Mitochondrial Dysfunction and Redox Homeostasis Impairment as Pathomechanisms of Brain Damage in Ethylmalonic Encephalopathy: Insights from Animal and Human Studies.

Ethylmalonic encephalopathy (EE) is a severe intoxication disorder caused by mutations in the ETHE1 gene that encodes a mitochondrial sulfur dioxygenase involved in the catabolism of hydrogen sulfide. It is biochemically characterized by tissue accumulation of hydrogen sulfide and its by-product thiosulfate, as well as of ethylmalonic acid due to hydrogen sulfide-induced inhibition of short-chain acyl-CoA dehydrogenase. Patients usually present with early onset severe brain damage associated to encephalopathy, chronic hemorrhagic diarrhea and vascular lesions with petechial purpura and orthostatic acrocyanosis whose pathophysiology is poorly known. Current treatment aims to reduce hydrogen sulfide accumulation, but does not significantly prevent encephalopathy and most fatalities. In this review, we will summarize the present knowledge obtained from human and animal studies showing that disruption of mitochondrial and redox homeostasis may represent relevant pathomechanisms of tissue damage in EE. Mounting evidence show that hydrogen sulfide and ethylmalonic acid markedly disturb critical mitochondrial functions and induce oxidative stress. Novel therapeutic strategies using promising candidate drugs for this devastating disease are also discussed.