TY  - JOUR
AB  - OBJECTIVE: Neuronal cell death and neuroinflammation are characteristic features of epilepsy, but it remains unclear whether neuronal cell death as such is causative for the development of epileptic seizures. To test this hypothesis, we established a novel mouse line permitting inducible ablation of pyramidal neurons by inserting simian diphtheria toxin (DT) receptor (DTR) cDNA into the Ccl17 locus. The chemokine CCL17 is expressed in pyramidal CA1 neurons in adult mice controlling microglial quiescence. METHODS: Seizure activity in CCL17-DTR mice was analyzed by electroencephalographic recordings following treatment with DT for 3 consecutive days. Neuroinflammation and neuronal cell death were evaluated by (immuno)histochemistry. Pharmacological inhibition of TNFR1 signaling was achieved by treatment with XPro1595, a dominant-negative inhibitor of soluble tumor necrosis factor. RESULTS: Neuronal cell death was detectable 7 days (d7) after the first DT injection in heterozygous CCL17-DTR mice. Spontaneous epileptic seizures were observed in the vast majority of mice, often with an initial peak at d6-9, followed by a period of reduced activity and a gradual increase during the 1-month observation period. Microglial reactivity was overt from d5 after DT administration not only in the CA1 region but also in the CA2/CA3 area, shortly followed by astrogliosis. Reactive microgliosis and astrogliosis persisted until d30 and, together with neuronal loss and stratum radiatum shrinkage, reflected important features of human hippocampal sclerosis. Granule cell dispersion was detectable only 3 months after DT treatment. Application of XPro1595 significantly reduced chronic seizure burden without affecting the development of hippocampal sclerosis. SIGNIFICANCE: In conclusion, our data demonstrate that sterile pyramidal neuronal death is sufficient to cause epilepsy in the absence of other pathological processes. The CCL17-DTR mouse line may thus be a valuable model for further mechanistic studies on epilepsy and assessment of antiseizure medication.
AU  - Eberhard, J.*
AU  - Henning, L.*
AU  - Fülle, L.*
AU  - Knöpper, K.*
AU  - Böhringer, J.*
AU  - Graelmann, F.J.*
AU  - Hänschke, L.*
AU  - Kenzler, J.*
AU  - Brosseron, F.*
AU  - Heneka, M.T.*
AU  - Domingos, A.I.*
AU  - Eyerich, S.
AU  - Lochner, M.*
AU  - Weighardt, H.*
AU  - Bedner, P.*
AU  - Steinhauser, C.*
AU  - Förster, I.*
C1  - 72563
C2  - 56649
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Ablation of CCL17-positive hippocampal neurons induces inflammation-dependent epilepsy.
JO  - Epilepsia
PB  - Wiley
PY  - 2024
SN  - 0013-9580
ER  - 

TY  - JOUR
AB  - Variants in γ-aminobutyric acid A (GABAA) receptor genes cause different forms of epilepsy and neurodevelopmental disorders. To date, GABRA4, encoding the α4-subunit, has not been associated with a monogenic condition. However, preclinical evidence points toward seizure susceptibility. Here, we report a de novo missense variant in GABRA4 (c.899C>T, p.Thr300Ile) in an individual with early-onset drug-resistant epilepsy and neurodevelopmental abnormalities. An electrophysiological characterization of the variant, which is located in the pore-forming domain, shows accelerated desensitization and a lack of seizure-protective neurosteroid function. In conclusion, our findings strongly suggest an association between de novo variation in GABRA4 and a neurodevelopmental disorder with epilepsy.
AU  - Vogel, F.D.*
AU  - Krenn, M.*
AU  - Westphal, D.S.*
AU  - Graf, E.*
AU  - Wagner, M.
AU  - Leiz, S.*
AU  - Koniuszewski, F.*
AU  - Augé-Stock, M.*
AU  - Kramer, G.*
AU  - Scholze, P.*
AU  - Ernst, M.*
C1  - 64334
C2  - 52181
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - e35-e41
TI  - A de novo missense variant in GABRA4 alters receptor function in an epileptic and neurodevelopmental phenotype.
JO  - Epilepsia
VL  - 63
IS  - 4
PB  - Wiley
PY  - 2022
SN  - 0013-9580
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Paroxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations. METHODS: Confounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses. RESULTS: Our analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations. SIGNIFICANCE: Our results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.
AU  - Stevelink, R.*
AU  - Luykx, J.J.*
AU  - Lin, B.D.*
AU  - Leu, C.*
AU  - Lal, D.*
AU  - Smith, A.W.*
AU  - Schijven, D.*
AU  - Carpay, J.A.*
AU  - Rademaker, K.*
AU  - Rodrigues Baldez, R.A.*
AU  - Devinsky, O.*
AU  - Braun, K.P.J.*
AU  - Jansen, F.E.*
AU  - Smit, D.J.A.*
AU  - Koeleman, B.P.C.*
AU  - The International League Against Epilepsy Consortium on Complex Epilepsies (Gieger, C.)
AU  - The International League Against Epilepsy Consortium on Complex Epilepsies (Strauch, K.)
C1  - 63307
C2  - 51265
SP  - 1518-1527
TI  - Shared genetic basis between genetic generalized epilepsy and background electroencephalographic oscillations.
JO  - Epilepsia
VL  - 62
IS  - 7
PY  - 2021
SN  - 0013-9580
ER  - 

TY  - JOUR
AB  - Objective: To evaluate the necessity of recording ictal electroencephalography (EEG) in patients with temporal lobe epilepsy (TLE) considered for resective surgery who have unilateral temporal interictal epileptiform discharges (IEDs) and concordant ipsitemporal magnetic resonance imaging (MRI) pathology. To calculate the necessary number of recorded EEG seizure patterns (ESPs) to achieve adequate lateralization probability.Methods: In a retrospective analysis, the localization and lateralization of interictal and ictal EEG of 304 patients with lesional TLE were analyzed. The probability of further contralateral ESPs was calculated based on a total of 1967 recorded ESPs, using Bayes' theorem.Results: Two hundred seventy-one patients had unilateral TLE, and in 98% of them (265 of 271), IEDs were recorded during video-EEG monitoring. Purely unilateral temporal IEDs were present in 61% (166 of 271 patients). Ipsilateral temporal MR1 pathology was found in 83% (138 of 166). Ictal EEG was concordant with the clinical side of TLE in 99% (136 of 138) of these patients. Two patients had discordant ictal EEG with both ipsilateral and contralateral ESPs. Epilepsy surgery with resection in the lesioned temporal lobe was still performed, and both patients remain seizure-free. Probability calculations demonstrate that at least 6 recorded unilateral ESPs result in a >95% probability for a concordance of >0.9 of any further ESPs.Significance: The combination of purely unilateral temporal IED with ipsitemporal MRI pathology is sufficient to identify the epileptogenic zone, and the recording of ictal ESP did not add any surgically relevant information in these 138 patients. Rarely, discordant ESPs might be recorded, but the surgical outcome remains excellent after surgery on the lesioned side.
AU  - Vollmar, C.*
AU  - Stredl, I.*
AU  - Heinig, M.
AU  - Noachtar, S.*
AU  - Rémi, J.*
C1  - 53954
C2  - 45133
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1577-1582
TI  - Unilateral temporal interictal epileptiform discharges correctly predict the epileptogenic zone in lesional temporal lobe epilepsy.
JO  - Epilepsia
VL  - 59
IS  - 8
PB  - Wiley
PY  - 2018
SN  - 0013-9580
ER  - 

TY  - JOUR
AU  - Potschka, H.*
AU  - Walker, A.*
AU  - Russmann, V.*
AU  - von Rueden, L.*
AU  - Goc, J.*
AU  - Kleinwort, K.J.*
AU  - Szober, C.M.*
AU  - von Toerne, C.
AU  - Deeg, C.A.*
AU  - Hauck, S.M.
C1  - 47586
C2  - 40667
SP  - 193-193
TI  - Differential proteome analysis during epileptogenesis: Focus on inflammation.
JO  - Epilepsia
VL  - 56
PY  - 2015
SN  - 0013-9580
ER  - 

TY  - JOUR
AU  - von Rueden, E.- L.*
AU  - Zellinger, C.*
AU  - Walker, A.*
AU  - Russmann, V.*
AU  - Kleinwort, K.J.*
AU  - Szober, C.M.*
AU  - von Toerne, C.
AU  - Deeg, C.A.*
AU  - Hauck, S.M.
AU  - Potschka, H.*
C1  - 47587
C2  - 40668
SP  - 4-4
TI  - Shared pathophysiology of temporal lobe epilepsy and Alzheimer´s disease -  a differential proteomics approach in a post-status epilepticus model.
JO  - Epilepsia
VL  - 56
PY  - 2015
SN  - 0013-9580
ER  - 

TY  - JOUR
AB  - PURPOSE: Structural variations disrupting the gene encoding the neuron-specific splicing regulator RBFOX1 have been reported in three patients exhibiting epilepsy in comorbidity with other neuropsychiatric disorders. Consistently, the Rbfox1 knockout mouse model showed an increased susceptibility of seizures. The present candidate gene study tested whether exon-disrupting deletions of RBFOX1 increase the risk of idiopathic generalized epilepsies (IGEs), representing the largest group of genetically determined epilepsies. METHODS: Screening of microdeletions (size: >40 kb, coverage >20 markers) affecting the genomic sequence of the RBFOX1 gene was carried out by high-resolution single-nucleotide polymorphism (SNP) arrays in 1,408 European patients with idiopathic generalized epilepsy (IGE) and 2,256 population controls. Validation of RBFOX1 deletions and familial segregation analysis were performed by quantitative polymerase chain reaction (qPCR). KEY FINDINGS: We detected five exon-disrupting RBFOX1 deletions in the IGE patients, whereas none was observed in the controls (p = 0.008, Fisher's exact test). The size of the exonic deletions ranged from 68 to 896 kb and affected the untranslated 5'-terminal RBFOX1 exons. Segregation analysis in four families indicated that the deletions were inherited, display incomplete penetrance, and heterogeneous cosegregation patterns with IGE. SIGNIFICANCE: Rare deletions affecting the untranslated 5'-terminal RBFOX1 exons increase risk of common IGE syndromes. Variable expressivity, incomplete penetrance, and heterogeneous cosegregation patterns suggest that RBFOX1 deletions act as susceptibility factor in a genetically complex etiology, where heterogeneous combinations of genetic factors determine the disease phenotype.
AU  - Lal, D.*
AU  - Trucks, H.*
AU  - Møller, R.S.*
AU  - Hjalgrim, H.*
AU  - Koeleman, B.P.*
AU  - de Kovel, C.G.F.*
AU  - Visscher, F.*
AU  - Weber, Y.G.*
AU  - Lerche, H.*
AU  - Becker, F.*
AU  - Schankin, C.J.*
AU  - Neubauer, B.A.*
AU  - Surges, R.*
AU  - Kunz, W.S.*
AU  - Zimprich, F.*
AU  - Franke, A.*
AU  - Illig, T.
AU  - Ried, J.S.
AU  - Leu, C.*
AU  - Nürnberg, P.*
AU  - Sander, T.*
AU  - EMINet Consortium (*)
AU  - EPICURE Consortium (*)
C1  - 23000
C2  - 30978
SP  - 265-271
TI  - Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy.
JO  - Epilepsia
VL  - 54
IS  - 2
PB  - Wiley-Blackwell
PY  - 2013
SN  - 0013-9580
ER  - 

TY  - JOUR
AB  - PURPOSE: Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). METHODS: We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. KEY FINDINGS: We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92-51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. SIGNIFICANCE: We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.
AU  - Møller, R.S.*
AU  - Weber, Y.G.*
AU  - Klitten, L.L.*
AU  - Trucks, H.*
AU  - Muhle, H.*
AU  - Kunz, W.S.*
AU  - Mefford, H.C.*
AU  - Franke, A.*
AU  - Kautza, M.*
AU  - Wolf, P.*
AU  - Dennig, D.*
AU  - Schreiber, S.*
AU  - Rückert, I.-M.
AU  - Wichmann, H.-E.
AU  - Ernst, J.P.*
AU  - Schurmann, C.*
AU  - Grabe, H.J.*
AU  - Tommerup, N.*
AU  - Stephani, U.*
AU  - Lerche, H.*
AU  - Hjalgrim, H.*
AU  - Helbig, I.*
AU  - Sander, T.*
AU  - EPICURE Consortium (*)
C1  - 22837
C2  - 30953
SP  - 256-264
TI  - Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy.
JO  - Epilepsia
VL  - 54
IS  - 2
PB  - Wiley-Blackwell
PY  - 2013
SN  - 0013-9580
ER  - 

TY  - JOUR
AU  - Zimprich, F.*
AU  - Stogmann, E.*
AU  - Bonelli, S.*
AU  - Baumgartner, C.*
AU  - Mueller, J.C.*
AU  - Meitinger, T.
AU  - *
AU  - Strom, T.M.
C1  - 2569
C2  - 25625
SP  - 1108-1109
TI  - A functional polymorphism in the SCN1A gene is not associated with carbamazepine dosages in Austrian patients with epilepsy.
JO  - Epilepsia
VL  - 49
IS  - 6
PB  - Wiley-Blackwell
PY  - 2008
SN  - 0013-9580
ER  -