EARS2 encodes mitochondrial glutamyl-tRNA synthetase, a non-discriminating enzyme that catalyzes aminoacylation of both mitochondrial tRNA(Glu) and tRNA(Gln) through a two-step reaction involving ATP-dependent glutamate activation and transfer to the tRNA acceptor end 1. This enzyme is essential for mitochondrial protein translation, specifically for synthesizing the 13 electron transport chain subunits encoded by mitochondrial DNA 2. Pathogenic biallelic EARS2 mutations cause Combined Oxidative Phosphorylation Deficiency 12 (COXPD12), presenting as leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) 3. Patients typically present within the first year of life with hypotonia, spasticity, neurodevelopmental delay, and elevated lactate 4. Disease phenotypes cluster into severe (neonatal lethality, progressive deterioration) and mild (variable improvement with striking MRI resolution) presentations, though no genotype-phenotype correlation has been definitively established 4. EARS2 deficiency impairs mitochondrial metabolism, disrupting TCA cycle and amino acid metabolism 2, with some cases demonstrating immune dysfunction including B-cell abnormalities and recurrent infections 5. Remarkably, LTBL is among the few reversible mitochondrial disorders, with documented cases showing clinical and radiological improvement 3. Recent Mendelian randomization studies identify EARS2 as a potential causal gene for Alzheimer's disease 6.