Hypokalemic periodic paralysis is caused by mutations in two voltage-gated cation channels in skeletal muscle, Cav1.1 and Nav1.4. The mutations neutralize positively charged amino acid in the voltage-sensing transmembrane segments S4 of the channels. The gating defects induced by these mutations reveal loss-of-function which does not explain the phenotype. Cut-open measurements on Xenopus oocytes and current-voltage relationships on native muscle preparations of patients are performed. A cation leak current that does not flow through the ion-conducting pore but rather through a crevice formed by the mutations called omega current is present in the oocytes A decrease of extracellular potassium decreases the conductance of the resting potential-maintaining rectifying potassium channels in native muscle. Weakness is associated with depolarization in native muscle. Omega current depolarize muscle membrane. Reduction of extracellular potassium reduces rectifying potassium currents. This process will lead to further depolarization resulting in inexcitablity and weakness of muscle (hypokalemic periodic paralysis). Because a hyperpolarization according to Nernst is expected, the depolarization is termed paradoxical.