Sodium channel slow inactivation as a therapeutic target for myotonia congenita

Ann Neurol. 2015 Feb;77(2):320-32. doi: 10.1002/ana.24331. Epub 2015 Jan 9.


Objective: Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the chloride channel in skeletal muscle, which causes spontaneous firing of muscle action potentials (myotonia), producing muscle stiffness. In patients, muscle stiffness lessens with exercise, a change known as the warmup phenomenon. Our goal was to identify the mechanism underlying warmup and to use this information to guide development of novel therapy.

Methods: To determine the mechanism underlying warmup, we used a recently discovered drug to eliminate muscle contraction, thus allowing prolonged intracellular recording from individual muscle fibers during induction of warmup in a mouse model of myotonia congenita.

Results: Changes in action potentials suggested slow inactivation of sodium channels as an important contributor to warmup. These data suggested that enhancing slow inactivation of sodium channels might offer effective therapy for myotonia. Lacosamide and ranolazine enhance slow inactivation of sodium channels and are approved by the US Food and Drug Administration for other uses in patients. We compared the efficacy of both drugs to mexiletine, a sodium channel blocker currently used to treat myotonia. In vitro studies suggested that both lacosamide and ranolazine were superior to mexiletine. However, in vivo studies in a mouse model of myotonia congenita suggested that side effects could limit the efficacy of lacosamide. Ranolazine produced fewer side effects and was as effective as mexiletine at a dose that produced none of mexiletine's hypoexcitability side effects.

Interpretation: We conclude that ranolazine has excellent therapeutic potential for treatment of patients with myotonia congenita.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetanilides / administration & dosage
  • Animals
  • Chloride Channels / antagonists & inhibitors*
  • Chloride Channels / physiology
  • Drug Delivery Systems / methods*
  • Mice
  • Mice, Transgenic
  • Muscle Contraction / drug effects
  • Muscle Contraction / physiology
  • Myotonia Congenita / drug therapy*
  • Myotonia Congenita / genetics
  • Myotonia Congenita / physiopathology*
  • Organ Culture Techniques
  • Piperazines / administration & dosage
  • Ranolazine
  • Sodium Channel Blockers / administration & dosage*


  • Acetanilides
  • CLC-1 channel
  • Chloride Channels
  • Piperazines
  • Sodium Channel Blockers
  • Ranolazine