Methylmalonic acidemia is an autosomal recessive disorder caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase, a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin, or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations usually is in early infancy, and varies from mild to life threatening. These manifestations include: lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, muscle hypotonia, hepatomegaly, and coma. Patients may also show signs of anemia (not megaloblastic), have potentially life-threatening ketoacidosis and/or hyperammonemia, and developmental delay and intellectual deficit, with metabolic stroke affecting the brain stem.

The cblC type methylmalonic acidemia with homocystinuria is the most frequent type of methylmalonic acidemia with homocystinuria. Mutations in the MMACHC gene are the cause of cblC type methylmalonic acidemia with homocystinuria. The exact function of the protein encoded by this gene is still unknown. It may play a role in the binding and intracellular trafficking of cobalamin.