Ion-channel defects and aberrant excitability in myotonia and periodic paralysis

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Abstract

The myotonias and periodic paralyses are a diverse group of skeletal muscle disorders that share a common pathophysiological mechanism: all are caused by derangements in the electrical excitability of the sarcolemma. Mutations within coding regions of ion-channel genes have been identified recently as the underlying molecular defects in these heritable disorders. Chloride-channel mutations cause a reduction in the resting conductance, which enhances excitability and gives rise to myotonia. By contrast, missense mutations in the L-type Ca2+ channel reduce the electrical excitability of the fiber and cause a form of periodic paralysis. Mutations of the sodium channel impair inactivation of the channel, which, depending on the type and severity of the functional defect, results in either paralysis or myotonia.

Trends Neurosci. (1996) 19, 3–10

Section snippets

Myotonia

Myotonia, from the Greek myo (muscle) and tonos (tension), is a clinical term used to describe an impairment of muscle relaxation (for review, see [2]). An affected individual complains of muscle stiffness and might, for example, have difficulty releasing the grip of a handshake or opening the eyelids after squinting in bright sunlight. Strength is not affected, and myotonia often diminishes with repeated contractions of the same muscle (warm-up phenomenon). Unlike a cramp, the sustained

Periodic paralysis

Periodic paralysis lies at the opposite end of the spectrum of membrane excitability. During attacks of weakness, the EMG is silent, the membrane is depolarized[4]at −60 to −50 mV from a normal value of −90 mV, and action potentials cannot be generated, even by direct galvanic shock. The attacks are episodic rather than having any regular periodicity, and last from minutes to hours. Interictally, muscle strength is normal, and there is no associated alteration in consciousness, seizure, cardiac

Elucidating the mechanisms of the disorders

The first insights into the mechanism of these disorders were derived from microelectrode recordings from excised fibers. Bryant and colleagues found that the membrane resistance was increased several-fold in muscle-fiber biopsies from goats with hereditary myotonia[5]. By varying the bath solution, they also showed that the anomalously high resistance was due to a tremendous reduction in the Cl conductance. Moreover, normal muscle fibers took on myotonic features when the bath Cl was

Na+-channel disorders

Sodium-channel mutations have been identified in HyperPP, PMC and a heterogeneous collection of myotonic syndromes known as the sodium-channel myotonias (SCM). All of these disorders are inherited as dominant traits and show linkage to the Na+-channel gene on 17q23–25 (9, 12). This gene codes for the α subunit of SkM1, the TTX-sensitive adult isoform of the skeletal muscle Na+ channel[13]. SkM1 is expressed at significant levels only in adult skeletal muscle; hence, other excitable tissues

Chloride-channel disorders

Chloride-channel mutations cause myotonic syndromes that are inherited as either dominant or recessive traits[2]. A dominantly inherited form, myotonia congenita (MC), was well-described over 100 years ago by Thomsen, a Danish physician who had the disorder himself and for whom the eponym Thomsen's disease has been applied. Myotonia appears within the first year or two with stiffness that is unaffected by cold or K+, and there is no disabling weakness. The recognition of a similar dominantly

Ca2+-channel disorders

Mutations in the α1 subunit of the skeletal muscle DHP receptor cause hypokalemic periodic paralysis (HypoPP); this is a dominantly inherited trait, but, unlike the Na+- and Cl-channel disorders, symptoms do not usually develop until puberty and the penetrance is reduced in females. These features suggest a possible role for hormonal modulation of disease expression. Maneuvers that lower serum K+ levels, such as carbohydrate ingestion or insulin injection, provoke attacks of weakness in

Epilogue

Over the past five years, the molecular genetic bases for all of the nondystrophic myotonias and periodic paralyses have been identified: HyperPP, PMC and SCM are caused by Na+-channel mutations, MC and GM result from Cl-channel mutations, and HypoPP arises from Ca2+-channel mutations. These discoveries have shifted the diagnostic classification of these disorders from a phenotype- to a genotype-based system. On clinical grounds, most familial myotonias without weakness were diagnosed

Acknowledgements

Work in the author's laboratory has been supported by the National Institutes of Health (AR42703), the Muscular Dystrophy Association, the Howard Hughes Medical Institute and the Alfred P. Sloan Foundation.

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