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Home , Febrile seizure, GABRG2, Genetic disorder

Inherited Syndromes and

Mary Kurian and Fabienne Picard2, Presurgical Epilepsy Evaluation Unit, “Functional and Neurosur- gery” Program of the University Hospitals Lausanne and Geneva 2Department of Neurology, University Hospital of Geneva

Summary Vererbte Epilepsiesyndrome und Channelopathien Inherited epileptic syndromes associated with in coding for ion channels (chan- Zu den hereditären epileptischen Syndromen, bei nelopathies) include generalized such as welchen Mutationen in der Kodierung von Ionenkanal- with Febrile plus (GEFS+) genen (Kanalopathien) vermutet werden, gehören die associated with and GABAA generalisierten Epilepsien, etwa die generalisierte Epi- mutations as well as focal epilepsies like Benign lepsie mit Fieberkrämpfen plus (GEFS+), welche Muta- Familial Neonatal (BFNC) associated with tionen des Natriumkanals und des GABAA-Rezeptors mutations and Autosomal Domi- zugeschrieben wird, ebenso wie fokale Epilepsien, so et- nant Nocturnal (ADNFLE) associa- wa die benignen familiären neonatalen Konvulsionen ted with neuronal nicotinic receptor mutations. Other (BFNC), welche in Verbindung gebracht werden mit Mu- paroxysmal neurological disorders like periodic paraly- tationen des Kaliumkanals, aber auch die autosomal sis, Familial Hemiplegic (FHM) and episodic dominante nächtliche Frontallappenepilepsie (ADNFLE), ataxias have also been shown to result from mutations bei welcher ein Zusammenhang mit Mutationen des in ion channels and are sometimes associated with neuronalen Nikotinrezeptors vermutet wird. Bei ande- epilepsy. Mutations of several different ion channels ren paroxystisch neuronalen Defekten wie einer peri- can cause remarkably similar , while distinct odischen Paralysie, der familiären hemiplegischen Mig- mutations of the same can cause variable räne (FMH) und episodischer Ataxie wurde auch die phenotypes, furthermore, the same could Mutation von Ionenkanälen als Kausalität und mögli- lead to variable neurological paroxysmal phenotypes cher Ursprung von Epilepsien nachgewiesen. Mutatio- depending on the individual and on age. On the basis nen von mehreren unterschiedlichen Ionenkanälen of genetic and electrophysiological studies of these können bemerkenswert ähnliche Phänotypen erzeu- channelopathies, novel therapeutic strategies can be gen, während unterschiedliche Mutationen eines sel- developed as in the case of the antiepileptic drug ben Gens zu verschiedenen Phänotypen führen können, retigabine which is a potassium channel opener. Insight zudem kann ein- und dieselbe Mutation in verschiede- into the relationships between abnormal nen paroxystisch neurologischen Phänotypen enden, je function, and channel sensitivity to nach Individuum und Alter. Aufgrund von genetischen antiepileptic drugs may be important for under- und elektrophysiologischen Studien der Kanalopathien standing how these drugs actually work to suppress können neue therapeutische Strategien entwickelt wer- seizures and why they show variability in efficacy from den, wie zum Beispiel Retigabin, ein Antiepileptikum, one patient to another. This review summarizes the welches die Rolle eines Kaliumkanalöffners übernimmt. clinical, genetic and certain pathophysiological Ein Einblick in die Zusammenhänge zwischen abnormer concepts of the known neuronal channelopathies Ionenkanalfunktion, Epileptogenese und der Sensibi- associated with epilepsy syndromes and considers the lität, mit welcher ein Kanal auf Antiepileptika anspricht, implications of the potential effects of these channel kann zum besseren Verständnis der Wirkungsweise die- mutations on the antiepileptic drugs’efficacy. ser Medikamente bei der Verhinderung von Anfällen beitragen und auch Erklärungen dafür liefern, weshalb Epileptologie 2006; 23: 75 – 85 sie bei einem Patienten besser wirken als bei einem an- deren. Der Artikel vermittelt einen Überblick über die klinischen, genetischen und einige pathophysiologische Keywords: epilepsy syndromes, channelopathies, genetic Konzepte der bekannten neuronalen Kanalopathien in Verbindung mit Epilepsiesyndromen und reflektiert über die Konsequenzen möglicher Auswirkungen dieser Kanalmutationen auf die Effizienz der Antieptileptika.

Schlüsselwörter: Epilepsiesyndrome, Channelopathien, genetisch

Inherited Epilepsy Syndromes and Channelopathies | Mary Kurian and Fabienne Picard Epileptologie 2006 75 Syndromes épileptiques héréditaires et Introduction canalopathies Ion channels play a central role in the generation Les syndromes épileptiques héréditaires attribués and control of neuronal excitability. Mutations in ion aux mutations des gênes de codage des canaux ioni- channel-encoding genes are found in a variety of inheri- ques (canalopathies) englobent les épilepsies généra- ted neurological associated with hyper- or lisées telles que l’épilepsie générale avec convulsions fé- hypoexcitability of the affected tissue [1]. Ion channel briles plus (GEFS+) due à des mutations du canal sodi- disorders (channelopathies) have been linked to a que et du récepteur GABAA, de même que les épilepsies variety of epilepsies considered idiopathic. Neuronal ion focales telles que les convulsions néonatales familiales channels associated with inherited epilepsies bénignes (BFNC) associées à des mutations du canal po- include voltage-gated channels (Na+, K+,Ca2+,Cl-) as well tassique et les épilepsies autosomiques dominantes as ligand-gated channels (nicotinic ACh receptors, GABA nocturnes du lobe frontal (ADNFLE) associées à des mu- receptors) [2]. - relationships in tations du récepteur nicotinique neuronal. Il a égale- epilepsy are complex. Mutations of several different ion ment été démontré que d’autres troubles neurologi- channels can cause remarkably similar phenotypes ques paroxysmiques tels que la paralysie périodique, la (locus heterogeneity), while distinct mutations of the migraine hémiplégique familiale (FHM) et les ataxies same gene can cause variable phenotypes (allelic hete- épisodiques résultent de mutations dans des canaux io- rogeneity), and furthermore, even the same mutation niques et sont parfois associées à une épilepsie. Les mu- could lead to variable phenotypes depending on factors tations de différents canaux ioniques peuvent provo- like age and brain maturation. quer des phénotypes d’une similitude remarquable et Neuronal channelopathies have been mainly identi- différentes mutations du même gène peuvent provo- fied on the basis of studies. An in- quer des phénotypes très variable, en plus, une même creasing number of epileptic syndromes belong to this mutation peut conduire à des phénotypes neurologi- group of disorders. They usually begin at a characteris- ques paroxysmaux variables selon l’individu et l’âge. Les tic age and are sometimes associated with specific EEG études génétiques et électrophysiologiques de ces patterns. They include generalized epilepsies such as canalopathies permettent de mettre au point des nou- Generalized Epilepsy with Febrile Seizures plus (GEFS+) velles stratégies thérapeutiques comme par exemple associated with sodium channel and GABAA receptor l’antiépileptique rétigabine qui est un ouvreur du canal mutations as well as focal epilepsies like Benign Famil- potassique. La compréhension intime des interrelations ial Neonatal Convulsions (BFNC) associated with potas- entre une anomalie de fonctionnement d’un canal ioni- sium channel mutations and Autosomal Dominant que, une épileptogenèse et la sensibilité du canal aux Nocturnal Frontal Lobe Epilepsy (ADNFLE) associated antiépileptiques pourrait être importante pour avoir with neuronal nicotinic receptor mutations. Certain une idée précise du fonctionnement de ces médica- forms of idiopathic generalized epilepsy, juvenile ments anticonvulsifs et de leur efficacité variable selon and absence epilepsy, may result les patients. Le présent papier résume les concepts clini- from mutations of Ca2+ channels. Mutations of the ques et génétiques, ainsi que certains concepts physio- gene have recently been found to be pathologiques associés aux syndromes épileptiques. Il associated with certain types of epilepsy. Parallels are s’interroge en outre sur les implications des effets po- seen in the molecular findings of non-epileptic paroxys- tentiels des mutations de ces canaux sur l’efficacité des mal neurological diseases where ion channels are also antiépileptiques. responsible, for example, mutations in Na+ or Ca2+ channels are associated with , calcium Mots clés : syndromes épileptiques, canalopathies, channel mutations are associated with Familial Hemi- génétique plegic Migraine (FHM) and (EA-2), arising from defects of the same gene (FHM and EA-2 can be considered as allelic channelopathies). These disorders provide interesting models to study the etiology and pathophysiology of the disturbed excitability in the in detail. On the basis of genetic and electrophysiological studies of these channelo- pathies, novel therapeutic strategies can be developed as it has been shown recently for the antiepileptic drug retigabine activating neuronal KCNQ potassium channels [3]. This review summarizes the clinical, genetic and pathophysiological concepts of the known neuronal channelopathies associated with epilepsy syndromes and the implications of the contribution of these channel mutations to the therapy and management of these syndromes.

76 Epileptologie 2006 Inherited Epilepsy Syndromes and Channelopathies | Mary Kurian and Fabienne Picard 1. Generalized epilepsy syndromes locus was observed on 2q (GEFS2) and corresponded to the sodium channel alpha subunit gene, SCN1A [9]. Nine different missense mutations in SCN1A have been a. Mendelian idiopathic generalized epilepsies reported to date [6, 7, 10-12]. Missense mutation in the gene SCN2A coding for the sodium channel α2 subunit, 1.1 Generalized epilepsy with febrile seizures plus (GEFS+) also localized on 2q, has been described in a Japanese GEFS+ was first identified by Scheffer and Berkovic family [13]. Voltage-gated sodium channels are essential in 1997 [4]. They described a family that had 25 indivi- for the generation and propagation of action poten- duals with generalized epilepsy over 4 generations, tials in neuronal tissues. Biochemically, they consist of a with many family members having seizures with large alpha subunit and 1 or 2 smaller beta subunits. that persisted beyond 6 years of age or were associated The alpha subunit alone can exhibit all the functional with afebrile generalized seizures. Thus GEFS+ corre- attributes of a voltage-gated Na+ channel, but requires sponds to a childhood onset-generalized genetic epilep- a beta subunit for normal inactivation kinetics. The mu- sy syndrome with Febrile Seizures (FS) and a variety of tations identified in sodium channel α and β subunits afebrile epileptic types within the same pedi- cause subtle changes in channel gating (increases in gree with autosomal dominant inheritance. Most affec- persistent sodium current, shifts in the voltage-depen- ted family members have the clinical picture of Febrile dence of steady state inactivation and/or resistance to Seizures plus (FS+) which is defined by classical febrile frequency-dependent cumulative inactivation) which seizures which persist beyond the age of 6 years or by are thought to increase neuronal excitability and thus the association of afebrile seizures to the classical fe- to predispose affected individuals to seizures. brile seizures. Another ion channel, the GABAA receptor, has been The phenotypic expression of GEFS+ has a spectrum involved in GEFS+. The involvement of the inhibitory of clinical epilepsy phenotypes including classical FS (FS neurotransmission mediated by gamma-aminobutyric confined to early childhood i.e. < 6 years), FS+, and in acid (GABA) had long been thought to be involved in 30% of the patients, FS+ and absences, FS+ and myoclo- epilepsy pathogenesis. Missense mutations have been nic seizures, FS+ and atonic seizures, or myoclonic-asta- identified in the gene coding for the γ2 subunit of the tic epilepsy. The overlap of febrile and afebrile seizures GABAA receptor (GABRG2) localized on 5q34 in four is typical of the disorder, but other scenarios are also families [14-17]. In two families, febrile seizures plus observed: isolated febrile seizures, afebrile epileptic were associated with absences similar to those of child- seizures without preceding FS or FS+ or a free interval hood absence epilepsy, which constitutes an atypical between FS or FS+ and subsequent afebrile seizures. phenotype in GEFS+. Comparing phenotypes between Absence seizures are commonly atypical in that they patients with SCN1A and those with GABRG2 muta- have a longer duration and are less frequent than in ty- tions, it was found that the SCNA1 mutations contribute pical Childhood Absence Epilepsy (CAE). Myoclonic- more frequently to the development of FS+ than Astatic Epilepsy (MAE) described by Doose [5] begins GABRG2 mutations [18]. More patients with GABRG2 with FS in one third of cases and afebrile Generalized mutations had isolated FS (offset before age 6 years, no Tonic-Clonic Seizures (GTCS) in other cases, then the associated or subsequent afebrile seizures). child develops a number of generalized in- Other syndromes with mutations in SCN1A have cluding the myoclonic-astatic seizures. Onset occurs been linked to GEFS+: between 1 and 5 years of age and boys are more com- - Severe Myoclonic Epilepsy of Infancy (SMEI) or monly affected than girls. MAE has a variable course Dravet’s syndrome has been suggested to constitute with being common but by no the most severe phenotype of the GEFS+ spectrum, as means universal. Affected relatives of MAE probands patients with SMEI could have a family history of most commonly have febrile and afebrile GTCS begin- seizure disorders compatible with GEFS+ [19]. It is an ning before 5 years. So the phenotypic variation in intractable epilepsy of early childhood, characterized GEFS+ ranges from mild to severe forms of epilepsy. It by fever-sensitive, refractory, generalized clonic, GTC has to be noted that even partial seizures can be part of or unilateral seizures, beginning in the first year of GEFS spectrum [6, 7]. Most phenotypes in GEFS have life. The seizures often culminate in . normal intellect, neurological examination and normal Development before seizure onset is normal. Appear- neuroradiological studies. Seizures usually cease by ance of myoclonic seizures during the course of the mid-childhood (10-12 years), in some patients they per- confirms SMEI diagnosis. Some patients have sist and are difficult to treat. EEG is characterized by a additional complex partial or absence seizures, and normal background and rarely the presence of genera- psychomotor development declines in almost all lized spike and wave patterns [4]. patients. Molecular have elucidated much Genetic heterogeneity in GEFS+ has been well of the etiology of this devastating disorder with established. The first locus was described on 19q about 80% of SMEI patients carrying mutations of (GEFS1) [4] and corresponded to a gene (SCN1B) the sodium channel subunit gene SCN1A [20-22]. encoding the sodium channel β1 subunit [8]; a second They generally correspond to de novo mutations.

Inherited Epilepsy Syndromes and Channelopathies | Mary Kurian and Fabienne Picard Epileptologie 2006 77 More severe sodium channel dysfunctions including b. Non-mendelian idiopathic generalized abnormal ion selectivity that are caused by muta- epilepsies tions in the pore regions of SCN1A are thought to be involved in the pathogenesis of SMEI [23]. Few genes have been implied in the common idio- - Intractable childhood epilepsy with GTCS (ICEGTC) pathic generalized epilepsies which seem to have a also showed mutations in SCNA1 [24]. The onset and multigenic mode of inheritance. A study using trans- severity is similar to SMEI but no other seizure type mission-disequilibrium test showed significant overall than GTC is seen in ICEGTC. EEG is characterized by association of CAE with a gene coding for the GABAA diffuse theta waves and spikes or sharp waves are receptor β3 subunit, GABRB3, suggesting that the rarely observed. SMEI and ICEGTC represent a tested polymorphism may be either directly involved in continuum with minor phenotypic and genotypic the etiology of CAE or in linkage disequilibrium with differences. disease-predisposing sites [29]. GABRD, encoding a pro- tein for extra or perisynaptic GABAA receptors has also 1.2. Autosomal dominant form of Juvenile Myoclonic been shown to be a susceptibility locus for generalized Epilepsy (JME) epilepsies [30]. A heterozygous missense mutation of the gene On the other , an association was reported GABRA1 encoding the α1 subunit of the GABAA receptor between Juvenile Absence Epilepsy (JAE) and poly- was recently detected in the autosomal dominant form morphisms in GRIK1 gene encoding a , of juvenile myoclonic epilepsy (ADJME) in a family [25]. involving glutamate transmission [31]. For recall, in JAE, All affected individuals had myoclonic and generalized absences are not as frequent as in CAE and association tonic-clonic seizures with generalized polyspike and with GTCS is frequent. wave discharges on EEG. The GABAA receptor harbour- ing the mutation impaired Cl--influx through the chan- nel in response to GABA. There is however no evidence 2. Partial epilepsies of the implication of the GABRA1 gene in sporadic cases of JME. a. Idiopathic focal epilepsies in neonates and in 1.3. Idiopathic generalized epilepsies associated with infancy following single gene inheritance mutations in CLCN2 The chloride channel CLC-2 is expressed in the brain, 2.1. Benign Familial Neonatal Convulsions (BFNC) especially in inhibited by GABA and is believed BFNC is a rare dominantly inherited epileptic syn- to play a role in maintaining the low intracellular chlo- drome characterized by frequent brief seizures within ride concentration that is necessary for an inhibitory the first days of life that typically disappear spontane- GABA response. Impairment of the neuronal inhibitory ously after weeks to months. In very rare cases, adult- - system controlled by Cl -influx can result in epilepsy. hood epilepsy occurs (in ~10% individuals). Although Mutations in the CLCN2 gene encoding CLC-2, a volt- regarded as a generalized epilepsy in ILAE classification age-gated Cl--channel, were found to be associated in 1989 (Commission, 1989) [32], video-EEG monitoring with idiopathic generalized epilepsy in three families could later show seizures of partial onset. Seizures have [26]. The mode of inheritance was autosomal dominant a variety of manifestations including tonic attacks, in two families, and the epilepsy was found in only one apnea, clonic, focal and autonomic features. generation in the third family. The phenotype was BFNC was thought to be genetically heterogeneous, variable, including patients with JME and patients with with two identified loci on 8q and 20q. absences (CAE and juvenile absence epilepsy (JAE)) and In 1998 the potassium channel gene KCNQ2 was identi- isolated GTCS. fied as the 20q gene and a closely related gene KCNQ3 was discovered to be responsible for the 1.4. Idiopathic generalized epilepsies associated with 8q-linked syndrome [33, 34]. In the nervous system mutations in subunit genes KCNQ2 and KCNQ3 gene products assemble to form Mutations in the calcium channel ß4 subunit gene potassium channels that generate M-currents [35]. CACNB4 have been identified in two small families in- M-currents modulate neuronal excitability by cluding each two affected members [27]. In one of dampening the tendency for repetitive firing. Neuronal these families the phenotypes corresponded to JME. M-currents are inhibited by muscarinic acetylcholine Another calcium channel subunit gene (CACNA1) was receptor agonists as well as activators of other types of found to be mutated in a small family with childhood neurotransmitter receptors. Mutations in either KCNQ2 absence epilepsy [28]. The functional analysis of the or KCNQ3 reduce function of the encoded potassium mutation (R2162H) showed a gain of function affecting channel by a dominant negative mechanism consistent the G- modulation of the P/Q type Ca2+ with the autosomal dominant inheritance pattern of channels. BFNC [36]. The early onset and remission of seizures in BFNC has long been a matter of interest. Okada et al.

78 Epileptologie 2006 Inherited Epilepsy Syndromes and Channelopathies | Mary Kurian and Fabienne Picard [37] proposed that these clinical features have a basis in herited as an autosomal dominant trait with incom- age-specific expression of the ion channels and that plete with both males and females being possible development or specific appearance of other equally affected. The age of onset is usually in the first channels may compensate for the loss of function of or second decade, and seizures can persist throughout the channel that has the mutation. Systematic adult life. The seizures are characterized by motor ac- functional studies may permit a genotype-phenotype tivity, with hyperkinetic (frantic movements of bipedal correlation and an improved understanding of how activity, pelvic thrashing), tonic or dystonic features specific mutations leading to seizures may reveal [49]. There is marked intrafamilial variability in severity targets for therapeutic intervention. and the inherited nature is often overlooked, as rela- tives may only be mildly affected. Mutations have been 2.2. Benign Familial Infantile Convulsions (BFIC) identified in genes coding for subunits of the nicotinic This autosomal dominant syndrome first described acetylcholine receptor (nAChR) in some families and in in Japan [38] and then in Italian families [39] presents one sporadic case [50]. NAChRs are pentameric ligand- with partial seizures between 2 and 20 months. gated ion channel receptors consisting of different Clusters of afebrile partial seizures occur over a few functional subunit combinations. Mutations have been days. Linkage to chromosome 19q [40], chromosome identified in the CHRNA4 gene encoding the nAChR α4 2q24 [41], and to the pericentromeric region of chromo- subunit and in the CHRNB2 gene encoding nAChR β2 some 16 has been reported in BFIC [42, 43]. This last subunit [51]. The α4 and β2 subunits assemble to form linkage is the same as in the distinctive syndrome of the main cerebral nAChR. Mutations were identified in familial infantile convulsions associated with paroxys- around only 10% of the reported families. Sporadic mal choreoathetosis (ICCA syndrome) [44] (see 3.a. cases of nocturnal frontal lobe epilepsy with a similar Epilepsies associated with paroxysmal dyskinesias). electroclinical picture have been reported and may re- present unrecognized familial cases or de novo mutations. 2.3. Benign Familial Neonatal-Infantile Seizures (BFNIS) A clinically intermittent variant between BFNC and BFIC called benign familial neonatal-infantile seizures 3. Channelopathies with association of epilepsies (BFNIS) was originally described in a large North and other paroxysmal neurological disorders American family [45]. This autosomal dominant dis- order presents with afebrile focal seizures beginning at A growing list of paroxysmal neurological disorders a mean age of 11 weeks (2 days to 6 months) in a associated with epilepsies has been shown to result previously well and developmentally normal infant. To from mutations in ion channels. For instance two date, a total of 8 families with this syndrome have been different inherited paroxysmal neurological syndromes, reported to have mutations in the sodium channel gene episodic ataxia and familial hemiplegic migraine, have SCN2A [46, 47]. been linked to mutations in a same neuronal calcium channel subunit gene [52]. Even a single gene mutation may sometimes lead to a variable including b. Autosomal dominant partial epilepsies different paroxysmal neurological disorders, depending on the individual and on the age. A genetic etiology in generalized epilepsies is widely accepted, but focal or partial epilepsies have been largely attributed to environmental factors such as a. Epilepsies associated with paroxysmal birth injuries, trauma, and brain lesions like dyskinesias tumours and vascular insults. However, in the past de- cade, there has been increasing recognition of families - The Infantile Convulsions and Choreoathetosis (ICCA) with dominantly inherited partial epilepsies. The main syndrome is a syndrome associating familial infantile familial focal epilepsies are Autosomal Dominant Noc- convulsions with paroxysmal choreoathetosis [44]. turnal Frontal Lobe Epilepsy (ADNFLE), Familial Mesial Afebrile partial seizures occur at age 3-12 months. (FMTLE), Familial Lateral TLE They start with psychomotor arrest and deviation of (FLTLE) and Familial Partial Epilepsy with Variable Foci head and eyes, and sometimes secondarily genera- (FPEVF). The only genes identified so far are those for lize. Paroxysmal choreoathetosis starts between 5 ADNFLE (coding for ion channel subunits) and FLTLE (see and 9 years of age in most patients and tends to re- paragraph 4 Non-ion channel epilepsy genes). mit in adulthood. The ICCA syndrome has been linked Autosomal dominant nocturnal frontal lobe epilep- to the pericentromeric region of chromosome 16 and sy (ADNFLE) was first reported in 1994 and has been is thought to be related to a single gene mutation, but recognized as a new clinical entity of epilepsy [48]. This the responsible gene has not been identified yet. partial epilepsy is characterized by clusters of brief sei- zures during light sleep and is often misdiagnosed as a - Generalized epilepsy and paroxysmal dyskinesia: parasomnia or a psychiatric disorder. ADNFLE is in- A syndrome of coexistent generalized epilepsy and

Inherited Epilepsy Syndromes and Channelopathies | Mary Kurian and Fabienne Picard Epileptologie 2006 79 Table 1: Human inherited neurological diseases associated with neuronal ion channel mutations

Type of channel Gene Ion Channel 1. Epilepsy syndromes a. Idiopathic generalized epilepsies Generalized epilepsy with febrile Voltage-gated SCN1A (2q21-33) NaV1.1 sodium channel α1 subunit seizures plus (GEFS+) Na+ channel SCN2A (2q21-33) NaV1.2 sodium channel α2 subunit SCN1B (19q13) β1 subunit of sodium channel Ligand-gated GABRG2 (5q31-33) GABAA γ2 subunit GABA receptor Childhood absence epilepsy Ligand-gated GABRG2 (5q31) GABAA γ2 subunit and febrile seizures GABA receptor Myoclonic-astatic epilepsy (MAE) Voltage-gated SCN1A, SCN1B Sodium channel and + Na channel GABRG2 GABAA receptor subunits Severe myoclonic epilepsy Voltage-gated SCN1A Sodium channel α subunit of infancy (SMEI) Na+ channel Intractable childhood epilepsy Voltage-gated SCN1A Sodium channel α subunit with GTCS (ICEGTC) Na+ channel Autosomal dominant juvenile Ligand-gated GABRA1 (5q34) α1 subunit of myoclonic epilepsy GABA receptor GABAA receptor Idiopathic generalized epilepsy Voltage-gated CLCN2 (3q26) chloride channel chloride channel subunit CLC-2 Voltage-gated CACNB4 calcium channel β4 calcium channel subunit EFHC1 * Childhood absence epilepsy P/Q type CACNA1 calcium channel α subunit calcium channel b. Idiopathic focal epilepsies Benign familial neonatal Voltage-gated KCNQ2 (20q13) M-type potassium convulsions (BFNC) potassium channel KCNQ3 (8q24) channel subunits Benign familial neonatal- Voltage-gated SCN2A (2q24) Sodium channel α subunit infantile seizures (BFNIS) Na+ channel Autosomal dominant nocturnal Ligand-gated nicotinic CHRNA4 (20q13) α subunit of nicotinic frontal lobe epilepsy (ADNFLE) ACh receptor receptor CHRNB2(1q21) β subunit of nicotinic receptor Autosomal dominant partial Leucine-rich LGI-1* (10q24) epilepsy with auditory features inactivated protein (ADPEAF)

2. Epilepsies associated with other paroxysmal neurological disorders Infantile convulsions and ** (chromosome 16) choreoathetosis (ICCA) syndrome Generalized epilepsy with Calcium-sensitive KCNMA1 (10q22) subunit of BK (or Maxi-K) paroxysmal dyskinesia potassium channel (BK) channel Episodic ataxia type 1 (EA1) Voltage-gated KCNA1 (12p13) α1 subunit of Kv1.1 with partial epilepsy potassium channel Generalized epilepsy with P/Q type CACNB4 Calcium channel β4 subunit episodic ataxia type 2 calcium channel Absence epilepsy with P/Q type CACNAIA α1A subunit of episodic ataxia calcium channel CaV2.1 channel Idiopathic epilepsy with migraine ATP1A2 Na+,K+-ATPase pump gene * (1q23)

80 Epileptologie 2006 Inherited Epilepsy Syndromes and Channelopathies | Mary Kurian and Fabienne Picard 3. Other non-epileptic neurological syndromes associated with neuronal ion channel mutations Familial hemiplegic migraine Voltage-gated CACNA1A α subunit of CaV2.1 (FHM) Ca2+ channel Episodic ataxia type 2 Voltage-gated CACNA1A α subunit of CaV2.1 (EA2) Ca2+ channel type 6 Voltage-gated CACNA1A α subunit of CaV2.1 Ca2+ channel Familial Ligand-gated glycine GLRA1 α-1 subunit of receptor

* non- ion channel epilepsy gene ** gene not identified yet

paroxysmal dyskinesia has been linked to chromo- This same gene was also reported to be mutated in some 10q22. A mutation has been identified in the families with only idiopathic generalized epilepsy. alpha subunit of the calcium-sensitive potassium (BK) channel [53]. The mutant BK channel has a - Absence epilepsy with episodic ataxia: Several loss of markedly greater macroscopic current. Single-chan- function mutations have been described in a gene, nel recordings show an increase in open-channel pro- CACNA1A, encoding a subunit of the P/Q type voltage- bability due to a three- to five-fold increase in Ca2+ gated Ca2+ channel (CaV2.1) in families with a com- sensitivity. It has been proposed that enhancement of plex phenotype including episodic ataxia and absen- BK channels in vivo leads to increased excitability by ce epilepsy [58]. A de novo heterozygous nonsense inducing rapid repolarization of action potentials, mutation in CACNAIA also has been reported in a resulting in generalized epilepsy and paroxysmal patient affected by generalized epilepsy (GTCS and dyskinesia by allowing neurons to fire at a faster rate. absence seizures), episodic and progressive ataxia and mild learning difficulties [59]. b. Epilepsies associated with episodic ataxias c. Epilepsies associated with myokymia - Episodic ataxia type 1 (associated with myokymia) is an autosomally dominant inherited disorder - A syndrome in which benign familial neonatal characterized by brief attacks of cerebellar incoordi- convulsions were followed later by myokymia was nation that last up to a few minutes and are triggered described in two families [60]. The muscular hyper- by stress or exertion. Between attacks, many patients excitability was caused by an altered excitability of have continuous motor unit activity, with characteris- the lower motor . The myokymic activity was tic myokymia on electromyography, although this continuous, contrary to the other neurological dis- feature is commonly subclinical. There are striking orders described in association with epilepsy, as differences in severity and response to drugs (mainly mentioned above. All the affected members of one carbamazepine and acetazolamide) used to treat the reported myokymia/BFNC family carried a mutation disorder among kindreds bearing different muta- in the KCNQ2 gene as found in other families with tions. Partial epileptic seizures were reported in five only BFNC. families, occurring in some family members affected by ataxia or myokymia [54, 55]. This disorder has been located to chromosome 12p13 and attributed 4. Non-ion channel epilepsy genes to mutations in the KCNA1 gene encoding the Kv1.1 potassium channel [55-57]. Autosomal Dominant Partial Epilepsy with Auditory Features (ADPEAF), also known as Familial Lateral - Idiopathic generalized epilepsy with episodic ataxia Temporal Lobe Epilepsy (FLTLE), is a familial epilepsy syn- type 2: Mutations were identified in a gene en- drome characterized by symptoms of lateral temporal coding a voltage-gated calcium channel, CACNB4, in lobe epilepsy, including mainly auditory auras (buzzing, patients with generalized epilepsy and episodic ata- roaring, ringing, etc) [61, 62]. Sometimes ictal aphasia xia [27]. This gene encodes the β4 subunit, a protein and visual misperceptions can occur, in some families. that modulates function and trafficking of P/Q type Secondary generalized tonic-clonic seizures are neuronal calcium channels. Voltage-gated calcium frequent. The age of onset is variable, usually in the channels, particularly the P/Q type channels, are second or third decade of life, and seizures are easily important for neurotransmitter release in the CNS. controlled with antiepileptic drugs. EEGs may show

Inherited Epilepsy Syndromes and Channelopathies | Mary Kurian and Fabienne Picard Epileptologie 2006 81 posterior temporal epileptiform discharges, but are activity is influenced by seizures, raising the question of frequently normal. Previous reports described normal whether they may play a role in epileptogenesis [71]. In MRIs in all patients, but abnormalities have been de- addition, the phenotypic range associated with indivi- scribed in the lateral cortex of the temporal lobe in one dual channels is likely to be broader than currently family [63]. Mutations in the Leucine rich glioma in- known. Apart from the focus on families with Mendeli- activated 1 (LGI-1 or epitempin) gene located on an inheritance, the finding of mutations in patients chromosome 10q have been found in one half of the with sporadic epilepsy prompts a more extensive search reported families with FLTLE [62, 64, 65]. Although the for channelopathies in the absence of family history. It Lgi1 protein is not an ion channel subunit, it has very re- is hoped that molecular insights gained from the mono- cently been shown to associate with the potassium genic epilepsies will help in further understanding epi- channel Kv1.1 [66]. The mutant Lgi1 are not lepsies with complex inheritance pattern. any more able to prevent inactivation of Kv1.1 by the A better understanding of the ion channels which Kvß1 subunit. By enhancing the inactivation of Kv1.1 are involved will contribute to finding more specific channels, they allow a broadening of action potentials antiepileptic drugs. Retigabine is an antiepileptic drug during repetitive neuronal firing and may thus cause with a recently described novel mechanism of action epilepsy. This discovery provides a new insight into our that involves opening of neuronal K(V)7.2-7.5 (formerly understanding of the genetics of idiopathic epilepsy. KCNQ2-5) voltage-activated K+ channels [72]. These Sporadic patients with lateral temporal lobe epilepsy channels (primarily K(V)7.2/7.3) enable generation of (without a positive family history) have been reported the M-current, that serves to stabilize the membrane [67] and this syndrome was termed by the authors potential and control neuronal excitability. In this re- “idiopathic partial epilepsy with auditory features”. gard, retigabine has been shown to have a broad-spec- Mutations in LGI-1 were excluded in all these patients trum of activity in animal models of electrically-induced although they had clinical manifestations identical to (amygdala-kindling, maximal electroshock) and chemi- those seen in FLTLE, including a good prognosis. cally-induced (pentylenetetrazole, picrotoxin, NMDA) A second gene which is not directly an ion channel epileptic seizures. These encouraging results suggest and is mutated in some families with idiopathic that retigabine may also prove useful in the treatment generalized epilepsy (JME or GTCS only) is the EFHC1 of other diseases associated with neuronal hyper- gene [68]. It encodes a protein that modulates and excitability. interacts with type R voltage-dependent calcium Current advances in pharmacology could allow channels and has apoptotic activity. the modulation of channel functions based on the A third gene which does not encode an ion channel characteristics of the channels (pharmacogenetic but which is involved in ion transportation, the ATP1A2 studies). Targeting channels may be a productive Na+, K+-ATPase pump gene on chromosome 1q23, was avenue to the production of antiepileptic drugs and can found to be mutated in a family including patients be carried out more precisely as more genetic defects with an idiopathic form of epilepsy and migraine. are identified. Certain antiepileptic drugs (e.g. Indeed in this family, BFIC and familial hemiplegic ) inhibit voltage-gated Na+ channels. There is migraine partially co-segregrated [69]. a hypothesis that the changes in channel gating may also alter channel sensitivity to antiepileptic sodium channel blockers, as a mutation in the β1 subunit of the Conclusions and future prospects voltage-gated sodium channel led in vitro to a reduced channel sensitivity to phenytoin [73]. In GEFS+, some Advances in the field of genetics of the epilepsies patients respond well to sodium channel blockers [4], continue to develop as new genes are discovered and so the mutations do not render these compounds the functional consequences of the disease-causing therapeutically ineffective in controlling epilepsy. mutations are unravelled. Genetic information Nevertheless, there has been no systematic study obtained from animal models of epilepsy either geneti- investigating whether patients with GEFS+ or other cally engineered or spontaneous mutants and from forms of epilepsy associated with sodium channel human epilepsy have prompted us to view certain epi- mutations show altered responsiveness to phenytoin or lepsy syndromes as disorders of ion channels. The other antiepileptic sodium channel blockers. This would idiopathic epilepsies appear indeed to be caused mainly be interesting and potentially important for future by mutations in genes coding for ion channels (Table 1). investigations. Many other ion channels are likely to be identified in In correlation with the high sensitivity of ADNFLE to neurological diseases including epilepsy syndromes in carbamazepine, it is interesting to note that most of the future. For instance the h-channel is a good the mutant nicotinic receptors are more sensitive to candidate [70]. The h-channels are voltage-gated ion this drug than normal receptors and readily inhibited at channels with unique biophysical properties. They exert pharmacological concentrations [74]. The broader im- a significant modulatory influence on neuronal plications of this idea are intriguing, because common excitability, are a target of antiepileptic drugs and their idiopathic epilepsies could in some cases involve subtle

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