Methylmalonic aciduria. An inborn error of metabolism leading to chronic metabolic acidosis.

Abstract

Two children of unrelated families are described who failed to thrive, and who manifested from the earliest days of life a persistent metabolic acidosis, punctuated by more severe crises of acidosis with ketosis, set off by infection, often trivial. In both, the acidosis was treated with alkalis, and in the severe episodes intravenous therapy was always required. The first, a boy, in whom the diagnosis was made by an examination of his stored plasma 7 years after death, became mentally and physically retarded, and died at 2 years of age in an acute metabolic acidosis with ketosis. The second, a girl, in whom the definitive diagnosis was not made till she was 5 1/2 years old, is now a well child, though still needing alkali therapy. In both cases the urea and creatinine clearances were impaired, and in the 2nd case there was also a low hydrogen ion clearance index. The first showed on several occasions moderate aminoaciduria, mainly glycine. The differences between this condition and primary renal tubular acidosis are discussed. An examination of the urine of the 2nd patient showed that she was excreting a large amount of methylmalonic acid, an intermediate in the metabolism of some amino acids of dietary origin, and of fatty acids with an odd number of carbon atoms. In both cases high plasma levels of the acid were found. In the 2nd case, the level in CSF [cerebrospinal fluid] was as high as in the plasma, indicating that methylmalonic acid was being produced in the brain. The accumulation of methylmalonic acid in the plasma and CSF suggested a metabolic block in the conversion of methylmalonyl coenzyme A to succinyl coenzyme A, a step catalyzed by the enzyme methylmalonyl coenzyme A isomerase, and this was supported by the effect of ingestion of sodium propionate. Stress tests of metabolism revealed that with a loading dose of either protein, valine, or propionate, hypoglycaemia and ketosis were induced, resulting from a secondary inhibition of gluconeogenesis by methylmalonyl CoA. Preliminary experiments showed a marked deficiency of the enzyme in leukocytes from the affected subject compared with those from normal people. The condition is therefore an inborn error of metabolism inherited as an auto-somal recessive. It is concluded from these 2 cases that without adequate treatment, there may be physical and mental retardation, and even death during an acute crisis. With adequate treatment, especially during the crisis, these may be averted.