NEUROLOGICAL REVIEW SECTION EDITOR: DAVID E. PLEASURE, MD Channels and Disease Past, Present, and Future Louis J. Ptácek, MD; Ying-Hui Fu, PhD pisodic neurological phenotypes make up an interesting and important group of dis- eases affecting humans. These include disorders of the skeletal and cardiac muscles, peripheral nerves, and brain. They range from episodic weakness syndromes to rare paroxysmal movement disorders. More common episodic phenomena include cardiac Earrhythmias, epilepsy syndromes, and headache. Molecular characterization of these disorders is shedding light on their pathophysiologic features and will ultimately lead to better diagnosis and treatment of patients. CLINICAL SIMILARITIES AMONG Several syndromes with episodic or VARIOUS EPISODIC DISORDERS electrophysiologic phenomena involve more than 1 organ system or combine Disorders such as the periodic paralyses, multiple central nervous system pheno- nondystrophic myotonias, episodic atax- types within individual patients. For ias, paroxysmal dyskinesias, long QT syn- example, Andersen-Tawil syndrome is drome, migraine headache, and epilepsy characterized by episodic weakness, car- all share the feature of being episodic in diac arrhythmias, and developmental nature. Affected individuals are often com- features. Paroxysmal kinesigenic dyski- pletely healthy between attacks. Stress and nesia is an episodic movement disorder fatigue precipitate attacks in all of these that is precipitated by sudden move- diseases, and various dietary factors can ments; these individuals frequently have also contribute to attack onset. The drugs benign convulsions during infancy prior used to treat these disorders overlap sig- to the development of their movement nificantly. For example, carbonic anhy- disorder.1 Some patients with episodic drase inhibitors are effective for many pa- ataxia type 1 also manifest attacks of tients with periodic paralysis, episodic paroxysmal kinesigenic dyskinesia. It ataxia, and migraine headache. Mexil- has been suggested that migraine head- etine hydrochloride, an effective anti- ache may be part of the clinical constel- arrhythmic medication, can be beneficial lation in patients with paroxysmal non- in treating myotonia in patients with para- kinesigenic dyskinesia.2 Finally, for myotonia congenita. The anticonvulsant disorders in which electrophysiologic carbamazepine is an extremely effica- studies can be obtained, a similarity of cious drug for treating the episodic move- abnormal but highly organized repeti- ments of paroxysmal kinesigenic dyski- tive action potentials is apparent, as nesia. All of these disorders have a shown in Figure 1. tendency to begin in infancy or child- hood and to worsen through adolescence MOLECULAR CHARACTERIZATION and young adult life. In some cases, they OF EPISODIC decrease in severity and frequency in NEUROLOGICAL PHENOMENA middle to late adult life. The periodic paralyses and nondystrophic Author Affiliations: Howard Hughes Medical Institute (Dr Ptácek) and myotonias were the first human disorders Department of Neurology (Drs Ptácek and Fu), University of California, to be characterized as defects in-voltage- San Francisco. gated ion channels.3,4 It is now known that (REPRINTED) ARCH NEUROL / VOL 61, NOV 2004 WWW.ARCHNEUROL.COM 1665 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 I II III IV A NaCh Periodic Paralysis, Epilepsy, COOH Long QT Syndrome NH2 III IV III KCh x 4 B COOH NH2 Periodic Paralysis, Episodic Ataxia, Epilepsy, Long QT Syndrome I II III IV CaCh COOH NH2 Periodic Paralysis, C Episodic Ataxia, Epilepsy, Familial Hemiplegic Migraine Figure 2. Voltage-gated ion channels. Potassium channels (KCh) are polypeptides with 6 transmembrane segments (red cylinders) and a region that lines the inside of the ion-conducting pore (loop between fifth and sixth transmembrane segments). Four such polypeptides must multimerize to form a functional channel. Sodium channels (NaCh) and calcium channels (CaCh) are homologous to KCh but, because of a gene duplication and reduplication sometime during evolution, now have 4 domains (each with Figure 1. Highly organized but abnormal electrophysiologic activity seen in 6 transmembrane-spanning segments) that form functional channels as some episodic disorders. A, Myotonia recorded by electromyography in a single polypeptides. Many episodic and electrophysiologic disorders patient with hyperkalemic periodic paralysis. B, Ventricular tachydysrhythmia on affecting the nervous system are known to result from mutations in an echocardiogram in a patient with Andersen-Tawil syndrome. C, Seizure members of these (and other) ion channel gene families. NH2 indicates recorded by electroencephalography in a patient with epilepsy. N-terminus; COOH, carboxy-terminus. hyperkalemic periodic paralysis, hypokalemic periodic pa- Channels in Development ralysis, paramyotonia congenita, potassium-aggravated myotonia, Andersen-Tawil syndrome, Thomsen myoto- It has previously been demonstrated that mutations in nia congenita, and Becker myotonia congenita are caused the gene encoding the G protein–coupled inwardly rec- by mutations in voltage-gated sodium, calcium, potas- tifying potassium channel 2 result in the “weaver” phe- sium, and chloride channel genes (Figure 2). Interest- notype in mice. These mice have multiple problems in- ingly, mutations in homologs of these channels have sub- cluding a developmental abnormality in which cerebellar sequently been shown to cause episodic ataxia, long QT granule cells do not migrate normally into the granular syndrome, familial hemiplegic migraine, and mendelian cell layer. The only human developmental phenotype now forms of epilepsy. Mutations in these episodic disorders recognized as resulting from ion channel variants is are not limited to voltage-gated channels; they have also Andersen-Tawil syndrome.7 These individuals have fa- been found in ligand-gated channels, transporters, and ex- cial features such as micrognathia, hypertelorism, and changers.3,4 The Table enumerates the growing list of epi- high-arched or cleft palate, structures that arise embryo- sodic disorders that have been shown to result from mu- logically from neural crest cells. In addition, they have tations in voltage-gated or ligand-gated channels as well terminal limb features (clinodactyly, brachydactyly, or as transporters and exchangers. It is fascinating that mul- syndactyly) and may also have short stature. How do in- tiple phenotypes can result from different mutations in a wardly rectifying potassium channels encoded by the po- single ion channel gene and that different ion channel genes, tassium channel J2 gene (KCNJ2) contribute to devel- when mutated, can give rise to phenotypes that are clini- opmental processes of the face and distal limbs? This will cally indistinguishable. certainly prove to be an interesting area for future ex- ploration. NEW DIRECTIONS Can New Phenotypes Be Recognized Secondary Channelopathies in Some of These Disorders? A growing body of work demonstrates that antibodies di- Patients with Andersen-Tawil syndrome have a triad of rected against ion channel proteins can cause episodic symptoms (muscle, heart, and developmental). Not sur- and electrophysiologic phenotypes in humans. These in- prisingly, the KCNJ2 gene, which causes approximately clude Lambert-Eaton syndrome and stiff-person syn- 60% of all cases of Andersen-Tawil syndrome, is ex- drome.5,6 In these cases, an autoimmune attack against pressed in the embryo, heart, and skeletal muscles. It is various ion channel proteins has been shown to result also expressed in several other tissues, including the brain. in the respective phenotypes. The recognition that KCNJ2 is the major gene for (REPRINTED) ARCH NEUROL / VOL 61, NOV 2004 WWW.ARCHNEUROL.COM 1666 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Andersen-Tawil syndrome raises interesting questions, such as whether there is a subtle cognitive or neurobe- Table. Recognized Human Channelopathies havioral phenotype in this disease as a result of the mu- tant channels being expressed in a tissue (brain) in which Disease Gene Ion Channel no phenotype has previously been recognized. These kinds Hyperkalemic periodic paralysis SCN4A Sodium channel of questions can be formulated and addressed based on Paramyotonia congenital SCN4A Sodium channel discovery of the causative genes and their temporospa- Potassium-aggravated myotonia SCN4A Sodium channel Hypokalemic periodic paralysis CACNLA3 Calcium channel tial expression patterns. type 1 Myotonia congenita CLCN1 Chloride channel Structural Proteins Contribute Andersen-Tawil syndrome KCNJ2 Potassium channel to Channel Localization and Function Congenital myasthenic syndrome CHRNA, Acetylcholine receptor CHRNB, Schwartz-Jampel syndrome was recently shown to result CHRNE Episodic ataxia KCNA1 Potassium channel from mutations in the perlecan gene, which encodes the ma- with myokymia (type 1) 4 jor proteoglycan of basement membranes. This protein may Episodic ataxia CACNA1A Calcium channel be important for the localization and anchoring of chan- with nystagmus (type 2) nels in the nerves (eg, causing the neuromyotonia that these Familial hemiplegic migraine CACNA1A Calcium channel individuals manifest clinically). More recently, long QT type type 1 Familial hemiplegic migraine ATP1A2 Sodium-potassium 4 cardiac arrhythmia syndrome in a large French family