Methylmalonic acidemia (MMA) is a group of rare (approx. 1:50,000) autosomal recessive disorders of amino acid metabolism, involving defects in the conversion of methylmalonyl-CoA to succinyl-CoA (which would normally enter the Krebs cycle). The defect is genetically heterogeneous, and can be due to the lack of the enzyme methylmalonyl-CoA mutase (mut⁰), a partial reduction in its activity (mut^-), or defects in cobalamin metabolism (vit B₁₂ is a cofactor required in the conversion of methylmalonyl-CoA to succinyl-CoA). These defects result in the accumulation of methylmalonic acid.

Clinical presentation varies and depends on the genetic diagnosis. The most severe form is mut⁰, which usually presents in the neonatal period, while other forms may present later in infancy and childhood when triggers of increased protein catabolism (infection, dehydration, trauma, surgery, stress) cause metabolic decompensation. The presentation may be non-specific, such as vomiting, lethargy and tachypnoea. Neurological manifestations include encephalopathy, seizures, hypotonia and stroke. Gastrointestinal complaints include recurrent vomiting, failure to thrive, and pancreatitis. If the acute crisis is untreated it may progress to coma and death.

Biochemical hallmarks of an acute metabolic decompensation are metabolic acidosis, an increased anion gap (caused by lactate, ketones and organic acids), elevated lactate and ketones ± hyperammonaemia.

Long-term complications include failure to thrive, chronic kidney disease or renal failure, pancreatitis, pancytopaenia, osteopaenia and intellectual disability. Cardiac involvement is rare, but includes dilated cardiomyopathy and prolonged QTc interval. Several patients have been reported with metabolic stroke and optic atrophy.

Long-term management is aimed at preventing metabolic decompensation. Patients are placed on a protein-restricted diet, given carnitine supplements (to promote the increased excretion of toxic metabolites) and hydroxycobalamin if cobalamin-responsive. Administration of metronidazole is aimed at reducing the burden of acid-producing bacteria in the gut. Ammonia scavenging drugs including carglumic acid, a synthetic analogue of N-acetyl glutamate, can be used to manage hyperammonaemia.

Kidney, liver, or a combined kidney-liver transplantation is increasingly being performed in patients with MMA. While transplanting either or both organs does not “cure” the disease, the aim is to supply a certain amount of the missing enzyme. Methylmalonyl–CoA mutase is mainly expressed in the liver, but renal transplantation will partially replace some mutase activity. Transplanting kidneys in MMA patients with renal failure both restores the impaired renal function and improves the metabolic enzyme defect, and thus reduces the number of episodes of metabolic decompensation and hospitalisation, and allows liberalisation of the diet. It does not prevent neurological complications. Liver transplantation is considered as a treatment option particularly in patients with frequent decompensations. Combined liver-kidney transplantation is a potential treatment option but it is associated with more post-operative complications than single organ transplantation.