Genetics of Methylmalonic Acidemia

Updated: Mar 15, 2019
  • Author: Brendan Lee, MD, PhD; Chief Editor: Maria Descartes, MD  more...
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Oberholzer et al and Stokke et al reported the first patients with methylmalonic acidemia (MMA). [1, 2] Clinical and genetic heterogeneity became evident very early when some patients responded to pharmacological doses of cobalamin (vitamin B-12) and others did not.

MMA encompasses a heterogeneous group of disorders characterized by accumulation of methylmalonic acid and its by-products in biological fluids. These disorders are due to a deficiency of the adenosylcobalamin-dependent enzyme methylmalonyl-CoA mutase (apoenzyme deficiency), a defect in intracellular cobalamin metabolism (coenzyme deficiency), transcobalamin II deficiency, intrinsic factor deficiency, or dietary cobalamin deficiency, which is found in vegetarians. [3, 4] A subset of children with defects of intracellular cobalamin metabolism may also have simultaneous homocystinuria. In addition, transient MMA can be detected in otherwise healthy infants.

In the context of this review, MMA refers to disorders resulting in methylmalonyl-CoA mutase deficiency and disorders of intracellular cobalamin metabolism.



Adenosylcobalamin-dependent methylmalonyl-CoA mutase is an enzyme that catalyses the isomerization of methylmalonyl-CoA to succinyl-CoA. Succinyl-CoA subsequently enters the tricarboxylic acid cycle, where it is converted through several steps to oxaloacetate. [5] Methylmalonyl-CoA is derived from propionyl-CoA by the action of propionyl-CoA carboxylase, the enzyme that is deficient in patients with propionic acidemia (see Propionic Acidemia). Propionyl-CoA is formed through the catabolism of isoleucine, valine, threonine, methionine, thymine, uracil, cholesterol, or odd-chain fatty acids. Gut bacteria may generate a significant amount of propionyl-CoA.

Methylmalonyl-CoA mutase is a dimer of identical subunits to which adenosylcobalamin is tightly bound. The complimentary deoxyribonucleic acid (cDNA) of methylmalonyl-CoA mutase has been cloned and its genomic structure delineated. The gene is mapped to 6p12. Mutations in this gene have been reported to cause MMA(0) or MMA(-). [6] Adenosylcobalamin is an essential cofactor of methylmalonyl-CoA mutase. Methylmalonyl epimerase converts the D racemer of methylmalonyl-CoA to the L racemer and substrate of the mutase. Deficiency of methylmalonyl epimerase leads to mild methylmalonic aciduria and minor clinical symptoms. [7]

Complementation studies revealed the presence of at least 8 different complementation groups (mut0, mut-, cblA, cblB, cblC, cblD [and CblD variant 2], cblF, cblJ) that cause MMA. [8, 9, 10] In the mut0 group, mutase activity in fibroblasts is undetectable, whereas fibroblasts of the mut- group show some residual mutase activity. [6] CblA, and cblB are defects in the pathway of adenosylcobalamin synthesis. [11, 12] CblC, which is the most common defect in cobalamin metabolism, is a defect in the common pathway of cobalamin reduction, leading to combined MMA and homocystinuria, secondary to impaired adenosylcobalamin and methylcobalamin formation. [13]

CblD can present as combined MMA and homocystinuria, isolated homocystinuria (cblD variant 1), or isolated methylmalonic aciduria (cblD variant 2), owing to its role in intracellular cobalamin trafficking. [14] CblF and cblJ are caused by impaired lysosomal cobalamin transport. [15, 16]

The molecular bases for all complementation groups have now been identified. All genetic forms of MMA are inherited as autosomal recessive traits.

Recently, combined malonic and methylmalonic aciduria (CMAMMA) has been shown to be caused by mutations in a putative methylmalonyl CoA and malonyl CoA synthetase (ACSF3). While also a cause of elevated MMA, the finding of elevated malonic acid in urine organic acid, and as evidenced on plasma acylcarnitine profile, is a distinguishing feature. [17]




United States

Screening of infants aged 3-4 weeks in Massachusetts revealed an approximate frequency for MMA of 1 case per 48,000 infants. [18]


Newborn screening programs in Germany and Austria have identified approximately 1 newborn with MMA (mutase deficiency) per 250,000 newborns screened. MMA is more frequent in populations with increased rates of consanguinity.


All children with genetic forms of MMA are at risk of metabolic decompensation with increased morbidity and mortality. The risk is greater for mut0 and mut- forms of MMA compared with cobalamin-responsive forms. Newborns and infants with mut0 or mut- forms of MMA may die early, before a diagnosis can be reached.


MMA is prevalent in populations with increased rates of consanguinity but has been reported in all ethnic groups.


No sex predilection is reported.


The mut0 and mut- forms of MMA typically present during the newborn period and early infancy, respectively.

CblA, cblB, cblC, and cblD variant 2 forms of MMA typically present during early infancy. MMA forms cblD and cblF typically present during later infancy or childhood. The cblC form of MMA may present during childhood or adolescence.

Theoretically, neonatal screening via tandem mass spectrometry should reveal all genetic forms of MMA. Some reports have shown that this may not be true for some forms of MMA, such as cblC. [19]