PNPO (pyridoxamine 5'-phosphate oxidase) catalyzes the rate-limiting oxidation of pyridoxine 5'-phosphate (PNP) or pyridoxamine 5'-phosphate (PMP) into pyridoxal 5'-phosphate (PLP), the active form of vitamin B6 1. PLP serves as an essential cofactor for enzymes involved in amino acid metabolism, neurotransmitter synthesis (including GABA), folate metabolism, and mitochondrial function 2. PNPO deficiency causes B6-responsive epilepsy, typically presenting as neonatal-onset seizures that are often resistant to pyridoxine but respond to PLP supplementation 23. The clinical spectrum varies with specific mutations, with some patients responding to pyridoxine while others require PLP 4. Disease phenotypes range from neonatal epileptic encephalopathy to later-onset seizures, with treatment response influenced by genotype, prematurity, and maternal B6 status 4. Beyond its metabolic role, recent studies suggest PNPO may have oncogenic functions, being overexpressed in multiple cancers and promoting tumor growth through autophagy regulation 56. PLP remains the primary treatment for most PNPO-deficient patients, though liver toxicity monitoring is recommended due to potential adverse effects at therapeutic doses 7.