This section considers a category of disorders that is characterized by disturbances of the electrical excitability of the skeletal muscle membrane. Although the main manifestations are episodes of generalized paralysis and myotonia, there are many others. Another related group of diseases are unified by spontaneous and persistent muscle fiber activity and these are addressed in a later part of this chapter. The myotonias have been historically categorized as a special group of muscle diseases unified by the clinical sign of myotonia and were aligned in older classifications with the muscular dystrophies. This view was based on myotonia as it was understood in the classic form of myotonic dystrophy, a subject discussed in Chap. 45. Similarly, before fundamental knowledge of their mechanism was revealed, the periodic paralyses (better called episodic paralysis) were considered to be metabolic diseases of muscle. However, it has become evident that most diseases that feature prominent myotonia and the processes that cause episodic muscular paralysis are neither degenerative nor dystrophic. Clinical and electrophysiologic studies show that myotonia is an elemental feature of many nondystrophic conditions, foremost among them are the hyperkalemic form of periodic paralysis and myotonia congenita. Most of these diseases are caused by mutations in genes that code for chloride, sodium, calcium, or potassium ion channels in the muscle membrane, and they are referred to as ion channel diseases, or “channelopathies” (see Ryan and Ptácek). Within this group there are also instances of muscle conditions that display no myotonia but only periodic paralysis.
Given that these are disorders of muscle membrane excitability, it is not surprising that the primary defects are in voltage-dependent ion channels. By analogy, it was anticipated that ion channelopathies would be implicated in 2 other categories of disease in which there is altered membrane excitability, namely the epilepsies and certain cardiac arrhythmias and indeed, this has proven to be the case (see discussion in Chap. 15 on the epilepsies). In the process, several new forms of nondystrophic myotonia have been defined. Molecular studies, notably those of Rüdel, Lehmann-Horn (2004), and Ricker and their associates, identified the fundamental defects in the myotonias and episodic paralyses and clarified their relationships. The biology of the ion channels and their disease-related mutations are reviewed by Hanna and colleagues, by
Cannon, and by Heatwole and colleagues.
Table 46-4 summarizes the main features of the ion channel diseases affecting muscle and the individual members of the group are described as follows.
This is an uncommon disease of skeletal muscle that begins in early life and is characterized by myotonia, muscular hypertrophy, nonprogressive course, and dominant inheritance. It is distinctly different from myotonic dystrophy, which is characterized by a progressive degeneration of muscle fibers and has a different genetic basis. Thomsen disease is caused by one of several inherited molecular defects in the voltage-dependent chloride channel gene (CLCN1), (see Koch et al). It is interesting that most mutations behave as dominant traits, whereas others have either a dominant or recessive pattern of inheritance (see Table 46-4). The physiologic mechanism whereby these mutations alter ion fluxes across the muscle membrane and cause myotonia is described further on.