Abstract
Ion channels are crucial for the normal function of excitable tissues such as neurons and skeletal muscle. Since the discovery that the paroxysmal muscle disorder periodic paralysis is caused by mutations in genes that encode voltage-gated ion channels, many genetic neurological channelopathies have been defined. These channelopathies include epilepsy syndromes that show a mendelian pattern of inheritance, certain forms of migraine and disorders of cerebellar function, as well as periodic paralysis. The clinical diversity of these disorders relates in part to the tissue-specific expression of the dysfunctional channel, but is probably influenced by other, as yet unidentified, genetic and non-genetic factors. The complementary disciplines of molecular genetics and cellular and in vitro electrophysiology have resulted in significant advances in understanding of the basic molecular pathophysiology of some of these disorders. The single-gene neurological channelopathies are generally regarded as a paradigm for understanding common human paroxysmal disorders, such as epilepsy and migraine. This article reviews the clinical and molecular features of some of the single-gene channelopathies that affect muscle and brain. The possible role of ion-channel functional and genetic variation in predisposing individuals to common forms of human epilepsy and migraine are also considered. The implications for accurate genetic diagnosis and therapeutic intervention are highlighted.
Key Points
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The normal function of neurological tissues, such as brain, peripheral nerves and skeletal muscle, relies on the complex interplay between key ion channels, which determine membrane excitability
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It is becoming clear that genetically induced dysfunction of ion channels is the underlying cause of many single-gene neurological diseases, including forms of periodic paralysis, myotonia, episodic ataxias, migraine and epilepsy
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Mutations in the voltage-gated sodium and calcium channel genes SCN4A and CACNA1S, and the voltage-independent potassium channel gene KCNJ2, are associated with human periodic paralysis
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Myotonia can result from mutations in either the muscle voltage-gated chloride channel gene CLCN1 or the voltage-gated sodium channel gene SCN4A
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Single-gene epilepsy disorders have been associated with mutations in genes that encode sodium channel subunits, potassium channels, nicotinic acetylcholine receptor subunits and chloride channels
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Episodic ataxia type 1 (EA1) is associated with mutations in the voltage-gated potassium channel gene KCNA1, whereas EA2 is caused by mutations in the calcium channel gene CACNA1A
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Mutations in three genes—CACNA1A, ATP1A2 and SCN1A—have been found to cause familial hemiplegic migraine
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Acknowledgements
Our research is supported by the Medical Research Council, Action Research, The National Institutes of Health–CINCH grant USA (NINDS/ORD) and the Guarantors of Brain. Our clinical channelopathy service is supported by the Department of Health Specialist commissioning (NSCAG) UK. I acknowledge my key collaborators NW Wood and DM Kullmann.
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Hanna, M. Genetic neurological channelopathies. Nat Rev Neurol 2, 252–263 (2006). https://doi.org/10.1038/ncpneuro0178
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DOI: https://doi.org/10.1038/ncpneuro0178