Ethylmalonic encephalomyopathy with petechiae: Reduction in ethylmalonic acid excretion with methionine restriction and delineation of coagulopathy

Ethylmalonic encephalomyopathy is a syndrome which consists of marked urinary excretion of ethylmalonic acid (EMA), intermittent lactic acidosis, remitting petechiae, episodic acrocyanosis, and progressive encephalopathy. Affected children also may have seizures, chronic diarrhea, and mildly dysmorphic fecies, as well as brain MRI findings consistent with Leigh syndrome. The syndrome appears to be inherited in an autosomal-racessive fashion, and most patients have come from consanguineous families. We describe a patient with this syndrome whose parants were consanguineous. An affected male sibling had encephalopathy, metabolic acidosis with lactic acidemia, severe seizures and relapsing petechiae. On MRI scans of the brain, both the brother and our patient had symmetric T2-weighted signal hyperintensities in the basal ganglia. On autopsy, microscopic examination of the brother's brain showed lesions in the basal ganglia consistent with subacute necrotizing encephalopathy. The brother most likely had ethylmalonic encephalomyopathy, and is the first report of a patient with this disease having undergone autopsy. Attempts to delineate the cause of the ethylmalonic aciduria have focused on a possible enzyme defect in isoleucine metabolism. However, fibroblast oxidation of isoleucine has been reported to be normal, as was that of butyrate, glucose, and long-, medium-, short-, and branched-chain fatty acids. Elevated urinary S-sulfocysteine and thiosulfate have also been described, suggesting a disorder of sulfur amino acid metabolism. Our patient was found to have no change in EMA excretion following an isoleucine load, but had a marked increase in EMA excretion after a methionine load. She was treated with a reduced methionine diet, and EMA excretion decreased. Previous attempts to elucidate the pathogenesis of the petechiae have also been unsuccessful. Platelet aggregation studies have been normal in several patients, and skin biopsy of petechial lesions in several patients has only shown fresh hemorrhage. Evaluation of our patient's petechiae showed normal PT, PTT, bleeding time, and vWF. There was a markedly elevated level of plasminogan activator inhibitor-1.