ETHYLMALONIC AND METHYLSUCCINIC ACIDURIA IN ETHYLMALONIC ENCEPHALOPATHY ARISE FROM ABNORMAL ISOLEUCINE METABOLISM

Ethylmalonic encephalopathy (EE), an organic aciduria of unknown etiol ogy characterized by developmental delay, hypotonia, and vascular inst ability associated with lactic acidemia and urinary excretion of ethyl malonic acid (EMA) and methylsuccinic acid (MSA), has been described i n 11 patients. To test the possibility that the underlying biochemical defect involves isoleucine catebolism, we determined the response to oral L-isoleucine (Ile) load (150 mg/kg) in a 5-year-old girl with EE and in three healthy, age-and sex-matched controls. Following lie load in the patient, there was accumulation of 2-methylbutyrylglycine (2-M BG) and a delayed and lower peak urinary excretion of tiglylglycine (T GL), suggesting a partial defect in 2-methyl-branched chain acylcoenzy me A dehydrogenase (2M-BCAD). In vitro measurements 2M-BCAD activity i n cultured skin fibroblasts from patients with EE have been reported t o be normal. Our results show that isoleucine is a source for the elev ated EMA and MSA in patients with EE, and suggest a functional, possib ly secondary, deficiency of activity of 2M-BCAD in vivo. Copyright (C) 1998 by W.B. Saunders Company.