T Sander

Publications of T Sander

• GLUT1 mutations are a rare cause of familial idiopathic generalized epilepsy.

  Authors: P Striano, Y G Weber, M R Toliat, J Schubert, C Leu, R Chaimana, S Baulac, R Guerrero, E Leguern, A-E Lehesjoki, A Polvi, A Robbiano, J M Serratosa, R Guerrini, P Nürnberg, T Sander, F Zara, H Lerche, C Marini

  Neurology. 02/2012; 78(8):557-562.

  OBJECTIVE: The idiopathic generalized epilepsies (IGE) are the most common genetically determined epilepsies. However, the underlying genes are largely unknown. We screened the SLC2A1 gene, encodingOBJECTIVE: The idiopathic generalized epilepsies (IGE) are the most common genetically determined epilepsies. However, the underlying genes are largely unknown. We screened the SLC2A1 gene, encoding the glucose transporter type 1 (GLUT1), for mutations in a group of 95 European patients with familial IGE. METHODS: The affected individuals were examined clinically by EEG and brain imaging. The coding regions of SLC2A1 were sequenced in the index cases of all families. Wild-type and mutant transporters were expressed and functionally characterized in Xenopus laevis oocytes. RESULTS: We detected a novel nonsynonymous SLC2A1 mutation (c.694C>T, p.R232C) in one IGE family. Nine family members were affected mainly by absence epilepsies with a variable age at onset, from early childhood to adulthood. Childhood absence epilepsy in one individual evolved into juvenile myoclonic epilepsy. Eight affected and 4 unaffected individuals carried the mutation, revealing a reduced penetrance of 67%. The detected mutation was not found in 846 normal control subjects. Functional analysis revealed a reduced maximum uptake velocity for glucose, whereas the affinity to glucose and the protein expression were not different in wild-type and mutant transporters. CONCLUSION: Our study shows that GLUT1 defects are a rare cause of classic IGE. SLC2A1 screening should be considered in IGE featuring absence epilepsies with onset from early childhood to adult life, because this diagnosis may have important implications for treatment and genetic counseling.

• DTNBP1 (Dysbindin) Gene Variants: In vivo evidence for effects on hippocampal glutamate status.

  Authors: C Wirth, F Schubert, M Lautenschlager, R Brühl, A Klär, T Majic, U E Lang, A Ehrlich, G Winterer, T Sander, M Schouler-Ocak, J Gallinat

  Current pharmaceutical biotechnology. 01/2012;

• Whole-genome linkage scan for epilepsy-related photosensitivity: a mega-analysis.

  Authors: C G F de Kovel, D Pinto, U Tauer, S Lorenz, H Muhle, C Leu, B A Neubauer, A Hempelmann, P M C Callenbach, I E Scheffer, S F Berkovic, G Rudolf, P Striano, A Siren, B Baykan, T Sander, D Lindhout, D G Kasteleijn-Nolst Trenité, U Stephani, B P C Koeleman

  Epilepsy research. 02/2010; 89(2-3):286-94.

  Photoparoxysmal response (PPR) is considered to be a risk factor for idiopathic generalised epilepsy (IGE) and it has a strong genetic basis. Two genome-wide linkage studies have been publishedPhotoparoxysmal response (PPR) is considered to be a risk factor for idiopathic generalised epilepsy (IGE) and it has a strong genetic basis. Two genome-wide linkage studies have been published before and they identified loci for PPR at 6p21, 7q32, 13q13, 13q31 and 16p13. Here we combine these studies, augmented with additional families, in a mega-analysis of 100 families. Non-parametric linkage analysis identified three suggestive peaks for photosensitivity, two of which are novel (5q35.3 and 8q21.13) and one has been found before (16p13.3). We found no evidence for linkage at four previously detected loci (6p21, 7q32, 13q13 and 13q31). Our results suggest that the different family data sets are not linked to a shared locus. Detailed analysis showed that the peak at 16p13 was mainly supported by a single subset of families, while the peaks at 5q35 and 8q21 had weak support from multiple subsets. Family studies clearly support the role of PPR as a risk factor for IGE. This mega-analysis shows that distinct loci seem to be linked to subsets of PPR-positive families that may differ in subtle clinical phenotypes or geographic origin. Further linkage studies of PPR should therefore include in-depth phenotyping to make appropriate subsets and increase genetic homogeneity.

• COMT Val 158 Met polymorphism is associated with cognitive flexibility in a signal discrimination task in schizophrenia.

  Authors: A H Neuhaus, C Opgen-Rhein, C Urbanek, E Hahn, T M T Ta, M Seidelsohn, S Strathmann, F Kley, N Wieseke, T Sander, M Dettling

  Pharmacopsychiatry. 08/2009; 42(4):141-4.

  BACKGROUND: Associations between the well-known functional single nucleotide polymorphism Val (158)Met in the gene encoding catechol- O-methyltransferase (COMT) and cognitive do-mains affected inBACKGROUND: Associations between the well-known functional single nucleotide polymorphism Val (158)Met in the gene encoding catechol- O-methyltransferase (COMT) and cognitive do-mains affected in schizophrenia are inconsistent regarding directionality and specific impact and call for a more fundamental cognitive endophenotype. Recent studies suggest that the COMT genotype contributes to cognitive flexibility, a fundamental cognitive ability that potentially influences an individual's performance in a variety of other neurocognitive tasks. METHODS: We investigated the association between COMT Val (158)Met genotype and cognitive flexibility as assessed by signal discrimination in the Continuous Performance Test - Identical Pairs version in a cohort of 111 German schizophrenic patients. RESULTS: COMT genotype was significantly associated with signal discrimination index d' in schizophrenia. The Val/Val genotype was associated with the highest and the Met/Met genotype with the lowest scores; heterozygous individuals displayed an intermediate performance. CONCLUSIONS: Our data suggest that allelic variation at the COMT Val (158)Met locus may influence signal discrimination capacity in schizophrenia and confirm that Val loading, probably due to decreased prefrontal dopamine availability, is associated with greater cognitive flexibility, which in turn may influence other cognitive measures that have been associated with COMT to date.

• The Met allele of the BDNF Val66Met polymorphism is associated with increased BDNF serum concentrations.

  Authors: U E Lang, R Hellweg, T Sander, J Gallinat

  Molecular psychiatry. 03/2009; 14(2):120-2.

• Gender-dependent Association of a Functional NGF Polymorphism with Anxiety-related Personality Traits.

  Authors: U E Lang, R Hellweg, M Bajbouj, V. Gaus, T Sander, J Gallinat

  Pharmacopsychiatry. 09/2008; 41(5):196-9.

  INTRODUCTION: Nerve growth factor (NGF) has been shown to be involved in anxiety behaviour and the expression of conditioned fear in mice. METHODS: We have tested a total of 337 (age: 39.2 +/- 14.6INTRODUCTION: Nerve growth factor (NGF) has been shown to be involved in anxiety behaviour and the expression of conditioned fear in mice. METHODS: We have tested a total of 337 (age: 39.2 +/- 14.6 years) unrelated subjects of German descent (166 males; 171 females) who were carefully screened for psychiatric health. The self-ratable State-Trait Anxiety Inventory, which enables anxiety to be quantified as a comparatively stable personality trait was applied and a recently described non-synonymous NGF SNP (rs6330,c.104C > T,p.Ala35Val) was examined. RESULTS: In the trait-related anxiety score, a significant gender-dependent effect of the genotype was observed (F=4.580, df=2, p=0.011) with higher levels of trait anxiety in females with C/C genotype when compared to females with T/T and C/T genotypes and an opposite effect in males. DISCUSSION: Our findings support the hypothesis that anxiety relates to a genetic variation of NGF and that genes modulate behaviour in a gender-dependent manner. Since anxiety and attention deficit hyperactivity disorder are related to NGF, the present results may represent a common biological link for the gender-specific occurrence and comorbidity of the diseases.

• KCNQ2 and KCNQ3 mutations contribute to different idiopathic epilepsy syndromes.

  Authors: B A Neubauer, S Waldegger, J Heinzinger, A Hahn, G Kurlemann, B Fiedler, F Eberhard, H. Muhle, U Stephani, S Garkisch, O Eeg-Olofsson, U Müller, T Sander

  Neurology. 08/2008; 71(3):177-83.

  OBJECTIVE: To explore the involvement of M-type potassium channels KCNQ2, Q3, and Q5 in the pathogenesis of common idiopathic epilepsies. METHODS: Sequence analysis of the KCNQ2, Q3, and Q5 codingOBJECTIVE: To explore the involvement of M-type potassium channels KCNQ2, Q3, and Q5 in the pathogenesis of common idiopathic epilepsies. METHODS: Sequence analysis of the KCNQ2, Q3, and Q5 coding regions was performed in a screening sample consisting of 58 nuclear families with rolandic epilepsy. Subsequently, an association study was conducted for all discovered variants in a case-control sample comprising 459 German patients with idiopathic generalized epilepsy (IGE) and 462 population controls. RESULTS: An in-frame deletion of codon 116 in KCNQ2 (p.Lys116del) and a missense mutation in KCNQ3 (p.Glu299Lys) were detected in two index cases exhibiting rolandic epilepsy and benign neonatal convulsions. Both mutations resulted in reduced potassium current amplitude in Xenopus oocytes. Mutation analysis of families with rolandic epilepsy without neonatal seizures discovered three novel missense variations (KCNQ2 p.Ile592Met, KCNQ3 p.Ala381Val, KCNQ3 p.Pro574Ser). The KCNQ2 p.Ile592Met variant displayed a significant reduction of potassium current amplitude in Xenopus oocytes and was present only once in 552 controls. Both missense variants identified in KCNQ3 (p.Ala381Val and p.Pro574Ser) were present in all affected family members and did not occur in controls, but did not show obvious functional abnormalities. The KCNQ3 missense variant p.Pro574Ser was also detected in 8 of 455 IGE patients but not in 454 controls (p = 0.008). In KCNQ2, a silent single nucleotide polymorphism (rs1801545) was found overrepresented in both epilepsy samples (IGE, p = 0.004). CONCLUSION: Sequence variations of the KCNQ2 and KCNQ3 genes may contribute to the etiology of common idiopathic epilepsy syndromes.

• Confirmation of association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and bipolar I disorder.

  Authors: F W Lohoff, T Sander, T N Ferraro, J P Dahl, J Gallinat, W H Berrettini

  American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 12/2005; 139B(1):51-3.

  Recent studies have indicated that the brain-derived neurotrophic factor (BDNF) gene is involved in the etiology of bipolar disorder (BPD). Two family-based association studies showed that the ValRecent studies have indicated that the brain-derived neurotrophic factor (BDNF) gene is involved in the etiology of bipolar disorder (BPD). Two family-based association studies showed that the Val allele of the functional polymorphism Val66Met in the BDNF gene is associated with BPD; however, others could not confirm the results. Here we performed a replication study in an independent sample and tested the hypothesis that the Val66 allele in the BDNF gene confers susceptibility to bipolar I disorder (BPI). Six hundred twenty-one patients with BPI and 998 control subjects were genotyped for the Val66Met polymorphism. All cases and controls were of European descent. All BPI patients had a positive family history of affective disorder. The frequency of the Val allele was significantly increased in BPI patient when compared to controls (chi2 = 4.8; df = 1; P = 0.028; two-sided; OR = 1.22; 95% CI: 1.02-1.47). Results confirm previous findings and suggest that the Val allele increases risk for BPI in patients of European descent. Further studies are necessary to elucidate the involvement of the BDNF gene in the pathophysiology of BPD.

• Supportive evidence for an allelic association of the human KCNJ10 potassium channel gene with idiopathic generalized epilepsy.

  Authors: K.P. Lenzen, A Heils, S. Lorenz, A. Hempelmann, S Höfels, F W Lohoff, B Schmitz, T Sander

  Epilepsy research. 03/2005; 63(2-3):113-8.

  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.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: rs1130183) 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 (chi2 = 3.52, d.f. = 1, P = 0.030, one-sided; OR(Cys271+) = 0.69; 95% CI: 0.50-0.95). Among the IGE subgroups, lack of the Cys271 allele was accentuated in the JME group (chi2 = 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.

• Photosensitivity: genetics and clinical significance.

  Authors: B A Neubauer, St Waltz, M Grothe, A Hahn, I Tuxhorn, T Sander, G Kurlemann, U Stephani

  Advances in neurology. 02/2005; 95:217-26.

• Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility.

  Authors: R J Buono, F W Lohoff, T Sander, M R Sperling, M J O'Connor, D J Dlugos, S G Ryan, G T Golden, H Zhao, T M Scattergood, W H Berrettini, T N Ferraro

  Epilepsy research. 03/2004; 58(2-3):175-83.

  PURPOSE: Our research program uses genetic linkage and association analysis to identify human seizure sensitivity and resistance alleles. Quantitative trait loci mapping in mice led to identificationPURPOSE: Our research program uses genetic linkage and association analysis to identify human seizure sensitivity and resistance alleles. Quantitative trait loci mapping in mice led to identification of genetic variation in the potassium ion channel gene Kcnj10, implicating it as a putative seizure susceptibility gene. The purpose of this work was to translate these animal model data to a human genetic association study. METHODS: We used single stranded conformation polymorphism (SSCP) electrophoresis, DNA sequencing and database searching (NCBI) to identify variation in the human KCNJ10 gene. Restriction fragment length polymorphism (RFLP) analysis, SSCP and Pyrosequencing were used to genotype a single nucleotide polymorphism (SNP, dbSNP rs#1130183) in KCNJ10 in epilepsy patients (n = 407) and unrelated controls (n = 284). The epilepsy group was comprised of patients with refractory mesial temporal lobe epilepsy (n = 153), childhood absence (n = 84), juvenile myoclonic (n = 111) and idiopathic generalized epilepsy not otherwise specified (IGE-NOS, n = 59) and all were of European ancestry. RESULTS: SNP rs#1130183 (C > T) alters amino acid 271 (of 379) from an arginine to a cysteine (R271C). The C allele (Arg) is common with conversion to the T allele (Cys) occurring twice as often in controls compared to epilepsy patients. Contingency analysis documented a statistically significant association between seizure resistance and allele frequency, Mantel-Haenszel chi square = 5.65, d.f. = 1, P = 0.017, odds ratio 0.52, 95% CI 0.33-0.82. CONCLUSION: The T allele of SNP rs#1130183 is associated with seizure resistance when common forms of focal and generalized epilepsy are analyzed as a group. These data suggest that this missense variation in KCNJ10 (or a nearby variation) is related to general seizure susceptibility in humans.

• No evidence for a susceptibility locus for idiopathic generalized epilepsy on chromosome 5 in families with typical absence seizures.

  Authors: C Windemuth, H Schulz, K Saar, E Gennaro, A Bianchi, F Zara, C Bulteau, A Kaminska, D Ville, C Cieuta, R Nabbout-Tarantino, J F Prud'homme, O Dulac, L. Bate, R M Gardiner, D. Lindhout, T F Wienker, D Janz, T Sander

  Epilepsy research. 10/2002; 51(1-2):23-9.

  A recent genome-wide scan revealed suggestive evidence for two susceptibility loci for idiopathic generalized epilepsy (IGE) in the chromosomal regions 5p15 and 5q14-q22 in families with typicalA recent genome-wide scan revealed suggestive evidence for two susceptibility loci for idiopathic generalized epilepsy (IGE) in the chromosomal regions 5p15 and 5q14-q22 in families with typical absence seizures. The present replication study tested the validity of the tentative IGE loci on chromosome 5. Our study included 99 multiplex families in which at least one family member had typical absence seizures. Parametric and non-parametric multipoint linkage analyses were carried out between the IGE trait and 23 microsatellite polymorphisms covering the entire region of chromosome 5. Multipoint parametric heterogeneity lod scores < -2 were obtained along chromosome 5 when a proportion of linked families greater than 50% was assumed under recessive inheritance and > 60% under dominant inheritance. Furthermore, non-parametric multipoint linkage analyses revealed no hint of linkage throughout the candidate region (P > 0.05). Accordingly, we failed to support previous evidence for common IGE loci on chromosome 5. If there is a susceptibility locus for IGE on chromosome 5 then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.

• Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy.

  Authors: O K Steinlein, B A Neubauer, T Sander, L Song, J Stoodt, D B Mount

  Epilepsy research. 06/2001; 44(2-3):191-5.

  Genetic predisposition plays a major role in the etiology of idiopathic epilepsies. The common epilepsy syndromes display a complex pattern of inheritance, with an unknown number of genesGenetic predisposition plays a major role in the etiology of idiopathic epilepsies. The common epilepsy syndromes display a complex pattern of inheritance, with an unknown number of genes contributing to seizure susceptibility. During the last decade linkage studies have narrowed down several candidate regions for susceptibility loci of idiopathic epilepsies. Several lines of evidence point to the existence of an epilepsy susceptibility gene on chromosome 15q14. Evidence for linkage to this region has thus been reported for juvenile myoclonic epilepsy, common subtypes of idiopathic generalized epilepsy (IGE), in addition to the EEG trait 'centrotemporal spikes' in families with rolandic epilepsy. The chromosomal region 15q14 harbours several candidate genes that are involved in the regulation of neuronal excitability. One of the most promising candidate genes is the brain-expressed potassium chloride cotransporter KCC3, given that this class of ion transporter has been implicated in the regulation of neuronal chloride activity. We therefore performed a mutation analysis of KCC3 in the index patients of 23 IGE-families as well as of 16 families with rolandic epilepsy which where selected by positive evidence for linkage to D15S165. Four novel single nucleotide exchanges (SNPs) were identified, none of which change the coding sequence. These results do not support a major role for KCC3 in the etiology of rolandic epilepsy or common subtypes of IGE.

• A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy.

  Authors: A Escayg, A Heils, B T MacDonald, K Haug, T Sander, M H Meisler

  American journal of human genetics. 05/2001; 68(4):866-73.

  We recently described mutations of the neuronal sodium-channel alpha-subunit gene, SCN1A, on chromosome 2q24 in two families with generalized epilepsy with febrile seizures plus (GEFS+) type 2. ToWe recently described mutations of the neuronal sodium-channel alpha-subunit gene, SCN1A, on chromosome 2q24 in two families with generalized epilepsy with febrile seizures plus (GEFS+) type 2. To assess the contribution that SCN1A makes to other types of epilepsy, 226 patients with either juvenile myoclonic epilepsy, absence epilepsy, or febrile convulsions were screened by conformation-sensitive gel electrophoresis and manual sequencing of variants; the sample included 165 probands from multiplex families and 61 sporadic cases. The novel mutation W1204R was identified in a family with GEFS+. Seven other coding changes were observed; three of these are potential disease-causing mutations. Two common haplotypes, with frequencies of .67 and .33, were defined by five single-nucleotide polymorphisms (SNPs) spanning a 14-kb region of linkage disequilibrium. An SNP located 18 bp upstream of the splice-acceptor site for exon 3 was observed in 7 of the 226 patients but was not present in 185 controls, suggesting possible association with a disease mutation. This work has confirmed the role of SCN1A in GEFS+, by identification of a novel mutation in a previously undescribed family. Although a few candidate disease alleles were identified, the patient survey suggests that SCN1A is not a major contributor to idiopathic generalized epilepsy. The SCN1A haplotypes and SNPs identified here will be useful in future association and linkage studies.

• Exonic variants of the GABA(B) receptor gene and panic disorder.

  Authors: P G Sand, C Godau, P Riederer, C Peters, P Franke, M M Nöthen, G Stöber, J Fritze, W Maier, P Propping, K P Lesch, O Riess, T Sander, H Beckmann, J Deckert

  Psychiatric genetics. 01/2001; 10(4):191-4.

  The enhancement of GABAergic neurotransmission has been closely linked to antipanic drug efficacy. This is the first study to investigate a putative association of exonic sequence variants of theThe enhancement of GABAergic neurotransmission has been closely linked to antipanic drug efficacy. This is the first study to investigate a putative association of exonic sequence variants of the human GABA(B) receptor 1 (GABA(B)R1) gene and susceptibility to panic disorder. Three DNA sequence variants in exons 1a1, 7 and 11 were assessed by polymerase chain reaction-based restriction fragment length polymorphism in a case-control study among patients with panic disorder with and without agoraphobia (DSM III-R criteria) and blood donors. There was no indication of an increased vulnerability to panic disorder or agoraphobia with respect to the allelic variants under study.

• Association analysis of GABAAbeta2 and gamma2 gene polymorphisms with event-related prefrontal activity in man.

  Authors: G Winterer, M Smolka, J Samochowiec, C Mulert, M Ziller, R Mahlberg, Y Wuebben, J Gallinat, H Rommelspacher, W M Herrman, T Sander

  Human genetics. 12/2000; 107(5):513-8.

  Gamma-aminobutyric acid (GABA)A-receptors play a crucial role in the generation of electroencephalogram (EEG) oscillations and evoked potentials (ERPs). The present association study was designed toGamma-aminobutyric acid (GABA)A-receptors play a crucial role in the generation of electroencephalogram (EEG) oscillations and evoked potentials (ERPs). The present association study was designed to test whether EEG and ERPs are modulated by genetic variations of the human GABAA beta2 (GABRB2) and gamma2 (GABRG2) genes on chromosome 5q33. The genotypes of two nucleotide substitution polymorphisms of the GABRB2 and GABRG2 genes were assessed in 95 psychiatrically healthy subjects of German descent. Neurophysiological phenotyping was performed with four factorized EEG/ERP parameters: EEG activation, anterior and posterior EEG synchronization, and event-related activity (N100/ P200-complex). No genotypic association was found for the GABRB2 nucleotide exchange polymorphism with any electrophysiological parameter. A significant association was found between the genotype of the intronic GABRG2 G-->A nucleotide exchange and the event-related N100/P200 (ANOVA: F=3.81; df=2; P=0.026). A comparison of homozygous subjects carrying either the G/G or A/A genotype of the GABRG2 polymorphism consistently revealed an even stronger difference in the effect-size (ANOVA: F=11.13; df=1; P=0.002). Post hoc analysis of this association with current density analysis in three-dimensional neuroanatomic Talairach space-time showed a reduction in the event-related signal power after 120 ms in the right dorsolateral prefrontal cortex. Taking into account the risk of false-positive association findings attributable to multiple testing, our results encourage further replication studies to examine the phenotype-genotype relationship of GABRG2 gene variants and event-related prefrontal activity.

• No evidence for association between the KCNQ3 gene and susceptibility to idiopathic generalized epilepsy.

  Authors: K Haug, K Hallmann, S Horvath, T Sander, C Kubisch, B Rau, J Dullinger, S Beyenburg, C E Elger, P Propping, A Heils

  Epilepsy research. 12/2000; 42(1):57-62.

  Idiopathic generalized epilepsy (IGE) comprises a heterogeneous group of disorders, in which a high genetic predisposition and a complex mode of inheritance have been suggested. Recent identificationIdiopathic generalized epilepsy (IGE) comprises a heterogeneous group of disorders, in which a high genetic predisposition and a complex mode of inheritance have been suggested. Recent identification of ion channel gene mutations in Mendelian epileptic disorders suggests genetically driven neuronal hyperexcitability as one important factor in epileptogenesis. Mutations in two neuronal voltage-gated potassium channel genes (KCNQ2 and KCNQ3) have already been shown to cause epilepsy (BFNC), and we now tested the hypothesis that genetic variation in the KCNQ3 gene confers liability to common IGE subtypes. Length variation of two intragenic polymorphic markers (D8S558 and D8S1835) were therefore assessed in 71 nuclear families ascertained for an affected child. However, the transmission-disequilibrium-test did not show significant differences between the transmitted and non-transmitted parental alleles. Thus, our findings do not provide evidence that genetic variation in the KCNQ3 gene exerts a relevant effect in the etiology of common IGE subtypes.

• [Molecular diagnosis of hereditary neurologic diseases. Position paper]

  Authors: T Gasser, M Dichgans, K Jurkat-Rott, T Klockgether, T Klopstock, H Kretzschmar, F Lehmann-Horn, H Reichmann, A Rolfs, T Sander, F Stögbauer

  Der Nervenarzt. 11/2000; 71(10):774-96.

• Genetic variation of the glutamate transporter EAAT2 gene and vulnerability to alcohol dependence.

  Authors: T Sander, A Ostapowicz, J Samochowiec, M Smolka, G Winterer, L G Schmidt

  Psychiatric genetics. 10/2000; 10(3):103-7.

  Glutamate-mediated excitatory pathways play an important role in the pathogenesis of alcohol dependence. The present association study tested the candidate gene hypothesis that variation of the geneGlutamate-mediated excitatory pathways play an important role in the pathogenesis of alcohol dependence. The present association study tested the candidate gene hypothesis that variation of the gene encoding the astroglial glutamate transporter EAAT2 confers vulnerability to alcohol dependence. Genotypes of a silent G603A nucleotide exchange in exon 5 of the EAAT2 gene were assessed in 565 subjects of German descent, comprising 342 alcohol-dependent subjects and 223 control subjects. Two more homogeneous subgroups of alcoholics were selected: (1) 112 alcoholics with a history of alcohol withdrawal seizure or delirium; and (2) 54 alcoholics with an antisocial personality disorder. The Tridimensional Personality Questionnaire was applied to assess personality dimensions in 106 alcohol-dependent males. The allele frequencies of the G603A polymorphism did not differ significantly between the control subjects and either the entire sample of alcoholics or the alcoholics with severe physiological withdrawal symptoms. Without correction for multiple testing, there was a significant increase of the frequency of the A603 allele in the antisocial alcoholics compared with either the control subjects [chi2 = 4.587, 1 degree of freedom (df), P = 0.032] or the alcoholics without ASPD (chi2 = 4.968, 1 df, P = 0.026). The personality trait of Harm Avoidance was significantly lower in alcoholics carrying the A603 allele compared with those lacking it (U-test; P = 0.009). These two consistent lines of evidence suggest that genetic variation of the EAAT2 gene confers vulnerability to risk-taking behavior in alcoholics.

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

  Authors: T Sander, W Berlin, A Ostapowicz, J Samochowiec, N Gscheidel, M R Hoehe

  Epilepsy research. 09/2000; 41(1):75-81.

  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 tuningSeveral 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.