Genetics of epilepsy

Introduction

The concept of a genetic predisposition to epilepsy was proposed over 40 years ago.[1] Twin studies have shown that genetic factors are particularly important in the generalized epilepsies but also play a role in the partial epilepsies.[2] The high frequency of monozygotic twins concordant with the same major syndrome suggests the existence of syndrome-specific determinants rather than a single broad predisposition to seizures.

Human genetic epilepsies can be categorized by mechanism of inheritance, whether they are idiopathic (primary) or symptomatic, whether they are generalized or partial and, where known, which class of gene is involved. The mechanism of inheritance identifies three major groups:

• mendelian epilepsies: mutations in a single gene can account for segregation of the disease trait
• non-mendelian or 'complex' epilepsies: several loci interact with environmental factors to produce the pattern of familial clustering. These include epilepsies which exhibit a maternal inheritance pattern due to mutations in mitochondrial DNA
• chromosomal disorders: in which the epilepsy results from a gross cytogenetic abnormality (see also).

The most commonly observed mendelian epilepsies arc 'symptomatic'. Recurrent seizures result from one or more identifiable structural lesions, and are often one component of a diverse neurological phenotype. Over 200 mendelian diseases include epilepsy as part of the phenotype, but the mechanism of seizure generation is often indirect.

The idiopathic epilepsies rarely display a mendelian inheritance pattern, but tend to show complex' inheritance and, often, age-dependant penetrance, with peak onset in childhood. Although rare, the idiopathic mendelian epilepsies have provided the major recent advances in the molecular basis of the epilepsies. Mutations have been identified in families segregating benign familial neonatal convulsions (BFNC), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), generalized epilepsy with febrile seizures plus (GEFS + ), childhood absence epilepsy with febrile seizures (CAE with FS), autosomal dominant partial epilepsy with auditory features (ADPEAF) and X-linked infantile spasms (ISSX) .

Other than ADPEAF and ISSX, all mutations occur in genes encoding ion channels, identifying some idiopathic mendelian epilep sies as channelopathies. These also demonstrate both locus heterogeneity (mutations in more than one gene causing the same clinical phenotype) and phenotypic heterogeneity (mutations in the same gene causing different clinical phenotypes). Successful determination of the molecular genetic basis of the common familial epilepsies has been relatively slow. No gene identified in a mendelian epilepsy has been shown to act as a major locus in any non mendelian epilepsy, and the extent of heterogeneity is likely to be far greater in the complex epilepsies.

Genes identified in idiopathic (primary) epilepsies
Gene class	Gene	Gene location	Epilepsy syndrome(s)	Inheritance	Key references
Voltage-dependent ion channels Sodium channels	SCN1A SCN2A SCN1B	2q24 2q23-q24 19q13	GEFS + SMEI GEFS +	AD	[3, 4, 5, 6]
Potassium channels	KCNQ2 KCNQ3 KCNA1	20q 8q24 12p13	BFNC EA1 with partial epilepsy	AD AD	[7, 8, 9, 10, 11]
Ligand-gated ion channels Nicotinic acetylcholine receptors	CHRNA4 CHRNB2	20q13.2 1p21	ADNFLE	AD	[12, 13, 14, 15]
6ABAA receptor	GABRG2 GABRA1	5q34 5q34	GEFS + FS with CAE ADJME	AD AD	[16, 17, 18]
Adhesive protein/receptor Leueine-rieh, glioma inactivated protein	LGI1	10q24	ADPEAF	AD	[19, 20]
Transcription factor Aristaless-related, homeobox gene	ARX	Xp22.3-p21.1	ISSX	X-linked	[21]
GEFSH , generalized epilepsy with febrile seizures plus; SMEI, severe myoelonie epilepsy of infancy; BFNC, benign familial neonatal convulsions; EA1, episodic ataxia type 1; ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; FS, febrile seizures; CAE, childhood absence epilepsy; ADJME, autosomal dominant juvenile myoclonic epilepsy; ADPEAF, autosomal dominant partial epilepsy with auditory features; ISSX, X-linked infantile spasms.

Strategies for molecular genetic analysis of childhood epilepsy

A range of approaches to the investigation of the molecular basis of human inherited disease have been most successful in mendelian diseases. Positional cloning, candidate gene identification and mutational analysis have allowed the identification of several mendelian epilepsy genes. The complex epilepsies have generally proved resistant to these strategies.

Strategies applied to mendelian diseases

Positional cloning

This approach uses linkage analysis to map a gene locus to a small chromosomal region. Linkage analysis tests polymorphic genetic markers distributed across the genome (a 'genome-wide' scan) for co-segregation (linkage) with the disease phenotype. A single large pedigree or several small pedigrees are required. A 'linked' marker has undergone few recombinations with the causative gene during meiosis and therefore lies on the same chromosomal segment. A physical map of a linked chromosomal region can then be constructed, and coding DNA sequences identified for mutation screening. Linkage analysis as a method for mapping disease genes in humans was revolutionized by the development of methods for detecting polymorphism at the DNA level and a comprehensive genetic marker map of the human genome consisting of 5264 simple sequence length polymorphisms.[22]

Positional cloning has led to the identification of disease genes for a large number of mendelian dis orders including several epilepsies . There has recently been some limited success in a non-mendelian disorder, Crohn disease.[23, 24] However, the statistical power of this approach is greatly reduced by genetic heterogeneity, uncertainty concerning the mode of inheritance and penetrance of disease alleles, and several other confounding factors. The family resource required is thus often unattainable, and linkage analysis has not yet led to the identification of a disease causing mutation in a non-mendelian epilepsy.

Candidate gene identification

Classes of candidate gene for human epilepsies can be identified from studies on the mechanisms of seizure generation, isolation of genes causing seizures in animal models of human epilepsy, and linkage and association studies in humans. There is much evidence for the role of ion channels and related proteins in neuronal excitability and seizure generation, and ion channel genes have been identified in several murine and human epilepsies. Over 220 ion channel genes have now been identified, of which at least 100 are neuronally expressed.

The neuronal ion channels are divided into those that are ligand-gated and those that are voltage-dependent (see also ). The former include the GABAA receptors, glutamate recep tors, neuronal nicotinic acetycholine receptors and lig and-gated potassium channels, whilst the latter include the voltage-dependent sodium, potassium, calcium and chloride channels. Once identified, the role of a candidate gene in the etiology of a genetic epilepsy can be examined either by linkage analysis or by direct mutational analysis of the gene in affected individuals.

Mutational analysis

Several methodologies are now available for the identifi eation of potential disease-causing mutations in candidate genes. These include single strand conformational polymorphism (SSCP), heteroduplex analysis, oligonu-eleotide arrays and direct sequencing. Functionally important regions of the gene are screened for mutations, and any identified sequence variant is then evaluated to determine its significance. The association of a mutation with the disease trait can be investigated both in family-based linkage studies and in population-based association studies.

The functional consequences of a sequence variation depend in part on the location relative to the gene, pathogenic mutations usually occurring within the coding sequence of the gene but also occurring in intragenic noncoding sequences or regulatory sequences outside exons. Similarly, a functional variant is likely to alter a highly conserved amino acid or affect a splice site or stop codon. Ultimately, the effect of a mutation on gene expression and protein function may be investigated using a variety of in vivo and in vitro techniques.

Strategies applied to non-mendelian diseases

The methods of linkage analysis and positional cloning which are so powerful when applied to mendelian disor ders are much less useful for those traits which display so-called 'complex' inheritance. Although there is increased familial clustering, segregation in families cannot be explained by the effect of a locus with dominant or recessive disease alleles. Interaction of several loci, each exerting a small effect, together with environmental factors is assumed. Such 'complex' traits include the common familial idiopathic generalized epilepsies.

Variation in the human genome

Two human genomes are, on average, 99.9 per cent identical. The 0.1 per cent which differs is mostly represented by so-called single-nucleotide polymorphisms (SNPs): single base pairs at which different alleles (bases) exist in normal individuals in some populations, with the minor allele frequency greater than 1 per cent. Most of these SNPs are 'neutral', but a subset with functional consequences are likely to include the allelic variation that accounts for common disease traits.

The second important issue is the nature and extent of linkage disequilibrium (LD) in the human genome. LD is the nonrandom occurrence of specific alleles at adjacent loci. Extensive blocks of ID arc present, at least in the northern European population, which create haplotypes between 25 and l00 kb long.[25] It appears that a small number of SNPs in each gene will allow the most common haplotypes of that gene present in a given population to be determined.

Genetic architecture of complex diseases

This has a major influence on the optimal strategy for detecting susceptibility loci responsible for 'complex' disease traits. Alleles at loci determining mendelian traits are rare (low frequency) and of major effect (highly penetrant). The same trait may be caused by rare, high-penetrance alleles at distinct loci (locus heterogeneity), and at a given locus many different disease alleles may occur (allelic heterogeneity).

Alleles at susceptibility loci are of small effect and likely to be of relatively high frequency (>1 per cent). The number of loci, the magnitude of their individual effect on risk, their mode of interaction and the number and population frequency of susceptibility alleles underlying any particular trait is unknown. Oligogenic traits with a few loci of significant effect represent one end of the spectrum, with truly polygenic traits caused by numerous loci of small effect at the other end. The 'common disease-common variant' hypothesis assumes that there is allelic homogeneity at each locus with the susceptibility allele present at high frequency (>5-10 per cent).[26]

Linkage or association

In linkage analysis co-segregation within pedigrees is sought between an anonymous polymorphism or candidate gene and a disease trait. Linkage can be carried out on large collections of nuclear pedigrees or affected sibling pairs. Unfortunately the power of linkage analysis is low if individual loci exert a small effect on the pheno-type, or if there is extensive locus heterogeneity.

Thus, adequate power to detect linkage can only be attained with numbers of pedigrees above the number it is practicable to ascertain. Numerous linkage analyses using a 'genome-wide' approach in other complex traits have failed to identify linked loci which have been highly significant (statistically), replicable or have led on to positional cloning of a susceptibility gene.

Anyhow, in 'complex' traits, linkage cannot provide high-resolution localization and positive results usually cover very large chromosomal regions. Association studies detect non-random associations between a trait and either an allele or group of alleles in linkage disequilibrium (a haplo type). The control sample of chromosomes can be taken from a population, or, transmission of alleles from a heterozygous parent can be analyzed (intrafamilial association).

Allelic association has greater power to detect susceptibility alleles of smaller effect, but is critically dependent on the 'common disease-common variant[24] hypothesis being true for a particular trait.[27] If a wide diversity of low-frequency alleles causes susceptibility, association would be difficult or impossible to detect.

Candidate gene or genome-wide search

Both linkage and association can be used to evaluate the role of candidate genes or used to scan the entire genome without making assumptions about the genes likely to be involved. Candidate genes are identified on functional grounds, based on the likely biological pathways involved in the trait. For idiopathic epilepsies it is possible to iden tify about 150 candidate genes encoding ion channels and related molecules.

Linkage analysis is undertaken using highly informative 'microsatellite' loci (usually dinucleotide repeats) either in or flanking the genes. Association analysis uses haplotype-tag SNPs, a set of 6-8 SNFs which identify the common haplotypes for the gene. These may or may not include the 'functional' SNPs which represent the actual disease-causing sequence variations.

For many 'complex' traits it is impossible to guess which genes are good candidates on functional grounds. The underlying biology is too obscure. Under these circumstances a 'genome-wide' scan is undertaken. For linkage this usually involves typing a grid of about 350 'microsatellite' loci which cover the entire genome at intervals of about 10 cM. In future, this will involve using a SNP-based HapMap, a map of haplotype 'blocks' in the genome-chromosomal regions within which a set of SNPs are in LD.

Technological factors

These strategies involve making several million observations: typing large numbers of SNPs in hundreds or thousands of individuals. Current methods for doing this are both slow and expensive, but new high-throughput procedures are developing rapidly.

Mendelian epilepsies

Over 200 mendelian diseases include epilepsy as part of the phenotype. The small number of primary epilepsies which are inherited in a mendelian fashion are described here. Although they account for only a small number of epilepsy cases, recognition of the characteristic features and presence of a family history enable a correct diagnosis to be made. Identification of genes responsible for some of these disorders has provided valuable insights into the molecular mechanisms underlying epilepsy.

Benign familial neonatal convulsions

Benign familial neonatal convulsions (BFNC), a rare autosomal dominant idiopathic epilepsy, was the first epilepsy to be localized by linkage analysis.[28]Seizures occur in otherwise well neonates from day 2 or 3 of life and remit by week 2-3. BFNC is a good illustration of both clinical and genetic heterogeneity, the latter of which can be explained by the underlying molecular genetics. The first locus (EBN1) was identified on chromosome 20q by linkage analysis in a 4-generation family with 19 affected individuals.[7] Six other pedigrees confirmed this linkage.[29] However, another family which showed linkage to EBN1 included members with seizures persisting up to 2 years of age, and in one individual, into adolescence.[30] Another family, none of whose members had seizures after 2 months of age, could be excluded from linkage to EBN1, and was subsequently linked to a second locus (EBN2) on chromosome 8q. [9]

The gene for EBN1, KCNQ2, was identified by characterization of a submicroscopic deletion on chromosome 20ql3.3 and shows significant homology with a voltage-dependent delayed rectifying potassium channel gene, KCNQ1.[8] Members of the KCNQ potassium channel family com prise six transmembrane-spanning segments (S1-S6), a pore-forming loop linking S5 and S6, and intracellular N- and C-termini. These channels are involved in the repolarization of the action potential and thus in the electrical excitability of nerve and muscle. Mutations in KCNQ1 can cause the paroxysmal cardiac dysrhythmias long QT syndrome and Jervell-Lange-Nielson cardioau ditory syndrome.[31, 32] Six allelic variants of KCNQ2 seg regate with the disease in families with BFNC, including one family whose affected members subsequently devel oped myokymia.[33] All mutations involve regions of the gene important for ion conduction.

Following identification of KCNQ2, a BLAST (basic local alignment search tool) search was made of the human expressed sequence tag (EST) database, to find cDNA sequences showing significant homology to KCNQ2. Rather fortuitously, a novel gene, KCNQ3, was identified with 69 per cent similarity to KCNQ2, which mapped to the EBN2 critical region on chromosome 8q24, and was found to be mutated in affected members of the BFNC/EBN2 family.[10] The missense mutation identified altered a conserved amino acid in the critical pore-forming region (the same amino acid found to be mutated in KCNQ1 in a patient with long QT syndrome).[31]

KCNQ2 and KCJNQ3 are co-expressed in most areas of the brain, especially the hippocampus, neocortex and cerebellum. They have been shown to co-assemble and form a heteromeric channel with essentially identical biophysical properties and pharmacologic sensitivities to the native neuronal M-channel.[34] The M-channel is a slowly activating and deactivating potassium conduc tance that plays a critical role in determining the sub threshold electroexcitability of neurons. Figure 4A. 1 shows how mutations in either KCNQ2 or KCNQ3 dis rupt the native M-current and result in an identical disease phenotype.

Benign familial infantile convulsions (BFIC)

This mendelian idiopathic epilepsy was first described as an autosomal dominant disorder in families of Italian origin,[35] and later in France and Singapore.[36, 37] Partial or generalized seizures commenced between 3 and 12 months. Response to conventional antiepilepsy drugs was good, with resolution of seizures and no psychomotor retardation.

Gene mapping has demonstrated locus heterogeneity. A locus,BFICI, was mapped to chromosome 19q.[38] A common haplotype was evident, suggesting a founder effect. A second locus, BFIC2, was mapped to 16pl2-ql2[39] and a third, BFIC3, to 2q24.[40] The disease genes have yet to he identified: it is possible that BFIC2 is an allelic variant of the gene causing infantile convulsions with choreoatheto sis (ICCA) which maps to the same region.

Familial infantile convulsions and paroxysmal choreoathetosis (ICCA)

First described in four families from northwestern France, benign infantile convulsions was inherited as an autosomal dominant trait combined with paroxysmal choreoathetosis. A genome-wide screen gave evidence of linkage to the pericentromeric region of chromosome 16 encompassing a l0cM interval 16pl2-q 12.[40]Confirmation of linkage to this region has subsequently been reported in a Chinese family.[41] Another phenotype, autosomal recessive rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp, maps to a region encompassed by the ICCA critical region.[42]

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)

First described in six families from Australia, Canada and the UK, ADNFLE is characterized by the occurrence of partial seizures almost exclusively during sleep.[43] There is a pronounced variation in severity among family members, and penetrance is incomplete (approximately 70 per cent). Seizures begin predominantly in childhood in individuals who are neurologically and intellectually normal, persist into adulthood, occur in clusters soon after falling asleep or before waking, and are characterized by brief tonic or hyperkinetic motor activity with retention of consciousness, although secondary generalization often occurs.

Linkage analysis in a single large Australian pedigree with 27 individuals assigned the gene to chromosome 20ql3.2.[12] The gene for the α 4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), CHRNA4, was known to map to the same chromosomal region, and also to be expressed in the frontal cortex. Mutational analysis of CHRNA4 identified a missense mutation that co-segregated with the disease in the chromosome 20-linked family[13] The mutation converts a serine to phenylalanine in the M2 transmembrane domain, a crucial structure mediating ionic permeability, and is likely to be disease causing. Further site specific mutations in CHRNA4 affecting pore-forming amino acids have been associated with ADNFLE.[14, 44, 45, 46, 47]

In another family, a second locus was mapped to chro mosome 15q24.[48] A cluster of nAChR genes (CHRNA3/ CHRNA5/CHRNB4) in this region seemed good candi dates, but no mutations were identified in the pore-forming regions. However, mutations have been identified in the gene for the (32 subunit of the nAChR, CHRNB2, on chromosome lp21.[15, 49] The main neuronal nAChR has a heteropentameric structure comprised of α 4 and (32 subunits. Thus mutations in the pore-forming M2 domains of both CHRNA4 and CHRNB2 can pro duce similar functional effects causing the ADNFLE phenotype.

Generalised epilepsy with febrile seizures plus severe myoclonic epilepsy of infancy(GEFS + )

GEFS + was first described in 1997.[50] Geneological infor mation was obtained on 2000 family members dating back to the mid-1700s, and clinical information on 289 individuals, of whom 28 had seizures. The commonest phenotype comprised a childhood onset of multiple febrile seizures persisting beyond the age of 6 years, as well as a spectrum of afebrile seizures including absences, myclonic seizures, atonic seizures and rarely myoclonic-astatic epilepsy. Inheritance was autosomal dominant. A second family with GEFS+ was linked to chromosome 19ql3.1, and a point mutation identified in SCN1B, which encodes the ß1 subunit of the voltage-gated sodium channel.[5]

Neuronal voltage-gated sodium channels contain a large α subunit associated with two smaller ß subunits. The pore-forming α subunit contains four homologous domains each containing six membrane-spanning units. The ß subunits contain a single transmembrane region, modulate the gating properties of the channel and are required for normal inactivation kinetics. Mutations in α subunit genes cause several paroxysmal disorders of muscle, including hyperkalemic periodic paralysis, paramyotonia congenita (SCN4A) and long QT syn drome (SCN5A).[51] Sodium channels are also modulated by AEDs such as phenytoin and carbamazepine.[52] They are thus good candidate genes for epilepsy.

The SCN1B mutation segregated with disease status in the 19q 13.1-linked GEFS+ family. It changes a conserved cysteine residue that disrupts a disulfide bridge normally maintaining an extracellular immunoglobulin-like fold in the ß subunit. After some intermediary effects, this results in persistent inward neuronal sodium currents, increased membrane depolarization, and neuronal hyperexcitabil ity. This may also exaggerate the normal effects of tem perature on both conductance and gating of neuronal sodium channels, explaining the apparent temperature dependence of the GEFS+ phenotype.

Two further families with GEFS+ showed linkage to chromosome 2q24, and mutations were identified in SCN1A, the gene encoding the sodium channel al sub unit.[3] De novo mutations in this gene have also been identified in patients with severe myoclonic epilepsy of infancy (SMEI), which also involves fever-associated seizures.[4] Many patients with SMEI have a family his tory of seizures consistent with the spectrum of seizure phenotypes seen in GEFS + , suggesting that SMEI is the most severe phenotype in the GEFS+ spectrum.[53] A mutation in the gene encoding the α2 sodium channel subunit, SCN2A, has now been identified in a patient with febrile seizures associated with afebrile seizures, consistent with GEFS + . This mutation also slows channel inactivation, suggesting involvement in the epilepsy phenotype.[6]

The GEFS+ phenotype is not only caused by muta tions in voltage-gated sodium channels. In one large GEFS+ family, mutations have been identified in the GABAA receptor γ subunit gene, GABRG2.[16] Binding of GABA opens an integral chloride channel, with resultant inhibition of neuronal activity. The GEFS+ mutation substitutes a serine for a methionine in the extracellular loop between transmembrane segments M2 and M3. Mutations in GABRG2 also cause a phenotype of child hood absence epilepsy and febrile seizures.

Autosomal dominant partial epilepsy with auditory features

Autosomal dominant partial epilepsy with auditory features (ADPEAF) was first described in a three-generation family with an idiopathic/cryptogenic epilepsy.[54] Starting between 8 and 19 years, infrequent, both simple and par tial complex seizures progressed to secondarily general ized tonic-clonic seizures. Six of the 11 affected members reported auditory disturbances as a simple partial com ponent of their seizures. A genome screen identified link age over a 10-cM region on chromosome 10q23.3-24.[54] This region was narrowed to 3 cM by a genome screen in a large family segregating lateral temporal lobe epilepsy with auditory and visual features.[55]

Construction of a physical map identified 28 putative genes of which 21 were sequenced in an affected individual from three families, and mutations subsequently checked in a further two families.[19] Mutations were identified in the leucine rich, glioma-inactivated 1 gene (LGI1) in all affected individuals and obligate carriers, as well as six unaffected members, consistent with a 71 per cent disease penetrance. The five mutations identified were not present in 123 unrelated controls.

LGI1 is a member of the leucine-rich repeat (LRR) superfamily, in particular the adhesive proteins and receptors. The LGI1 protein consists of an extracellular domain with LRR repeat motifs, a transmembrane segment and an intracellular segment of unknown function.[56] The extracellular portion aligns most closely with a group of proteins involved in CNS development and in which the LRRs bind nerve growth factor and other neu-rotrophins.

Interestingly, a C-terminal repeat motif, now referred to as the EAR (epilepsy-associated repeat) domain, has been identified in both LGI1 and the MASS1 gene, which is mutated in the Frings mouse model of audio genic epilepsy.[20] This EAR domain is likely to play a role in the pathogenesis of epilepsy. LGI1 is expressed pre dominantly in brain, muscle and spinal cord. Of the five mutations identified in ADPEA, three were missense mutations with predicted premature truncation of the LGI1 protein, one was a nonsynonymous point mutation in the highly conserved extracellular and C-terminal region, and one was an intronic mutation predicted to alter a splice site. LGI1 is therefore the first non-ion-channel gene identified as causing an idiopathic epilepsy in humans.

Familial partial epilepsy with variable foci(FPEVF)

This idiopathic epilepsy displays autosomal dominant inheritance with reduced penetrance and locus heterogeneity. In an Australian pedigree, linkage with chromosome 2 was suggested,[57] and, subsequently, in two large French-Canadian families, with chromosome 22qll-ql2[58] Recurring partial seizures originate from different cortical areas, usually in the frontal or temporal lobes. The epileptic focus varies between family members.

Infantile spasms (West syndrome)

Infantile spasms are divided into those that are sympto matic and those that are cryptogenic or idiopathic. The majority (70-80 per cent) are symptomatic and may be attributed to a prenatal, perinatal or postnatal cause, of which prenatal etiologies are the most common (50 per cent). Many of these are genetically determined, including disorders of brain development, neurocutaneous syndromes, metabolic disorders and chromosomal abnor malities. These conditions are dealt with elsewhere.

Most cases of idiopathic infantile spasms are sporadic, and the recurrence risk is less than 1 per cent.[59] However, several familial cases have been identified consistent with X-linked inheritance. Feinberg and Leahy first reported live affected males in four sibships of a three-generation family[60] Subsequently, five further families have been identified, some of which also include individuals with X linked mental retardation without infantile spasms.[21, 61] Linkage analysis in these families mapped the disease gene to chromosome Xp21.3-Xp22.1.[62, 63, 64]

The aristaless related homeobox gene, ARX, was considered a candidate on the basis of its expression pattern in fetal, infant and adult brain. Screening of this gene identified mutations in four of the five families with infantile spasms.[21] Mutations were also identified in five families with mental retardation together with myoclonic seizures or dystonia, hut no infantile spasms. Two recurrent mutations identi fied in seven of the nine families result in expansion of polyalanine tracts of the ARX protein. These are likely to cause protein aggregation, as has been demonstrated in other human diseases caused by alanine expansions.[65] Homeobox-containing genes are known to be important in the regulation of key stages of development. ARX encodes one of a class of proteins incorporating a C-terminal aristaless domain thought to be particularly important in the differentiation and maintenance of specific neuronal subtypes in the cerebral cortex.[66]

Non-mendelian epilepsies

Juvenile myocloic epilepsy(JME)

JME accounts for 5-10 per cent of all epilepsy. It was first described as a distinct electroclinical syndrome in 1957.[67] In addition to myoclonic seizures, which occur predominantly in the morning, nearly all affected individuals have generalized tonic-clonic seizures, often fol lowing a series of myoclonic jerks, and about 20-40 per cent have absence seizures. Photosensitivity is common.

A genetic contribution to the etiology of JME is well established,[67, 68, 69, 70] but the mode of inheritance is uncer tain. Autosomal dominant[71] autosomal recessive1 and two-locus models have all been proposed[72] Evidence for linkage of the JME trait to the serologic markers HLA and properdin factor B on chromosome 6p was first found in 1988,[73] and the locus designated EJM1. Subse quently confirmation was obtained in a separately ascer tained group of 23 families using HLA serologic markers.[74] Analysis of a subset of these families, together with one new family, using HLA-DQ restriction fragment length polymorphisms (RFLPs), gave similar results.[75] Further work on a larger group of families confirmed linkage to the serologic markers HLA and properdin factor B, with a maximum lod score of 4.2 obtained at^Ө m,f (recombina tion fraction) of 0.01.76 Another study in a single large pedigree, using microsatellite markers on chromosome 6p, gave a maximum lod score of 3.67 (Ө = 0) between the marker D6S257 and a trait defined as the presence of clinical JME or an EEG showing diffuse 3.5-6 Hz multi-spike and slow wave complexes[76] In addition, linkage analysis in 28 families ascertained through a JME patient in which family members with IGE were classified as affected gave a lod score for the DQB1 locus of 4.2 at Өm,f = 0.5,0.1. The linkage pattern observed suggested heterogeneity and an excess of transmission from mothers.[77]

Two studies from a single group have failed to find evidence for the existence of a locus on chromosome 6p [78, 79]These results suggest that genetic heterogeneity may exist within the JME phenotype.

Chromosomal regions harboring genes for subunits of the neuronal nicotinic acetylcholine receptor were tested for linkage to the JME trait in 35 pedigrees. Two-point lod scores were negative for all loci except D15S128 and D15S118 on chromosome 15ql4. Seven additional marker loci encompassing a 20.1-cM region were selected in order to investigate this region further. A maximum multipoint lod score of 4.18 was obtained under the assumption of heterogeneity at α = 0.64 (where a is the proportion of linked families). Analysis of recombinant events defined the 10-cM interval between DI5S 144 and D15S1012 as being the region in which the gene lies. The α 7 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA7) maps within this interval and therefore represents an excellent candidate gene. These results indicate that a major susceptibility locus for JME may map to this region of chromosome 15q.[80]

More recently, linkage analysis with 7 microsatellite markers encompassing the CHRNA7 region failed to replicate evidence of linkage in 11 families with at least two JME members. No evidence in favor of linkage to 15ql4 was found under a broadened diagnostic scheme in 21 families of JME probands or in 30 families of probands with idiopathic absence epilepsy.[81] A sub sequent study has clarified the linkage data in relation to the current map of the region under study.[82] The CHRNA7 gene and its partial duplication CHRFAM7A were screened for mutations, but no causative sequence variants could be identified.

Linkage analysis in an extended autosomal dominant JME pedigree mapped the locus to 5q34, and a missense mutation (Ala 322 Asp) was identified in the GABRA1

Childhood absence epilepsy (CAE)

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In CAE a genetic component is well established, but the mechanism of inheritance and the genes involved are unknown. Studies of familial clustering indicate that CAE has a 'complex' non-mendelian mode of inheritance.[83] Approximately 1.6 per cent of siblings of probands with CAE will have absence epilepsy, giving a λs (the risk to a sibling of an affected proband compared with the population risk) of at least 27.[84] However one segregation analysis was consistent with autosomal dominant inheritance with reduced penetrance.[85] From studies on the mechanism by which spike-wave seizures are generated; isolation of genes causing spike-wave seizures in rodents; and initial linkage and association studies in humans, a number of candidate genes and chromosomal regions can be identified for CAE.

Possible mechanisms for the generation of abnormal spike-wave activities in cortical and thalamic neurons include the loss of GABAA receptor-mediated inhibition between thalamic reticular cells, strong activation of tha lamic GABAergic neurons by corticothalamic or thalamo cortical afferents, or the enhancement of the low-threshold Ca2+ current.[86, 87, 88, 89, 90] Four mouse models of spike-wave epi lepsy are caused by mutations in genes for different sub units of voltage-dependent calcium channels (VDCCs): tottering tg, Cacnala;[91] lethargic ih, Cacnb4;[92] stargazer stg, Cacng2;[93] ducky du, Cacna2d2.[94]

In addition, an asso ciation has been documented between polymorphisms in CACNA1A and ICE including CAE,[95] and novel CACNAIA mutations have been identified in a boy with episodic ataxia type 2 and absence epilepsy,[96] and in another boy with progressive and episodic ataxia, learning difficulties and absence epilepsy.[97]

Linkage analysis of a five-generation family in which affected patients had a persisting form of CAE provided evidence for a locus on chromosome 8q24.[98] The candi date region for this locus, designated ECAl, has been refined, but a gene remains to be identified.[99] Study of another extended pedigree in which affected individuals manifested both CAE and febrile seizures revealed a linked marker on chromosome 5 close to a cluster of genes encoding GABAA receptor subunits.[17] A mutation was found in GABRG2 which changes a conserved amino acid and this appeared to contribute to the CAE pheno type. Mutations in this gene have also been identified in a family segregating GEFS + .[16]

A possible association has also been documented between a polymorphism in GABRB3 and patients with CAE,[100] and suggestive linkage to this gene found in eight families.[101] GABRB3 maps to 15qll-ql3, the region deleted in Angelman syn drome,[102] and mice with targeted disruption of the GABRB3 gene have the epilepsy phenotype and behav ioral characteristics of Angelman syndrome.[103]

The hypothesis that mutations in genes encoding GABAA receptor subunits, GABAB receptors or brain expressed voltage-dependent calcium channels, as well as unidentified candidate genes in the ECAl region on chromosome 8q24, may underlie CAE was tested by linkage analysis in 33 families.[104] Twenty-seven of 29 genes tested, as well as the ECAl region, were excluded as major loci in these families. One voltage-dependent calcium channel gene, CACNG3 on chromosome 16pl2-pl3.1, and the cluster of GABAA receptor genes, GABRA5, GABRB3, and GABRG3 on chromosome 15qll-ql3, could not be excluded.

Benign childhood epilepsy with centrotemporal spikes (BCECTS)

BCECTS was first described in 1958.[105] Seizures begin between the ages of 3 and 13 in a child who is neurologi cally intact. Typically, they often occur at night and are preceded by a somatosensory aura around the mouth and followed by excessive salivation and speech arrest with retention of consciousness. Unilateral motor seizures of the face follow and can progress to a second ary generalization.[106] The pattern of the seizures varies diurnally, with nocturnal seizures more likely to general ize secondarily.[107] Seizures rarely persist beyond the age of 16 years. The EEC is characteristic. About 20 per cent of children who have Rolandic discharges on EEG will not have seizures.[108]

A family history of epilepsy is common, although the proportion varies from study to study, from 9 to 59 per cent.[109, 110] In families of 40 patients with seizures and centrotemporal spikes, 36 per cent of siblings and 19 per cent of parents had focal epileptiform activity on the EEG [111] In a further 19 probands with BCECTS,[112] 15 of 34 siblings had Rolandic discharges and seizures, and a further 19 per cent had Rolandic discharges in isolation. These findings tend to support the suggestion of an autosomal dominant gene with age-dependent penetrance.

Generalized epileptiform activity has also been found in the EEGs of 26 out of 69 (38 per cent) siblings of 43 probands with BCECTS.[113] Among those siblings aged 3-12 years, 54 per cent had abnormal EEGs: the proportion declined in the younger and older age groups. This pattern of age-dependent penetrance and the finding of generalized EEG abnormalities in the siblings of patients has led to the suggestion that BCECTS and absence epilepsy may be linked.[114]

Twenty-two nuclear families segregating BCECTS were examined for linkage to chromosomal regions known to harbor neuronal nicotinic acetylcholine receptor (nAChR) subunit genes. Evidence was found for linkage with heterogeneity to a region on chromosome 15ql4 in the vicinity of the α 7 nAChR subunit gene, CHRNA7.[115]

Febrile seizures

Susceptibility to febrile seizures clearly has a strong genetic basis, and a significant proportion of patients have a family history of febrile convulsions or other epilepsies. The proportion of probands with an affected first-degree relative has been estimated as between 8 per cent and 49 per cent.[116, 117] The mode of inheritance seems to depend on the frequency of febrile seizures in the proband.

Complex segregation analysis performed on 467 nuclear families, ascertained through probands with febrile seizures, showed clear evidence for polygenic inheritance in those families in which the proband had a single febrile seizure,[116] where the heritability of liability was estimated at 68 per cent. However, in the families of probands with more than three febrile seizures, there appeared to be a single major locus contributing to seizure susceptibility. Another study of the families of 52 probands with febrile seizures found that 40 families (77 per cent) had at least one further affected member, and this was consistent with an autosomal dominant mode of inheritance with reduced penetrance (64 per cent).[118]

The investigation of large pedigrees has led to the identification of several putative loci: FEB1 on chromo some (Sql3-q21;[119] FEB2 on chromosomel9pl3.3;[120] FEB3 on chromosome 2q23-24;[121] and FEB4 on chro mosome 5ql4-ql5.[122] A mutation in GABRG2 was iden tified in a family whose individuals manifested febrile seizures with or without CAE.[5] Febrile seizures occur as a part of the syndrome of GEFS + , for which several genes have been identified. The phenotype of the FEB2 family did resemble GEFS + , and FEB2 may correspond to one two of the two GEFS + loci on chromosome 2q.

Genetic counselling

The provision of genetic counseling requires knowledge of the mode of inheritance and recurrence risk of a particular epilepsy syndrome. The wide variety of conditions in which epilepsy can occur necessitates a completely accurate diagnosis. Any associated symptoms and signs must be considered and appropriate investigations arranged to differentiate a symptomatic from an idiopathic epilepsy, identify any underlying structural lesion and define the epilepsy syndrome involved. Construction of a pedigree may suggest the mode of inheritance, and in some cases help to diagnose a particular epilepsy syndrome.

For epilepsies displaying mendelian inheritance, the increasing availability of DNA-based diagnostics will allow presymptomatic diagnosis of individuals at risk. However, variable penetrance introduces an element of uncertainty. In the more common familial epilepsies displaying complex inheritance, the identification of susceptibility genes should help to delineate specific epilepsy syndromes and allow DNA analysis to improve the accuracy of recurrence risk calculation. However, at present, recurrence risks remain empirical.

The overall incidence of epilepsy in the offspring of epileptic parents is between 1.7 and 7.3 per cent, including febrile seizures and single seizures.[123] This compares with a cumulative incidence of epilepsy in the general population up to the age of 40 years of approximately 1.7 per cent.[124] However, unless the pedigree reveals a particular inheritance pattern, the recurrence risk quoted must depend on available information for the particular epilepsy concerned. Table 4A.2 provides a guide to recurrence risks to offspring or siblings for particular epilepsy diagnoses, although the diagnostic criteria used in the various studies are not always consistent.

The future

The major challenge is the identification of susceptibility genes for the common familial epilepsies. Publication of the draft version of the complete human genome sequence was a significant advance, but huge challenges remain in the field of human genomics. These include completion of the human genome sequence, annotation of the genome by assigning function to all genes, and characterization of the pattern and extent of human genetic variation. Approximately 50 per cent of putative gene products have been tentatively assigned functions, leaving almost 13 000 predicted proteins of unknown function. Similarly, the pattern and extent of LD across the human genes is only just beginning to emerge.

Data indicate that extensive blocks of LD are present, often allowing the main haplotypes of a particular gene to be determined by a small number of SNPs. The current efforts to generate a SNP map of the human genome should allow the identification of susceptibility loci by association analysis, as long as the genetic architecture of the common epilepsies is favorable. However, DNA from large collections of well-characterized patients may be required to reveal small genetic contributions to diseases. Some encouragement is provided by the identification of a gene for another complex disease, Crohn's disease.[23, 24] If the underlying biology is favorable, this could provide a model for the identification of susceptibility genes for the complex epilepsies.

Risk of epilepsy in children and siblings of subjects with epilepsy
Epilepsy	Parent affected (o/o)	Sibling affected (°/o)	Reference
Juvenile myoclonic epilepsy	5.1-14.8	4.4-7	[69, 123, 125]
Childhood absence epilepsy	6.7-6.8	4.9-10	[84, 123, 126, 127]
Benign epilepsy with centrotemporal spikes	11 (incidence in parents of affected child)	15	114
Photosensitive epilepsy	7 (females) 1.8 (males) (incidence in parents of affected child)	9 (female) 6.5 (male)	[128]
Infantile spasms	0.7 (all first-degree relatives)	1.5-25	[60, 61, 129]

Success in determining the molecular genetic basis of the common familial epilepsies will provide a greater understanding of the physiological defects involved. Improved diagnosis and the development of new targets for AEDs should follow. In the long term, microarray analysis of multiple susceptibility genes in an individual will allow a precise molecular diagnosis to be made, and a drug prescribed that is specifically designed for the particular electrophysiological dysfunction present.

Key points

• At least 40 per cent of all epilepsies are genetic in origin, with the proportion being higher in epilepsies of childhood onset .
• Human genetic epilepsies may be categorized as mendelian epilepsies, non-mendelian or 'complex' epilepsies, and epilepsies associated with chromo somal disorders.
• Twelve genes causing idiopathic mendelian epilepsies in humans have been identified, of which ten encode ion channels and cause idio pathic generalized epilepsies.
• Novel strategies will be required for identification of susceptibility genes for the common familial epilepsies displaying complex inheritance.
• Identification of susceptibility genes for epilepsy allows new approaches to diagnosis and treatment.

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     Robert Robinson and R Mark Gardiner Chapter 4a Genetics

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