KCNQ2 encodes the pore-forming subunit of the voltage-gated potassium M-channel, which assembles with KCNQ3 to regulate the M-current—a slowly activating and deactivating potassium conductance critical for controlling neuronal excitability and synaptic responsiveness. The channel is selectively permeable to potassium over other cations and is suppressed by muscarinic acetylcholine receptor activation. Pathogenic KCNQ2 variants cause developmental and epileptic encephalopathy and benign familial neonatal seizures through distinct mechanisms. Loss-of-function variants reduce M-current, increasing neuronal hyperexcitability 1, while gain-of-function variants such as A317T and L318V stabilize the channel in a constitutively open state, increasing current density and altering gating kinetics 2. Recent evidence suggests that TDP-43 dysfunction in ALS/FTD causes disease-specific mis-splicing of KCNQ2, producing a nonfunctional protein that triggers motor neuron hyperexcitability 3. Clinically, KCNQ2 encephalopathy typically presents with neonatal-onset tonic seizures and suppression-burst EEG patterns; seizure frequency often declines with age, and sodium channel blockers such as oxcarbazepine and lamotrigine are effective in seizure control 45. Multiple KCNQ2-selective activators including retigabine, ezogabine, cannabidiol, and experimental agents like HN37 (pynegabine) and Ebio1 have demonstrated efficacy in cellular models and clinical applications 678, while selective inhibitors such as Ebio3 show promise for rescuing gain-of-function variants 9.