Abstract
Ethylmalonic encephalopathy (EE) is a rare autosomal recessive disorder characterized by early onset encephalopathy, chronic diarrhoea, petechiae, orthostatic acrocyanosis and defective cytochrome c oxidase (COX) in muscle and brain. High levels of lactic, ethylmalonic and methylsuccinic acids are detected in body fluids. EE is caused by mutations in ETHE1, a mitochondrial sulphur dioxygenase. By studying a suitable mouse model, we found that loss of ETHE1 leads to accumulation of sulphide, which is a poison for COX and other enzymatic activities thus accounting for the main features of EE. We report here the first autopsy case of a child with a genetically confirmed diagnosis of EE, and compare the histological, histochemical and immunohistochemical findings with those of the constitutive Ethe1 −/− mice. In addition to COX depleted cells, widespread endothelial lesions of arterioles and capillaries of the brain and gastrointestinal tract were the pathologic hallmarks in both organisms. Our findings of diffuse vascular damage of target critical organs are in keeping with the hypothesis that the pathologic effects of ETHE1 deficiency may stem from high levels of circulating hydrogen sulphide rather than the inability of specific organs to detoxify its endogenous production.
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Acknowledgements
This work was supported by Telethon Grants GGP07019 and GPP10005 to MZ; AFM grant 2010/14458 to MZ, Fondazione Pierfranco e Luisa Mariani (MZ), Associazione Serena Talarico per i Giovani nel Mondo (GdA) and Fondazione Giuseppe Tomasello ONLUS (MZ and GdA).
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Communicated by: Shamima Rahman
Competing interests: None declared.
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Giordano, C., Viscomi, C., Orlandi, M. et al. Morphologic evidence of diffuse vascular damage in human and in the experimental model of ethylmalonic encephalopathy. J Inherit Metab Dis 35, 451–458 (2012). https://doi.org/10.1007/s10545-011-9408-3
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DOI: https://doi.org/10.1007/s10545-011-9408-3