Methylmalonic acidemia

Gerard T Berry MD (Dr. Berry of Harvard Medical School has received consulting fees from Biomarin Pharmaceuticals and honorarium from Hyperion Therapeutics.)
Barry Wolf MD PhD, editor. (Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.)
Originally released March 30, 1995; last updated January 29, 2017; expires January 29, 2020

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


The authors provide an overview of the hereditary 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. 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 (Fenton and Rosenberg 1995). The key finding in methylmalonic acidemia is the accumulation of methylmalonic acid in body fluids and tissues. Association of methylmalonic acid with human disease was first made by Cox and White (Cox and White 1962) and Barness and colleagues (Barness et al 1963), who recognized that patients with vitamin B12 or cobalamin deficiency excrete increased quantities in urine. Aside from patients with pernicious anemia, infants of vegetarian mothers exclusively fed breast milk (Higginbottom et al 1978; Specker et al 1990; Kuhne et al 1991), patients with a history of gastric surgery, and the elderly (Pennypacker et al 1992) are at risk for cobalamin deficiency. The hereditary disease, methylmalonic acidemia, was first described by Oberholzer and colleagues (Oberholzer et al 1967) and Stokke and colleagues (Stokke et al 1967).

Methylmalonic acidemia may be due to several different enzyme defects, some of which primarily involve cobalamin metabolism (Fenton and Rosenberg 1995; Fowler 1998; Manoli et al 2016c). 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 Image: Conversion of propionyl-CoA in succinyl CoA
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 The human gene and protein product encoding this enzyme have been identified (Bobik and Rasche 2001). 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.
Conversion of propionyl-CoA in succinyl CoA Image: Conversion of propionyl-CoA in succinyl CoA
Vitamin B12 dependent conversion of L-methylmalonyl-CoA to succinyl-CoA and homocysteine conversion to methionine Image: Vitamin B12 dependent conversion of L-methylmalonyl-CoA to succinyl-CoA and homocysteine conversion
Pathway of cellular processing of cobalamin and the relationship of the metabolic steps of propionyl-CoA metabolism Image: Pathway of cellular processing of cobalamin and the relationship of the metabolic steps of propionyl
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 (Fenton and Rosenberg 1995).

Most cases of methylmalonic acidemia are secondary to a complete or partial deficiency of L-methylmalonyl-CoA mutase, termed mut methylmalonic acidemia (Fenton and Rosenberg 1995). 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 (Fenton and Rosenberg 1995). 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 (Rosenberg et al 1968a; Rosenberg et al 1968b; Lindblad et al 1969; Matsui et al 1983). Thus, methylmalonic acidemia in more than a third of patients is a vitamin-responsive inborn error of metabolism (Matsui et al 1983). 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 (Matsui et al 1983).

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