The natural history of the inherited methylmalonic acidemias

N Engl J Med. 1983 Apr 14;308(15):857-61. doi: 10.1056/NEJM198304143081501.


Six biochemical and genetic forms of methylmalonic acidemia have been defined previously: two (mut degrees and mut-) resulting from defects in the mutase apoenzyme, and four (cbl A, cbl B, cbl C, and cbl D) resulting from deficient adenosylcobalamin synthesis. We retrospectively surveyed the clinical presentation, response to cobalamin supplementation, and long-term outcome in the four most prevalent mutant classes by collecting detailed information on 45 patients (15 mut degrees, 5 mut-, 14 cbl A, and 11 cbl B). Most patients presented acutely with a common set of clinical and laboratory findings; however, there were significant differences between mutant classes: mut degrees patients presented earlier in infancy than did cbl A and cbl B patients; in response to cobalamin supplements, marked decreases in the concentration of methylmalonic acid in blood or urine were reported in most cbl A patients and in nearly half the cbl B patients, but not in mut degrees or mut- patients; and finally, most cbl A, cbl B, and mut- patients were still living, whereas most mut degrees patients died during the first few months of life. Our data indicate that genotypic classification of the methylmalonic acidemias has prognostic and therapeutic use as well as diagnostic value.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Metabolism, Inborn Errors / diagnosis
  • Amino Acid Metabolism, Inborn Errors / drug therapy
  • Amino Acid Metabolism, Inborn Errors / genetics*
  • Cobamides / biosynthesis
  • Humans
  • Infant
  • Infant, Newborn
  • Malonates / blood*
  • Methylmalonic Acid / blood*
  • Methylmalonyl-CoA Mutase / deficiency
  • Mutation
  • Prognosis
  • Retrospective Studies
  • Vitamin B 12 / therapeutic use


  • Cobamides
  • Malonates
  • Methylmalonic Acid
  • Methylmalonyl-CoA Mutase
  • cobamamide
  • Vitamin B 12