PLPBP (pyridoxal phosphate binding protein) is a conserved intracellular protein that plays a critical role in vitamin B6 homeostasis by regulating pyridoxal 5'-phosphate (PLP), the active form of vitamin B6 1. The protein functions as a PLP-binding protein that maintains proper B6 vitamer pools and prevents the toxic accumulation of pyridoxine 5'-phosphate (PNP) 23. PLPBP localizes to mitochondria and cytosol, where it likely facilitates the efficient turnover of protein-bound B6 vitamers and helps balance different B6 metabolite pools 4. Loss of PLPBP function disrupts vitamin B6 homeostasis and impairs PLP-dependent enzymatic pathways including amino acid metabolism, neurotransmitter synthesis (particularly GABA), and one-carbon metabolism 43. Biallelic mutations in PLPBP cause autosomal-recessive vitamin B6-dependent epilepsy with early neonatal onset 15. Most patients present with seizures within the first 24 hours of life, often accompanied by antenatal anomalies, microcephaly, and white matter abnormalities 5. Disease severity correlates with variant type: missense and compound heterozygous variants produce attenuated phenotypes, while truncating variants cause severe disease with potential early mortality 5. All affected individuals show lifelong responsiveness to high-dose pyridoxine or PLP treatment, enabling seizure control and improved neurodevelopmental outcomes 1. Recent expert consensus endorses PLPBP screening in newborn genetic screening programs due to the treatable nature of this disorder 6.