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PubMed2002

Association of mu-opioid receptor subunit gene and idiopathic generalized epilepsy.

OBJECTIVE: To replicate and extend the previously reported association between the opioid receptor mu subunit gene (OPRM1) and idiopathic absence epilepsy (IAE), using a sample of 230 probands with idiopathic generalized epilepsy (IGE). BACKGROUND: In humans and in animal models, several lines of evidence implicate opioid receptors with seizures. The G118 allele of OPRM1 was associated with IAE (p = 0.019). METHODS: Three single nucleotide polymorphisms (SNP) of OPRM1 were investigated by association studies with IGE using a case/control design, one of which also used a within-family design. RESULTS: Association was found for G118 with IGE (p = 0.00027, odds ratio [OR] = 1.86), replicating the previous association. Within-family tests of linkage and association (haplotype-based haplotype relative risk and transmission disequilibrium test) confirmed this result. Further evidence for involvement of OPRM1 in IGE was provided by an association with G-172T, located in the 5' untranslated region (p = 0.0015, OR = 2.36). Haplotypes of the two SNPs were associated with IGE with a greater level of significance (p = 0.000087) suggesting that both SNPs might be in linkage disequilibrium with a single functional variant. Analysis of the results by subgroups of IGE showed association with all subgroups tested. CONCLUSIONS: These results confirm the previous association and support the hypothesis of a role for OPRM1 in IGE, including absence syndromes. However, the authors found no evidence for a specific association between OPRM1 and idiopathic absence epilepsy. The data suggest that the functional variant predisposing to IGE is located within 60kb of exon 1.

Adult↗

PubMed1997

Prospective, open-label, add-on study of lamotrigine in 56 children with intractable generalized epilepsy.

The role of lamotrigine (LTG) in childhood epilepsy is emerging. We evaluated the efficacy and adverse effects of LTG in an open, prospective study of 56 children with generalized epilepsies. Six (11%) children became seizure-free, and 24 (43%) had greater than 50% reduction in seizure frequency. LTG was effective against a broad range of generalized seizure types. Three of 15 patients with Lennox-Gastaut syndrome achieved complete seizure control and eight demonstrated 50 to 99% improvement in seizure control. Increase in seizures (7) and rash (5) were the most common side effects. After valproate was discontinued, LTG therapy was resumed, with no recurrence of rash in any patient. This study suggests that LTG may be a useful drug in the treatment of generalized epilepsies in children.

Adolescent↗

PubMed2005

Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy.

Heron and colleagues (Ann Neurol 2004;55:595-596) identified three missense mutations in the Cav3.2 T-type calcium channel gene (CACNA1H) in patients with idiopathic generalized epilepsy. None of the variants were associated with a specific epilepsy phenotype and were not found in patients with juvenile absence epilepsy or childhood absence epilepsy. Here, we introduced and functionally characterized these three mutations using transiently expressed human Cav3.2 channels. Two of the mutations exhibited functional changes that are consistent with increased channel function. Taken together, these findings along with previous reports, strongly implicate CACNA1H as a susceptibility gene in complex idiopathic generalized epilepsy.

Calcium Channels, T-Type↗

PubMed2003

Exploration of a putative susceptibility locus for idiopathic generalized epilepsy on chromosome 8p12.

PURPOSE: A recent genome-wide scan revealed a major susceptibility locus for idiopathic generalized epilepsies (IGEs) in the chromosomal region 8p12 in 32 IGE families without members with juvenile myoclonic epilepsy (JME). This study explored the presence of an IGE locus in the chromosomal region 8p12. METHODS: Our study included 176 multiplex families of probands with common IGE syndromes. Parametric and nonparametric multipoint linkage analyses were carried out between the IGE trait and six microsatellite polymorphisms encompassing the putative susceptibility locus. To explore the associated phenotype-genotype relation, two distinct subgroups of families were selected by the presence (n = 64) or absence (n = 112) of a family member with JME. To adjust the phenotypic spectrum toward adolescent-onset IGEs, a third subgroup of 28 families without JME was chosen through an IGE proband with seizure onset at age 10-20 years. RESULTS: Parametric and nonparametric multipoint linkage analyses provided no evidence for linkage between IGE and markers encompassing the putative IGE locus in the chromosomal region 8p12. Furthermore, we found no hint of linkage along the candidate region in any of the three family subgroups. CONCLUSIONS: We failed to provide evidence for a major IGE locus in the chromosomal region 8p12. On the contrary, these parametric linkage results provide strong evidence against linkage across the candidate region under a broad range of genetic models. If there is a susceptibility locus for IGE in the chromosomal region 8p12, then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.

Adult↗

PubMed2006

Candidate gene analysis of the succinic semialdehyde dehydrogenase gene (ALDH5A1) in patients with idiopathic generalized epilepsy and photosensitivity.

Succinic semialdehyde dehydrogenase (SSADH) is involved in the degradation of the inhibitory neurotransmitter GABA and about 50% of patients with SSADH deficiency suffer from seizures. The gene encoding SSADH (gene symbol: ALDH5A1) maps in proximity to susceptibility loci for juvenile myoclonic epilepsy (JME) and photosensitivity on chromosome 6p22. The present study tested whether variation of the ALDH5A1 gene confers susceptibility to common syndromes of idiopathic generalized epilepsy (IGE) and an abnormal photoparoxysmal response (PPR). Mutation screening of the ALDH5A1 coding sequence of 35IGE/PPR patients and four healthy control subjects identified 17 sequence variants, of which three resulted in an exchange of amino acids (H180Y, P182L, A237S). Association analysis was carried out for six single nucleotide polymorphisms (SNPs) and one trinucleotide repeat polymorphism (TNR, intron 1), covering the genomic ALDH5A1 sequence. The study sample comprised 566 unrelated German IGE patients, including 218 JME and 95 photosensitive IGE patients, 78 PPR probands without IGE, and 662 German population controls. None of the investigated ALDH5H1 polymorphisms showed evidence for an allelic or genotypic association with either IGE, JME, or PPR, when corrected for multiple tests. A tentative haplotypic association of the two-marker haplotype (rs1883415-TNR) covering the 5'-regulatory region in IGE patients (chi2=11.65, d.f.=3, P=0.009) warrants further replication studies. The present results do not provide evidence that any ALDH5A1 missense variant itself contributes a common and substantial susceptibility effect (RR>2) to IGE syndromes or an increased liability to visually-induced cortical synchronization.

Epilepsy, Generalized↗

PubMed2000

Variation of the genes encoding the human glutamate EAAT2, serotonin and dopamine transporters and Susceptibility to idiopathic generalized epilepsy.

Several interacting genetic factors are likely to be involved in the epileptogenesis of idiopathic generalized epilepsies (IGE). Neurotransmitter transporters play a central role in the fine tuning of neurotransmission by removal of released neurotransmitters from the synaptic cleft. The present association study tested the hypotheses that variation of the genes encoding neurotransmitter transporters confers susceptibility to IGE. The genotypes of 133 German IGE subjects and 223 ethnically matched controls were assessed for DNA polymorphisms of genes encoding the glutamate (EAAT2), the serotonin (SERT), and dopamine (DAT) transporters. To increase genetic homogeneity, a subgroup of 76 patients with idiopathic absence epilepsy (IAE) was analyzed separately. We found no evidence for an allelic association of either the silent G603A substitution polymorphism in exon 5 of the EAAT2 gene or the regulatory promoter polymorphism of the SERT gene with either IGE or IAE. The frequency of the nine-copy allele of the 40 base pair repeat polymorphism in the 3' un pop popd region of the DAT gene was significantly increased in the IGE patients (chi2 = 4.11, degrees of freedom (d.f.) = 1, P = 0.043) and, in particular, in the IAE patients (chi2 = 7.81, d.f. = 1, P = 0.005) compared with the controls. The present findings strengthen previous evidence that genetic variation of the DAT gene modulates neuronal network excitability and contributes to the epileptogenesis of IAE.

Alleles↗

PubMed1997

[GABAergic mechanisms in generalized epilepsies: the neuroanatomical dimension].

Generalized epileptic seizures are underlied by specific circuits where GABAergic synapses are involved at different levels. The role of these synapses depends on (i) the type of epilepsy and (ii) their localization within the central nervous system. This dual complexity can be illustrated by two examples from animal experimentation. Clinical, as well as experimental data have shown that the neural mechanisms underlying generalized non-convulsive seizures (e.g., absence-epilepsy) are distinct from those involved in convulsive generalized seizures. Pharmacological reactivity to anti-epileptic compounds is different between these two forms of seizures. Hippocampus and amygdala are key-structures in convulsive seizures whereas they are not involved in absence-epilepsy. A thalamo-cortical circuit generates the spike-and-wave discharges in absence epilepsy. Global activation of GABAergic transmission by systemic administration generally suppresses convulsive seizures whereas it aggravates absence in both humans and animals. Further investigations using a genetic model of absence seizures in the rat have suggested that this aggravation may be related to the role of post-synaptic GABA-B receptors in slow hyperpolarization, in the relay nuclei of the thalamus. By "de-inactivating" low-threshold calcium currents, activation of these receptors facilitates rhythmic activity in the thalamo-cortical circuit. In addition, regulation of transmitter release by presynaptic GABA-B receptors in the thalamus and the cortex may also contribute to the control of absence seizures. A blockade of the GABA-B receptors, either locally in the thalamus or systemically suppresses absence seizures. The critical role of the substantia nigra in the control of different forms of seizures has been demonstrated recently in the rat. This structure is one of the richest regions of the brain for GABAergic terminals, neurons and receptors. Local applications of GABA mimetics resulting in the desinhibition of their target neurons in the superior colliculus were shown to suppress both convulsive and non-convulsive seizures. This circuitry involving the basal ganglia may exert a "remote inhibitory control" over generalized epilepsies generated in other areas. In conclusion, the pharmacological manipulation of GABAergic transmission has different consequences on epilepsy depending on the form of seizures and the connections and functions of the GABAergic neurons in a given structure. The design of new therapeutical tools based on the manipulation of GABAergic mechanisms in the central nervous system requires to take into account this neuroanatomical dimension.

Animals↗

PubMed2007

Lack of evidence of an allelic association of a functional GABRB3 exon 1a promoter polymorphism with idiopathic generalized epilepsy.

PURPOSE: Mutation screening and linkage disequilibrium mapping of the gene encoding the GABA(A) beta(3) subunit (GABRB3) identified a common genetic variant in the exon 1a promoter region (C-allele of rs4906902) which displayed a reduced transcriptional activity and showed a strong allelic association with childhood absence epilepsy (CAE). The present population-based association study tested whether the C-allele of rs4906902 confers susceptibility to CAE or other common syndromes of idiopathic generalized epilepsy (IGE) in a German sample. METHODS: Seven hundred and eighty unrelated German IGE patients (250 CAE, 123 juvenile absence epilepsy, 303 juvenile myoclonic epilepsy (JME), 104 epilepsy with generalized tonic-clonic seizures on awakening) and 559 healthy population controls were genotyped for the single nucleotide polymorphism (SNP) rs4906902. RESULTS: The frequency of the risk-conferring C-allele did not differ significantly between CAE patients (f(C)=0.190) and controls (f(C)=0.183; P=0.376, one-tailed). Similarly, no evidence for an allelic association was found for 373 patients with idiopathic absence epilepsy, 303 JME patients, and the entire IGE sample (P>0.77, two-tailed). CONCLUSION: Our study failed to replicate an association of the common GABRB3 exon 1a promoter SNP rs4906902 with CAE. Moreover, the present results do not provide evidence that the common functional C-variant confers a substantial epileptogenic effect to a broad spectrum of IGE syndromes in the German population.

Alleles↗

PubMed1984

Neuropathological findings in primary generalized epilepsy: a study of eight cases.

On neuropathological investigation of eight cases with primary generalized epilepsy, none showed elective parenchymal necrosis, which is regarded (qualitatively and topologically) as characteristic of epilepsy in classical neuropathology. In seven of the eight cases, however, marked microdysgenesis with varying regional distribution was found. These maturation disturbances are to be interpreted as pathological and refute the currently held view that there is no evidence of pathological brain damage in primary generalized epilepsy.

Adolescent↗

PubMed1992

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.

Chromosomes, Human, Pair 6↗

PubMed1999

The generalized tonic-clonic seizure in partial versus generalized epilepsy: semiologic differences.

PURPOSE: To study differences in the clinical manifestations of generalized tonic-clonic seizures (GTCS) of partial versus generalized onset. METHODS: We studied 10 GTCSs in nine patients with idiopathic generalized epilepsy (IGE) and 10 GTCSs in 10 patients with temporal lobe epilepsy (TLE). Videotaped seizures were reviewed for all clinical features, focusing on asymmetries during different phases of each seizure. RESULTS: In the IGE group, focal features were seen before generalized motor activity in seven seizures. The most common was adversive head turn (six seizures). One patient had opposite direction of head turning in two recorded seizures. The tonic phase was always symmetric. In the last generalized clonic phase, asymmetry or asynchrony of motor activity was seen transiently in three seizures. The TLE group showed focal features before generalization in all seizures. Adversive head turning occurred in nine patients and was always contralateral to the focus. Focal clonic activity occurred before generalization in three and was always contralateral to the focus. The generalized tonic phase was usually asymmetric, and in the last clonic phase, motor activity was asymmetric or asynchronous in eight seizures (p<0.05, IGE vs. TLE). CONCLUSIONS: Brief focal features or asymmetry at onset are common in the GTCSs of IGE. However, asymmetry or asynchrony during the last clonic phase are uncommon in IGE, in contrast to TLE.

Adolescent↗

PubMed2004

Imaging idiopathic generalized epilepsy.

It has been traditionally held that there is no radiological abnormality in patients with idiopathic generalized epilepsy (IGE). Sophisticated image processing and quantitative magnetic resonance imaging (MRI) studies suggest that, in some cases, there may be a subtle structural abnormality. Magnetic resonance spectroscopy indicates neuronal dysfunction with differing patterns of abnormality in the IGE sub-syndromes, and high levels of glutamate and glutamine have been suggested in the frontal lobes, and low GABA levels in the occipital lobe. Studies reflecting cerebral blood flow at the time of absences have given complex results. The principal consensus is of an increase in the thalamus and broad decreases in the neocortex, reflecting a suppression of neuronal activity, but with the possibility of some increases, that could perhaps reflect focal areas of neuronal activation. PET ligand studies with an opioid tracer have implied neocortical release of endogenous opioids at the time of serial absences. In combination with high time-resolution neurophysiological methods, static and dynamic PET studies with specific ligands have the potential to elucidate the functional anatomy and neurochemical circuits that under-lie IGE.

Cerebrovascular Circulation↗

PubMed2003

Idiopathic generalized epilepsy and choice of antiepileptic drugs.

The authors reviewed 58 patients with EEG-confirmed idiopathic generalized epilepsy (IGE). When initially seen, 17 (29%) were on broad-spectrum (adequate) antiepileptic drugs (AED) only, 28 (48%) on ill-advised AED only, and 13 (22%) on a combination of both. Thus, a majority of patients with IGE initially receive ill-advised AED, which cause IGE to appear intractable.

Adult↗

PubMed1999

[A case of inv dup (15) mosaic with mental retardation and symptomatic generalized epilepsy].

We report a case of inv dup (15) mosaic with moderate mental retardation and symptomatic generalized epilepsy whose attacks were successfully controlled by phenytoin. Battaglia et al. (1997) reported four cases of inv dup (15) syndrome, whose symptoms contained intractable Lennox-Gastaut syndrome, moderate or severe mental retardation, diffuse hypotonia, and minor anomaly. The present case was diagnosed as mosaicism of inv dup (15) syndrome. It was suspected that the patient had a treatable epileptic seizure and no minor anomaly because of the mosaicism.

Adult↗

PubMed2004

Treatment of refractory primary generalized epilepsy.

Although complete seizure control is achievable in 54% to 82% of patients with primary (idiopathic) generalized epilepsy syndromes, there remains a substantial group with inadequate control. Valproate has been considered the drug of choice but is not always effective and might produce unacceptable adverse effects. Several newer drugs have emerged as potential alternatives to valproate, including lamotrigine, levetiracetam, topiramate, and zonisamide. Sedation and tolerance limit the utility of benzodiazepines. For severely refractory patients, drug combinations, vagal nerve stimulation, or felbamate might be considered. Only a few controlled clinical trials have been conducted for these syndromes; more are needed.

Adolescent↗

PubMed1998

The efficacy of lamotrigine in children and adolescents with refractory generalized epilepsy: a randomized, double-blind, crossover study.

PURPOSE: We report a double-blind, placebo-controlled crossover study of lamotrigine (LTG) as add-on treatment in therapy-resistant, generalized epilepsy in children and adolescents (n = 30). METHODS: Twenty patients had Lennox-Gastaut syndrome. Each patient acted as his or her own control. LTG and placebo were randomly added to existing antiepileptic medication (AEDs). The LTG dosage was individualized in an open phase preceding the placebo/treatment phase. Patients who responded to LTG in the open phase went on to the double-blind phase. "Responders " were defined as patients with a >50% seizure reduction or less severe seizures or both, or improved behavior or improved motor skills or both. "Nonresponders" were defined as children who showed no positive effects of LTG with plasma levels of < or = 10 microg/ml or children who had adverse events during the open phase. RESULTS: There was a clear statistically significant reduction of seizure frequency in LTG compared with placebo treatment. None of the children studied showed abnormal biochemical or hematologic findings, or changes in plasma levels of concomitantly administered AEDs. CONCLUSIONS: LTG is a well-tolerated and effective treatment in children with intractable generalized epilepsies, including those with Lennox-Gastaut syndrome. The study design allowed a double-blind placebo-controlled assessment of LTG although the participating children used 19 different AED combinations at entry.

Adolescent↗

PubMed1981

Complexities of primary generalized epilepsy.

Abnormal arousal responses paired with paroxysmal discharges and photosensitivity are the principal mechanisms in the precipitation of seizures in primary generalized epilepsy. The abnormal arousal responses show a consistent maximum over the frontal midline region. An exception from this rule was found in two children with primary generalized epilepsy (petit mal absences, one also with grand mal) with a strongly positive family history. In these patients, the generalized-synchronous bursts showed a maximum over the vertex (Cz electrode). Both of these children also had single spikes over the Rolandic region. A relationship between primary generalized and benign Rolandic epilepsy is demonstrated. Both forms of seizure disorder are based on dysfunction (hyperexcitability) rather than on a structural epileptogenic lesion. A dichotomy of dysfunctional and structural epilepsies is presented but gray zones of overlap indubitably exist. The limitations of the dichotomy concept are pointed out.

Arousal↗

PubMed2001

Idiopathic generalized epilepsies: do sporadic and familial cases differ?

PURPOSE: Genetic factors are the only identified cause of idiopathic generalized epilepsies (IGEs), but the majority of cases do not have affected first-degree relatives. Here we investigate whether subjects with sporadic and familial IGE differ in terms of antecedent events and clinical and EEG features. Differences would support the hypothesis of a different etiology for sporadic cases, which has implications for choice of subjects for genetic association studies. METHODS: We analyzed 98 patients with IGE, diagnosed on clinical and EEG criteria. All patients and, if possible, one relative were interviewed, with special emphasis on potential antecedent events and family history. Patients with first-degree relatives affected with epileptic seizures were regarded as "familial," and the other patients were regarded as "sporadic." RESULTS: Of the 98 IGE patients, 32 (33%) patients were familial. The risk for seizures was 13.2% for siblings, and 7.7% for parents. The distribution of the IGE subsyndromes, the presence of antecedent events, and other electroclinical features did not differ between familial and sporadic IGE groups. CONCLUSIONS: No differences were found between familial and sporadic IGE patients. This does not the support the hypothesis that sporadic and familial IGE cases have separate etiologies.

Adult↗