RARS2 encodes mitochondrial arginyl-tRNA synthetase 2, which catalyzes the attachment of arginine to tRNA(Arg) in a two-step reaction essential for mitochondrial protein synthesis 1. The enzyme first activates arginine with ATP to form Arg-AMP, then transfers it to the acceptor end of tRNA(Arg) 1. RARS2 is a nuclear-encoded protein imported into mitochondria after cytosolic translation 2. RARs2 pathogenic variants cause pontocerebellar hypoplasia type 6 (PCH6), an autosomal recessive mitochondrial encephalopathy 34. The phenotypic spectrum has expanded to include early-onset developmental and epileptic encephalopathy (DEE), infantile myoclonic encephalopathy, and Lennox-Gastaut syndrome 51. Notably, 85% of reported RARS2 variants disrupt splicing or gene expression, leading to protein truncation 5. Clinical features include progressive microcephaly, hypotonia, seizures (often pharmacoresistant), failure to thrive, and developmental delay 1. Some patients develop hypoglycemia and lactic acidosis 6. Pathogenic mechanisms involve defective mitochondrial translation and dysregulated cellular physiology, including elevated oxidative stress and apoptosis, rather than primary energy metabolism defects 4. Yeast models confirm pathogenicity of missense variants and suggest arginine supplementation as potential therapeutic intervention 2. Ketogenic diet may reduce seizure frequency 1.