The electrical excitability of skeletal muscle enables action potentials to be generated at the motor end plate and propagated along the sarcolemma and into the transversetubule (T-tubule) membranes of muscle fibres. This spread of electrical activity is critical for coupling the local synaptic depolarization at the neuromuscular junction to the release of intracellular calcium from the sarcoplasmic reticulum. Several primary and secondary disorders of skeletal muscle are associated with abnormal excitability. An increase in sarcolemmal excitability manifests as a tendency for the autonomous generation of repetitive action potentials, persistent contraction and delayed relaxation, the hallmarks of myotonia. By contrast, intermittent failure of muscle membrane excitability causes paroxysmal weakness or paralysis that is characteristic of periodic paralysis. These alterations in muscle excitability produce a spectrum of clinical syndromes in which a patient may have myotonia, periodic paralysis, or a combination of both (Fig. 71.1).

The physiological basis for the generation of muscle action potentials is now well understood at the cellular and molecular levels. The rapid opening of voltage-gated sodium channels is responsible for the initial upstroke in the muscle action potential and for its propagation along sarcolemmal membranes. The somewhat slower activation of potassium channels contributes to repolarization, while chloride conducting ion channels help stabilize the membrane potential at the resting level to guard against spurious action potential triggering. Many of the ion channel molecules that participate directly in generating muscle action potentials have been defined at the primary nucleotide sequence level, and this work has enabled investigation into the genetic basis of disorders of sarcolemmal excitability. In parallel, advances in cellular electrophysiology coupled with the use of recombinant ion channels have contributed greatly to advancing our knowledge of the molecular pathophysiology of such disorders.

This chapter focuses upon the clinical characteristics and pathophysiology of two categories of abnormal sarcolemmal excitability: myotonia and periodic paralysis. In the past decade, the discovery of the underlying molecular defects responsible for many of the inherited myotonias and periodic paralyses has led to a revised classification of these disorders. The functional consequences of the genetic defects on the physiology of voltage-gated sodium and chloride channels serves as a framework from which to understand the mechanistic basis of these disorders at the molecular level. Finally, the symptomatic treatment of myotonia and periodic paralysis is discussed in relation to the therapeutic principles of compensating for the biophysical defects of mutant ion channels.