Six biochemical and genetic forms of methylmalonic acidemia have been defined previously: two (mut° 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°, 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° 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° or mut ^- patients; and finally, most cbl A, cbl B, and mut ^- patients were still living, whereas most mut ^- 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. (N Engl J Med. 1983; 308:857–61.)