Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency is an inborn error of metabolism characterized biochemically by the accumulation of methylmalonic acid.

Methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency is part of a group of metabolic diseases known as methylmalonic acidemias or MMA. It is caused by a partial or total deficiency in the activity of the mitochondrial enzyme methylmalonyl-CoA mutase (mut) as a result of alterations in the MMUT gene.

When alterations occur in the mut enzyme, which needs vitamin B-12 to function properly, the metabolism of certain proteins and lipids, such as cholesterol, are affected, generating toxic substances. These include methylmalonic acid, which accumulates in the blood and causes its acidification (acidemia).

The prevalence of methylmalonic acidemia is unknown and is thought to be less than one case per 100,000 births, although in certain populations this figure may vary.


The disease usually appears in the first weeks of life, however, cases of later onset have been reported.

Clinical manifestations include lethargy, growth retardation, recurrent vomiting, dehydration, respiratory distress, muscular hypotonia, developmental delay, intellectual deficit, hepatomegaly and coma. Patients may show signs of anemia, ketoacidosis and/or hyperammonemia with potential life-threatening renal and neurological complications, metabolic failure and cardiomyopathy.

Disease management

When the first crisis occurs after birth, initial treatment focuses on stabilizing the patient. If the acidemia is caused by a partial enzyme deficiency (mut- subtype) it is usually less severe than if the acidemia is resistant to vitamin B12 treatment (mut0 subtype).

Standard long-term therapy includes the use of L-carnitine, antibiotics, vitamin B12 (if the patient responds), low-protein diet and the use of specialized amino acid formulas containing valine, isoleucine, methionine and threonine.

Genes analyzed



Acquaviva C, Benoist JF, Pereira S, et al. Molecular basis of methylmalonyl-CoA mutase apoenzyme defect in 40 European patients affected by mut(o) and mut- forms of methylmalonic acidemia: identification of 29 novel mutations in the MUT gene. Hum Mutat. 2005 Feb;25(2):167-76.

Almási T, Guey LT, Lukacs C, et al. Systematic literature review and meta-analysis on the epidemiology of methylmalonic acidemia (MMA) with a focus on MMA caused by methylmalonyl-CoA mutase (mut) deficiency. Orphanet J Rare Dis. 2019 Apr 25;14(1):84.

Worgan LC, Niles K, Tirone JC, et al. Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. Hum Mutat. 2006 Jan;27(1):31-43.

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