MELAS Associated With a Large-Scale MT-ND2 Deletion

INTRODUCTION: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a clinically and genetically heterogeneous mitochondrial disorder. Although the m.3243A>G variant in MT-TL1 is the most common molecular cause, atypical cases with negative routine genetic testing and nondiagnostic muscle biopsy may pose a substantial diagnostic challenge. Here, we report a clinically diagnosed MELAS case with supportive neuropathological findings and a large-scale deletion involving MT-ND2. CASE REPORT: A 20-year-old man presented with recurrent seizures and encephalopathic episodes over 1.5 years. His clinical course was characterized by episodic visual disturbance, hearing impairment, hemiparesis, and progressive encephalopathic deterioration. Serial magnetic resonance imaging revealed recurrent migratory cortical lesions involving the occipital, temporal, and frontal lobes, and magnetic resonance spectroscopy demonstrated a lactate peak. Cerebrospinal fluid analysis and autoimmune and infectious investigations were unremarkable. Electromyography, muscle biopsy, and initial next-generation sequencing, including testing for the common m.3243A>G variant, were nondiagnostic. Subsequent brain biopsy demonstrated laminar cortical necrosis, supporting a mitochondrial encephalopathic process. Multiplex ligation-dependent probe amplification further identified a large-scale pathogenic deletion involving MT-ND2. Based on the characteristic clinical course, neuroimaging pattern, neuropathological findings, and complementary genetic analysis, a diagnosis of MELAS was established. CONCLUSION: This case expands the diagnostic spectrum of MELAS and highlights that typical clinical and radiologic features may still be present even when routine lactate testing, muscle biopsy, and standard genetic screening are nondiagnostic. In highly suspected cases, brain biopsy and complementary methods for mitochondrial structural variation analysis, such as MLPA, may provide crucial diagnostic evidence.