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Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy

Abstract

Ethylmalonic encephalopathy is caused by mutations in ETHE1, a mitochondrial matrix sulfur dioxygenase, leading to failure to detoxify sulfide, a product of intestinal anaerobes and, in trace amounts, tissues. Metronidazole, a bactericide, or N-acetylcysteine, a precursor of sulfide-buffering glutathione, substantially prolonged the lifespan of Ethe1-deficient mice, with the combined treatment being additive. The same dual treatment caused marked clinical improvement in five affected children, with hardly any adverse or side effects.

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Figure 1: Clinical, morphological and biochemical features of Ethe1−/− mice and human subjects.

References

  1. Tiranti, V. et al. Nat. Med. 15, 200–205 (2009).

    Article  CAS  Google Scholar 

  2. Szabó, C. Nat. Rev. Drug Discov. 6, 917–935 (2007).

    Article  Google Scholar 

  3. Mancardi, D. et al. Biochim. Biophys. Acta 1787, 864–872 (2009).

    Article  CAS  Google Scholar 

  4. Kang, S.S. et al. PLoS Med. 5, e41 (2008).

    Article  Google Scholar 

  5. Marí, M., Morales, A., Colell, A., García-Ruiz, C. & Fernández-Checa, J.C. Antioxid. Redox Signal. 11, 2685–2700 (2009).

    Article  Google Scholar 

  6. Hildebrandt, T.M. & Grieshaber, M.K. FEBS J. 275, 3352–3361 (2008).

    Article  CAS  Google Scholar 

  7. Liu, J. et al. Nature 459, 387–392 (2009).

    Article  CAS  Google Scholar 

  8. Whitehead, N.P., Pham, C., Gervasio, O.L. & Allen, D.G. J. Physiol. 586, 2003–2014 (2008).

    Article  CAS  Google Scholar 

  9. Durham, W.J. et al. Cell 133, 53–65 (2008).

    Article  CAS  Google Scholar 

  10. Atkuri, K.R., Mantovani, J.J., Herzenberg, L.A. & Herzenberg, L.A. Curr. Opin. Pharmacol. 7, 355–359 (2007).

    Article  CAS  Google Scholar 

  11. Wredenberg, A. et al. Proc. Natl. Acad. Sci. USA 99, 15066–15071 (2002).

    Article  CAS  Google Scholar 

  12. Sörensen, L. et al. J. Neurosci. 21, 8082–8090 (2001).

    Article  Google Scholar 

  13. Mineri, R. et al. J. Med. Genet. 45, 473–478 (2008).

    Article  CAS  Google Scholar 

  14. Tiranti, V. et al. Am. J. Hum. Genet. 74, 239–252 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Pierfranco and Luisa Mariani Foundation Italy, Fondazione Telethon-Italy grant number GGP07019 and grant RF-INN-2007-634163 of the Italian Ministry of Health. We thank E. Lamantea for assistance in the preparation of figures and S. Ravaglia for help in statistical analyses.

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Authors

Contributions

Study design: V.T. and M.Z.; clinical evaluation and sample collection: A.B.B. and I.D.; neuroradiological evaluation: M.S.; histochemical evaluation: C.L.; biochemical assays: A.B.B. and T.H.; mouse treatment and evaluation: C.V.; statistical analysis: C.V.; manuscript writing: M.Z.; critical revision of the manuscript: C.V., V.T. and M.Z.

Corresponding authors

Correspondence to Valeria Tiranti or Massimo Zeviani.

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The authors declare no competing financial interests.

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Viscomi, C., Burlina, A., Dweikat, I. et al. Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy. Nat Med 16, 869–871 (2010). https://doi.org/10.1038/nm.2188

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