Abstract

Background: Ethylmalonic encephalopathy (EE) is a rare autosomal recessive metabolic disorder caused by biallelic mutations in the ETHE1 gene, resulting in defective mitochondrial detoxification of hydrogen sulfide (H₂S). The classical form is characterized by early-onset progressive neurological deterioration, multisystem involvement, and poor prognosis, with death typically occurring within the first years of life. Although liver transplantation is currently the only intervention shown to modify disease course, medical therapies aimed at reducing H₂S toxicity – such as metronidazole and N-acetylcysteine (NAC) – are widely used as supportive treatment. However, only limited data are currently available on long-term outcomes under medical therapy.

Case Report: We report a patient with genetically confirmed classical EE and a severe early-onset phenotype who survived into adolescence, showing prolonged clinical stabilization under long-term treatment with metronidazole, NAC, and antioxidant supplementation. Following rapid neurological deterioration in infancy, epilepsy and extra-neurological manifestations, including chronic diarrhea and growth failure, subsequently stabilized. Although biochemical abnormalities persisted and fluctuated over time, they did not show a clear correlation with clinical status.

Conclusions: This case documents an unusually long-term survival in classical EE in the absence of liver transplantation and provides valuable insight into the long-term clinical course under medical management. While stabilization cannot be unequivocally attributed to therapy alone, our observations suggest the potential role of sustained medical treatment – possibly in combination with dietary interventions – as a supportive strategy to slow disease progression and improve quality of life in patients who are not candidates for transplantation or who are awaiting liver transplantation. Systematic collection of longitudinal data is essential to better define prognosis and optimize management in this devastating disorder.