Voltage-gated sodium channels initiate and propagate electrical signaling in excitable tissues by conducting sodium ions through a central pore module, formed by four domains (DI-DIV) that also contain homologous voltage sensor modules. Changes in membrane potential drive conformational changes of the voltage sensors (promoting activation, inactivation, or deactivation), that open or close the central pore. Voltage sensor module mutations disrupt channel gating, causing diseases of electrical excitability such as hypokalemic periodic paralysis. This disease is characterized by skeletal muscle weakness associated with low serum potassium and is caused by mutations in the voltage-sensitive S4 segments within the DI-DIII voltage sensor modules. Here, I use electrophysiological and multi-scale modelling approaches to isolate gating defects caused by three homologous hypokalemic periodic paralysis mutations, identify novel roles for gating defects in the pathology of this disease, and define electrostatic interactions and critical residues within the DI and DIV voltage sensors that drive activation.