-allelic variants in MMAB causing cblB-type methylmalonic aciduria. PMID:34796408
• Clinical genetics • 2015 • Methylmalonic aciduria cblB type: characterization of two novel mutations and mitochondrial dysfunction studies. PMID:24813872
• Stem cell research • 2018 • Generation and characterization of two human iPSC lines from patients with methylmalonic acidemia cblB type. PMID:29660608
• Human molecular genetics • 2013 • Pharmacological chaperones as a potential therapeutic option in methylmalonic aciduria cblB type. PMID:23674520
• Human mutation • 2010 • Functional and structural analysis of five mutations identified in methylmalonic aciduria cblB type. PMID:20556797

Evidence Based Scoring (AI generated)