Periodic paralysis: understanding channelopathies

Abstract

Familial periodic paralyses are typical channelopathies (i.e., caused by functional disturbances of ion channel proteins). The episodes of flaccid muscle weakness observed in these disorders are due to underexcitability of sarcolemma leading to a silent electromyogram and the lack of action potentials even upon electrical stimulation. Interictally, ion channel malfunction is well compensated, so that special exogenous or endogenous triggers are required to produce symptoms in the patients. An especially obvious trigger is the level of serum potassium (K+), the ion responsible for resting membrane potential and degree of excitability. The clinical symptoms can be caused by mutations in genes coding for ion channels that mediate different functions for maintaining the resting potential or propagating the action potential, the basis of excitability. The phenotype is determined by the type of functional defect brought about by the mutations, rather than the channel effected, because the contrary phenotypes hyperkalemic periodic paralysis (HyperPP) and hypokalemic periodic paralysis (HypoPP) may be caused by point mutations in the same gene. Still, the common mechanism for inexcitability in all known episodic-weakness phenotypes is a long-lasting depolarization that inactivates sodium ion (Na+) channels, initiating the action potential.