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.

乙基丙二酸脑病 (EE) 是一种由ETHE1 基因突变引起的严重中毒疾病。编码参与硫化氢分解代谢的线粒体硫双加氧酶的基因。它的生化特征是硫化氢及其副产物硫代硫酸盐以及由于硫化氢诱导的短链酰基辅酶A脱氢酶抑制而导致的乙基丙二酸的组织积累。患者通常出现与脑病、慢性出血性腹泻和血管病变相关的早发性严重脑损伤伴瘀点性紫癜和直立性肢端发绀，其病理生理学知之甚少。目前的治疗旨在减少硫化氢的积累，但不能显着预防脑病和大多数死亡。在本次审查中，我们将总结从人类和动物研究中获得的现有知识，表明线粒体和氧化还原稳态的破坏可能代表 EE 中组织损伤的相关病理机制。越来越多的证据表明，硫化氢和乙基丙二酸显着扰乱关键的线粒体功能并诱导氧化应激。还讨论了使用有希望的候选药物治疗这种破坏性疾病的新治疗策略。