SCN4A and congenital myasthenic syndrome: In contrast, an R3 mutation R1454W and R4 mutation R1457H, associated with CMS, commonly exhibited a hyperpolarizing shift in steady-state availability, delayed recovery from inactivation and profound use-dependent current attenuation [27,28], resulting in a severe loss-of-function of Nav1.4 and theoretically causing CMS, although these mutations also exhibited a delayed fast inactivation that leads to a gain-of-function of Nav1.4.