Should PNPO Deficiency Be Treated In Utero? Clinical Findings From Prenatal Pyridoxine Therapy

Pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency is characterized by early-onset epileptic encephalopathy refractory to standard antiseizure medications. It is caused by variants in the PNPO gene, resulting in deficient PNPO enzyme activity, which normally converts pyridoxine-5'-phosphate and pyridoxamine-5'-phosphate (two vitamers of vitamin B6) into the active cofactor, pyridoxal-5'-phosphate (PLP). Treatment relies on PLP or pyridoxine in some cases. Long-term outcomes remain suboptimal. We describe two cases of unrelated children treated with vitamin B6 (pyridoxine) in utero: one with a confirmed prenatal PNPO diagnosis and one at risk due to family history but ultimately unaffected. In utero pyridoxine, combined with early postnatal PLP treatment, allowed excellent seizure control and normal neurodevelopment in the long term. Notably, our first patient, treated from birth, is now 10 years old, representing the oldest reported PNPO-deficient individual treated from birth. Case 2 highlights the safety of prenatal B6 supplementation even in unaffected fetuses. These observations support prenatal pyridoxine supplementation as a safe and potentially beneficial strategy in at-risk PNPO pregnancies.