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  • Updated 05.14.2024
  • Released 11.15.2004
  • Expires For CME 05.14.2027

Ethylmalonic encephalopathy and SCAD deficiency



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, and lactic acidemia associated with developmental delay, orthostatic acrocyanosis, recurrent petechiae, chronic diarrhea, and abnormalities on brain MRI.

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. Clinical phenotypes range 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.

Key points

• Ethylmalonic encephalopathy is a progressive, often fatal neurometabolic disorder characterized by ethylmalonic and methylsuccinic aciduria and lactic acidemia.

• Ethylmalonic encephalopathy is associated with developmental delay, acrocyanosis, petechiae, and chronic diarrhea.

• Ethylmalonic encephalopathy is caused by mutations in the ETHE1 gene, the gene product of which is a mitochondrial sulfur dioxygenase involved in the catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy.

• It is unclear if clinical symptoms previously ascribed to short-chain acyl-CoA dehydrogenase (SCAD) deficiency are due to ascertainment bias or if early identification and treatment prevent complications that may have occurred due to interaction between genetic susceptibility and environmental stressors. Likely, SCAD deficiency is mostly a biochemical phenotype without clinical manifestations.

Historical note and terminology

Ethylmalonic encephalopathy (MIM 602473) is a neurometabolic disorder characterized by ethylmalonic and methylsuccinic aciduria as well as lactic acidemia associated with developmental delay, acrocyanosis, petechiae, and chronic diarrhea. The underlying metabolic defect was identified in a mitochondrial matrix protein. German pediatrician Georg Hoffmann and colleagues first described this inborn error of metabolism as ethylmalonic aciduria (34). Since the initial report, less than 50 cases have been described worldwide, suggesting that the disorder is rare (73).

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, 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 by Turnbull and colleagues (74). 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.

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