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  • Updated 03.23.2020
  • Released 03.30.1995
  • Expires For CME 03.23.2023

Methylmalonic acidemia


This article includes discussion of methylmalonic acidemia, methylmalonic aciduria, L-methylmalonyl-CoA mutase deficiency, Mut methylmalonic acidemia, cbIA, cbIB deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


The author provides an overview of the hereditary isolated methylmalonic acidemias, a group of metabolic disorders with varied clinical presentations. This includes the most severe form of L-methylmalonyl-CoA mutase deficiency, termed mut(o) methylmalonic acidemia, which, together with the less severe deficiencies of L-methylmalonyl-CoA mutase, are the most common causes of methylmalonic acidemia, but also the other biochemical differential diagnoses, cblA and cblB deficiency. They review the natural history, clinical phenotypes, and available treatment modalities as well as the metabolic investigations required to establish the diagnosis. The newest advances in molecular genetics are updated.

Key points

• Acute metabolic decompensation in a patient with methylmalonic acidemia is a medical emergency.

• “Metabolic stroke” involving the basal ganglia is usually a life-changing event.

• Liver transplantation usually eliminates acute episodes of ketolactic acidosis but is not a cure as CSF levels of methylmalonic acid remain massively elevated.

• Patients with severe mut enzyme (L-methylmalonyl-CoA mutase) deficiency usually develop renal insufficiency/failure in the second-third decade of life.

• Both mut enzyme deficiency and defects in cobalamin (cbl) metabolism lead to methylmalonic acidemia, and some cobalamin defects may also be associated with homocystinuria.

Historical note and terminology

Methylmalonic acidemia and the disease associated with the more proximal defect in the same pathway, propionic acidemia, are the most common clinically significant genetic disorders of organic acid metabolism (41). The key finding in methylmalonic acidemia is the accumulation of methylmalonic acid in body fluids and tissues. The hereditary disease, methylmalonic acidemia, was first described by Oberholzer and colleagues (110) and Stokke and colleagues (141).

Methylmalonic acidemia may be due to several different enzyme defects, some of which primarily involve cobalamin metabolism (41; 88; 43). All are inherited as autosomal recessive traits. In these biochemical genetic disorders, as well as in simple nutritional cobalamin deficiency, the accumulation of methylmalonic acid is secondary to the buildup of mitochondrial methylmalonyl-CoA, an intermediate in the conversion of propionyl-CoA to succinyl-CoA.

Conversion of propionyl-CoA in succinyl CoA
The major precursors are indicated with their approximated contribution to whole body propionate metabolism in the fasting state. Propionyl-CoA is converted into D-methylmalonyl-CoA by the action of the biotin-dependent enzyme, pr...

There are 2 isomers of methylmalonyl-CoA, the D- and the L-form. The latter is thought to be derived by the action of D-methylmalonyl-CoA epimerase activity (EC Propionyl-CoA, the immediate precursor of D-methylmalonyl-CoA, is the breakdown product of isoleucine, valine, methionine, threonine, and thymine, as well as cholesterol and odd-chain fatty acids. Subsequently, propionyl-CoA is converted to D-methylmalonyl-CoA via the enzyme propionyl-CoA carboxylase (EC Following racemization, L-methylmalonyl-CoA is converted to succinyl-CoA via the enzyme L-methylmalonyl-CoA mutase (E.C., which requires adenosylcobalamin for activity.

The synthesis of this coenzyme, in turn, depends on adequate delivery of vitamin B12 to tissues such as liver and brain; transport into cells through the phagolysosomal system; export and release of cob(III)alamin from lysosomes, cytosolic, and possibly mitochondrial reduction to cob(II)alamin; transport into the mitochondrion; mitochondrial reduction to cob(I)alamin; and conversion to adenosylcobalamin. Methylmalonic acidemia may result from a defect in any of these steps. When it is secondary to an enzymatic block that is proximal in the pathways of cobalamin reduction or lysosomal efflux, it is also associated with homocystinuria because of impaired production of methylcobalamin, in the cytosol, cobalamin cofactor is required for the conversion of homocysteine to methionine (41).

Most cases of methylmalonic acidemia are secondary to a complete or partial deficiency of L-methylmalonyl-CoA mutase, termed mut methylmalonic acidemia (41). The deficiency of L-methylmalonyl-CoA mutase as a cause of methylmalonic acidemia was first reported by Morrow and Barness (Morrow and Barness 1969). The mut(o) and mut(-) designations refer to complete and partial deficiencies, respectively, determined by in vitro studies with cultured cells (41). Some patients with primary defects in cobalamin metabolism such as impaired reduction of cobalamin (II) to cobalamin (I) or adenosylcobalamin synthase deficiency are responsive to cobalamin megatherapy (92). Thus, methylmalonic acidemia in more than a third of patients is a vitamin-responsive inborn error of metabolism (92). Although the residual enzyme activity in the mut(-) state may be stimulated by high concentrations of hydroxycobalamin and adenosylcobalamin in vitro, most patients with L-methylmalonyl-CoA mutase deficiency do not respond to pharmacologic doses of cobalamin (92).

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