Discovery and Treatment of Action Potential-Independent Myotonia in Hyperkalemic Periodic Paralysis

Objective: Hyperkalemic periodic paralysis (hyperKPP) is characterized by attacks of transient weakness. A subset of hyperKPP patients suffers from transient involuntary contraction of muscle (myotonia). The goal of this study was to determine mechanisms causing myotonia in hyperKPP. Methods: Intracellular electrophysiology, single-fiber Ca2+ imaging, and whole muscle contractility studies were performed in a mouse model of hyperKPP. Results: Myotonia in hyperkPP was caused by both involuntary myogenic action potentials (AP myotonia) lasting less than 5 min and action potential-independent myotonia (non-AP myotonia) lasting over 1 h. Non-AP myotonia was caused by prolonged subthreshold depolarization and elevated intracellular Ca2+ in the absence of action potentials. Treatment with dantrolene effectively mitigated non-AP myotonia, suggesting that the source of Ca2+ was the sarcoplasmic reticulum. Although non-AP myotonia occurred in the absence of action potentials, Na+ channel blockers were effective as therapy. Discussion: We propose myotonia in hyperKPP occurs via two mechanisms: (1) suprathreshold depolarization triggering action potentials that are detectable with EMG and (2) sustained subthreshold depolarization resulting in Na+ overload and Ca2+ leak from the sarcoplasmic reticulum. Notably, clinical diagnostics such as EMG cannot detect the second mechanism as it occurs in the absence of action potentials. Currently, only a minority of patients with hyperKPP are treated with Na+ channel blockers and none are treated with dantrolene. Our data suggest hyperKPP patients, as well as patients with a number of other neuromuscular disorders, may benefit from trials of these therapies, even if they do not have myotonia detectable clinically or by EMG.