Arch Dis Child 2001;84:277–280 277

CURRENT TOPIC Arch Dis Child: first published as 10.1136/adc.84.3.277 on 1 March 2001. Downloaded from

Ion channels and neurology

S M Zuberi, M G Hanna

Rapid communication between cells is depend- Basic science of function ent on electrical signals produced by the Ion channels are made up of subunits, which passage of charged ions through specialised combine to form structures with a central embedded in cell membranes.1 These aqueous pore. Channels are selective for ion channels have been essential to the health particular ion species and can be gated, altering and survival of organisms since life began. One conformation to open or close. The two princi- might therefore expect that diseases of ion pal classes are voltage and ligand gated channels or channelopathies would not be channels. compatible with life. The past decade has The action potential, which is central to nor- shown this not to be the case with a rapidly mal function within the nervous system, is entirely dependent on voltage gated ion expanding list of disorders, many of which have channels. As the transmembrane voltage their onset in childhood and aVect the nervous changes a voltage gated sodium channel opens system and muscle. Abnormalities of ion chan- and ions pass rapidly down an electrochemical nel function are responsible for a variety of gradient from a high concentration outside the non-neurological disorders including Bartter cell through the channel pore into the cell. The syndrome, X linked nephrolithiasis, neonatal normally negatively charged cell interior depo- hyperinsulinism, long QT syndromes, and Fraser of Allander larises, causing voltage gated potassium chan- Neurosciences Unit, most notably defects in function of the CFTR nels to open and potassium ions to leave the Royal Hospital for Sick chloride channel causing cystic fibrosis. cell, restoring the resting membrane potential. Children, Yorkhill, Many of the neurological channelopathies This sequential depolarisation and repolarisa- Glasgow G3 8SJ, UK recognised to date are rare forms of common tion of the cell membrane is the fundamental S M Zuberi diseases and potentially give us clues to disease basis of the action potential.2 Muscle and mechanisms in common disorders such as epi- A ligand gated ion channel opens following Neurogenetics Section, lepsy and migraine. Some of the disorders are binding of a ligand to the receptor portion of http://adc.bmj.com/ University common but unrecognised or, because of their the channel. Other factors influencing ion Department of Clinical paroxysmal nature, misdiagnosed. channel function include intracellular messen- Neurology, Queen gers, phosphorylation of channel residues, pH, Square, London One of the most exciting aspects of work in WC1N 3BG, UK this field is that collaboration between clini- and temperature. This multitude of potentially M G Hanna cians, molecular geneticists, and cell physiolo- influential variables may explain the paroxys- gists is providing new insights into the biologi- mal nature of many of the genetic channelopa- Correspondence to: thies and their propensity to be precipitated by

cal basis of diseases. The fruits of these on September 25, 2021 by guest. Protected copyright. Dr Zuberi a variety of factors. sameer.zuberi@ collaborations include recognition that diseases yorkhill.scot.nhs.uk In an eVort to understand the functional caused by ion channel dysfunction may have consequences of particular channel mutations, Accepted 21 November 2000 genetic and autoimmune aetiologies. cDNA techniques have been utilised to express mutant and normal channels in in vitro Table 1 Central nervous system channelopathies biological systems, allowing currents to be Ion channel Disorder Inheritance Gene measured across either groups of channels in membrane patches or single channels. Voltage gated Sodium, â1 subunit GEFS+ Dominant SCN1B 19q Sodium, á1 subunit GEFS+ Dominant SCN1A 2q Potassium BNFC Dominant KCNQ2 20q Central nervous system channelopathies Potassium BNFC Dominant KCNQ3 8q Potassium EA1, EA1 and epilepsy, Dominant Kv1.1 12p Table1presentsaclassificationofCNSchannel- epilepsy and myokymia opathies. Calcium FHM, SCA6, EA2 Dominant CACNL1A4 19p Ligand gated Neuronal nicotinic ADNFLE Dominant CHRNA4 20q EPILEPSY receptor, At least 60% of childhood epilepsies are á4 subunit Neuronal nicotinic ADNFLE Dominant CHRNB2 1p termed idiopathic—that is, not related to a , structural brain lesion and with a strong â2 subunit genetic influence to their expression. By study- Hyperekplexia Dominant, GLRA-1 5q recessive ing large families and adopting a syndromic approach to epilepsy classification, several GEFS+, generalised epilepsy with febrile seizures plus; BNFC, benign neonatal familial convul- causing idiopathic epilepsies have been sions; EA1, episodic ataxia type 1; FHM, familial hemiplegic migraine; SCA6, spinocerebellar ataxia type 6; EA2, episodic ataxia type 2; ADNFLE, autosomal dominant nocturnal frontal lobe identified. All these genes code for ion epilepsy. channels.

www.archdischild.com 278 Zuberi, Hanna

Autosomal dominant nocturnal frontal lobe epi- years, febrile seizures and afebrile generalised Arch Dis Child: first published as 10.1136/adc.84.3.277 on 1 March 2001. Downloaded from lepsy (ADNFLE) is not a rare syndrome. tonic–clonic seizures, febrile seizures and Symptoms may be mild, with only a few absences, myoclonic astatic epilepsy, and se- seizures in childhood, or severely disabling with vere myoclonic epilepsy of infancy. The famil- 50 seizures in a single night, refractory to anti- ial nature of the epilepsy may remain unrecog- epileptic medication. Presentation is in child- nised unless there is a family member with a hood with brief partial seizures arising from more severe epilepsy phenotype. The com- sleep. These are characterised by arousal, monest phenotype is simple febrile seizures. A dystonic posturing of one or more limbs, clonic Tasmanian family showed linkage to chromo- jerking, screaming, and kicking of the legs.3 some 19q and a mutation was discovered in the Seizures may be misdiagnosed as night terrors voltage gated sodium channel â1 subunit or psychological problems. Interictal and ictal gene.11 Expression studies show that this muta- surface EEG is usually normal as the dis- tion results in a loss of function of the sodium charges arise in deep cortical regions. The most channel. Recently mutations in the á1A voltage helpful investigation is home video of the gated sodium channel subunit have been events and the most eVective medication for shown to segregate with disease in GEFS+.12 the syndrome is carbamazepine. A detailed study of a Melbourne family led MIGRAINE to the discovery of the first genetic cause of an Familial hemiplegic migraine (FHM) is a sub- idiopathic epilepsy, a point mutation in the á4 type of dominantly inherited migraine with subunit of the neuronal nicotinic acetylcholine aura in which attacks of hemiplegia, typically receptor.4 Most ADNFLE families do not link lasting 30–60 minutes, begin in the aura phase. to this locus, suggesting that although the clini- In several pedigrees with FHM, missense cal phenotype is fairly uniform, there is a mutations in a voltage gated calcium channel heterogeneous genetic aetiology. Expression gene, CACLN1A4, segregate with the dis- studies of mutant channels have shown a loss in ease.13 In FHM families there are individuals function.5 It can be hypothesised, as these who have classical migraine with aura, without receptors are principally located presynapti- hemiplegia, who have the calcium channel cally, that channel dysfunction leads to abnor- mutation. malities of inhibitory neuronal networks in sleep and thus to the epilepsy. MOVEMENT DISORDERS Benign familial neonatal convulsions (BFNC) Mutations in the CACNL1A4 gene are respon- is a dominant epilepsy syndrome presenting in sible for two other dominantly inherited disor- the first week of life with brief seizures involv- ders, spinocerebellar ataxia type 6 (SCA6) and ing tonic extensions, head and eye deviation, episodic ataxia type 2 (EA2).14 SCA6 is an adult apnoea, and clonic limb movements in other- onset, progressive, cerebellar ataxia with cere- wise well infants. The epilepsy remits within bellar degeneration associated with a CAG tri- days, weeks, or months, although 10% of cases plet repeat insertion in the gene, resulting in an will have seizures when older. Ictal EEG shows expanded polyglutamine tract in the C termi- http://adc.bmj.com/ onset in one or other hemispheres. This, like nal region of the channel . Chronic dis- ADNFLE, is a non-lesional partial epilepsy ruption of calcium homoeostasis may be the syndrome, not a generalised epilepsy as previ- cause of the cerebellar degeneration in SCA6 ously thought. patients. EA2 is a paroxysmal ataxia with onset Mutations in one of two voltage gated potas- in childhood, characterised by episodes of cere- sium channel subunit genes, KCNQ2 and bellar ataxia and nystagmus lasting hours or 67

KCNQ3, cause BNFC. A slow, repolarising days, precipitated by stress or exercise. Be- on September 25, 2021 by guest. Protected copyright. brain current, the “M” current, flows through a tween episodes individuals may have cerebellar channel made up by the KCNQ2 and KCNQ3 signs and in some cases a slowly progressive subunits coassembling. Functional studies on ataxia. Conversely individuals with SCA6 may mutant subunits show a partial reduction in the present with a paroxysmal ataxia. Headache M current.8 A reduction in critical current may be a feature in all three disorders amplitude through this channel at a physiologi- associated with CACLN1A4 mutations, illus- cally vulnerable age leaves neurones relatively trating that though they are clinically distinct in depolarised and excitable, producing a benign, their “pure” forms, overlap exists and the par- neonatal epilepsy. allels with common forms of migraine are Mutations in other members of the KCNQ notable. family of channels are responsible for a form of A voltage gated potassium channel, Kv1.1, is the long QT syndrome and inherited deafness. expressed in cerebral cortex, cerebellum, and An “arrhythmia” of the brain shares a similar peripheral nerve. Channel dysfunction is re- aetiology to an “epilepsy” of the heart. The flected in symptoms related to each region. endolymph of the cochlear requires a very spe- Mutations in this gene cause episodic ataxia type cific potassium concentration and therefore 1 (EA1).15 AVected individuals have cerebellar mutations in channels, which maintain this ataxia lasting seconds or minutes, precipitated concentration, may cause deafness. by sudden movement or emotion. Hyperexcit- Generalised epilepsy with febrile seizures plus ability of peripheral nerves causes subtle, (GEFS+) is a common, dominant, epilepsy rippling muscle movements (myokymia) and in syndrome with variable penetrance in which more severe cases neuromyotonia and flexion family members express a variety of generalised contractures of limbs, so infants may be misdi- epilepsy phenotypes.910 These include typical agnosed as having cerebral palsy. Some febrile seizures, febrile seizures beyond six individuals have epilepsy reflecting cortical

www.archdischild.com Ion channels and neurology 279

Table 2 and nerve channelopathies

subunits lead to prolonged channel opening Arch Dis Child: first published as 10.1136/adc.84.3.277 on 1 March 2001. Downloaded from and desensitisation of the postsynaptic mem- Ion channel Disorder Inheritance Gene Chromosome brane. The onset and severity of symptoms are Voltage gated determined by the site of the mutation. As this Potassium Familial generalised Dominant Kv1.1 12p disorder is caused by an abnormally prolonged myokymia Sodium HyperPP Dominant SCNA4 17q response to acetylcholine it is unresponsive to Paramyotonia congenita Dominant acetylcholinesterase inhibitors, responding in- PAM Dominant stead to the channel blocker . Calcium HypoPP Dominant CACLN1A3 1q Malignant hyperthermia Dominant In the fast channel recessive syndromes there is Calcium Central core disease Dominant RYR1 19q a reduced response to acetylcholine with Malignant hyperthermia Dominant mutations resulting in either reduced aYnity to Chloride Myotonia congenita CLCN1 7q Thomsen’s disease Dominant acetylcholine at the receptor binding site, Becker’s myotonia Recessive reduced probability of the channel opening, the Potassium (cochlea) Jervell and Lange–Nielsen Recessive KCNQ1 11p channel opening and closing too rapidly, or a syndrome (Long QT and deafness) Recessive KCNE1 21q reduction in total receptor numbers. Autosomal dominant Dominant KCNQ4 1p Once acetylcholine has bound to the recep- deafness type 2 Calcium (retina) Stationary night blindness X linked CACNA1F Xp tor portion of the channel, cations, principally sodium, enter the cell causing membrane Ligand gated Nicotinic acetylcholine Congenital myasthenia Dominant CHRNA 2q depolarisation. This in turn activates voltage- receptor and recessive CHRNG gated sodium channels and the action potential CHRND CHRNB 17p spreads across the muscle fibre causing T CHRNE tubule calcium channels to activate and in turn trigger the release of calcium from the HyperPP, hyperkalaemic periodic paralysis; PAM, potassium aggravated myotonia; HypoPP, hypokalaemic periodic paralysis. sarcoplasmic reticulum and muscle contrac- tion. The muscle membrane is then returned to dysfunction.16 There is considerable variability resting potential by the action of voltage gated in the phenotypic expression of mutations in chloride channels. this gene, such that presentation may vary from Inherited myotonias are caused by sodium “idiopathic” toe walking to complex partial and chloride channel mutations.20 Myotonia epileptic seizures.17 congenita is characterised by attacks of muscle stiVness that are usually painless and are HYPEREKPLEXIA relieved by exercise (the so called warm up Hyperekplexia is characterised by excessive eVect). It exists in a dominant phenotype startle responses. Infants have hypertonia when (Thomsen’s disease) and a more severe recessive awake and in response to a minor stimulus can form (Becker’s myotonia). Both are caused by have periods of generalised muscle contraction mutations in a chloride channel, CLCN1. leading to apnoea and life threatening syncope. Mutations lead to a reduction in chloride ions Older children and adults continue to have entering the cell so it remains relatively excessive startle leading to falls. Glycine is the depolarised, resulting in spontaneous oscilla- http://adc.bmj.com/ principal inhibitory neurotransmitter in the tions in membrane potential and clinical myo- spinal cord. Hyperekplexia is caused by domi- tonia. The symptoms may respond to the class nant and recessive mutations in the glycine I antiarrhythmic drug mexilitene. receptor, GLRA1, a ligand gated chloride Paramyotonia congenita is a dominantly inher- channel.18 ited condition in which myotonia paradoxically worsens with exercise and exposure to low

Neuromuscular channelopathies temperatures. Mutations in the voltage gated on September 25, 2021 by guest. Protected copyright. Table 2 presents a classification of skeletal sodium channel, SCNA4, underlie this disor- muscle and nerve channelopathies. der. Channels open later or for longer after When an action potential arrives at the depolarisation, so that persistent sodium flux presynaptic terminal, voltage gated calcium initiates repeated depolarisations. DiVerent channels are activated, allowing calcium to mutations in the SCNA4 gene are responsible enter the terminal and trigger the release of for hyperkalaemic periodic paralysis. This may acetylcholine into the synaptic cleft. In the exist as a distinct syndrome from paramyotonia Lambert–Eaton myasthenic syndrome antibodies congenita or in combination with it. These are directed against these calcium channels, channels have impaired fast inactivation with resulting in reduced acetylcholine release. prolonged sodium currents leading to desensi- Autoimmune myasthenia gravis has long been tisation of the membrane and inactivity of a known to be caused by antibodies directed proportion of the channels. The failure of against subunits of the acetylcholine receptor. repolarisation leads to accumulation of potas- Transient neonatal myasthenia and recurrent neo- sium in the extracellular space. natal arthrogryposis (secondary to reduced fetal Hypokalaemic periodic paralysis is caused by movement in utero) may be caused by mutations in the voltage gated calcium channel transplacental transfer of these maternal anti- CACNL1A3, although the precise mechanism bodies. These paediatric disorders can be pre- is unclear. Mutation in this gene may also be vented or ameliorated by appropriate treat- responsible for the potentially fatal malignant ment of the mother. hyperthermia syndrome; however, a more com- Congenital myasthenic syndromes are caused mon form of this syndrome is caused by muta- by a variety of abnormalities in neuromuscular tions in the ryanodine voltage gated channel transmission.19 In the slow channel syndrome, gene.21 The ryanodine channel allows calcium dominantly inherited mutations in channel to leave the sarcoplasmic reticulum to initiate

www.archdischild.com 280 Zuberi, Hanna

1 Hille B. Ion channels of excitable membranes, 2nd edn.

muscle contraction. The mutant channel, Arch Dis Child: first published as 10.1136/adc.84.3.277 on 1 March 2001. Downloaded from Sunderland, MA: Sinauer, 1992. when exposed to volatile anaesthetics or depo- 2 Hodgkin AL, Huxley AF. A quantitative description of larising muscle relaxants, allows excess calcium membrane current and its application to conduction and out of the sarcoplasmic reticulum resulting in excitation in nerve. J Physiol 1952;117:500–44. 3 ScheVer IE, Bhatia KP, Lopes-Cendes I, et al. Autosomal hyperthermia, muscle rigidity and rhabdomyo- dominant nocturnal frontal lobe epilepsy. A distinctive losis. DNA diagnosis should reduce the need clinical disorder. Brain 1995;118:61–73. for invasive provocation studies (the in vitro 4 Steinlein O, Mulley JC, Propping P, et al. A missense muta- tion in the neuronal nicotinic acetylcholine receptor á4 contracture test) on muscle biopsies from subunit is associated with autosomal dominant nocturnal potentially aVected individuals. frontal lobe epilepsy. Nat Genet 1995;11:201–3. 5 Weiland S, Witzemann V, Villaroel A, et al. An amino acid exchange in the second transmembrane segment of a neu- Conclusion ronal nicotinic receptor cause partial epilepsy by altering its The spectrum of neurological channelopathies desensitization kinetics. FEBS Lett 1996;398:91–6. 6 Singh NA, Charlier C, StauVer D, et al. A novel potassium continues to expand. In our view the majority channel gene, KCNQ2, is mutated in an inherited epilepsy of the idiopathic epilepsy syndromes are likely of newborns. Nat Genet 1998;18:25–9. to be channelopathies. A particular clinical 7 Charlier C, Singh NA, Ryan SG, et al. A pore mutation in a novel KQT like potassium channel gene in an idiopathic phenotype such as an epilepsy syndrome may epilepsy family. Nat Genet 1998;18:53–5. be the consequence of dysfunction in more 8 Wang HS, Pan Z, Shi W, et al. KCNQ and KCNQ3 potas- than one ion channel in an individual. The role sium channel subunits: molecular correlates of the M-channel. Science 1998;282:1890–3. that variation in gene expression plays in the 9 ScheVer IE, Berkovic SF. Generalised epilepsy with febrile age related phenotypes of these disorders is seizures plus. A genetic disorder with heterogenous clinical phenotypes. Brain 1997;120:479–90. likely to be better understood in the future. 10 Singh R, ScheVer IE, Crossland K, Berkovic SF. General- The critical role of ion channels means that ised epilepsy with febrile seizures plus: a common they are conserved throughout evolution, childhood-onset genetic epilepsy syndrome. Ann Neurol 1999;45:75–81. allowing us to gain insights from homologous 11 Wallace RH, Wang DW, Singh R, et al. Febrile sizures and channels in animal models of human disease.22 epilepsy associated with a mutation in the Na+ channel â1 subunit gene SCN1B. Nat Genet 1998;19:366–70. DNA based diagnosis is now possible for 12 Escayg A, MacDonald BT, Meisler MH, et al. Mutations of many of the ion channel disorders, although the SCN1A, encoding a neuronal sodium channel, in two process may be complex as the number of families with GEFS+2. Nat Genet 2000;24:343–5. 13 OphoV RA, Terwindt Gm, Vergouwe MN, et al. Familial potential mutations within a single gene may be hemiplegic migraine and episodic ataxia type 2 are caused high and the same clinical disorder may be by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996;87:543–52. caused by mutations in diVerent genes. In view 14 Greenber DA. Calcium channels in neurological disease. of their often paroxysmal nature, misdiagnosis Ann Neurol 1997;42:275–82. and labelling of symptoms as psychological is a 15 Browne DL, Gancher ST, Nutt JG, et al. Episodic ataxia/myokymia syndrome is associated with point muta- common feature of ion channel disorders. A tions in the human potassium channel gene KCNA1. Nat meticulous history remains the cornerstone of Genet 1994;8:136–40. 16 Zuberi SM, Eunson LH, Spauschus A, et al. A novel muta- the diagnostic process. With the current pace of tion in the human voltage gated potassium channel gene scientific progress it is inevitable that several new (Kv1.1) associates with episodic ataxia and sometimes with ion channel disorders will be described in the partial epilepsy. Brain 1999;122:817–25. 17 Eunson LH, Rea R, Zuberi SM, et al. Clinical, genetic and http://adc.bmj.com/ next decade. Many will be clearly paroxysmal expression studies of mutations in the human voltage-gated but we suspect that channel dysfunction will be potassium channel KCNA1 reveal new phenotypic vari- increasingly implicated in more chronic neuro- ability. Ann Neurol 2000;48:647–56. 18 Shiang R, Ryan SG, Zhu Y, et al. Mutations in the á1A logical and possibly neuropsychiatric disorders. subunit of the inhibitory glycine receptor cause the As the biological basis of each disease is dominant neurological disorder hyperekplexia. Nat Genet 1993;5:351–8. understood it opens up exciting prospects for 19 Beeson D, Palace J, Vincent A. Congenital myasthenic syn- pharmacological and genetic therapies targeted dromes. Curr Opin Neurol 1997;10:402–7. 20 Hudson AJ, Ebers GC, Bulman DE. The skeletal muscle

to specific ion channel defects. on September 25, 2021 by guest. Protected copyright. sodium and chloride channel muscle diseases. Brain 1995; 118:547–63. Addendum 21 Quane KA, Healy JM, Keating KE, et al. Mutations in the Mutations in the beta 2 subunit of the neuronal nicotinic acetyl- ryanodine receptor gene in central core disease and malig- receptor have recently been shown to be associated with nant hyperthermia. Nat Genet 1993;5:51–5. ADNFLE in an Italian family23 and a large Scottish family.24 22 Steinlein OK, Noebels JL. Ion channels and epilepsy in man The epilepsy phtnotype seems to be identical to that caused by and mouse. Curr Opin Genet Dev 2000;10:286–91. CHRNA4 mutations. 23 Fusco MD, Becchetti A, Patrignani A et al. The nicotinic receptor beta2 subunit is mutant in nocturnal frontal lobe We would like to acknowledge the support of the Brain Research epilepsy. Nat Genet 2000;26:275–6. Trust, The Wellcome Trust, and the Epilepsy Research 24 Phillips HA, Favre I, Kirkpatrick M, et al. CHRNB2 is the Foundation for supporting our ion channel research. Additional second acetylcholine receptor subunit associated with information on the DNA based diagnosis of ion channelopathies autosomal dominant nocturnal frontal lobe epilepsy. Am J is available from Dr Hanna. Hum Genet 2001;68:225–31.

www.archdischild.com