Newborn screening · Organic acid disorder
Methylmalonic Acidemia, Mutase Deficiency · MMA-mut
Severe organic acidemia. Crisis presentation common. Liver and kidney transplants increasingly offered.
Description
Methylmalonic acidemia, mutase deficiency (MMA-mut) is an autosomal recessive organic acid disorder. The MMUT gene on chromosome 6p12 encodes methylmalonyl-CoA mutase, a mitochondrial enzyme that converts methylmalonyl-CoA to succinyl-CoA in the catabolic pathway shared by the branched-chain amino acids isoleucine, valine, methionine, and threonine, plus odd-chain fatty acids and cholesterol. Two damaging copies of MMUT abolish or sharply reduce enzyme activity. Methylmalonic acid and propionyl-CoA derivatives accumulate, and the resulting organic acidemia drives metabolic decompensation.
Affected newborns with the severe mut0 form typically present in the first days to weeks of life with poor feeding, vomiting, lethargy, hypotonia, tachypnea from metabolic acidosis, and progression to coma if untreated. The mut- form retains residual activity and can present later in infancy or childhood. Long-term complications across the cohort include failure to thrive, intellectual disability, movement disorders from basal-ganglia injury (the classic metabolic stroke pattern), chronic kidney disease that often progresses to end-stage renal failure by adolescence or young adulthood, optic atrophy, and pancreatitis.
Detection is by newborn screening on the dried blood spot using tandem mass spectrometry, which flags an elevated propionylcarnitine (C3) and an elevated C3 to acetylcarnitine (C2) ratio. Confirmation uses urine organic acids showing methylmalonic acid elevation, plasma acylcarnitines, total plasma homocysteine to separate isolated MMA from combined MMA with homocystinuria, and MMUT sequencing. Cobalamin-responsiveness testing distinguishes MMA-mut from the cobalamin disorders that share the C3 screening signal. Reported incidence of all isolated MMA combined is roughly 1 in 50,000 to 1 in 100,000 live births, with MMA-mut accounting for a substantial share.
Treatments to date
Standard of care is lifelong protein-restricted diet using medical formula free of isoleucine, valine, methionine, and threonine, paired with carefully measured natural protein, calorie support, and L-carnitine supplementation to clear propionyl groups as propionylcarnitine. Oral metronidazole or an alternative antibiotic is used in some centers to reduce gut propionate production. Hydroxocobalamin is trialed at diagnosis; mut0 by definition does not respond, while the mut- subgroup shows variable response. During acute illness families follow a sick-day protocol with high-calorie low-protein intake, and emergency presentations are managed with intravenous dextrose, insulin if needed, ammonia scavengers, and dialysis for severe acidosis or hyperammonemia.
No FDA-approved disease-specific drug exists for MMA-mut. Liver transplantation, alone or combined with kidney transplantation when renal function has declined, is offered at multiple centers and reduces metabolic crises and stabilizes neurologic outcomes, although residual extrahepatic disease persists because mutase activity is required throughout the body.
mRNA replacement therapy and AAV-delivered MMUT gene therapy programs have entered early-phase clinical trials. Moderna's mRNA-3705 program for MMA-mut began Phase 1/2 dosing in 2022. LogicBio's LB-001 nuclease-free gene-insertion program in MMA-mut was an early entrant before development was halted.