Ethylmalonic encephalopathy (EE) is a rare and devastating neurodegenerative disease caused by mutations in the ETHE1 gene. It is characterized by early-onset encephalopathy, chronic diarrhea, petechiae, orthostatic acrocyanosis, and high levels of methylsuccinic, lactic, and ethylmalonic acids in body fluids. In this study, we report a patient with EE, who was identified through newborn screening, and the diagnosis was confirmed by targeted next-generation sequencing (NGS). The patient displayed recurrent petechiae, intermittent jaundice, protracted diarrhea, and extensive developmental regression. Genetic testing identified a homozygous nonsense variant, c.295C > T (p. Q99*), in the ETHE1 gene. A review of all known ETHE1 variants observed in other EE patients was conducted. This revealed the current difficulties in EE diagnosis. Besides, it also showed that patients with truncated variants of ETHE1 might exhibit pathological symptoms earlier and present more severe manifestations. Finally, a novel nonsense variant was identified, which supported and expanded our current knowledge of the variant spectrum for ETHE1. This novel variant also deepened our understanding of the genotype-phenotype associations that occur in EE patients.
