Ethylmalonic encephalopathy caused by biallelic truncating variants in ETHE1: A case report

Ethylmalonic encephalopathy is a rare autosomal recessive mitochondrial disorder caused by biallelic pathogenic variants in ETHE1, the gene encoding mitochondrial persulfide dioxygenase, an enzyme crucial for hydrogen sulfide (H₂S) detoxification. Loss of this enzyme results in H₂S accumulation, cytochrome c oxidase inhibition, oxidative stress, and disrupted energy metabolism. Clinically, ethylmalonic encephalopathy manifests during early infancy with developmental delay, hypotonia, progressive encephalopathy, seizures, chronic diarrhea, and microvascular abnormalities such as petechiae and acrocyanosis. Fewer than 100 cases have been reported globally, mostly among Mediterranean and Arab populations, with scarce data from Latin America. We report the first documented case of ethylmalonic encephalopathy in a Mexican patient. The affected male infant, born to healthy nonconsanguineous parents of indigenous Maya origin from Yucatán, presented at 2 weeks of age with persistent hemorrhagic diarrhea, followed by metabolic acidosis, hyperammonemia, hyperlactatemia, elevated C4-acylcarnitine, and increased urinary ethylmalonic acid. Neurological findings included developmental delay, hypotonia, and myoclonic epilepsy. Whole-exome sequencing revealed a homozygous frameshift pathogenic variant in ETHE1 (NM_014297.5):c.19_20dup (p.Val8Glyfs*7), predicted to introduce a premature stop codon and abolish protein function. Despite targeted interventions-antiepileptic therapy, ammonia-lowering treatment, and metabolic support-the patient's condition progressively worsened, culminating in death at 15 months after metabolic decompensation and brain death. This case broadens the known mutational spectrum of ETHE1 by identifying a previously unreported pathogenic variant and underscores the need to include ethylmalonic encephalopathy in the differential diagnosis of infants presenting with chronic diarrhea, vascular lesions, and neurological deterioration, even in regions where the condition is not typically observed.