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Episodic Disorders: Channelopathies and Beyond Louis J. Pt´acˇ ek Department of Neurology, Howard Hughes Medical Institute, University of California, San Francisco, California 94158-2324; email: [email protected]

Annu. Rev. Physiol. 2015. 77:475–79

Keywords

The Annual Review of Physiology is online at physiol.annualreviews.org

channelopathies, genetic disorders, paroxysmal, epilepsy, headache

This article’s doi: 10.1146/annurev-physiol-021014-071922 c 2015 by Annual Reviews. Copyright  All rights reserved

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Hereditary episodic diseases are a remarkable group of phenotypes ranging from rare muscle diseases and movement disorders to more common forms of epilepsy and migraine headache. Despite the fact that affected individuals carry the relevant mutation for their entire life, attacks occur intermittently. Patients are often completely normal between attacks. Although on the surface these disorders appear quite different, striking similarities exist across all these diseases (Figure 1). In addition to these disorders being episodic, factors that can precipitate attacks overlap significantly among these disorders. Stress is the most uniform in this regard, although the specific pathway is not understood. Sleep deprivation is another—however, it is unclear whether this is simply one form of stress or whether something specific about sleep is required for maintaining homeostasis of membrane excitability in these disorders. Certain dietary factors can lower the threshold for having an attack and include manipulations of dietary potassium, caffeine, and alcohol. Therapies that benefit patients in prevention of attacks also overlap. For example, carbonic anhydrase inhibitors decrease attack frequency for many patients with periodic paralysis, episodic ataxia, and migraine. Some anticonvulsant drugs have carbonic anhydrase inhibitory activity, although whether this activity contributes to antiseizure effects is unknown. This similarity among many different episodic diseases suggests that carbonic anhydrase inhibition may have an antiepileptic effect. Anticonvulsant drugs are also very effective in treating hyperexcitability phenotypes in many patients (e.g., seizures, paroxysmal dyskinesia, and myotonia). The natural history of these disorders is also similar—they often come on in childhood, worsen through adolescence and young-adult life, and improve (and sometimes completely resolve) in middle- and late-adult life. The reason for this pattern is unknown. Finally, for conditions for which a clinical electrophysiological test is available, hyperexcitable phenotypes can sometimes be seen (Figure 2). These phenotypes include myotonia on electromyograms, cardiac arrhythmias on

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Epilepsy

Migraine LQTS

Periodic paralysis

Episodic movement disorders

AHC, CVS

Figure 1 Many different electrical and episodic diseases affect skeletal muscle, the brain, and the heart. Although quite different in some ways, these disorders share similarities such as their episodic nature, precipitating factors, natural history, apparent hormonal influences, and therapeutic responses. Abbreviations: AHC, alternating hemiplegia of childhood; CVS, cyclic vomiting syndrome; LQTS, long-QT syndrome.

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Figure 2 The physiologies of muscle, nerve, and heart tissues are somewhat different. Shown are recordings from (a) skeletal muscle [electromyogram (EMG)], (b) the heart [electrocardiogram (ECG)], and (c) the brain [electroencephalogram (EEG)]. Also shown are physiological abnormalities seen in some periodic paralyses (myotonia on EMG), in cardiac arrhythmias (ventricular tachycardia on ECG), and in epilepsy (focal electrographic seizure on EEG). These disorders share the abnormal physiological phenomenon of highly repetitive, organized, but abnormal activity manifest clinically as myotonia, ventricular tachycardia, or seizure. Adapted with permission from Reference 8.

electrocardiograms, and seizures on electroencephalograms. Although the physiologies of muscle, the heart, and the brain are somewhat different, all these electrophysiological findings represent abnormal, but highly organized, repetitive firing of the respective tissues. Studies of a rare group of muscle diseases, the familial periodic paralyses, established the genetic paradigm for these episodic disorders. The first reports of channel mutations in episodic or electrical diseases were for hyperkalemic periodic paralysis and paramyotonia congenita (1–4). These developments led us to propose the term channelopathies to connote disorders of ion channels resulting from genetic mutations (5). With the cloning of the first human

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I

NaCh

II

III

IV

Periodic paralysis, epilepsy, LQTS, pain syndromes

COOH

NH2

KCh Periodic paralysis, episodic ataxia, epilepsy, LQTS

×4 NH2

I II IV III

COOH

CaCh

I

II

III

IV

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Periodic paralysis, LQTS, episodic ataxia, epilepsy, familial hemiplegic migraine NH2

COOH

Figure 3 Voltage-gated cation channels were the first channels to be implicated in electrical disorders. Systematic study of the periodic paralyses and nondystrophic myotonias led to identification of mutations in voltagegated sodium and calcium channels and, later, voltage-gated chloride (anion) and inwardly rectifying potassium channels. Shown here is a graphical representation of the homologous sodium (NaCh), calcium (CaCh), and potassium (KCh) channels first defined in this fascinating group of muscle diseases. KChs must tetramerize (denoted by ×4) to form functional channels. Subsequent work from many labs has shown that mutations in other genes from this family can give rise not only to muscle diseases, but also to epilepsy, migraine headache, episodic movement disorders, cardiac dysrhythmias, and peripheral sensory/pain syndromes. The symptom complex is predictably dependent on the expression pattern of the specific channel gene. Adapted with permission from Reference 8.

mutation, we had predicted that mutations in homologous genes were outstanding candidates for hereditary forms of epilepsy, cardiac arrhythmias, and peripheral nerve disorders (3). Subsequent work by our group and others has indeed shown this prediction to be true (Figure 3). There are now many reports of ion channel genes responsible for periodic paralyses and nondystrophic myotonias; episodic ataxias; epilepsies; hyperekplexia; familial hemiplegic migraine; and sensory syndromes like congenital insensitivity to pain, erythromelalgia, and paroxysmal itch (6, 7). The term channelopathy has been misused by many to describe any bizarre disorder with fluctuating symptoms. We suggest that channelopathy should be reserved as a term to describe disorders in which there is molecular and genetic understanding of abnormal channel function. Clearly, all episodic disorders of the nervous system and heart ultimately result in abnormal electrical signaling. We suggest the term primary channelopathy for those cases in which mutations occur in the primary determinants of membrane excitability (e.g., voltage-gated channels, inwardly rectifying ion channels, ligand-gated channels, ion transporters, and ion exchangers) (Figure 4). In this special section of reviews, particular attention is paid to classifying episodic or electrical disorders into primary and secondary channelopathies, acquired channelopathies, and circuit-level disorders that do not specifically affect ion channels but rather affect networks of neurons, with a net effect of abnormal electrical signaling.

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Trafficking and localization

Interacting proteins regulating function

Autoantibodies (acquired channelopathies)

Ion channels

Developmental disorders

Cell membrane excitability

Synaptopathies

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Transcriptional regulation

Posttranslational regulation of function

Primary channelopathies

Secondary channelopathies

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Synaptic regulation

Developmental circuit regulation

Excitability of brain circuits Figure 4 Proposed classification scheme for electrical and episodic disorders.

DISCLOSURE STATEMENT The author is not aware of any affiliations, memberships, funding or financial holding that might be perceived as affecting the objectivity of this review. LITERATURE CITED 1. McClatchey AI, Van den Bergh P, Pericak-Vance MA, Raskind W, Verellen C, et al. 1992. Temperaturesensitive mutations in the III–IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita. Cell 68:769–74 2. Pt´acˇ ek LJ, George AL Jr, Barchi RL, Griggs RC, Riggs JE, et al. 1992. Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita. Neuron 8:891–97 3. Pt´acˇ ek LJ, George AL Jr, Griggs RC, Tawil R, Kallen RG, et al. 1991. Identification of a mutation in the gene causing hyperkalemic periodic paralysis. Cell 67:1021–27 4. Rojas CV, Wang JZ, Schwartz LS, Hoffman EP, Powell BR, Brown RH Jr. 1991. A Met-to-Val mutation in the skeletal muscle Na+ channel α-subunit in hyperkalaemic periodic paralysis. Nature 354:387–89 5. Lehmann-Horn F, Rudel R, Ricker K. 1993. Non-dystrophic myotonias and periodic paralyses: a European Neuromuscular Center Workshop held 4–6 October 1992, Ulm, Germany. Neuromuscul. Disord. 3:161–68 6. Russell JF, Fu Y-H, Pt´acˇ ek LJ. 2013. Episodic neurologic disorders: syndromes, genes, and mechanisms. Annu. Rev. Neurosci. 36:25–50 7. Ryan DP, Pt´acˇ ek LJ. 2010. Episodic neurological channelopathies. Neuron 68:282–92 8. Ptacek LJ, Fu Y-H. 2002. Molecular biology of episodic movement disorders. Adv. Neurol. 89:453–58

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Contents

Annual Review of Physiology

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Volume 77, 2015

PERSPECTIVES, David Julius, Editor A Conversation with Oliver Smithies Oliver Smithies and Tom Coffman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 CARDIOVASCULAR PHYSIOLOGY, Marlene Rabinovitch, Section Editor Exosomes: Vehicles of Intercellular Signaling, Biomarkers, and Vectors of Cell Therapy Stella Kourembanas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p13 Mechanisms of Ventricular Arrhythmias: From Molecular Fluctuations to Electrical Turbulence Zhilin Qu and James N. Weiss p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p29 CELL PHYSIOLOGY, David E. Clapham, Section Editor Lysosomal Physiology Haoxing Xu and Dejian Ren p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p57 Phosphoinositide Control of Membrane Protein Function: A Frontier Led by Studies on Ion Channels Diomedes E. Logothetis, Vasileios I. Petrou, Miao Zhang, Rahul Mahajan, Xuan-Yu Meng, Scott K. Adney, Meng Cui, and Lia Baki p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p81 ENDOCRINOLOGY, Holly A. Ingraham, Section Editor Hedgehog Signaling and Steroidogenesis Isabella Finco, Christopher R. LaPensee, Kenneth T. Krill, and Gary D. Hammer p p p p p 105 Hypothalamic Inflammation in the Control of Metabolic Function Martin Valdearcos, Allison W. Xu, and Suneil K. Koliwad p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 131 Regulation of Body Fat in Caenorhabditis elegans Supriya Srinivasan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 161

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GASTROINTESTINAL PHYSIOLOGY, Linda Samuelson, Section Editor Cellular Homeostasis and Repair in the Mammalian Liver Ben Z. Stanger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 179 Hippo Pathway Regulation of Gastrointestinal Tissues Fa-Xing Yu, Zhipeng Meng, Steven W. Plouffe, and Kun-Liang Guan p p p p p p p p p p p p p p p p 201 Regeneration and Repair of the Exocrine Pancreas L. Charles Murtaugh and Matthew D. Keefe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 229 NEUROPHYSIOLOGY, Roger Nicoll, Section Editor

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Homeostatic Control of Presynaptic Neurotransmitter Release Graeme W. Davis and Martin Muller ¨ p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 251 Intrinsic and Extrinsic Mechanisms of Dendritic Morphogenesis Xintong Dong, Kang Shen, and Hannes E. Bulow ¨ p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 271 RENAL AND ELECTROLYTE PHYSIOLOGY, Peter Aronson, Section Editor Concurrent Activation of Multiple Vasoactive Signaling Pathways in Vasoconstriction Caused by Tubuloglomerular Feedback: A Quantitative Assessment Jurgen Schnermann p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 301 The Molecular Physiology of Uric Acid Homeostasis Asim K. Mandal and David B. Mount p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 323 Physiological Roles of Acid-Base Sensors Lonnie R. Levin and Jochen Buck p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 347 The Role of Pendrin in Renal Physiology Susan M. Wall and Yoskaly Lazo-Fernandez p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 363 RESPIRATORY PHYSIOLOGY, Augustine M.K. Choi, Section Editor Cilia Dysfunction in Lung Disease Ann E. Tilley, Matthew S. Walters, Renat Shaykhiev, and Ronald G. Crystal p p p p p p p p p 379 Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling Lee J. Quinton and Joseph P. Mizgerd p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 407 Nitrogen Chemistry and Lung Physiology Nadzeya V. Marozkina and Benjamin Gaston p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 431 Unmasking the Lung Cancer Epigenome Steven A. Belinsky p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 453

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SPECIAL TOPIC: GENETIC AND MOLECULAR BASIS OF EPISODIC DISORDERS, Louis J. Pt´acˇek, Section Editor Episodic Disorders: Channelopathies and Beyond Louis J. Pt´acˇek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 475 Sodium Channel β Subunits: Emerging Targets in Channelopathies Heather A. O’Malley and Lori L. Isom p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 481

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Alternative Paradigms for Ion Channelopathies: Disorders of Ion Channel Membrane Trafficking and Posttranslational Modification Jerry Curran and Peter J. Mohler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 505 Episodic and Electrical Nervous System Disorders Caused by Nonchannel Genes Hsien-yang Lee, Ying-Hui Fu, and Louis J. Pt´acˇek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 525 Indexes Cumulative Index of Contributing Authors, Volumes 73–77 p p p p p p p p p p p p p p p p p p p p p p p p p p p 000 Cumulative Index of Article Titles, Volumes 73–77 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 000 Errata An online log of corrections to Annual Review of Physiology articles may be found at http://www.annualreviews.org/errata/physiol

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