To determine the incidence of elevated levels of serum methylmalonic acid in patients with cobalamin deficiency, we utilized a new capillary gas chromatographic-mass spectrometric technique to measure methylmalonic acid in the serum of 73 patients with clinically confirmed cobalamin deficiency. Values ranged from 55 to 22,300 ng/ml, and 69 of the 73 patients had values above the normal range of 19-76 ng/ml as determined for 50 normal blood donors. In the cobalamin-deficient patients, serum methylmalonic acid was significantly correlated with the serum folate level and the degree of neurologic involvement. Some patients with pernicious anemia who were intermittently treated with cyanocobalamin were found to have elevated serum levels of methylmalonic acid while free of hematologic and neurologic abnormalities. A cobalamin-deficient patient is described with a normal serum cobalamin and an elevated serum methylmalonic acid. We conclude that the ability to measure methylmalonic acid in human serum will be useful in studies designed to determine the incidence of cobalamin deficiency in various patient populations.
IntroductionPrevious investigators have shown that most patients with cobalamin (Cbl, vitamin B12)' deficiency have elevated levels of methylmalonic acid in their urine (1-12). The origin of the methylmalonic acid has recently been elucidated (13) and is illustrated in Fig. 1. In Cbl deficiency, reduced levels ofadenosylCbl result in decreased activity of L-methylmalonyl-coenzyme A (CoA) mutase and a resultant increase in intracellular levels ofL-methylmalonyl-CoA. D-methylmalonyl-CoA is also elevated due to the activity of D,L-methylmalonyl-CoA racemase (14) and is cleaved to coenzyme A and methylmalonic acid by the recently recognized and characterized enzyme, D-methylmalonyl-CoA hydrolase (13). Methylmalonic acid is then released into blood in unknown amounts and is excreted in the urine. In normal individuals (15) and laboratory animals (13), about