Vitamin B12-unresponsive methylmalonic acidemia

Vitamin B12-unresponsive methylmalonic acidemia (also known as methylmalonic aciduria, mut-type, or MMA) is a rare inherited metabolic disorder caused by a deficiency of the enzyme methylmalonyl-CoA mutase (encoded by the MMUT gene, formerly known as MUT). This enzyme is essential for the breakdown of certain amino acids (isoleucine, valine, methionine, threonine) and odd-chain fatty acids. Unlike vitamin B12-responsive forms of methylmalonic acidemia, this form does not improve with cobalamin (vitamin B12) supplementation, as the defect lies in the apoenzyme itself rather than in cofactor metabolism. Two subtypes exist: mut0 (complete enzyme deficiency, more severe) and mut- (partial enzyme deficiency, somewhat milder). The disease primarily affects the nervous system, kidneys, and metabolic homeostasis. Affected individuals typically present in the neonatal or early infantile period with metabolic acidosis, hyperammonemia, lethargy, vomiting, failure to thrive, hypotonia, and developmental delay. Recurrent metabolic crises can be life-threatening and may be triggered by illness, fasting, or high protein intake. Long-term complications include chronic kidney disease, pancreatitis, intellectual disability, movement disorders (including metabolic stroke affecting the basal ganglia), optic nerve atrophy, and cardiomyopathy. Growth retardation is common. Management centers on dietary restriction of propiogenic amino acids (isoleucine, valine, methionine, threonine) using specialized medical formulas, along with carnitine supplementation to help remove toxic metabolites. Emergency protocols for metabolic decompensation include intravenous glucose, bicarbonate correction, and sometimes dialysis. Liver transplantation or combined liver-kidney transplantation may be considered in severe cases to reduce metabolic burden, though it does not fully prevent neurological complications. Kidney transplantation may be needed for end-stage renal disease. Newborn screening programs in many countries now detect methylmalonic acidemia through elevated propionylcarnitine (C3) on tandem mass spectrometry, enabling earlier diagnosis and intervention.

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