ARTICLE

Introduction
Epileptogenesis is thought to represent an alteration in the balance between excitatory and inhibitory neural networks. The electrophysiological excitability of neurons and the communication between them rely on axonal conduction and on signal transduction, which are mediated by action potentials and by synaptic transmission, respectively. Both processes are strongly dependent on ionic channels. The propagation of the electrical impulse in neurons is initiated by the influx of sodium ions followed by the efflux of potassium ions. Conversion of the electrical signal to a chemical one is achieved by the influx of calcium ions in the axon terminal, thus allowing the release of neurotransmitters into the synapse. The binding of the neurotransmitters to their receptors and the subsequent ion flux initiate the electrical impulse in the downstream neuron. Any alteration in the function of ion channels may cause a change in brain excitability, thus inducing epileptic seizures. Epilepsies can basically be divided into two broad categories: symptomatic epilepsies, arising from separate brain lesions or disorders, and idiopathic epilepsies, which are presumed to be of genetic origin. An inherited contribution to the etiology of idiopathic epilepsies had been suspected for a long time. Twin studies clearly demonstrated a major genetic contribution to idiopathic epilepsies, especially those with generalized seizures. Genetic defects may thus play an etiologic role in about 40% of all the epilepsies. In most forms of human epilepsy, as in many other common human diseases such as autism, multiple sclerosis or diabetes, familial segregation does not fit with a simple Mendelian mode of inheritance [1]. Interaction of several genes with each other, as well as with environmental factors, influence the disease. These interactions may differ from one epileptic syndrome to another, increasing the complexity of genetic analyses. By contrast, many rare epileptic syndromes are inherited as monogenic traits (mutation in one given gene is sufficient to cause the disease), facilitating linkage analyses and the identification of epilepsy genes. Genetic linkage studies performed on large families have been (and still are) used to identify a specific chromosomal region in which the disease gene has to be looked for. Once significant LOD score has been obtained, positional cloning approaches are used in order to identify the disease-causing gene. Nowadays, progress in the sequencing of the human genome help bypass some of the positional cloning steps and direct mutation screen on candidate genes situated within the region of interest is currently employed. So far, all known gene defects have been identified in monogenic epileptic disorders. While progressive epilepsies in which epileptic seizures are associated with mental deterioration and often a fatal evolution can be due to mutations in genes of very different functions [2], most genes responsible for actual idiopathic epilepsies encode ionic channels (table I). Ion channels are transmembrane proteins that contain selective pores for ions of different types. They can be regulated by voltage, ligand-binding, intracellular ions, nucleotides, or cell volume. Only the two first, i.e. voltage-gated and ligand-gated channels, have proved to be altered in human epilepsies to date.

Idiopathic epilepsies with mutations in ligand-gated channel genes

Ligand-gated channels can be activated by various neurotransmitters such as glycine, glutamate, gamma-aminobutyric-acid (GABA), acetylcholine. The binding of the ligand opens the channel. As the ligand keeps binding, desensitization of the channel occurs. Once the transmitter is removed, the channel comes to a closed state and can thus be re-opened. Ligand-gated channels are proteins usually composed of several subunits, each contributing equally to the ion-conducting pore. All subunits share a similar structure with 2-4 transmembrane segments. The M2 domains of each subunit form the active pore that is permeable to either cations or anions.

Mutations in the neuronal nicotinic acetylcholine receptor alpha4- and beta2subunit genes
Autosomal dominant nocturnal frontal lobe epilepsy is characterized by seizures that usually begin in childhood. They originate in the frontal lobe, are mainly of the motor type and occur at night. Linkage to chromosome 20q13 had been obtained in a single large Australian pedigree [3] and further confirmed in additional pedigrees [4]. Mutations within the coding sequence of the CHRNA4 gene were found [4, 5]. This gene encodes the neuronal nicotinic acetylcholine receptor alpha4 subunit, and the mutations (one missense mutation S248F, one insertional mutation 776ins3) led to alterations within the second transmembrane domain of the protein (M2), supposed to form the ion-conductive pore of the receptor. Since then, additional genetic analyses have been performed. Several families clearly are not linked to chromosome 20q13, proving genetic heterogeneity. A second locus has been reported at chromosome 15q24 [6]. Moreover, linkage of additional families to chromosome 1p21 helped identify two missense mutations (V287L and V287M) in the CHRNB2 gene [7, 8], which encodes the beta2 subunit of the neuronal acetylcholine receptor. Functional studies using Xenopus oocytes or human embryonic kidney cells revealed different (and somehow opposite) electrophysiological effects for theCHRNA4 mutations: decrease of the channel activity, including a reduction of calcium flux through the receptor, was described [9]. This could lead to synaptic disinhibition via a decrease in the release of neurotransmitters from presynaptic terminals, which in turn would trigger epileptic seizures. However, increase in the activity of the channel has also been shown [4]. Similarly, reduction in the rate

of desensitization was observed in one CHRNB2 mutation (V287L), while V287M led to increased channel activity without any change in the desensitization properties [7, 8]. Whatever those variations are, the way they may induce frontal lobe seizures remains unclear. The major isoform of the acetylcholine receptor in the brain actually is composed of the alpha4 and beta2 subunits, the expression of which is not restricted to the frontal lobe. Other brain areas may have higher thresholds than the frontal lobe, or may better compensate an alteration in the alpha4 or beta2 functioning.

Mutations in the GABAA receptor gamma2-subunit gene

The syndrome of generalized epilepsy with febrile seizures plus (GEFS ) is characterized by febrile seizures that + may persist beyond the age of six, and non-febrile seizures of various types [10]. GEFS is an autosomal + dominant disorder with incomplete penetrance. Several GEFS loci have been identified and evidence for more + genetic heterogeneity was recently obtained [11, 12]. Two GEFS loci, at 2q24 and 19q13, are associated with mutations in the sodium channel genes SCN1A [13, 14] and SCN1B [15], respectively (see below). Moreover, a new locus was recently identified on chromosome 5q34, and two mutations in the gene encoding the gamma subunit of the type A GABA receptor have been found [16, 17]. GABAA receptors are ligand-gated ion channels that hyperpolarize the neuron by increasing inward chloride conductance. One mutation (R43Q) was located in the benzodiazepine-binding domain of the protein and apparently abolished sensitivity to benzodiazepines, while GABA-activated currents remained normal [17]. The other missense mutation (K289M) occurred in between transmembrane domains M2-M3 and led to reduced GABA-activated currents [16]. In this latter case, loss of activity would lead to hyperexcitability, while in the former one, the existence of endogenous "endozepines" that would prevent the development of seizures was postulated.
+

Idiopathic epilepsies with mutations in voltage-gated channel genes

Voltage-gated channels are in a closed state at the resting membrane potential. When the cell membrane depolarizes, the gate of the channel opens. During sustained depolarization, the channel inactivates and remains in this refractory state for a limited period of time during repolarization. Recovery from inactivation then occurs, + ++ + allowing further opening to happen. Voltage-gated channels (K , Ca , Na ) share a common domain structure and are composed of several subunits. The main one, alpha, has a tetrameric structure of homologous domains. Each domain is composed of six transmembrane segments, S1 to S6. S4 represents the voltage sensor of the ion channel, while the S5-S6 loop form the selective pore of the protein. The alpha-subunit plays the gating and permeation roles. Other subunits (beta, delta, gamma) have modifying functions.

Mutations in the sodium channel subunit genes

In addition to mutations in the GABAA receptor gamma-subunit gene, other GEFS genes previously had been identified. Linkage to chromosome 19q had been shown in one large pedigree, and a point-mutation in SCN1B, which encodes the beta1 chain of the voltage-gated sodium channel, was found [15]. The mutation changed a cysteine to a tryptophan. This would lead to disruption of a putative disulphide bridge, which could play a critical role in the structure of an immunoglobulin-like fold in the extracellular domain. Preliminary oocytes experiments showed that co-expression of the mutant beta1-subunit with the alpha-subunit resulted in sodium channels that inactivated slower than when the alpha-subunit was expressed alone, while inactivation was even more rapid when wild-type beta1 subunit was used. Slower inactivation would lead to persistent sodium current in a hyperexcitable neuron. GEFS is genetically heterogeneous and had been linked to human chromosome 2q24 in several large families [18-20]. Missense mutations (R1648H, T875M) in the SCN1A gene were found [13, 14]. Both mutations corresponded to aminoacid residues in the voltage sensor domain of the channel. Functional experiments in Xenopus oocytes and in human embryonic kidney cells suggested that the mutations could act by a loss-offunction mechanism, via enhanced inactivation of the channel. While additional missense mutations within SCN1A have been identified in GEFS pedigrees, new SCN1A mutations responsible for a more severe phenotype were detected. Children with severe myoclonic epilepsy of infancy were screened for mutation in SCN1A and seven de novo mutations were found [21]. Most of them were frameshift or nonsense mutations, thus resulting in a predicted truncated protein with no function. These results were recently confirmed in an independent study based on the screening of SCN1A mutations in twelve unrelated Japanese patients with SMEI (Sugawara et al., 2002) [22]. At least a subset of severe myoclonic epilepsy of infancy can thus be caused by haploinsufficiency of SCN1A and could be considered a severe allelic + variant of GEFS .
+ + +

Mutations in the KCNQ potassium channel genes

Benign neonatal familial convulsions (BNFC) is a syndrome characterized by seizures that usually begin in the first days of life and remit by six months of age. Epileptic seizures recur later in life in 15% of patients. The disorder is transmitted as an autosomal dominant trait. Linkage to chromosome 20q13 was first established [23]. Then genetic heterogeneity was shown, with linkage of additional families to chromosome 8q24 [24].

In both the genomic regions, the disease-genes (KCNQ2 and KCNQ3) have been identified [25-27]. They encode potassium channel subunits that are homologous to each other as well as to KCNQ1, which in turn is responsible for cardiac long QT syndrome [28]. So far, the KCNQ gene subfamily is composed of five delayed rectifier + K channels, KCNQ1-5, that contribute to the repolarization of the action potential. KCNQ2 and KCNQ3 products apparently can associate to form heteromers and are likely to produce the neuronal M-current [29, 30]. Coexpression in Xenopus oocytes of mutant KCNQ2 with wild-type KCNQ2 and KCNQ3 led to reduction of currents. A moderate loss of KCNQ2/KCNQ3 heteromer function, and hence a small decrease in the level of M-currents, could be sufficient to cause neuronal hyperexcitability [29]. Mutations described so far mainly involve either the S5-S6 pore-forming loop of the channel, or the C-terminus part that probably is responsible for the formation of the functional heteromeric channel. Several issues obviously remain to be addressed. In particular, expression of the phenotype only during the neonatal period, and recurrence later in life for a subset of patients, still are unexplained. Generally, maturation of the brain during the first days of life would lead to rapid qualitative and/or quantitative changes in the expression of ion channels and of their regulatory proteins.

Mutations in the KCNA1 potassium channel gene

KCNA1 is a voltage-gated potassium channel, which participates in the recovery phase of the action potential. Loss of function of this potassium channel would lead to prolonged sodium currents. Consequently, Kcna1 knockout mice displayed spontaneous tonic-clonic seizures [31]. Mutations in KCNA1 were found in several families with episodic ataxia type 1, myokimia and partial epileptic seizures [32]. Defects in ion channels could thus lead to the phenotypic association of different paroxysmal disorders of the brain.

Place of ion channels in epilepsies

The clinical and epidemiological relationships between epilepsies and other paroxysmal disorders such as episodic ataxia, migraine, or dyskinesia, are well known. Families with epilepsy and hemiplegic migraine [33, 34], epilepsy and dyskinesia [35-37], migraine and dyskinesia [38], episodic ataxia and dyskinesia [39], episodic ataxia and epilepsy [32], have been described. Ion channel diseases share several features, including paroxysmal symptoms and high level of clinical variability. Mutations in ion channel genes could therefore account for the variable association and co-segregation of different paroxysmal cerebral disorders. Several human genes encoding ion channels are responsible for rare epileptic disorders inherited as Mendelian traits. These epilepsies can thus be considered as channelopathies. Moreover, spontaneous mutations in several calcium channel subunits have been found in various murine epilepsies [40]. On the one hand, these findings could indicate that most idiopathic epilepsies actually are channelopathies. On the other hand, identification of the best candidate genes (ion channel genes) as "epilepsy genes" was expected to occur before the less obvious ones are considered and consequently checked for putative mutations. The following arguments tend to prove that this latter hypothesis (i.e. that ion channel genes appear as being predominantly involved in familial epilepsy, because they are the most obvious candidates) should not be ruled out.

Ion channels and polygenic epilepsies

As stated above, most epilepsies are not inherited as monogenic traits. This is the case for idiopathic generalised epilepsies (IGE), which comprise several different syndromes: generalised tonic-clonic seizures, absence epilepsy of childhood, juvenile absence epilepsy, and juvenile myoclonic epilepsy. Similarly, most febrile convulsions are inherited as complex traits. The genes that are involved in the monogenic forms obviously represent good candidates to be tested in the majority of febrile convulsions that are inherited in a more complex way. This strategy could be complementary to more exhaustive complex genetic analyses, such as sib-pair studies. Candidate gene strategies have thus been employed as an alternative approach. Numerous association studies have been performed on genes with various functions, but no association has been clearly demonstrated yet. In particular, several ion channel genes have been checked: no association was found in the case of KCNQ2, KCNQ3, KCNJ3, KCNJ6, SCN1B. Direct mutation screening has also been performed in order to detect alterations of ion channel genes in IGE. While KCNQ2 and KCNQ3 are mutated in benign neonatal familial convulsions, no additional mutation could be found when a large collection of patients with common forms of IGE was screened. Mutation screening of the calcium channel gene CACNB4 in a large number of families and patients with IGE helped detect only few mutations [41]; moreover, whether these mutations actually participate to the phenotype observed remains to be established. This issue represents a major challenge in the identification of the multiple genes participating in a combined manner to the polygenic epilepsies. The systematic identification of single nucleotide polymorphisms (SNPs) across the genome [42], together with the use of new genotyping technologies [43], will make it feasible to perform large-scale association studies with SNPs specific to all putative candidate genes for the epilepsies.

Mutation in the LGI1 gene in partial epilepsy with auditory features: epilepsies as cortical malformations?

The inherited nature of partial epilepsies has long been neglected [44]. Evidence now exists, that several types of partial epilepsies can be due to genetic defects [45]. In particular, partial epilepsies with auditory features, a rare form of idiopathic lateral temporal lobe epilepsy inherited as an autosomal dominant trait, had been linked to chromosome 10q24 in one large family [46]. Confirmation of linkage was obtained in additional families with temporal lobe epilepsy [47]. Very recently, mutations of various types (frameshift, missense, aberrant splicing) in one copy of the LGI1 gene were found in five families [48]. LGI1 is not homologous to any known ion channel gene and the predicted protein structure contains three leucine-rich repeats which could indicate a role in cell-cell communication. Interestingly, loss of both copies of the LGI1 gene seems to promote glial tumor progression. The LGI1 protein could play a role in neuronal-cell migration and axon guidance in the developing central nervous system. Generally, abnormal cortical development could be involved in epileptogenesis [49]. Certain cortical malformations are known to be genetically determined. Several genes have been identified, including the gene for filamin 1 in X-linked bilateral periventricular nodular heterotopia, the LIS1 gene in lissencephaly, and the DCX (doublecortin) gene in several families with X-linked lissencephaly in hemizygous males, and subcortical band heterotopia in heterozygous females. Severe malformations of the cerebral cortex would thus lead to severe and mixed phenotypes (polymicrogyria, lissencephaly, etc.), while discrete malformations may only cause familial epilepsy.

Therapeutic approaches
The identification of several epilepsy genes, and the progress in the human genome sequence, will lead to the definition of new therapeutic strategies. First, pharmacogenomics [50] will lead to the determination of the relationship between interindividual genomic variability and variability in drug action. As about 30% of all patients with epilepsy do not respond well to antiepileptic drugs, this represent a major health care issue. New highly targeted, genotype-specific therapies, could thus be developed. As some epilepsies can be considered channelopathies, lessons could be learned from paroxysmal cardiac and muscle disorders that are due to mutations in ion channel genes. For example, it has been shown that mexiletine is more effective in long QT (LQT) phenotype associated with mutations in SCN5A (LQT3) than in LQT2 patients with mutations in KCNH2 [51]. Second, the genes that are mutated in human epilepsies represent obvious targets for the design of new drugs that would antagonize the epilepsy-causing mechanisms. In the case of the KCNQ2/KCNQ3 genes, a new drug, namely retigabine, acts as an activator of the M-currents via the opening of the heteromeric channel [52]. As the KCNQ2/KCNQ3 channels seem to be expressed in brain only, side effects (cardiac toxicity, for example) should be avoided. Moreover, the therapeutics provided by the study of rare epileptic disorders could benefit a large number of patients with polygenic inheritance, or even with little or no genetic determinant. Received April 22, 2002 Accepted July 2, 2002
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