Ethylmalonic encephalopathy: Clinical course and therapy response in an uncommon mild case with a severe ETHE1 mutation

Abstract

Ethylmalonic encephalopathy (EE) is a rare metabolic disorder caused by dysfunction of ETHE1 protein, a mitochondrial dioxygenase involved in hydrogen sulfide (H₂S) detoxification. EE is usually a fatal disease with a severe clinical course mainly associated with developmental delay and regression, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhoea. Treatment includes antioxidants, antibiotics that lower H₂S levels and antispastic medications, which are not curative. The mutations causing absence of the ETHE1 protein, as is the case for the described patient, usually entail a severe fatal phenotype. Although there are rare reported cases with mild clinical findings, the mechanism leading to these milder cases is also unclear. Here, we describe an 11-year-old boy with an ETHE1 gene mutation who has no neurocognitive impairment but chronic diarrhoea, which is controlled by oral medical treatment, and progressive spastic paraparesis that responded to Achilles tendon lengthening.

Keywords: 3-MST, 3-mercaptopyruvate sulfurtransferase; CAT, cysteine aminotransferase; CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; EE, ethylmalonic encephalopathy; EMA, ethylmalonic acid; ETHE1 gene; GSH, glutathione; H2S; H2S, hydrogen sulfide; H2SO3, persulfide; MTZ, metronidazole; Mild course; NAC, N-acetylcysteine; SCAD, short-chain acyl-CoA dehydrogenase; SDO, sulfur dioxygenase; SQR, sulfide quinone oxidoreductase; SUOX, sulfite oxidase; TST, thiosulfate sulfur transferase; Therapy response; UQ, quinone; cIII, complex III; cIV, complex IV.

Fig. 1

The pathways of H₂S synthesis and removal (CBS: cystathionine β-synthase; CSE: cystathionine γ-lyase; CAT: cysteine aminotransferase; 3-MST: 3-mercaptopyruvate sulfurtransferase; SQR: sulfide quinone oxidoreductase; SDO/ETHE1: sulfur dioxygenase; SUOX: sulfite oxidase; TST: thiosulfate sulfur transferase; GSH: glutathione; UQ: quinone; cIII: complex III; cIV: complex IV).

Fig. 2

Virtual absence of ETHE1 protein in the case according to western blotting.