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The genetic neurological Review

Neurological disorders caused by inherited ion-channel

Dimitri M Kullmann and Michael G Hanna

Several neurological diseases—including neuromuscular different ion channels can cause remarkably similar disorders, movement disorders, migraine, and epilepsy—are phenotypes ( heterogeneity). Conversely, distinct caused by inherited mutations of ion channels. The list of mutations of the same can cause variable phenotypes these “channelopathies” is expanding rapidly, as is the (allelic heterogeneity). Thus, classification of channelo- phenotypic range associated with each channel. At present pathies presents difficulties, whether it is based on gene or the best understood channelopathies are those that affect by phenotype. muscle-fibre excitability. These channelopathies produce a The molecular biology, structure, and function of ion range of disorders which include: , channels have been comprehensively reviewed elsewhere,4 myotonias, malignant , and congenital as have the basic principles of studying the consequences of myasthenic syndromes. By contrast, the mechanisms of abnormal ion-channel function for cellular excitability.5 diseases caused by mutations of ion channels that are Some of the earlier muscle channelopathies were identified expressed in neurons are less well understood. However, as on the basis of electrophysiological recordings from for the muscle channelopathies, a striking feature is that isolated muscle fibres, which pointed to disturbances of many neuronal channelopathies cause paroxysmal ion-channel function, followed by examination of symptoms. This review summarises the clinical features of candidate .6,7 The neuronal channelopathies, however, the known neurological channelopathies, within the context have mainly been identified on the basis of genetic linkage of the functions of the individual ion channels. studies, although homology among related channels has also pointed to likely candidate genes.8 Lancet 2002; 1: 157–66 Muscle channelopathies Several neurological diseases caused by inherited At present, the best understood channelopathies are those mutations of ion channels of muscle, neuron, and glia have that affect muscle-fibre excitability (table 1).9 been discovered in the past decade. These diseases have come to be known as the “channelopathies”.1,2 Ion channels can also be affected by and possibly by DMK and MGH are at the Institute of Neurology, University College 3 London, and the National Hospital for Neurology and Neurosurgery, acquired disorders of RNA processing, but those acquired London, UK. channelopathies (autoimmune and transcriptional, Correspondence: Prof Dimitri M Kullmann, Institute of Neurology, respectively) are not discussed here. A recurring theme in Queen Square, London WC1N 3BG, UK. Tel +44 (0)20 78373611 ext the genetic channelopathies is that mutations of several 4100; fax +44 (0)20 72785616; email [email protected]

Table 1. Ion channels associated with human inherited muscle diseases

Type of channel Gene Channel Disease Voltage-gated channels + Na channels SCN4A subunit of Nav1.4 () Hyperkalaemic periodic paralysis Hypokalaemic periodic paralysis Other myotonic disorders K+ channels KCNJ2 subunit of Kir2.1 inward rectifier (skeletal and smooth muscle) Andersen’s syndrome

KCNE3 Accessory subunit MiRP2 (assembles with KV3.4) Hypokalaemic periodic paralysis 2+ Ca channels CACNA1S subunit of CaV1.1 (skeletal muscle dihydropyridine-sensitive channel) Hypokalaemic periodic paralysis RYR1 (sarcoplasmic channel) Malignant hyperthermia Cl- channels CLCN1 ClC1 (skeletal muscle ) congenita (dominant and recessive)

Ligand-gated channels Nicotinic ACh receptors CHRNA1 1 subunit (skeletal muscle) Congenital myasthenic syndromes CHRNB1 1 subunit (skeletal muscle) Congenital myasthenic syndromes CHRND subunit (skeletal muscle) Congenital myasthenic syndromes CHRNE subunit (skeletal muscle) Congenital myasthenic syndromes

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Sodium-channel mutations: periodic paralysis, paramyotonia, and other disorders Among the first channels to be linked to human disease was the major voltage-dependent I II III IV

of skeletal muscle, NaV1.4, mutations **** of which account for most cases of N Extracellular the autosomal dominant disease hyperkalaemic periodic paralysis.10,11 Patients generally present in Intracellular childhood with attacks of limb- muscle weakness lasting minutes to hours, often precipitated by rest after CC exercise. Consciousness is preserved, N and ocular and respiratory muscles subunit subunit tend to be spared. Hyperkalaemia is frequently missed by physicians, and, Figure 1. Transmembrane structure of NaV1.4, the principal muscle sodium channel. The subunit indeed, many patients diagnosed as contains four homologous domains (I–IV), each of which consists of six helical transmembrane having normokalaemic periodic segments. The fourth segment of each domain (+) contains positively charged amino acids, which paralysis also carry Na 1.4 sense the transmembrane voltage. The loops between the fifth and sixth segments (*) come V together to line the central pore of the and determine its ionic selectivity. A subunit mutations. With age, the frequency with a single transmembrane segment is associated with the subunit. and severity of the attacks diminish, although a progressive vacuolar can intervene. Sodium-channel physiology Hyperkalaemic periodic paralysis is associated with a In common with other voltage-gated sodium and

characteristic decrement in the amplitude of compound channels, NaV1.4 is made up of a principal pore-forming muscle action potentials after a period of sustained and voltage-sensing subunit (the subunit), together with exercise.12 Patients generally benefit from treatment to several accessory subunits.17 The mutations in prevent hyperkalaemia (thiazide diuretics, -adrenoceptor hyperkalaemic periodic paralysis and other muscle sodium- agonists),13 or from inhibitors of carbonic anhydrase channel diseases affect this subunit. The subunit is (acetazolamide, dichlorphenamide), which may act made up of a four-fold repeated domain (figure 1). Each of through several mechanisms including acidification of the these domains resembles a single subunit of a voltage-gated channel microenvironment.14 channel, to which sodium and calcium channels

The phenotypic range of NaV1.4 mutations extends are evolutionarily related. It contains six transmembrane beyond hyperkalaemic and normokalaemic periodic segments linked by intracellular or extracellular loops. The paralysis. Potassium-aggravated myotonia, paramyotonia fourth transmembrane segment (S4) of each domain congenita, and myotonia fluctuans are all autosomal contains several positively charged amino acids, which sense dominant disorders characterised by impaired muscle- the voltage gradient across the membrane. Another critical fibre repolarisation.9 Patients present with muscle stiffness area is the extracellular loop between the fifth and sixth and variable degrees of weakness that can fluctuate in segments, which dives into the membrane. The severity. By contrast with chloride-channel-associated corresponding S5–6 loops from the four domains come myotonia (see below), paramyotonia does not improve together to line the pore of the ion channel. The amino with exercise. Some cases of hypokalaemic periodic acids of this loop determine the ionic selectivity of the paralysis, commonly associated with calcium-channel channel, allowing sodium but not other ions mutations (see below) are also associated with to permeate. 15,16 NaV1.4 mutations. After membrane depolarisation, sodium channels open How can we explain the phenotypic variability rapidly because of a conformational change imparted by the associated with sodium-channel mutations? Among voltage-sensing S4 segments. The inward sodium flux substrates for genetic diseases, ion channels are marked through the channels accounts for the rapid upstroke of the out by the fact that their function can be studied with . They then close rapidly even if the high precision by electrophysiological methods depolarisation persists, a process known as fast inactivation. in vitro. Voltage-clamp techniques can be used to In an intact muscle fibre, inactivation helps to curtail the document the behaviour of populations of ion channels action potential. The channels only come out of this in individual cells, either in tissue removed from inactivated state after membrane repolarisation.

patients or in heterologous expression in various Several mutations of NaV1.1 occur in the cytoplasmic experimental preparations. When combined with patch- linker between domains III and IV (figure 1). This region is clamp techniques, the functional consequence thought to act as a hinged lid, which occludes the channel of mutations can even be studied at the level of individual pore on fast inactivation. Other mutations affect amino acids channels. on the cytoplasmic side of the channel that act as receptors for

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this lid, or in the voltage sensor of domain IV. Several The pore-forming and voltage-sensing subunit of

mutations associated with myotonia that have been examined CaV1.1 has the same general topology as the sodium channel, functionally impair the rate of inactivation or shift the voltage with four repeated domains, each containing six dependence of inactivation so that a larger depolarisation is transmembrane segments.22 However, different amino acids required for inactivation. Some of these changes were actually form the selectivity filter of the S5–6 pore loop, explaining observed in myotubes cultured from patients, before the the preference for calcium over sodium ions. Inactivation is mutations were identified.18 The consequence of these much slower. alterations is that channels can continue to flicker between Few mutations have been identified in hypokalaemic open and shut states in the face of continued depolarisation periodic paralysis, in the subunits of either calcium or and therefore contribute a persistent sodium current. In a sodium channels.16 Muscle fibres tend to be depolarised muscle fibre expressing mutant sodium channels, this relative to the normal range,23 but the mechanisms persistent current is thought to impair repolarisation, and underlying this process are poorly understood. A reduction muscle fibres can therefore fire repeatedly, giving rise to in calcium-channel current density has also been reported,24 myotonia. Myotonia associated with some sodium-channel but why this should give rise to attacks of profound muscle mutations is exacerbated by rises in extracellular potassium, weakness in association with hypokalaemia is far from clear. presumably because this stimulus also contributes to the depolarisation of the membrane. Nevertheless, attacks of Potassium-channel mutations: periodic paralysis paralysis are not a constant part of the phenotype in the Mutations of another channel, the inwardly rectifying myotonic disorders, possibly because channels can eventually Kir2.1, can cause attacks of periodic inactivate through a second, slower mechanism that occurs on paralysis with high, low, or normal serum potassium.25 These a timescale of seconds. Failure of this slower mechanism may attacks occur as part of the autosomal-dominant disorder account for many cases of hyperkalaemic periodic paralysis.19 Andersen’s syndrome (which also includes cardiac Muscle fibres become depolarised and inexcitable because of a and craniofacial abnormalities). The positive feedback loop: persistent sodium influx promotes mechanisms underlying this disease are poorly understood, depolarisation, which promotes further potassium efflux, although preliminary data point to loss of function; that is, a resulting in an attack of periodic paralysis. The paralysis only reduction in potassium current density. A further cause of resolves when the extracellular potassium is decreased by periodic paralysis is mutations of the accessory subunit active transport and renal clearance. MiRP2.26 This subunit associates with voltage-gated Both alterations in channel behaviour described above potassium channels expressed in muscle, and the wild-type could be crudely thought of as representing a “gain of form increases the potassium current flowing through these function”, a common mechanism seen in dominantly channels. Two identified mutations have been reported to inherited diseases, in that the mutant channels mediate an decrease this current.26 increased sodium flux. Nevertheless, this concept fails to capture the complexity of the role of sodium channels in Chloride-channel mutations: myotonias controlling the excitability of muscle fibres, and only A large number of mutations of CLC1, the principal chloride through understanding of the detailed consequences of the channel expressed in muscle, are associated with myotonia alterations can the distinct phenotypes be explained. congenita. This disorder has conventionally been named Thomsen’s or Becker’s disease, depending on whether it is Calcium-channel mutations: hypokalaemic periodic dominantly or recessively inherited. However, an individual paralysis and other disorders can sometimes behave dominantly or recessively

The account given above does not explain why some NaV1.4 in different families, although this behaviour may reflect the mutations are associated with hypokalaemia.15,16 presence of an additional unrecognised mutation in some Hypokalaemic periodic paralysis is more typically members (compound heterozygosity). Moreover, the disease 20,21 associated with mutations of the CaV1.1. is commonly milder in female patients, for reasons that This is also an autosomal dominant disorder, and it is remain obscure. commoner than the hyperkalaemic variant described above. presents in the first or second It generally presents with paralysis triggered by decade of life, in most cases. Some patients develop muscle carbohydrate ingestion and is similar to hyperkalaemic hypertrophy, possibly resulting from excessive spontaneous periodic paralysis, although the duration of paralytic attacks muscle-fibre activity. However, muscle weakness, sometimes is much longer (typically 12–24 h). The post-exercise accompanied by atrophy, is also recognised. Many patients decrease in compound muscle action potential does not report an amelioration of stiffness with repeated distinguish between hypokalaemic and hyperkalaemic contraction, the so-called “warm-up” phenomenon. periodic paralysis. In the absence of a family history, the Characteristic myotonic discharges are seen on neurologist should consider thyrotoxic periodic paralysis . These features do not distinguish the and look for other causes of electrolyte disturbance. In disease from or proximal myotonic common with the hyperkalaemic variant, hypokalaemic myopathy. If patients require treatment, several drugs acting periodic paralysis also frequently responds to on sodium channels (mexiletine, tocainide, ) have acetazolamide, although agents that lower the serum all been reported to be useful. Of these, mexiletine is the potassium concentration exacerbate it. most effective in our experience.

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The topology and function of chloride channels are quite CMS), or arise from acetylcholinesterase deficiency distinct from those of sodium and calcium channels.27 The (“synaptic” CMS). muscle chloride channel is probably homodimeric,28 Depending on the severity and subtype of the disorder, although there is uncertainty about whether it has a single patients with acetylcholine-receptor mutations present in pore or two separate pores. Muscle fibres have a moderately infancy or later with weakness and fatiguability affecting high resting chloride conductance, which normally increases ocular, pharyngeal, respiratory, or limb muscles. Neonatal further on membrane depolarisation. Because the chloride arthrogryposis is also recognised, implying abnormalities of reversal potential is relatively negative, the channel intrauterine movements.42,43 Different mutations are contributes to membrane repolarisation. The CLC1 inherited dominantly or recessively. Electromyography mutations that have been examined lead to a reduction in reveals the characteristic decremental response on repetitive current, often accompanied by a shift in the activation stimulation, and increased latency jitter and block with threshold to more depolarised values.29,30 Abnormalities in single-fibre recordings, also seen in . chloride conductance were originally predicted from studies However, some cases associated with a slow-channel in myotonic goats.31 This impairment in repolarisation is phenotype (see below) can also show characteristic thought to give rise to repetitive action potentials in situ, the repetitive discharges in response to a single supramaximal hallmark of myotonia.32 Whether a mutation behaves in a stimulus. dominant or recessive manner depends on the severity of its A more detailed insight into the pathophysiology comes effect on kinetics and current density, and this feature can be from examination in vitro of the responses in muscle fibres probed by coexpressing wild-type channels in vitro.30 to spontaneous release of acetylcholine from vesicles. Three distinct patterns are recognised. In the fast-channel variant, Other voltage-gated channelopathies of muscle miniature end-plate potentials are shorter in duration than Another rare muscle is malignant normal.44 In the commoner slow-channel variant, they are hyperthermia, which is generally uncovered after general longer than normal. These changes result from distinct anaesthesia. This disorder is potentially fatal and typically abnormalities in channel gating, which either accelerate or follows exposure of susceptible individuals to volatile retard the opening and closing of the channels. Because anaesthetics (eg, ) and depolarising muscle gating and -binding are intimately related, slow- relaxants (eg, suxamethonium).33 In its full-blown form, channel mutations are also associated with an increase in patients develop muscle rigidity, , acetylcholine affinity.45 Although, at first sight, an increase , hyperthermia, , hyperkalaemia, and in affinity should further increase neuromuscular shock. The mortality rate has fallen from 70% to 10% with transmission, receptors can also enter a desensitised closed the advent of therapy.34 This autosomal state if the ligand does not dissociate. Some slow-channel dominant disorder is a striking example of phenotypic syndromes are also associated with a progressive myopathy, convergence (or locus heterogeneity): malignant which possibly reflects an excitotoxic effect of increased 46 hyperthermia can result from mutations of either CaV1.1 cation influx into muscle fibres. A third form results from (the channel associated with hypokalaemic periodic a deficiency in numbers of acetylcholine receptors without paralysis, see above)35 or its structurally distinct partner, the ryanodine receptor, which mediates calcium efflux from the sarcoplasm.36 The development of DNA-based diagnosis has implications for the screening of susceptible individuals for N this potentially lethal disorder.37 Ryanodine-receptor mutations are also associated with a rare progressive myopathy, central core disease.38,39

Muscle nicotinic acetylcholine-receptor mutations: C congenital myasthenic syndromes One of the most extensively studied, and best understood, Extracellular muscle channelopathies affects a ligand-gated channel—the muscle nicotinic acetylcholine receptor (figure 2). Skeletal muscle is depolarised when this Intracellular receptor is activated by acetylcholine released from motor endplates. Many mutations have been identified in congenital myasthenic syndromes.40,41 (This must be distinguished from neonatal myasthenia, caused by passive transfer of from a mother with myasthenia Figure 2. Transmembrane structure of a member of the nicotinic-receptor gravis.) Congenital myasthenic syndromes (CMS) are family. Five subunits come together to form a functional channel. The large extracellular amino terminus contains the ligand-binding domain. heterogeneous, and only some are caused by mutations of The second transmembrane segment lines the central pore of the ion acetylcholine receptors (“postsynaptic” CMS). Other channel and also gates ion flux, possibly through a hinge-like movement. forms are caused by presynaptic acetylcholine Different mutations disrupt channel biogenesis, ligand binding, synthesis/packaging or release disorders (“presynaptic” transduction from binding to opening, kinetics, and ion permeation.

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kinetic alterations.47 This form is associated with a decrease in the Table 2. Neuronal and glial ion channels associated with human inherited amplitude of spontaneous end-plate neurological diseases potentials. The slow-channel disease Type of channel Gene Channel Disease arguably results from a gain of Voltage-gated Na+ channels SCN1A subunit of Na 1.1 Generalised epilepsy with febrile function, in that the total current v flowing through the receptor is (somatic sodium channel) seizures plus Severe myoclonic epilepsy of infancy prolonged. (And conversely, the fast- SCN2A subunit of Nav1.2 Generalised epilepsy with febrile channel and receptor-deficiency (axonal sodium channel) seizures plus forms represent loss of function.) SCN1B 1 subunit of sodium channels Generalised epilepsy with febrile The histological features of seizures plus congenital myasthenic syndromes + K channels KCNA1 subunit of Kv1.1 (axonal/ type 1 caused by acetylcholine-receptor presynaptic delayed rectifier) mutations are generally similar to KCNQ2 M-type potassium channel Benign familial neonatal convulsions those seen in acquired myasthenia subunit (with KCNQ3) gravis, with loss of junctional folds and KCNQ3 M-type potassium channel Benign familial neonatal convulsions widening of the synaptic cleft. Some subunit (with KCNQ2) 2+ patients affected by the fast-channel Ca channels CACNA1A subunit of Cav2.1 (P/Q-type Familial hemiplegic migraine variant respond to anticholinesterases channel in cerebellar neurons Episodic ataxia type 2 and 3,4-diaminopyridine, whereas and presynaptic terminals) Spinocerebellar ataxia type 6 Ligand-gated those with the slow-channel syndrome Nicotinic ACh CHRNA4 2 subunit of nicotinic Autosomal dominant nocturnal frontal- may benefit from quinidine. In receptors receptors (with 4) lobe epilepsy contrast to acquired myasthenia CHRNB2 4 subunit of nicotinic Autosomal dominant nocturnal frontal- gravis, immunosuppression is receptors (with 2) lobe epilepsy ineffective. Glycine receptors GLRA1 1 subunit (spinal-cord Familial hyperekplexia The acetylcholine receptor (in inhibitory synapses) common with many other ligand-gated GABAA receptors GABRG2 2 subunit (brain inhibitory Generalised epilepsy and febrile seizures channels) consists of five subunits, each synapses) plus of which has a large extracellular Glial channels amino-terminus, which binds the Gap-junction GJB1 32 (paranodal ) X-linked Charcot-Marie-Tooth disease agonist, and four transmembrane domains (figure 2).4 The second of Channelopathies causing deafness or blindness are not listed these domains lines the pore, and forms the selectivity filter (it allows only small cations to permeate). mutations of the pore-forming subunit of the voltage-gated 48 It also undergoes a conformational change on ligand binding. potassium channel KV1.1. Patients generally present with Two acetylcholine molecules must bind to the pentamer brief attacks of cerebellar incoordination that last for up to before the channel can open fully, and the channel closes a few minutes and are triggered by stress or exertion. when the ligand dissociates, or through desensitisation Between attacks, many patients have continuous motor- (a process akin to inactivation) if the ligand is not cleared. Five unit activity, with characteristic on distinct genes code for muscle-receptor subunits: 1, 1, , , electromyography, although this feature is commonly and . Adult nicotinic receptors have the stoichiometry subclinical. Since the original discovery of mutations in the ( 1)2 1 , but in the fetus the subunit takes the place of the KCNA1 gene, which codes for the subunit of KV1.1, subunit. Mutations have been identified in all the subunits further kindreds have been identified, with a broader range other than .40,41 Overall, the congenital myasthenic of phenotypes including alone or with syndromes provide some of the clearest examples of seizures.49,50 There are striking differences in severity and phenotype–genotype correlations: the severity of the disorder, response to drugs used to treat the disorder (mainly its electromyographic features, and associated myopathy can, and acetazolamide) among kindreds to some extent, be accounted for by the site and nature of the bearing different mutations.

mutation and its consequences for channel function. KV1.1 is one of a large family of voltage-gated potassium channels. These channels are normally closed at resting Neuronal channelopathies membrane potentials and open rapidly upon depolarisation, Potassium-channel mutations: episodic ataxia type 1 accounting for a large part of the repolarisation of action By comparison with the muscle channelopathies, the potentials. Kv1.1 is the human orthologue of , the first mechanisms of diseases caused by mutations of ion potassium channel gene to be cloned in Drosophila channels that are expressed in neurons are less well melanogaster. The channel contains four pore-forming understood. As before, a striking feature is that many subunits, each of which has the six transmembrane channelopathies cause paroxysmal symptoms (table 2). structure of one of the four repeated domains of sodium

One such disease is a form of autosomal dominant channels (figure 3). Although KV1.1 describes a homomeric paroxysmal cerebellar ataxia, episodic ataxia type 1, due to channel composed of four identical subunits, native channels

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incoordination are not obviously associated with electrolyte disturbances in episodic ataxia type 1.

K+ Calcium-channel mutations: FHM, EA2, SCA6 In common with the muscle channelopathies, those

Extracellular affecting the CNS also show evidence of locus heterogeneity. Another form of episodic ataxia (type 2; EA2) results from

mutation of the CaV2.1, the pore-forming subunit of P/Q- type calcium channels.60 Attacks are longer than in episodic ataxia type 1, and are associated with severe nausea and vomiting. Interictal myokymia is not a feature, but patients Intracellular frequently develop nystagmus and slowly progressive cerebellar degeneration. The disorder is also inherited in a dominant manner.

The channelopathies affecting CaV2.1 also show striking allelic heterogeneity. Other dominantly inherited mutations are associated with familial hemiplegic migraine (FHM) and

Figure 3. Voltage-dependent potassium channels such as KV1.1 are with a pure progressive cerebellar ataxia—spinocerebellar composed of four subunits, each of which resembles a single domain ataxia type 6 (SCA6).61 Although these disorders appear very of an subunit of a sodium or calcium channel. The fourth segment of each subunit contains the voltage sensor, and the loops between the fifth distinct, close examination of affected families shows some 62 and sixth segments line the central pore of the ion channel. Additional overlap in features. The full phenotypic range of CaV2.1 cytoplasmic subunits (not shown) have an important role in mediating mutations is probably not known, although an interesting inactivation. Because the channel is heteromultimeric, mutant and wild- recent finding is that some patients may be at risk of coma type subunits can interact to affect channel trafficking, targeting, and and cerebral oedema.63 kinetics. CaV2.1 is expressed abundantly in the cell bodies and are thought to consist of combinations of different members dendrites of cerebellar Purkinje and granule cells, which may 51 of the KV1 family (especially KV1.2 and KV1.4). Four help to explain the episodic ataxia and progressive cerebellar cytoplasmic accessory subunits are also associated, with the degeneration. CaV2.1 also accounts for much of the calcium result that many channel stoichiometries potentially exist. influx at presynaptic nerve terminals at many central and

KV1.1 is expressed widely in the CNS, especially in the peripheral synapses, where it helps trigger of principal (glutamatergic) and inhibitory release.22 Because the cerebellum is not obviously implicated (GABAergic) neurons. It is especially abundant in in hemiplegia or migraine, disorders of neurotransmitter membrane specialisations surrounding the initial segments release may be at the root of these features. Interestingly, of the axons of Purkinje cells.52 Impaired repolarisation of abnormalities of neurotransmission at the neuromuscular GABAergic axons in this region may contribute to cerebellar junction have been reported in some patients with EA2.64 53 ataxia. KV1.1 is also expressed in the juxtaparanodal regions Distinct types of mutations appear to underlie the of motor axons, a location that helps to explain the different disorders: mis-sense mutations occur in familial occurrence of spontaneous motor-unit firing.54 hemiplegic migraine, whereas episodic ataxia type 2 tends to As hinted above, many of the features of episodic ataxia be associated with premature stop codons and splice-site 60 type 1 could result from loss of function of KV1.1. This idea is mutations, predicted to result in truncated peptides. As for supported by detailed electrophysiological studies of mutated SCA6, this disease is associated with a small expansion of a channels.49,50,55–59 However, the consequences of distinct polyglutamine sequence in the carboxyl terminus.61 Mis- mutations vary substantially, from small increases in the sense mutations have, however, also been identified in voltage threshold or time taken for channel activation, to families with episodic or pure progressive ataxia.65,66 complete absence of potassium flux. These differences seem Attempts to explain the phenotypes on the basis of the to contribute to the allelic heterogeneity, in that mutations functional consequences of the mutations have met with associated with a more profound impairment of channel mixed success; different mutations seen in familial function are seen in families with severe or drug-resistant hemiplegic migraine have been reported to cause various disease, or with additional features such as epilepsy. To alterations in channel density and kinetics,67–69 and explore this correlation further the mutated channel has to be inconsistent results have been reported for the coexpressed not only with its wild-type counterpart—to polyglutamine expansion associated with SCA6.70–72 As for

reproduce the heterozygous situation in affected patients— premature truncations of CaV2.1, these are expected to result 73 but also with other members of the KV1 family and accessory in a non-functional peptide. Surprisingly, one premature subunits. This is difficult because of the large number of stop codon identified in a sporadic patient with absence possible channel stoichiometries. Nevertheless, this approach epilepsy in addition to episodic ataxia was found to exert a has revealed that some mutants exert a dominant negative dominant negative effect on the wild-type allele.74 This effect on the wild-type allele. A simple explanation for the finding is unexpected because multiple CaV2.1 subunits are paroxysmal nature of episodic ataxia type 1 remains elusive. not known to interact. This mutation is especially interesting Unlike hyperkalaemic periodic paralysis, attacks of cerebellar because several spontaneous mutations of this subunit and

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accessory ones in mice are associated with the same epileptic phenotype is most simply explained by a reduction combination of ataxia and absence seizures, as is targeted in fast inhibition. The other mutation, however, has been deletion of the CaV2.1 subunit. The role of this channel in reported to have no effect on current amplitude, but to sporadic absence epilepsy remains to be elucidated.75 reduce the potentiating effect of , a result that the authors interpret as implying that endogenous

Sodium channel and GABAA-receptor mutations: agonists normally increase GABAergic generalised epilepsy with febrile seizures plus inhibition.82 The principle of genetic heterogeneity is most striking in the The account of GEFS+ given above agrees with the case of another epileptic syndrome consisting of febrile and principle that generalised epilepsy can result from excessive afebrile seizures persisting beyond childhood: generalised neuronal excitation, or insufficient synaptic inhibition. epilepsy with febrile seizures plus (GEFS+). This disorder is However, this view is challenged by a recent report that

associated with mutations of two different sodium-channel heterozygous non-sense mutations of NaV1.1 frequently occur 76,77 83 subunits (NaV1.1 and NaV1.2), the accessory sodium- in a severe sporadic form of epilepsy. Severe myoclonic 78 channel subunit 1, and with the GABAA-receptor epilepsy of infancy is characterised by drug resistance and a 79,80 subunit 2. These mutations are all inherited in a poor prognosis. Tonic, clonic, and tonic-clonic seizures occur, dominant manner, and a major breakthrough was the frequently associated with febrile illnesses. Other seizure types recognition that they could give rise to very variable occur later, including myoclonic, absence, and partial phenotypes even within affected families. The range of seizures, akin to a severe form of GEFS+. In addition, patients seizure types includes not only febrile and afebrile are affected by ataxia and by developmental, speech, and generalised tonic-clonic seizures that arise in childhood, but motor arrest. Life expectancy is severely curtailed, which also myoclonic, absence, and atonic seizures. Some affected possibly explains why the mutations are sporadic. The individuals are affected by a severe drug-resistant form mutations that have been identified are predicted to cause

associated with intellectual impairment, myoclonic-astatic major truncations of NaV1.1 and are thus expected to cause a epilepsy. The variability in manifestation contrasts with the reduction in sodium-channel function, by contrast with the relatively uniform phenotypes of many other pattern seen in GEFS+. channelopathies, and it is unclear to what extent it reflects environmental factors or modifying genes. Neuronal nicotinic-receptor mutations:

The neuronal sodium channels NaV1.1 and NaV1.2 are autosomal dominant nocturnal frontal-lobe epilepsy critical for the initiation and propagation of action potentials. Two other distinct epileptic channelopathy phenotypes are Although they are widely distributed throughout the CNS, recognised. Autosomal dominant nocturnal frontal-lobe they show a differential localisation in the dendritic and axonal epilepsy is due to mutations of either of two neuronal 17 84–86 compartments of many neurons. 1 is one of two accessory nicotinic acetylcholine receptor subunits: 4 and 2. subunits and it assembles with either of the subunits. It Interestingly, these two subunits coassemble to form one of accelerates the inactivation of the sodium channels. In a the common heteromeric receptors in the brain.87 Most striking parallel with the muscle sodium-channel disorders, patients present in childhood or adolescence, many with several GEFS+ mutations are predicted to result in an violent seizures occurring during sleep, sometimes with impairment of inactivation, resulting in a prolongation of the preserved consciousness.88 The disorder is commonly sodium flux after depolarisation (a gain of function). This misdiagnosed as a parasomnia, and electroencephalography result occurs either because of a defect of fast inactivation abnormalities can be overlooked. Carbamazepine is intrinsic to the subunit, or because the subunit is non- generally effective. Although the disease is inherited in a functional.78 Thus, GEFS+ in these cases can be tentatively dominant manner, penetrance is incomplete. attributed to an increase in neuronal excitability. Whether this The mechanisms of this disorder are poorly understood. increase results from repetitive action-potential initiation in Several different functional consequences for acetylcholine- the or from improved dendritic boosting of synaptic receptor function have been reported for distinct mutations, depolarisation remains to be determined. without an obvious common theme.85,89–91 Furthermore, the Interestingly, the genetic heterogenity shown by GEFS+ normal function of 4 2 nicotinic receptors is unclear. Many crosses the boundary between voltage-gated and ligand- CNS nicotinic receptors are presynaptic, and their activation 92 gated channels. GABAA receptors are the main mediator of seems to increase the release of other . fast inhibitory transmission in the brain. They have a similar However, the circumstances under which they themselves pentameric structure to nicotinic acetylcholine receptors, are activated remain to be elucidated. with the main functional difference being that they are selectively permeable to chloride and bicarbonate anions. M-current disorder: benign familial neonatal Although many different subunits exist, most neuronal convulsions

GABAA receptors fall into a few common stoichiometries. Benign familial neonatal convulsions are caused by another The 2 subunit is commonly associated with one or more autosomal dominant epileptic channelopathy with high and subunits, and it has an important role in localising penetrance. Brief generalised seizures begin in the first week 81 93 GABAA receptors to inhibitory synapses. One of the of life, and they resolve in most cases within 6 weeks. There mutations identified in GEFS+ reduces the maximum is a higher than normal risk of epilepsy later in life, but current when coexpressed with and subunits.79 Thus, the development is otherwise unaffected. The potassium

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channel KCNQ2 was discovered by positional cloning in families with this disorder.94,95 Homology screening Search strategy and selection criteria subsequently revealed a closely related channel, KCNQ3, Data for this review were identified from surveys of medical and scientific journals and Medline searches. Peer-reviewed papers which also bears mutations in other affected families.96 This on the clinical presentation, management, genetics, and search also led to an unexpected breakthrough in the functional consequences of ion-channel mutations were included. understanding of neuronal signalling mechanisms. The function of these channel subunits was unclear until they were coexpressed: KCNQ2 and KCNQ3 coassemble and give demyelinating and axonal forms). Many mutations of the rise to a potassium current that is inhibited by muscarinic connexin 32 gene have been identified.108 are small receptors.97,98 Mutations of either KCNQ2 or KCNQ3 seem proteins that contain two transmembrane segments. They to produce a small reduction in the amplitude of this so- assemble in hexamers to form connexons. Two connexons, in called M current. The normal role of the M current is apposed cell membranes, pair up to form a . thought to suppress burst firing of neurons, and failure of These specialisations are thought to represent diffusional this mechanism may account for the lower seizure threshold paths for small molecules, enabling rapid communication in carriers of KCNQ2 or KCNQ3 mutations. However, why between distinct cells, or, in the case of connexin 32, between the seizures tend to resolve spontaneously remains unclear. concentric layers of myelin sheaths contacting axons. Connexin 32 is expressed in Schwann cells and also in the Glycine-receptor mutations: familial hyperekplexia CNS, where it is thought to be localised to the myelinating Familial hyperekplexia was one of the first neuronal . Impaired gap-junction function is thought channelopathies to be discovered. It is caused by mutations to underlie the pathogenesis of X-linked Charcot-Marie- 99 of the 1 subunit of glycine receptors. Together with Tooth disease, possibly because of disruption of cytoplasmic

GABAA receptors, glycine receptors mediate fast inhibition homoeostasis in the innermost layers of myelin. in the spinal cord and brainstem but not in the forebrain. Distinct mutations are inherited in an autosomal dominant Conclusions or recessive pattern.99–102 Patients can present in infancy with Many other ion channels are likely to be implicated in muscle stiffness and muscle spasms, but more commonly the neurological diseases in the future.109 In addition, the disorder manifests as excessive, non-habituating startle phenotypic range associated with individual channels is responses evoked by sensory or auditory stimuli. Falls can likely to be broader than currently known. Until now, occur. The stiffness and startle responses tend to resolve with attention has been focused mainly on families with age, and clonazepam and sodium valproate are effective in mendelian inheritance. However, the finding of mutations many cases. in patients with sporadic epilepsy74,83 prompts a more Glycine receptors belong to the nicotinic superfamily of extensive search for channelopathies in the absence of a ligand-gated channels and share a pentameric structure with family history. Another situation that needs to be explored 103 acetylcholine and GABAA receptors. In the adult, the is the possibility that sequence variations of ion-channel stoichiometry of synaptic glycine receptors is thought to be genes may be silent when inherited in isolation but cause three 1 subunits, which bind the agonist, and two subunits, disease when they occur in combination (compound which act to anchor the receptors at synapses. The mis-sense heterozygosity). mutations that have been identified tend to be clustered in the The genetic channelopathies have helped us to agonist-binding amino-terminus, and in the M1–M2 loop, understand the pathogenesis of several classes of disease. which is thought to be important for transduction of ligand Many puzzles remain, however. Not least among these are binding to channel opening. However, a frame-shift mutation the mechanisms that underlie migraine and hemiplegia in

has also been reported, which is predicted to disrupt almost association with CaV2.1 mutations, and epilepsy with the whole channel.104 Interestingly, this mutation is inherited nicotinic-receptor mutations. Some mutations are in the in a recessive manner, which has several implications. First, process of being expressed in animal models.110 complete absence of 1 is not lethal, unlike the effect of a In combination with a detailed understanding similar non-sense mutation in mice.105 Second, because of molecular and cellular signalling by ion channels, heterozygous carriers are unaffected, only one allele is this approach may well give a unique insight into required for normal inhibition in the spinal cord. Finally, common mechanisms of a wide range of diseases including familial hyperekplexia is predicted to result from loss of neuromuscular and movement disorders, epilepsy, function. The latter conclusion has been supported by and headache. 106,107 functional analyses of several mutations. Authors’ contributions Both authors contributed equally to all parts of the review. Further information about DNA-based diagnosis of neurological channelopathies is available from MGH Glial channelopathies (email [email protected]). Connexin 32: X-linked Charcot-Marie-Tooth disease Conflict of interest Only one glial channelopathy is known to cause a neurological We have no conflict of interest. disease (table 2). X-linked Charcot-Marie-Tooth disease is Role of the funding source characterised by a progressive motor and sensory neuropathy, We acknowledge the support of the Medical Research Council, the Brain Research with moderately slowed conduction (with velocities Trust, University College London NHS-Trust Special Trustees, and the Wellcome Trust. None of these funding bodies had a role in the preparation of the review, or in intermediate between those seen in the common the decision to submit it for publication.

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