The motion of the contact line at the oil/water interface caused by chemical reactions is well known as a typical example of artificial active matter in the field of nonlinear science. When water (containing trimethylstearylammonium chloride) and nitrobenzene (containing iodide anion) phases are in contact, the regulated traveling-wave patterns appear along the inner wall of the glass container. In this study, we demonstrate a new dynamical mode of the contact line, an up-and-down motion, which becomes dominant with the decrease in the size of a glass tube, and the probability of occurrence is extremely high when the diameter of the glass tube is below 1 mm. A physicochemical model of the contact line motion that incorporates the spatiotemporal variation of the surfactant concentration on a glass surface is proposed, and its effect on the wettability of oil/water phases on the walls of the glass tubes is studied. The present model can reproduce the mode bifurcation of the dynamical motion depending on the inner diameter of the glass tubes.

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy characterised by absence seizures manifested by transitory loss of awareness with 2.5–4 Hz spike–wave complexes on ictal EEG. A genetic component to aetiology is established but the mechanism of inheritance and the genes involved are not fully defined. Available evidence suggests that genes encoding brain expressed voltage-gated calcium channels, including CACNG3 on chromosome 16p12–p13.1, may represent susceptibility loci for CAE. The aim of this work was to further evaluate CACNG3 as a susceptibility locus by linkage and association analysis. Assuming locus heterogeneity, a significant HLOD score (HLOD=3.54, α =0.62) was obtained for markers encompassing CACNG3 in 65 nuclear families with a proband with CAE. The maximum non-parametric linkage score was 2.87 ( P <0.002). Re-sequencing of the coding exons in 59 patients did not identify any putative causal variants. A linkage disequilibrium (LD) map of CACNG3 was constructed using 23 single nucleotide polymorphisms (SNPs). Transmission disequilibrium was sought using individual SNPs and SNP-based haplotypes with the pedigree disequilibrium test in 217 CAE trios and the 65 nuclear pedigrees. Evidence for transmission disequilibrium ( P ≤0.01) was found for SNPs within a ∼35 kb region of high LD encompassing the 5’UTR, exon 1 and part of intron 1 of CACNG3 . Re-sequencing of this interval was undertaken in 24 affected individuals. Seventy-two variants were identified: 45 upstream; two 5’UTR; and 25 intronic SNPs. No coding sequence variants were identified, although four variants are predicted to affect exonic splicing. This evidence supports CACNG3 as a susceptibility locus in a subset of CAE patients.

In order to assess the chloride channel gene CLCN2 as a candidate susceptibility gene for childhood absence epilepsy, parametric and non-parametric linkage analysis was performed in 65 nuclear pedigrees. This provided suggestive evidence for linkage with heterogeneity: NPL score=2.3, p<0.009; HLOD=1.5, alpha=0.44. Mutational analysis of the entire genomic sequence of CLCN2 was performed in 24 unrelated patients from pedigrees consistent with linkage, identifying 45 sequence variants including the known non-synonymous polymorphism rs2228292 (G2154C, Glu718Asp) and a novel variant IVS4+12G>A. Intra-familial association analysis using the pedigrees and a further 308 parent-child trios showed suggestive evidence for transmission disequilibrium of the G2154C minor allele: AVE-PDT chi(1)2 = 5.17, p<0.03. Case-control analysis provided evidence for a protective effect of the IVS4+12G>A minor allele: chi(1)2 = 7.27, p<0.008. The 65 nuclear pedigrees were screened for three previously identified mutations shown to segregate with a variety of idiopathic generalised epilepsy phenotypes (597insG, IVS2-14del11 and G2144A) but none were found. We conclude that CLCN2 may be a susceptibility locus in a subset of cases of childhood absence epilepsy.

The gene encoding the β3‐subunit regulatory subunit (KCNMB3) of large conductance calcium‐sensitive potassium (BK) channels represents a positional and functional candidate gene for idiopathic generalized epilepsy (IGE). A single base pair deletion in exon 4 of KCNMB3 (delA750) alters/truncates the terminal 21 amino acids of the 3‐subunit and affects channel inactivation of the β3b‐isoform. The present association study tested whether the KCNMB3 delA750 mutation confers susceptibility to common IGE syndromes. In total, 592 unrelated German IGE patients and 462 healthy population controls were genotyped for the delA750 truncation mutation. The frequency of the delA750 mutation was significantly increased in the IGE patients (7.9%) compared to that in the controls (5.5%; P = 0.016, one‐sided; OR = 1.52; 95%‐CI: 1.05–2.21). The increase of the delA750 frequency was accentuated in 312 patients exhibiting typical absence seizures (8.8%, P = 0.005, one‐sided; OR = 1.72; 95%‐CI: 1.13–2.62) relatively to that observed in the 237 patients with myoclonic seizures on awakening (7.2%; P = 0.11, one‐sided; OR = 1.36; 95%‐CI: 0.85–2.19), when compared with controls. The present results suggest that the functional KCNMB3 β3b‐truncation confers a common epileptogenic effect preferentially to the ictogenesis of typical absence seizures. © 2006 Wiley‐Liss, Inc.

Purpose: Although complex idiopathic generalized epilepsies (IGEs) are recognized to have a significant genetic component, as yet there are no known common susceptibility variants. It has recently been suggested that variation in the BRD2 gene confers increased risk of juvenile myoclonic epilepsy (JME), which accounts for around a quarter of all IGE. Here we examine the association between the candidate causal SNP (the promoter variant rs3918149) and JME in five independent cohorts comprising in total 531 JME cases and 1,390 healthy controls.Methods: The strongest candidate causal variant from the original report (rs3918149) was genotyped across all five cohorts. In an effort to identify novel candidate causal polymorphisms, previously unscreened regions of UTR were resequenced.Results: We observed a significant effect in a small sample recruited in Britain (genotype p = 0.001, allele p = 0.001), a borderline significant effect in a sample recruited in Ireland and no association in larger samples of German, Australian, and Indian populations. There was no association with other common forms of epilepsy or any other clear candidate casual variants in or near the BRD2 region.Conclusions: The replication of an effect in the British cohort and suggestive evidence from that recruited in Ireland but lack of replication from the larger German, Australian, and Indian cohorts is surprising and difficult to explain. Further replication in carefully matched populations is required. Results presented here do not, however, support a strong effect for susceptibility to JME across populations of European descent.

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 1 a promoter SNP rs4906902 with CAE. Moreover, the present results do not provide evidence that the common functional C-variant confers a substantial epiteptogenic effect to a broad spectrum of IGE syndromes in the German population. (c) 2006 Elsevier B.V. All rights reserved.

Juvenile myoclonic epilepsy (JME) is a genetically determined common subtype of idiopathic generalized epilepsy. Recently, linkage of JME to the chromosomal region 15q14, as well as an allelic and genotypic association between the synonymous coding single nucleotide polymorphism c.588C>T (dbSNP: rs3743123, S196S) of the positional candidate gene connexin-36 (CX36) and JME have been reported. The present replication study examined this tentative association in 247 German JME patients and 621 population controls. The frequency of the c.588T allele was significantly increased in the JME patients (35%) compared to controls (29.7%; P=0.016, one-tailed). Consistent to the original report, we also observed a significant increase of T/T homozygotes (13.4%) in the JME patients compared to controls (8.7%; P=0.019, one-tailed; ORT/T+=1.62; 95%-CI: 1.02–2.57). The present results provide confirmatory evidence for an allelic and genotypic association of the CX36 gene with JME.

Jeder Zwanzigste hat in seinem Leben mindestens einmal einen epileptischen Anfall. Doch erst, wenn bei einem Menschen wiederholt derartige Anfälle auftreten, spricht man von der Krankheit Epilepsie. Dahinter verbirgt sich eine große Anzahl unterschiedlicher Erkrankungen. Im NeuroNet des Nationalen Genomforschungsnetzes (NGFN) beschäftigen sich mehrere Arbeitsgruppen mit Epilepsie, um den genetischen Ursachen des Anfallsleidens auf die Spur zu kommen.

Summary: Purpose: Idiopathic generalized epilepsy (IGE) accounts for ∼20% of all epilepsies and affects about 0.2% of the general population. The etiology of IGE is genetically determined, but the complex pattern of inheritance suggests an involvement of a large number of susceptibility genes. The objective of the present study was to explore the genetic architecture of common IGE syndromes and to dissect out susceptibility loci predisposing to absence or myoclonic seizures. Methods: Genome‐wide linkage scans were performed in 126 IGE‐multiplex families of European origin ascertained through a proband with idiopathic absence epilepsy or juvenile myoclonic epilepsy. Each family had at least two siblings affected by IGE. To search for seizure type–related susceptibility loci, linkage analyses were carried out in family subgroups segregating either typical absence seizures or myoclonic and generalized tonic–clonic seizures on awakening. Results: Nonparametric linkage scans revealed evidence for complex and heterogeneous genetic architectures involving linkage signals at 5q34, 6p12, 11q13, 13q22‐q31, and 19q13. The signal patterns differed in their composition, depending on the predominant seizure type in the families. Conclusions: Our results are consistent with heterogeneous configurations of susceptibility loci associated with different IGE subtypes. Genetic determinants on 11q13 and 13q22‐q31 seem to predispose preferentially to absence seizures, whereas loci on 5q34, 6p12, and 19q13 confer susceptibility to myoclonic and generalized tonic–clonic seizures on awakening.

OBJECTIVE:To detect mutations in GABRA1 in idiopathic generalized epilepsy.METHODS:GABRA1 was sequenced in 98 unrelated idiopathic generalized epilepsy patients. Patch clamping and confocal imaging was performed in transfected mammalian cells.RESULTS:We identified the first GABRA1 mutation in a patient with childhood absence epilepsy. Functional studies showed no detectable GABA-evoked currents for the mutant, truncated receptor, which was not integrated into the surface membrane.INTERPRETATION:We conclude that this de novo mutation can contribute to the cause of "sporadic" childhood absence epilepsy by a loss of function and haploinsufficiency of the GABA(A) receptor alpha(1)-subunit, and that GABRA1 mutations rarely are associated with idiopathic generalized epilepsy.

CACNA1H was evaluated in a resource of Caucasian European patients with childhood absence epilepsy by linkage analysis and typing of sequence variants previously identified in Chinese patients. Linkage analysis of 44 pedigrees provided no evidence for a locus in the CACNA1H region and none of the Chinese variants were found in 220 unrelated patients.

Photosensitivity or photoparoxysmal response (PPR) is a common and highly heritable electroencephalographic trait characterized by an abnormal visual sensitivity of the brain in reaction to intermittent photic stimulation. PPR occurs frequently associated with idiopathic generalized epilepsies (IGEs). The present genomewide linkage scan was designed to map susceptibility loci for PPR and to explore their genetic relationship with IGE. The study included 60 families with at least two siblings displaying PPR. To dissect PPR-specific and IGE-related susceptibility loci, we defined two distinct family subgroups, comprising 19 families with predominantly pure PPR and photosensitive seizures (PPR-families) and 25 families, in which PPR was strongly associated with IGE (PPR/IGE-families). MOD score analyses provided significant evidence for linkage to the region 6p21.2 in the PPR-families (empirical p = 0.00004) and suggestive evidence for linkage to the region 13q31.3 in the PPR/IGE families (p = 0.00015), both with a best-fitting recessive mode of inheritance. In the PPR/IGE-families, linkage evidence was even stronger (p = 0.00003) when the trait definition was broadened by IGE traits. Our study shows two PPR-related susceptibility loci, depending on the familial background of IGE. The locus on 6p21.2 seems to predispose to PPR itself, whereas the locus on 13q31.3 also confers susceptibility to IGE.

Purpose: Quantitative trait loci (QTL) mapping in mice revealed a seizure-related QTL (Szs1), for which the inward-rectifying potassium channel Kcnj10 is the most compelling candidate gene. Association analysis of the human KCNJ10 gene identified a common KCNJ10 missense variation (Arg271Cys) that influences susceptibility to focal and generalized epilepsies. The present replication study tested the initial finding that the KCNJ10 Cys271 allele is associated with seizure resistance to common syndromes of idiopathic generalized epilepsy (IGE).Methods: The study sample comprised 563 German IGE patients and 660 healthy population controls. To search for seizure type-specific effects, two IGE subgroups were formed, comprising 258 IGE patients with typical absences (IAE group) and 218 patients with juvenile myoclonic epilepsy (JME group). A TaqMan nuclease assay was used to genotype the KCNJ10 single nucleotide polymorphism c. 1037C > T (dbSNP: rs 1130183) that alters amino acid at position 271 from arginine to cysteine.Results: Replication analysis revealed a significant decrease of the Cys271 allele frequency in 446 IGE patients compared to controls (X-2 = 3.52, d.f. = 1, P= 0.030, one-sided; ORCys271+, = 0.69; 95% CI: 0.50-0.95). Among the IGE subgroups, lack of the Cys271 allele was accentuated in the JME group (X-2 = 5.20, d.f. = 1, P= 0.011, one-sided).Conclusion: Our results support previous evidence that the common KCNJ10 Arg271Cys missense variation influences seizure susceptibility of common IGE syndromes. (c) 2005 Elsevier B.V. All rights reserved.

Purpose: Linkage disequilibrium mapping revealed allelic and haplotypic associations between single-nucleotide polymorphisms (SNPs) of the gene encoding the malic enzyme 2 (ME2) and adolescent-onset idiopathic generalized epilepsy (IGE). Homozygote carriers of the associated ME2 haplotype had a sixfold higher risk of IGE compared with any other genotype. The present population-based association study tested whether genetic variation of the ME2 gene confers susceptibility to common IGE syndromes in the German population.Methods: The study included 666 German healthy control subjects and 660 German IGE patients (IGE group), of which 416 patients had an age at onset in adolescence (IGEado group). Genotyping was performed for six SNPs and one dinucleotide repeat polymorphism, all located in the ME2 region.Results: Neither allele nor genotype frequencies of any ME2 polymorphism differed significantly between the controls and the IGE groups (p > 0.22). No hint of an association of the putative risk-conferring haplotype was seen, when present homozygously, in both IGE groups compared with controls (p > 0.18).Conclusions: These results do not support previous evidence that genetic variation of the ME2 gene predisposes to common IGE syndromes. Thus if a recessively inherited ME2 mutation is present, then the size of the epileptogenic effect might be too small or not frequent enough to detect it in the present IGE sample.

Photosensitivity or photoparoxysmal response (PPR) is an epilepsy-related electroencephalographic trait evoked by standardised intermittent photic stimulation. It is characterised by a brain response with spike wave discharges, ranging from occipital spikes only to generalised spike waves (type I – IV). PPR is a common finding in the general population (up to 8%) and is frequently associated with idiopathic epilepsies. It has an especially high prevalence (up to 90%) in idiopathic generalised epilepsies (IGE). The molecular genetic dissection of the photoparoxysmal response as an endophenotype seems to be a suitable approach to elucidate the molecular genetic basis of IGE.

Genetic factors play a major role in the etiology of idiopathic generalized epilepsies (IGE). An oligogenic or polygenic predisposition is suspected in the majority of families with common IGE syndromes. It has been hypothesized that some IGE genes might increase the general level of neuronal excitability while others specify the age of onset and the seizure type. The EFHC1 gene on 6p12-p11 was previously described as the first susceptibility gene for juvenile myoclonic epilepsy (JME). EFHC1 codes for a protein of unknown function that is characterized by Ca2+-binding EF-hand motifs and DM10 domains. We have now cloned the brain-expressed paralog EFHC2 (Xp11.3) and carried out an association study of six single nucleotide polymorphisms (SNPs) in a large sample of 654 German IGE patients and 662 population controls. A tentative association was found between the amino acid exchange S430Y in exon 9 of EFHC2 and 97 male JME patients (χ2=4.705, d.f.=1, P=0.030; OR=2.17; 95-CI: 1.06–4.43). The allelic association was even stronger for the 81 males with “classical” JME (JME without absence seizures) (χ2=6.06, d.f.=1, P=0.014; OR=2.46; 95-CI: 1.18–5.13). An association with the gonosomal gene EFHC2 would be in accordance with the observed preponderance of maternal inheritance in JME maternal inheritance of JME. Independent replication studies are needed to further analyse the tentative association described here.