Elsevier

Pediatric Neurology

Volume 38, Issue 2, February 2008, Pages 73-85
Pediatric Neurology

Review article
Channelopathies: A Review

https://doi.org/10.1016/j.pediatrneurol.2007.09.007Get rights and content

Channelopathies are a recently delineated, emerging group of neurologic disorders united by genetically determined defects in ion-channel function. These disorders are characterized by a prominent genetic and phenotypic heterogeneity that can make them challenging and bewildering to understand. This systematic review attempts to categorize these disorders according to their predominant clinical manifestations (i.e., myotonia, weakness, migraine, ataxia, epilepsy, and movement disorders) within the context of what is presently known about the molecular basis of recognized clinical syndromes. Areas of both genetic and phenotypic overlap are highlighted. The review is intended to assist clinicians in enhancing their diagnostic acumen and in targeting specific genetic tests.

Introduction

Channelopathies are disorders caused by inherited mutations of ion channels. Channel mutations causing disease were first described in inherited neuromuscular disorders [1]. They are now described in many other tissues. Symptoms may represent either an abnormal gain of function (e.g., epilepsy, myokymia, and myotonia) or a loss of function (e.g., weakness).

Two related concepts are important in these diseases. The first concept is that of phenotypic heterogeneity. Different mutations in the same gene can cause different diseases (e.g., mutations in the same voltage-dependent sodium channel in skeletal muscle can result in hyperkalemic periodic paralysis, hypokalemic periodic paralysis, potassium-aggravated myotonia, and paramyotonia congenita). The second concept is that of genetic heterogeneity. Mutations in different genes can result in the same apparent disease phenotype (e.g., hyperkalemic periodic paralysis is caused by mutations in different genes coding for the skeletal muscle sodium channel).

Section snippets

Neurophysiology

Ion channels are transmembrane glycoprotein pores important in cell excitability, which is mediated by the ion flow in and out of cells. Channels can exist in three different states: open, closed (resting state), or inactivated (refractory period after opening of the channel, during which the channel will not let ions pass through). Channels are composed of different subunits, with each subunit encoded by a different gene. There are two major classes of ion channels: voltage-gated and

Channelopathies: An Overview

Channelopathies can be classified according to the abnormal channel or affected organ (muscle or brain). Figure 1 classifies different channelopathies according to the mutated channel. Table 1 classifies channelopathies according to the principal organ affected. Table 2 includes all known channelopathies, and summarizes whether or not commercially available genetic testing is available at this time.

One characteristic of the channelopathies is a significant phenotypic overlap in clinical

Muscle Diseases

Muscle diseases under consideration include the periodic paralyses and nondystrophic myotonias (hypokalemic periodic paralysis, hyperkalemic periodic paralysis, paramyotonia congenita, myotonia congenita, potassium-aggravated myotonia, and Andersen-Tawil syndrome), malignant hyperthermia, central core myopathy, and the congenital myasthenic syndromes.

Brain Diseases

Channelopathies involving neurons include disease-causing migraines (familial hemiplegic migraine), ataxia (episodic ataxias, or spinocerebellar ataxia type 6), exaggerated responses to exogenous sensory stimuli (hereditary hyperekplexia), and epilepsy (e.g., autosomal-dominant frontal lobe epilepsy, or benign familial neonatal convulsions).

Conclusion

It is apparent that the scope of channelopathies in neurologic disorders is both broad and continually expanding. It is reasonable to expect that increasing clinical recognition and sensitivity to this class of disorders, together with the application of molecular genetic approaches to explaining their pathogenesis, will expand the spectrum of these disorders and increase what is known regarding their intrinsic heterogeneity. It may also be expected that the delineation of the pathogenesis of

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