Refined mapping of the epilepsy susceptibility locus EJM1 on chromosome 6.

Juvenile myoclonic epilepsy (JME) is a genetically determined common subtype of idiopathic generalized epilepsy. Linkage to the HLA complex on chromosome 6p21.3 and an allelic association with HLA-DR13 and -DQB1 alleles suggest that a susceptibility locus for JME, designated as "EJM1," is located within or near the HLA region. However, further studies revealed controversial results, and genetic heterogeneity has been suspected. The present study was designed to evaluate the validity of the association and linkage findings and to refine the map position of EJM1. Our association analysis showed no significant difference of the frequency of HLA-DR13 carriers in 62 German JME patients compared with that in 77 German controls (X2 = 0.98, df = 1, p = 0.161, one-tailed). Multipoint linkage analysis with use of microsatellite markers from the chromosomal region 6p25-q13 in 29 German families of JME patients provided significant evidence that an epilepsy locus (EJM1) close to the HLA locus confers susceptibility to "idiopathic" generalized seizures (Zmax = 3.27 at theta max = 0.033 centromeric to the HLA-DQ locus), assuming an autosomal dominant mode of inheritance with 70% penetrance. Haplotype analyses revealed key recombinations in five families, which locate EJM1 to the centromeric side of the HLA-DQ locus. This study confirms a causative role of EJM1 in the pathogenesis of idiopathic generalized seizures in the majority of German families of JME patients and refines a candidate region of 10.1 cM in the chromosomal region 6p21 between the flanking loci HLA-DQ and D6S1019. A possible explanation for the current controversial results in families of different populations might be ethnic variation of interfering polygenic effects that could be permissive for heterogeneous susceptibility alleles.

Allelic association of juvenile absence epilepsy with a GluR5 kainate receptor gene (GRIK1) polymorphism.

Juvenile absence epilepsy (JAE) is a common subtype of idiopathic generalized epilepsy (IGE). Hereditary factors play a major role in its etiology. The important function of glutamate receptors (GluRs) in excitatory neurotransmission, synaptic plasticity, and neurodevelopment suggests their involvement in epileptogenesis. A tetranucleotide repeat polymorphism in the non-coding region of the kainate-selective GluR5 receptor gene (GRIK1) on chromosome 21q22.1 provides the tool to investigate this candidate gene. The present association and linkage study tested the hypothesis that allelic variants of GRIK1 confer genetic susceptibility to the pathogenesis of JAE. Our family-based association analysis using the haplotype-based haplotype relative risk statistic revealed an association of JAE with the nine-repeat containing allele of the GRIK1 tetranucleotide polymorphism (chi2 = 8.31, df = 1, P = 0.004). Supportive evidence for linkage to a JAE related IGE spectrum (Zmax = 1.67 at GRIK1) under an autosomal dominant mode of inheritance and significant allele sharing (P < 0.05) among the affected family members suggest that allelic variants of GRIK1 contribute a major genetic determinant to the pathogenesis of JAE-related phenotypes.

Linkage analysis between idiopathic generalized epilepsies and the GABA(A) receptor alpha5, beta3 and gamma3 subunit gene cluster on chromosome 15.

INTRODUCTION: We tested the hypothesis that genetic variants within the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster on chromosome 15q11-q13 confer genetic susceptibility to common subtypes of idiopathic generalized epilepsy (IGE). MATERIAL AND METHODS: Ninety-four families were selected from IGE patients with either juvenile myoclonic epilepsy (JME), juvenile (JAE) or childhood absence epilepsy (CAE). Cosegregation was tested between dinucleotide polymorphisms associated with the human GABA(A) alpha5, beta3 and gamma3 subunit gene cluster and three different IGE trait models. RESULTS: Evidence against linkage to the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster was found in the entire family set and subsets selected from either CAE or JAE. In 61 families of JME patients, a maximum lod score (Zmax=1.40 at Theta(max)=0.00) was obtained for a broad IGE spectrum ("idiopathic" generalized seizure or generalized spike and wave discharges in the electroencephalogram) assuming genetic heterogeneity (alpha=0.37; P=0.06) and an autosomal recessive mode of inheritance. CONCLUSION: The possible hint of linkage in families of JME patients emphasizes the need for further studies to determine whether a recessively inherited gene variant within the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster contributes to the pathogenesis of "idiopathic" generalized seizures and associated EEG abnormalities in a proportion of families.

Lack of linkage between idiopathic generalized epilepsies and the gene encoding the neural cell adhesion molecule.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). The frequent neuropathological occurrence of microdysgeneses in the brain of IGE patients implies that genes regulating neural migration and cell adhesion might be involved in epileptogenesis of age-related generalized seizures. Our present linkage study tested the hypothesis that DNA sequence variants associated with the gene encoding the neural cell adhesion molecule (NCAM) confer genetic susceptibility to IGE traits in 57 families ascertained through patients with either juvenile myoclonic epilepsy, juvenile or childhood absence epilepsy. Our consistently negative results provide evidence against a common major effect of NCAM gene variants to the expression of IGEs with age-related onset from childhood to adolescence.

Exclusion of linkage between idiopathic generalized epilepsies and the GABAA receptor alpha 1 and gamma 2 subunit gene cluster on chromosome 5.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). The pivotal function of ionotropic gamma-aminobutyric acid type A receptors (GABRs) in inhibitory neurotransmission in the mammalian central nervous system suggests that they may be involved in epileptogenesis and genetic predisposition to IGEs. Dinucleotide repeat polymorphisms associated with the human GABAA receptor alpha 1 (GABRA1) and gamma 2 subunit (GABRG2) gene cluster on chromosome 5q32-q35 offer the opportunity to test whether these candidate genes confer susceptibility to IGEs. Our linkage analyses in 63 families ascertained through IGE patients with either juvenile myoclonic epilepsy, juvenile absence epilepsy or childhood absence epilepsy do not support the hypothesis that variants within the GABRA1 and GABRG2 gene cluster contribute a frequent major gene effect to the expression of the common familial IGEs.

Common subtypes of idiopathic generalized epilepsies: lack of linkage to D20S19 close to candidate loci (EBN1, EEGV1) on chromosome 20.

Hereditary factors play a major role in the etiology of idiopathic generalized epilepsies (IGEs). A trait locus (EBN1) for a rare subtype of IGEs, the benign neonatal familial convulsions, and a susceptibility gene (EEGV1) for the common human low-voltage electroencephalogram have been mapped close together with D20S19 to the chromosomal region 20q13.2. Both loci are potential candidates for the susceptibility to IGE spectra with age-related onset beyond the neonatal period. The present study tested the hypothesis that a putative susceptibility locus linked to D20S19 predisposes to spectra of IGEs with age-related onset from childhood to adolescence. Linkage analyses were conducted in 60 families ascertained through IGE patients with juvenile myoclonic epilepsy, juvenile absence epilepsy or childhood absence epilepsy. Our results provide evidence against linkage of a putative susceptibility gene for four hierarchically broadened IGE spectra with D20S19 assuming tentative single-locus genetic models. The extent of an "exclusion region" (lod scores below-2) varied from 0.5 cM up to 22 cM on either side of D20S19 depending on the trait assumed. These results are contrary to the expectation that a susceptibility gene in vicinity to D20S19 confers a common major gene effect to the expression of IGE spectra with age-related onset from childhood to adolescence.

Do idiopathic generalized epilepsies share a common susceptibility gene?

Molecular genetic research in epilepsy is most promising in the homogeneous, genetically determined forms of the disease. The phenotype-genotype strategy used makes some epileptic syndromes more suitable for such study than others. Unequivocal clinical presentation, mendelian transmission with similar clinical expression in close relatives, and sufficiently large numbers of affected families are requisites. This makes idiopathic generalized epilepsies (IGEs), particularly absence and juvenile myoclonic epilepsies (JMEs), suitable subtypes for genetic analysis. Results of family studies to date show that five IGE syndromes have a common genetic origin. Linkage studies have localized a gene defect on chromosome 6p that predisposes to a group of IGEs: JME, absence epilepsy, and generalized tonic-clonic seizures in epilepsy families with JME probands. Environmental and additional genetic factors are other areas requiring further study to elucidate the discriminant factors associated with different varieties of IGE.

Localization of idiopathic generalized epilepsy on chromosome 6p in families of juvenile myoclonic epilepsy patients.

Juvenile myoclonic epilepsy (JME) is a distinct subform of idiopathic generalized epilepsy of adolescence. Linkage studies with Bf and serologic HLA markers in families of JME patients have shown a tight linkage on chromosome 6. We present a linkage analysis with HLA-DQ restriction fragment length polymorphisms on more extended families, paying particular attention to the epilepsy type of the affected family members. We studied 21 families of JME patients with a total of 143 family members and obtained a highest logarithm of the odds (lod) score of 3.9 (theta m = 0.01, theta f = 0.01) assuming a dominant mode of inheritance and 70% penetrance when family members with JME, absence epilepsy, or epilepsy with generalized tonic-clonic seizures (GTCS) were considered as affected. When we also classified clinically normal family members with generalized spike-wave discharges in the EEG as "affected," the maximum lod score was 4.1 (theta m = 0.01, theta f = 0.3) under a dominant mode of inheritance and 90% penetrance. These findings support the conclusion that a gene locus for a group of idiopathic generalized epilepsies (JME, epilepsy with absences, and epilepsy with GTCS) maps to chromosome 6p.

Change of seizure frequency in pregnant epileptic women.

The effect of pregnancy on seizure frequency was monitored prospectively in 136 pregnancies of 122 epileptic women. Pregnancy did not influence the seizure frequency in 68 pregnancies (50%). In 50 pregnancies (37%) the number of seizures increased during pregnancy or puerperium. The seizure frequency decreased in 18 pregnancies (13%). In 34 out of 50 pregnancies (68%) the increase was associated with non-compliance with the drug regimen or sleep deprivation. In seven out of 18 pregnancies (39%) improvement was related to correction of non-compliance or sleep deprivation during the pregestational nine months. Insufficiently low plasma concentrations of antiepileptic drugs were found in 47% of the women with uncontrolled epilepsy during pregnancy. The course of epilepsy during pregnancy is primarily influenced by non-compliance, sleep deprivation during pregnancy, and inadequate therapy before and during pregnancy. With good medical attention pregnancy itself seems to have only a minimal influence on the course of epilepsy.

Teratogenic and pharmacokinetic studies of primidone during pregnancy and in the offspring of epileptic women.

Fourteen epileptic women treated with primidone, either alone or in combination with other antiepileptic drugs, were studied prospectively during their pregnancy. Plasma levels of primidone and its metabolites were monitored and correlated to findings in the offspring. Maternal serum concentrations of primidone and metabolites were generally low during pregnancy. The levels of its main metabolites--phenobarbital and PEMA--were found to drop within the first month of pregnancy in two cases. The plasma concentrations remained low until birth and rose sharply thereafter. The phenobarbital/primidone ratio (mean 0.84) and PEMA/primidone ratio (mean 0.56) in pregnant patients were found to be lower than in non-pregnant patients, except when primidone was given in combination with phenytoin in which case the expected phenobarbital/primidone (mean 2.5) and PEMA/primidone (mean 1.5) ratios were found. A ventricular septal defect was found in one of the offspring of the fourteen mothers and five children had microcephaly. There was a high incidence of poor somatic development with dystrophy (n=3) and short stature (n=2). Head circumferences (n=8), lengths (n=4) and/or weights (n=8) were below the 10th percentile in a number of children. Four children showed marked facial dysmorphy. Our preliminary data suggest that primidone intake during pregnancy may be important in the pathogenesis of minor anomalies and in the induction of poor somatic development.