Journal of Inherited Metabolic Disease

, Volume 35, Issue 3, pp 451–458

Morphologic evidence of diffuse vascular damage in human and in the experimental model of ethylmalonic encephalopathy

  • Carla Giordano
  • Carlo Viscomi
  • Maurizia Orlandi
  • Paola Papoff
  • Alberto Spalice
  • Alberto Burlina
  • Ivano Di Meo
  • Valeria Tiranti
  • Vincenzo Leuzzi
  • Giulia d’Amati
  • Massimo Zeviani
Original Article

DOI: 10.1007/s10545-011-9408-3

Cite this article as:
Giordano, C., Viscomi, C., Orlandi, M. et al. J Inherit Metab Dis (2012) 35: 451. doi:10.1007/s10545-011-9408-3

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.

Copyright information

© SSIEM and Springer 2011

Authors and Affiliations

  • Carla Giordano
    • 1
  • Carlo Viscomi
    • 2
  • Maurizia Orlandi
    • 1
  • Paola Papoff
    • 3
  • Alberto Spalice
    • 4
  • Alberto Burlina
    • 5
  • Ivano Di Meo
    • 2
  • Valeria Tiranti
    • 2
  • Vincenzo Leuzzi
    • 4
  • Giulia d’Amati
    • 1
  • Massimo Zeviani
    • 2
  1. 1.Department of Radiological, Oncological and Pathological SciencesSapienza UniversityRomeItaly
  2. 2.Unit of Molecular Neurogenetics Foundation “C. Besta” Neurological Institute-IRCCS, Pierfranco and Luisa Mariani Center for Diagnostics and Research on Infantile Mitochondrial DisordersMilanItaly
  3. 3.Department of Pediatrics, Pediatric Emergency and Intensive CareSapienza University of RomeRomeItaly
  4. 4.Division of Child Neurology, Department of Paediatrics, SapienzaUniversity of RomeRomeItaly
  5. 5.Unit of Inherited Metabolic Diseases, Clinic of PaediatricsUniversity of Padua School of MedicinePaduaItaly

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