ABSTRACT

Ethylmalonic encephalopathy (EE) is a rare mitochondrial disorder usually presenting with severe early-onset manifestations. This report contributes to the expanding phenotypic spectrum of EE by describing a genetically confirmed case with a clinically mild course, thereby underlining the diagnostic relevance of early gastrointestinal and cutaneous findings.

We describe a 4-year-8-month-old girl diagnosed with EE due to a homozygous ETHE1 c.3G>T (p.Met1?) mutation. She initially presented with persistent diarrhea beginning in early infancy, followed by livedo reticularis-like rash and progressive gait disturbance. Unlike the classical EE phenotype, the patient exhibited a stable clinical course without encephalopathic crises or rapid neuroregression. Biochemical investigations revealed markedly elevated urinary ethylmalonic acid and mildly increased plasma C4 acylcarnitine. Brain magnetic resonance imaging revealed a small T2/FLAIR hyperintense focus within the left basal ganglia, consistent with a mild and asymmetric pattern. Treatment with oral metronidazole, N-acetylcysteine, riboflavin, coenzyme Q10, carnitine, and supportive supplementation led to transient motor improvement, although petechiae and mild regression persisted during follow-up.

This case reinforces published evidence that the ETHE1 c.3G>T (p.Met1Ile) mutation is consistently associated with attenuated disease severity. By highlighting the sequence of early gastrointestinal and vascular manifestations preceding neurological decline, this study adds to the literature on genotype-phenotype correlations in EE. Recognition of these non-neurological clues is essential for timely diagnosis, and adjunctive metabolic therapies may contribute to stabilization in atypical, milder presentations.