Benign Methylmalonic Aciduria

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency is usually considered to be a serious, often life-threatening disease. However, through routine screening of urine in neonates or screening of siblings of clinically affected neonates, we have identified eight children who have a benign clinical variant of this disorder. Their urinary methylmalonic acid levels have ranged from 1.0 to 3.4 mg per milligram of creatinine, with serum values ranging from an undetectable level to 1.7 mg per deciliter (130 nmol per liter). The children have not received dietary or vitamin therapy, have had normal growth and development (age range, 18 months to 13 years), and have performed as well as their unaffected siblings on psychometric testing. These children have no evidence of a deficiency of vitamin B 12 , which acts as a cofactor with methylmalonyl-CoA mutase, and they did not respond to the administration of vitamin B 12 . Two siblings were found by complementation analysis to have a defect in the methylmalonyl-CoA mutase apoenzyme; complementation analysis was not performed on the other patients. We conclude that the clinical spectrum of methylmalonyl-CoA mutase deficiency is wider than indicated by previously reported cases. (N Engl J Med 1984;311:1015–8.) METHYLMALONIC acidemia is an inborn error of organic acid metabolism resulting from deficient activity of methylmalonyl-CoA mutase, an enzyme that converts methylmalonyl-CoA to succinyl-CoA. 1 This enzyme requires a cobalamin (B 12 ) cofactor; a genetic deficiency of holoenzyme activity can result either from mutations in the apoenzyme or from defects in synthesis of the cobalamin cofactor. The major metabolic consequence of methylmalonyl-CoA mutase deficiency is an accumulation of methylmalonic acid, most readily demonstrated in the urine. This biochemical defect has been associated with metabolic acidosis, developmental delay, mental retardation, and in some instances, neonatal death. 1 , 2 Routine screening of urine for . . .