Ethylmalonic encephalopathy is a devastating, infantile, autosomal recessive, metabolic disorder caused by defects in the mitochondrial sulfur dioxygenase, ETHE1, and characterized by ethylmalonic and methylsuccinic aciduria, lactic acidemia associated with developmental delay, orthostatic acrocyanosis, recurrent petechiae, chronic diarrhea, and abnormalities on brain MRI. The authors also report on novel treatment options for ethylmalonic encephalopathy.
Short-chain acyl-CoA dehydrogenase deficiency, a defect in the mitochondrial beta-oxidation pathway, also leads to ethylmalonic aciduria, but only variable symptoms have occurred in a few patients. Thus, it remains a poorly defined entity exhibiting a wide clinical spectrum. The authors report a variety of clinical phenotypes from mostly asymptomatic individuals to individuals with brain malformations and infantile spasms. In addition to disruptive mutations, several prevalent polymorphic variations in the SCAD gene may lead to variable elevations of ethylmalonic acid in the urine, again with uncertain clinical relevance.
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• Ethylmalonic encephalopathy is a progressive, often fatal neurometabolic disorder characterized by ethylmalonic and methylsuccinic aciduria and lactic acidemia.
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• It is associated with developmental delay, acrocyanosis, petechiae, and chronic diarrhea.
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• Ethylmalonic encephalopathy is caused by mutations in the ETHE1 gene, a mitochondrial sulfur dioxygenase involved in the catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy.
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• Clinical symptoms ascribed to SCAD deficiency may be reflective of ascertainment bias. Alternatively, early identification and treatment may prevent complications that may have occurred due to interaction between genetic susceptibility and other genetic factors or environmental stressors. Likely, SCAD deficiency is mostly solely a biochemical phenotype without clinical manifestations.
Historical note and terminology
Ethylmalonic encephalopathy (MIM 602473) is a neurometabolic disorder characterized by ethylmalonic and methylsuccinic aciduria, lactic acidemia associated with developmental delay, acrocyanosis, petechiae, and chronic diarrhea. The underlying metabolic defect was identified in a mitochondrial matrix protein. Hoffmann and colleagues first described this inborn error of metabolism as ethylmalonic aciduria (32). Since the initial report, less than 50 cases have been described worldwide, suggesting that the disorder is probably very rare (67).
Short-chain acyl-CoA (butyryl-CoA) dehydrogenase (SCAD) deficiency (MIM 201470) is a defect in the mitochondrial beta-oxidation pathway. The deficient enzyme, short-chain acyl-CoA dehydrogenase (EC 188.8.131.52), is the first enzyme of the intramitochondrial beta-oxidation spiral catalyzing the dehydrogenation of C4 and C6 fatty acids. The first report of symptomatic SCAD deficiency was done by Turnbull and colleagues (68). The impaired metabolism of short-chain CoAs leads to short-chain dicarboxylic aciduria (ethylmalonic and adipic acids) and increased C4 species on an acylcarnitine profile.