Hundreds of distinct epilepsy-causing genes have been identified.1 The vitamin B6-dependent epilepsies are a heterogeneous group of genetic disorders due to incomplete formation, transport, or inactivation of pyridoxal 5′-phosphate (PLP).2 The ALDH7A1, PNPO, ALPL, ALDH4A1, and more recently PLPBP genes have been implicated.3 Characteristic presentation of vitamin B6-dependent epilepsies includes neonatal onset of encephalopathy and seizures refractory to first-line antiseizure medications (ASMs) followed by cessation or dramatic improvement of seizures after administration of pyridoxine or PLP. Because initiation of proper treatment is essential for seizure control, timely diagnosis is critical to optimizing clinical outcome. We describe the case of a 3-year-old boy who presented with progressively worsening refractory seizures starting at 14 months of age and was subsequently diagnosed with pyridoxal phosphate homeostasis protein (PLPHP) deficiency via rapid genome sequencing during a critical care hospitalization for status epilepticus. He was started on pyridoxine with immediate cessation of seizure activity and has remained seizure-free. We review the diagnosis, management, and outcome of PLPHP deficiency, as well as implications for use of rapid genetic testing in the acute care setting.