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.

Clinical Trials in Mitochondrial Disease

“…Furthermore, plasma ethylmalonic acid and serum thiosulfate, a toxic marker of disease, decreased during combined therapy. 52 Cysteamine bitartrate (cysteamine), an established therapy for cystinosis, works by decreasing the abnormal lysosomal storage of cystine. Cysteamine also promotes the transport of cysteine into cells, which has the potential to increase intracellular glutathione levels.…”

Altered Sulfide (H2S) Metabolism in Ethylmalonic Encephalopathy

“…Combined exposure to metronidazole and NAC has been effective in prolonging the survival of Ethe1 2/2 mice and in improving the main symptoms in a pilot study on EE patients (Viscomi et al 2010), including marked attenuation or disappearance of the vascular lesions and diarrhea, as well as amelioration of some neurological abnormalities. These encouraging results suggest that the invariably fatal clinical course of EE could be modified by a pharmacological protocol based on the off-label use of low-cost, relatively safe drugs.…”

Drug-Induced Encephalopathy

“…For instance, some mutations can promote development of an encephalopathy, i.e. a mutation in ETHE1, a mitochondrial matrix sulphur dioxygenase causing an ethlymalonic encephalopathy (Viscomi et al, 2010). In a patient with the rare missense variant methionine synthetase c.2756A>G (D919G), a methotrexate encephalopathy was observed probably due to a modified effect of methotrexate on homocysteine metabolism (Linnebank et al, 2007).…”