Excretion Of Ethylmalonic Acid Research Articles

The urinary excretion of ethylmalonic acid: What level requires further attention?

The urinary excretion of ethylmalonic acid was studied in various patients, including children with glutaric aciduria type II and with β-ketothiolase deficiency. An increased excretion at a modest level was found in 20 out of 5000 children who were referred for screening of inherited metabolic disease. Two children were studied longitudinally, but no clue to the origin of ethylmalonic acid was found in these cases. It is concluded that follow-up investigation of abnormal ethylmalonic acid excretion is only indicated when additional organic acids such as dicarboxylic acids are excreted in large amounts.

538 ETHYLMALONIC-ADIPIC ACIDURIA: A NEW DEFECT OF BUTYRATE OXIDATION ASSOCIATED WITH HYPOGLYCEMIA

A 5 year old girl with recurrent hypoglycemia, acidosis and normal development was found to excrete in her urine massive quantities of ethylmalonic acid (EMA), adipic acid (AA) and hexonyl-glycine (HG): 670-780, 210-740 and 190-390 μg/mg creatinine, respectively, vs. normal values of <9 μg/mg for each. Since butyry CoA can be carboxylated to form EMA, and hexanoyl CoA can be either ω-oxidized to AA or conjugated with glycine to form HG, this pattern of urinary metabolites suggested a deficiency of butyryl CoA dehydrogenase, a mitochondrial enzyme oxidizing both butyryl and hexanoyl CoA. Such a deficiency was supported by a medium chain triglyceride challenge which markedly augmented EMA excretion, and by studies on oxidation of [1-14C]butyrate by cultured skin fibroblasts which revealed 14CO2 production by patient's cells consistently <15% of that in 6 control lines.The urinary findings in our patient resemble those seen in Jamaican vomiting sickness and glutaric aciduria type II, both characterized by defects of multiple acyl CoA dehydrogenases. The cultured cell findings noted above, however, the excretion of only minimal amounts of glutarate and the results of oral lysine and leucine loading tests make these diagnoses most unlikely. We suggest that our patient suffers from an inheritent isolated deficiency of butyryl CoA dehydrogenase. The hypoglycemia may be explained by accumulation of EMA, which has been shown to inhibit mitochondrial malate transport, a rate limiting step in gluconeogenesis.