Schematic representation of mechanisms proposed to explain seizure responsiveness to pyridoxine and the potential link with KCNQ2

Several etiopathogenic mechanisms have been proposed to explain the responsiveness of some neonatal seizures to pyridoxine, and particularly to its active form, pyridoxal 5′ phosphate (PLP). PLP acts as a cofactor of several enzymes, such as glutamic acid decarboxylase (GAD), which regulates the synthesis of the inhibitory neurotransmitter gamma-amino butyric acid (GABA) from the excitatory neurotransmitter glutamate (GLUT); consequently, a reduction of PLP may lower GABA and raise GLUT, decreasing the seizure threshold. PLP is also involved in the synthesis of serine and glycine; a reduction of PLP may cause lower levels of these two amino acids, which is associated with epileptic phenotypes. SHMT is involved in the metabolic pathway, eventually leading to the formation of 5-methyltetrahydrofolate (5-mTHF), the main circulating form of folate, a reduction of which has been reported in some patients suffering from pyridoxine-dependent epilepsies. Furthermore, the reduction of 5-mTHF may be associated with oxidative stress, with excessive production of reactive oxygen species (ROS), possibly a consequence of low levels of pyridoxine, an antioxidant. ROS contribute to the peroxidation of several molecules, also affecting ion channels, potentially including KCNQ2. PLP also acts as an antagonist of specific ion channels with a possible anticonvulsant effect, so low pyridoxine levels may have a convulsant effect in part through action on these ion channels: this may apply to KCNQ2 (potassium voltage-gated channel subfamily Q member 2). Finally, some antiepileptic drugs may contribute to the depletion of pyridoxine and, indirectly, hyperhomocysteinemia, which is known to lower the seizure threshold. (Source: Amore G, Butera A, Spoto G, et al. KCNQ2-related neonatal epilepsy treated with vitamin B6: a report of two cases and literature review. Front Neurol 2022;13:826225. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)