Abstract Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke‐like episodes (MELAS) is a rare multisystem mitochondrial disorder primarily caused by mutations in mitochondrial DNA. While it typically presents with stroke‐like episodes, seizures, and lactic acidosis, recent evidence highlights a broader clinical spectrum, including neuropsychiatric manifestations such as psychosis. Although mutations in the MT‐ND3 gene are primarily associated with Leigh syndrome, they have also been linked to MELAS‐like presentations, underscoring the diagnostic complexity and the need for thorough genetic evaluation. We report the case of an 18‐year‐old Afghan female with a complex clinical history, including early‐onset seizures, Wilms tumor treated with chemotherapy, progressive peripheral neuropathy, and recent‐onset catatonia. Initial assessments suggested Charcot–Marie–Tooth disease; however, Whole mitochondrial genome sequencing identified a homoplasmic mitochondrial DNA variant in the MT‐ND3 gene, designated according to standard mitochondrial nomenclature as m.10158 T > C (MT‐ND3), which results in a missense amino acid substitution (p. Ser34Pro). Variant interpretation was conducted in accordance with ACMG/AMP guidelines adapted for mitochondrial DNA and was cross‐referenced with MITOMAP and ClinGen mitochondrial expert panel classifications. Laboratory findings indicated lactic acidosis, elevated ammonia, and increased CPK levels. The patient responded rapidly to lorazepam for catatonia and showed functional recovery following the initiation of a mitochondrial cocktail and integrated neurorehabilitation. Although MELAS is most commonly linked to the m.3243 A > G mutation in MT‐TL1, emerging reports associate MT‐ND3 variants with a broader phenotypic spectrum, including neuropathy and psychiatric symptoms. Neuropsychiatric features are increasingly recognized in mitochondrial disorders and may precede classical neurological signs. Genetic testing and metabolic profiling are essential for accurate diagnosis, particularly in atypical cases or resource‐limited settings. Treatment remains largely supportive, with variable responses to mitochondrial cocktails and symptomatic management. This case expands the phenotypic spectrum of MT‐ND3–related mitochondrial encephalopathy with MELAS‐like features, including catatonia and peripheral neuropathy, and highlights the clinical variability associated with pathogenic complex I–related mitochondrial DNA mutations. A multidisciplinary approach—including psychiatry, neurology, genetics, and rehabilitation—is crucial for managing these complex presentations.
Khorshidian et al. (Thu,) studied this question.