Ptáček, Louis J

Annual Review of Physiology

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UCSFUC San Francisco Previously Published WorksTitleEpisodic Disorders: Channelopathies and BeyondPermalinkhttps://escholarship.org/uc/item/0vn598j5JournalAnnual Review of Physiology, 77(1)ISSN0066-4278AuthorPtáček, Louis JPublication Date2015-02-10DOI10.1146/annurev-physiol-021014-071922 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaPH77CH23-Ptacek-Intro ARI 30 October 2014 13:1RE VI E WSINAD V ANCEEpisodic Disorders:Channelopathies and BeyondLouis J. PtáčekDepartment of Neurology, Howard Hughes Medical Institute, University of California,San Francisco, California 94158-2324; email: ljp@ucsf.eduAnnu. Rev. Physiol. 2015. 77:23.1–23.5The Annual Review of Physiology is online atphysiol.annualreviews.orgThis article’s doi:10.1146/annurev-physiol-021014-071922Copyright c© 2015 by Annual Reviews.All rights reservedKeywordschannelopathies, genetic disorders, paroxysmal, epilepsy, headache23.1PH77CH23-Ptacek-Intro ARI 30 October 2014 13:1Hereditary episodic diseases are a remarkable group of phenotypes ranging from rare musclediseases 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, attacksoccur intermittently. Patients are often completely normal between attacks.Although on the surface these disorders appear quite different, striking similarities exist acrossall these diseases (Figure 1). In addition to these disorders being episodic, factors that can pre-cipitate attacks overlap significantly among these disorders. Stress is the most uniform in thisregard, 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 isrequired for maintaining homeostasis of membrane excitability in these disorders.Certain dietary factors can lower the threshold for having an attack and include manipulationsof dietary potassium, caffeine, and alcohol. Therapies that benefit patients in prevention of attacksalso overlap. For example, carbonic anhydrase inhibitors decrease attack frequency for manypatients with periodic paralysis, episodic ataxia, and migraine. Some anticonvulsant drugs havecarbonic anhydrase inhibitory activity, although whether this activity contributes to antiseizureeffects is unknown. This similarity among many different episodic diseases suggests that carbonicanhydrase inhibition may have an antiepileptic effect. Anticonvulsant drugs are also very effectivein 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, worsenthrough adolescence and young-adult life, and improve (and sometimes completely resolve) inmiddle- and late-adult life. The reason for this pattern is unknown. Finally, for conditions forwhich a clinical electrophysiological test is available, hyperexcitable phenotypes can sometimes beseen (Figure 2). These phenotypes include myotonia on electromyograms, cardiac arrhythmias onLQTS Periodicparalysis AHC,CVS Episodicmovementdisorders Epilepsy MigraineFigure 1Many different electrical and episodic diseases affect skeletal muscle, the brain, and the heart. Although quitedifferent in some ways, these disorders share similarities such as their episodic nature, precipitating factors,natural history, apparent hormonal influences, and therapeutic responses. Abbreviations: AHC, alternatinghemiplegia of childhood; CVS, cyclic vomiting syndrome; LQTS, long-QT syndrome.23.2 PtáčekPH77CH23-Ptacek-Intro ARI 30 October 2014 13:1abcFigure 2The 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 (focalelectrographic seizure on EEG). These disorders share the abnormal physiological phenomenon of highlyrepetitive, organized, but abnormal activity manifest clinically as myotonia, ventricular tachycardia, orseizure. 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 representabnormal, but highly organized, repetitive firing of the respective tissues.Studies of a rare group of muscle diseases, the familial periodic paralyses, established the ge-netic paradigm for these episodic disorders. The first reports of channel mutations in episodicor electrical diseases were for hyperkalemic periodic paralysis and paramyotonia congenita(1–4). These developments led us to propose the term channelopathies to connote disordersof ion channels resulting from genetic mutations (5). With the cloning of the first humanwww.annualreviews.org • Channelopathies and Beyond 23.3PH77CH23-Ptacek-Intro ARI 30 October 2014 13:1NaChKChCaCh× 4COOHNH2I II III IVNH2COOHPeriodic paralysis,epilepsy, LQTS,pain syndromesPeriodic paralysis,episodic ataxia,epilepsy, LQTSPeriodic paralysis, LQTS,episodic ataxia, epilepsy,familial hemiplegic migraineCOOHNH2I II III IVIV IIII IIFigure 3Voltage-gated cation channels were the first channels to be implicated in electrical disorders. Systematicstudy of the periodic paralyses and nondystrophic myotonias led to identification of mutations in voltage-gated sodium and calcium channels and, later, voltage-gated chloride (anion) and inwardly rectifyingpotassium 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 musttetramerize (denoted by ×4) to form functional channels. Subsequent work from many labs has shown thatmutations 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/painsyndromes. The symptom complex is predictably dependent on the expression pattern of the specific channelgene. Adapted with permission from Reference 8.mutation, we had predicted that mutations in homologous genes were outstanding candidatesfor hereditary forms of epilepsy, cardiac arrhythmias, and peripheral nerve disorders (3). Sub-sequent 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 nondys-trophic myotonias; episodic ataxias; epilepsies; hyperekplexia; familial hemiplegic migraine; andsensory 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 withfluctuating symptoms. We suggest that channelopathy should be reserved as a term to describedisorders 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 abnormalelectrical signaling. We suggest the term primary channelopathy for those cases in which mutationsoccur in the primary determinants of membrane excitability (e.g., voltage-gated channels, inwardlyrectifying ion channels, ligand-gated channels, ion transporters, and ion exchangers) (Figure 4). Inthis special section of reviews, special attention is paid to classifying episodic or electrical disordersinto primary and secondary channelopathies, acquired channelopathies, and circuit-level disordersthat do not specifically affect ion channels but rather affect networks of neurons, with a net effectof abnormal electrical signaling.23.4 PtáčekPH77CH23-Ptacek-Intro ARI 30 October 2014 13:1Cell membrane excitability Autoantibodies(acquired channelopathies)  Ion channels Excitability of brain circuitsPosttranslationalregulation of functionDevelopmentalcircuit regulation Interacting proteinsregulating function Synaptic regulation Transcriptional regulationSynaptopathies Trafficking andlocalization SecondarychannelopathiesPrimarychannelopathiesDevelopmentaldisorders Figure 4Proposed classification scheme for electrical and episodic disorders.DISCLOSURE STATEMENTThe author is not aware of any affiliations, memberships, funding or financial holding that mightbe perceived as affecting the objectivity of this review.LITERATURE CITED1. McClatchey AI, Van den Bergh P, Pericak-Vance MA, Raskind W, Verellen C, et al. 1992. Temperature-sensitive mutations in the III–IV cytoplasmic loop region of the skeletal muscle sodium channel gene inparamyotonia congenita. Cell 68:769–742. Ptacek LJ, George AL Jr., Barchi RL, Griggs RC, Riggs JE, et al. 1992. Mutations in an S4 segment of theadult skeletal muscle sodium channel cause paramyotonia congenita. Neuron 8:891–973. Ptáček LJ, George AL Jr., Griggs RC, Tawil R, Kallen RG, et al. 1991. Identification of a mutation in thegene causing hyperkalemic periodic paralysis. Cell 67:1021–274. Rojas CV, Wang JZ, Schwartz LS, Hoffman EP, Powell BR, Brown RH Jr. 1991. A Met-to-Val mutationin the skeletal muscle Na+ channel α-subunit in hyperkalaemic periodic paralysis. Nature 354:387–895. Lehmann-Horn F, Rudel R, Ricker K. 1993. Non-dystrophic myotonias and periodic paralyses: a EuropeanNeuromuscular Center Workshop held 4–6 October 1992, Ulm, Germany. Neuromuscul. Disord. 3:161–686. Russell JF, Fu Y-H, Ptáček LJ. 2013. Episodic neurologic disorders: syndromes, genes, and mechanisms.Annu. Rev. Neurosci. 36:25–507. Ryan DP, Ptáček LJ. 2010. Episodic neurological channelopathies. Neuron 68:282–928. Ptacek LJ, Fu Y-H. 2002. Molecular biology of episodic movement disorders. Adv. Neurol. 89:453–58www.annualreviews.org • Channelopathies and Beyond 23.5

Episodic disorders: channelopathies and beyond.

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