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3. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

Author

Abou-Khalil, B, Auce, P, Avbersek, A, Bahlo, M, Balding, DJ, Bast, T, Baum, L, Becker, AJ, Becker, F, Berghuis, B, Berkovic, SF, Boysen, KE, Bradfield, JP, Brody, LC, Buono, RJ, Campbell, E, Cascino, GD, Catarino, CB, Cavalleri, GL, Cherny, SS, Chinthapalli, K, Coffey, AJ, Compston, A, Coppola, A, Cossette, P, Craig, JJ, de Haan, G-J, De Jonghe, P, de Kovel, CGF, Delanty, N, Depondt, C, Devinsky, O, Dlugos, DJ, Doherty, CP, Elger, CE, Eriksson, JG, Ferraro, TN, Feucht, M, Francis, B, Franke, A, French, JA, Freytag, S, Gaus, V, Geller, EB, Gieger, C, Glauser, T, Glynn, S, Goldstein, DB, Gui, H, Guo, Y, Haas, KF, Hakonarson, H, Hallmann, K, Haut, S, Heinzen, EL, Helbig, I, Hengsbach, C, Hjalgrim, H, Iacomino, M, Ingason, A, Jamnadas-Khoda, J, Johnson, MR, Kalviainen, R, Kantanen, A-M, Kasperaviciute, D, Trenite, DK-N, Kirsch, HE, Knowlton, RC, Koeleman, BPC, Krause, R, Krenn, M, Kunz, WS, Kuzniecky, R, Kwan, P, Lal, D, Lau, Y-L, Lehesjoki, A-E, Lerche, H, Leu, C, Lieb, W, Lindhout, D, Lo, WD, Lopes-Cendes, I, Lowenstein, DH, Malovini, A, Marson, AG, Mayer, T, McCormack, M, Mills, JL, Mirza, N, Moerzinger, M, Moller, RS, Molloy, AM, Muhle, H, Newton, M, Ng, P-W, Noethen, MM, Nuernberg, P, O'Brien, TJ, Oliver, KL, Palotie, A, Pangilinan, F, Peter, S, Petrovski, S, Poduri, A, Privitera, M, Radtke, R, Rau, S, Reif, PS, Reinthaler, EM, Rosenow, F, Sander, JW, Sander, T, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Sham, PC, Shih, JJ, Sills, GJ, Sisodiya, SM, Slattery, L, Smith, A, Smith, DF, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Steinhoff, BJ, Stephani, U, Stevelink, R, Strauch, K, Striano, P, Stroink, H, Surges, R, Tan, KM, Thio, LL, Thomas, GN, Todaro, M, Tozzi, R, Vari, MS, Vining, EPG, Visscher, F, von Spiczak, S, Walley, NM, Weber, YG, Wei, Z, Weisenberg, J, Whelan, CD, Widdess-Walsh, P, Wolff, M, Wolking, S, Yang, W, Zara, F, Zimprich, F, Abou-Khalil, B, Auce, P, Avbersek, A, Bahlo, M, Balding, DJ, Bast, T, Baum, L, Becker, AJ, Becker, F, Berghuis, B, Berkovic, SF, Boysen, KE, Bradfield, JP, Brody, LC, Buono, RJ, Campbell, E, Cascino, GD, Catarino, CB, Cavalleri, GL, Cherny, SS, Chinthapalli, K, Coffey, AJ, Compston, A, Coppola, A, Cossette, P, Craig, JJ, de Haan, G-J, De Jonghe, P, de Kovel, CGF, Delanty, N, Depondt, C, Devinsky, O, Dlugos, DJ, Doherty, CP, Elger, CE, Eriksson, JG, Ferraro, TN, Feucht, M, Francis, B, Franke, A, French, JA, Freytag, S, Gaus, V, Geller, EB, Gieger, C, Glauser, T, Glynn, S, Goldstein, DB, Gui, H, Guo, Y, Haas, KF, Hakonarson, H, Hallmann, K, Haut, S, Heinzen, EL, Helbig, I, Hengsbach, C, Hjalgrim, H, Iacomino, M, Ingason, A, Jamnadas-Khoda, J, Johnson, MR, Kalviainen, R, Kantanen, A-M, Kasperaviciute, D, Trenite, DK-N, Kirsch, HE, Knowlton, RC, Koeleman, BPC, Krause, R, Krenn, M, Kunz, WS, Kuzniecky, R, Kwan, P, Lal, D, Lau, Y-L, Lehesjoki, A-E, Lerche, H, Leu, C, Lieb, W, Lindhout, D, Lo, WD, Lopes-Cendes, I, Lowenstein, DH, Malovini, A, Marson, AG, Mayer, T, McCormack, M, Mills, JL, Mirza, N, Moerzinger, M, Moller, RS, Molloy, AM, Muhle, H, Newton, M, Ng, P-W, Noethen, MM, Nuernberg, P, O'Brien, TJ, Oliver, KL, Palotie, A, Pangilinan, F, Peter, S, Petrovski, S, Poduri, A, Privitera, M, Radtke, R, Rau, S, Reif, PS, Reinthaler, EM, Rosenow, F, Sander, JW, Sander, T, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Sham, PC, Shih, JJ, Sills, GJ, Sisodiya, SM, Slattery, L, Smith, A, Smith, DF, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Steinhoff, BJ, Stephani, U, Stevelink, R, Strauch, K, Striano, P, Stroink, H, Surges, R, Tan, KM, Thio, LL, Thomas, GN, Todaro, M, Tozzi, R, Vari, MS, Vining, EPG, Visscher, F, von Spiczak, S, Walley, NM, Weber, YG, Wei, Z, Weisenberg, J, Whelan, CD, Widdess-Walsh, P, Wolff, M, Wolking, S, Yang, W, Zara, F, and Zimprich, F

Abstract

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.

Published
2018

4. Exon-disrupting deletions ofNRXN1in idiopathic generalized epilepsy

Author

Møller, R.S., Weber, Y.G., Klitten, L.L., Trucks, H., Muhle, H., Kunz, W.S., Mefford, H.C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I.M., Wichmann, H.E., Ernst, J.P., Schurmann, C., Grabe, H.J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D.B., Lehesjoki, A.E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M.R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C.E., Kleefuß Lie, A.A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K.M., Reif, P.S., Oertel, W.H., Hamer, H.M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M.T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B.P.C., De Kovel, C., Lindhout, D., De Haan, G.J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., Agan, K., R. S. Møller, Y. G. Weber, L. L. Klitten, H. Truck, H. Muhle, W. S. Kunz, H. C. Mefford, A. Franke, M. Kautza, P. Wolf, D. Dennig, S. Schreiber, I. Rückert, H. Wichmann, J. P. Ernst, C. Schurmann, H. J. Grabe, N. Tommerup, U. Stephani, H. Lerche, H. Hjalgrim, I. Helbig, T. Sander, P. Tinuper, F. Bisulli, EPICURE Consortium, Suls, Arvid, Weckhuysen, Sarah, Claes, Godelieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Jordanova, Albena, Møller, R, Weber, Yg, Klitten, Ll, Trucks, H, Muhle, H, Kunz, W, Mefford, Hc, Franke, A, Kautza, M, Wolf, P, Dennig, D, Schreiber, S, Rückert, Im, Wichmann, He, Ernst, Jp, Schurmann, C, Grabe, Hj, Tommerup, N, Stephani, U, Lerche, H, Hjalgrim, H, Helbig, I, Sander, T, Epicure, Consortium, DEL GIUDICE, Ennio, Coppola, Antonietta, and YÜCESAN, EMRAH

Subjects
Male, Idiopathic generalized epilepsy, Neuronal, Idiopathic Generalized Epilepsy, 1q21, 1 Microdeletion, Two-hit Hypothesis, Nrxn1, Neuropsychological Tests, Immunoglobulin E, Cell Adhesion Molecules, Neuronal/genetics, Adult, Age of Onset, Anticonvulsant, Exon, 1q21.1 microdeletion, Exons/genetics, Odds Ratio, Nerve Tissue Proteins/genetics, Copy-number variation, Valproic Acid/therapeutic use, Age of Onset, Neural Cell Adhesion Molecules, genetics, DNA Copy Number Variations, Electroencephalography, Epilepsy, Genetics, biology, Triazines, Anticonvulsants/therapeutic use, Electroencephalography, genetics, Family, Female, Fructose, Exons, Middle Aged, Settore MED/39 - Neuropsichiatria Infantile, Pedigree, therapeutic use, Valproic Acid, Neurology, Settore MED/26 - Neurologia, Anticonvulsants, Epilepsy, Generalized, Female, Adult, Case-Control Studies, Cell Adhesion Molecules, Neuronal, DNA Copy Number Variations, Family, Fructose, Gene Deletion, Genotype, Humans, Infant, Microarray Analysis, Nerve Tissue Proteins, Valproic Acid, analogs /&/ derivatives/therapeutic use, Gene Deletion, Genotype, Humans, Infant, Male, Microarray Analysis, Middle Aged, Nerve Tissue Protein, therapeutic use, Case-Control Studies, Cell Adhesion Molecule, drug therapy/genetics/psychology, Exon, genetics, Neuropsychological Tests, Odds Ratio, Pedigree, Triazine, Lamotrigine, NRXN1, Topiramate, Epilepsy, Generalized/drug therapy, medicine, Allele, Biology, Gene, Generalized, Point mutation, Calcium-Binding Proteins, Odds ratio, medicine.disease, Triazines/therapeutic use, Settore MED/03 - Genetica Medica, therapeutic use, biology.protein, Fructose/analogs & derivatives, Human medicine, Neurology (clinical), Two-hit hypothesis
Abstract

Summary 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.

Published
2013
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5. Interictal dysphoric disorder and periictal dysphoric symptoms in patients with epilepsy

Author

Mula, M, Jauch, R, Cavanna, A, Gaus, V, Kretz, R, Collimedaglia, L, Barbagli, D, Cantello, R, Monaco, F, Schmitz, B, Mula M, Jauch R, Cavanna A, Gaus V, Kretz R, Collimedaglia L, Barbagli D, Cantello R, Monaco F, Schmitz B., Mula, M, Jauch, R, Cavanna, A, Gaus, V, Kretz, R, Collimedaglia, L, Barbagli, D, Cantello, R, Monaco, F, Schmitz, B, Mula M, Jauch R, Cavanna A, Gaus V, Kretz R, Collimedaglia L, Barbagli D, Cantello R, Monaco F, and Schmitz B.

Abstract

Purpose: The issue of phenomenology of mood disorders in epilepsy still remains controversial. It has been suggested that a subgroup of patients may develop an affective syndrome also known as interictal dysphoric disorder (IDD). However, the number of behavioral changes that may occur around the ictus needs to be taken into account for an accurate distinction between "true" psychiatric phenomenology and periictal phenomena. This study aimed at identifying clinical correlates of the IDD, with special attention to the relationship between symptoms and seizures. Methods: A sample of 142 consecutive adult outpatients with epilepsy were assessed using the Interictal Dysphoric Disorder Inventory (IDDI), a 38-item, self-report questionnaire specifically developed to evaluate presence and severity of IDD symptoms as well as their habitual association with seizures (coded as before, after, during, or when seizure-free) and their duration. Results: IDD was diagnosed in 31 subjects but symptoms showed a clear-cut relationship with epileptic seizures in 54.8% of cases, leading to an operative distinction between true IDD and periictal dysphoric symptoms (PDS). There was no significant difference among patients with IDD, PDS, or those without psychopathology. In the IDD group, symptoms were chronic and unremitting in one-third of cases, with labile affective symptoms being correlated with age at onset of seizures (rho = )0.612, p = 0.020) and duration of the epilepsy (rho = 0.833, p < 0.001). Discussion: An operative distinction between IDD and PDS bears the opportunity to identify different clinical endophenotypes that may have different prognoses and require different treatment strategies.

Published
2010

6. Erratum: Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy (Epilepsia (2013) 54 (256-264) DOI:10.1111/epi.12517)

Author

Møller, R. S., Weber, Y. G., Klitten, L. L., Trucks, H., Muhle, H., Kunz, W. S., Mefford, H. C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I. -M., Wichmann, H. -E., Ernst, J. P., Schurmann, C., Grabe, H. J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D. B., Lehesjoki, A. -E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M. R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C. E., Kleefuß-Lie, A. A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K. M., Reif, P. S., Oertel, W. H., Hamer, H. M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M. T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B. P. C., De Kovel, C., Lindhout, D., De Haan, G. -J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., Agan, K., Møller, R. S., Weber, Y. G., Klitten, L. L., Trucks, H., Muhle, H., Kunz, W. S., Mefford, H. C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I. -M., Wichmann, H. -E., Ernst, J. P., Schurmann, C., Grabe, H. J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D. B., Lehesjoki, A. -E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M. R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C. E., Kleefuß-Lie, A. A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K. M., Reif, P. S., Oertel, W. H., Hamer, H. M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M. T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B. P. C., De Kovel, C., Lindhout, D., De Haan, G. -J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., and Agan, K.

Published
2013

7. Manic/hypomanic symptoms and quality of life measures in patients with epilepsy

Author

Mula, M, Jauch, R, Cavanna, A, Collimedaglia, L, Barbagli, D, Gaus, V, Kretz, R, Viana, M, Cantello, R, Monaco, F, Schmitz, B, Mula M, Jauch R, Cavanna A, Collimedaglia L, Barbagli D, Gaus V, Kretz R, Viana M, Cantello R, Monaco F, Schmitz B., Mula, M, Jauch, R, Cavanna, A, Collimedaglia, L, Barbagli, D, Gaus, V, Kretz, R, Viana, M, Cantello, R, Monaco, F, Schmitz, B, Mula M, Jauch R, Cavanna A, Collimedaglia L, Barbagli D, Gaus V, Kretz R, Viana M, Cantello R, Monaco F, and Schmitz B.

Abstract

Purpose: Although several studies pointed out an association between depression and quality of life (QoL) of patients with epilepsy, data about manic/hypomanic symptoms (MHS) remain scanty. In this study, we sought to investigate their relationship with social and health-related QoL measures in patients with epilepsy. Methods: Consecutive adult outpatients with epilepsy were assessed using the M.I.N.I. Plus version 5.0.0 and the QOLIE-31. Results: Among 117 evaluated patients, 17 fulfilled DSM-IV criteria for manic/hypomanic episodes. Patients with MHS, as compared to those without, showed lower scores in emotional well-being, energy and fatigue, medication effects, social function and total QOLIE score. However, there was no between-groups difference in educational achievements, employment status, living situation, comorbid psychiatric disorders, history of suicide or abuse of illicit drugs. Conclusions: MHS are associated with poor QoL measures in patients with epilepsy, though without differences in educational achievements, employment status and independent living.

Published
2009

8. Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

Author

EPICURE Consortium, Leu C., de Kovel C. G., Zara F., Striano P., Pezzella M., Robbiano A., Bianchi A., Coppola A., Giallonardo A. T., Beccaria F., Trenité D. K., Lindhout D., Gaus V., Schmitz B., Janz D., Weber Y. G., Becker F., Lerche H., Kleefuss Lie A. A., Hallman K., Kunz W. S., Elger C. E., Muhle H., Stephani U., Møller R. S., Hjalgrim H., Mullen S., Scheffer I. E., Berkovic S. F., Everett K. V., Gardiner M. R., Marini C., Guerrini R., Lehesjoki A. E., Siren A., Nabbout R., Baulac S., Leguern E., Serratosa J. M., Rosenow F., Feucht M., Unterberger I., Covanis A., Suls A., Weckhuysen S., Kaneva R., Caglayan H., Turkdogan D., Baykan B., Bebek N., Ozbek U., Hempelmann A., Schulz H., Rüschendorf F., Trucks H., Nürnberg P., Avanzini G., Koeleman B. P., Sander T., BISULLI, FRANCESCA, TINUPER, PAOLO, YÜCESAN, EMRAH, EPICURE Consortium, Leu C., de Kovel C.G., Zara F., Striano P., Pezzella M., Robbiano A., Bianchi A., Bisulli F., Coppola A., Giallonardo A.T., Beccaria F., Trenité D.K., Lindhout D., Gaus V., Schmitz B., Janz D., Weber Y.G., Becker F., Lerche H., Kleefuss-Lie A.A., Hallman K., Kunz W.S., Elger C.E., Muhle H., Stephani U., Møller R.S., Hjalgrim H., Mullen S., Scheffer I.E., Berkovic S.F., Everett K.V., Gardiner M.R., Marini C., Guerrini R., Lehesjoki A.E., Siren A., Nabbout R., Baulac S., Leguern E., Serratosa J.M., Rosenow F., Feucht M., Unterberger I., Covanis A., Suls A., Weckhuysen S., Kaneva R., Caglayan H., Turkdogan D., Baykan B., Bebek N., Ozbek U., Hempelmann A., Schulz H., Rüschendorf F., Trucks H., Nürnberg P., Avanzini G., Koeleman B.P., Sander T., and Tinuper P.

Subjects
Male, Chromosomes, Human, Pair 13, Genotype, Genetic Linkage, Chromosome Mapping, complex inheritance, Pedigree, genetic generalized epilepsy, myoclonic seizure, Phenotype, Genetic Loci, Chromosomes, Human, Pair 2, Humans, Epilepsy, Generalized, Family, Female, Genetic Predisposition to Disease, linkage analysis, absence seizure, Genome-Wide Association Study
Abstract

PURPOSE: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. METHODS: Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. KEY FINDINGS: For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). SIGNIFICANCE: Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.

Published
2012

9. Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

Author

Leu C, de Kovel CG, Zara F, Striano P, Pezzella M, Robbiano A, Bianchi A, Bisulli F, Coppola A, Giallonardo AT, Beccaria F, Trenité DK, Lindhout D, Gaus V, Schmitz B, Janz D, Weber YG, Becker F, Lerche H, Kleefuss Lie AA, Hallman K, Kunz WS, Elger CE, Muhle H, Stephani U, Møller RS, Hjalgrim H, Mullen S, Scheffer IE, Berkovic SF, Everett KV, Gardiner MR, Marini C, Guerrini R, Lehesjoki AE, Siren A, Nabbout R, Baulac S, Leguern E, Serratosa JM, Rosenow F, Feucht M, Unterberger I, Covanis A, Suls A, Weckhuysen S, Kaneva R, Caglayan H, Turkdogan D, Baykan B, Bebek N, Ozbek U, Hempelmann A, Schulz H, Rüschendorf F, Trucks H, Nürnberg P, Avanzini G, Koeleman BP, Sander T, EPICURE Consortium, COPPOLA, ANTONIETTA, DEL GIUDICE, ENNIO, Leu, C, de Kovel, Cg, Zara, F, Striano, P, Pezzella, M, Robbiano, A, Bianchi, A, Bisulli, F, Coppola, A, Giallonardo, At, Beccaria, F, Trenité, Dk, Lindhout, D, Gaus, V, Schmitz, B, Janz, D, Weber, Yg, Becker, F, Lerche, H, Kleefuss Lie, Aa, Hallman, K, Kunz, W, Elger, Ce, Muhle, H, Stephani, U, Møller, R, Hjalgrim, H, Mullen, S, Scheffer, Ie, Berkovic, Sf, Everett, Kv, Gardiner, Mr, Marini, C, Guerrini, R, Lehesjoki, Ae, Siren, A, Nabbout, R, Baulac, S, Leguern, E, Serratosa, Jm, Rosenow, F, Feucht, M, Unterberger, I, Covanis, A, Suls, A, Weckhuysen, S, Kaneva, R, Caglayan, H, Turkdogan, D, Baykan, B, Bebek, N, Ozbek, U, Hempelmann, A, Schulz, H, Rüschendorf, F, Trucks, H, Nürnberg, P, Avanzini, G, Koeleman, Bp, Sander, T, Epicure, Consortium, DEL GIUDICE, Ennio, and Coppola, Antonietta

Published
2012

10. Contribution of psychiatric comorbidity to quality of life of patients with migraine

Author

Viana, M, Mula, M, Jauch, R, Cavanna, A, Strigaro, G, Collimedaglia, L, Barbagli, D, Gaus, V, Kretz, R, Tota, M, Israel, H, Reuter, U, Martus, P, Cantello, R, Schmitz, B, Monaco, F, Viana M, Mula M, Jauch R, Cavanna A, Strigaro G, Collimedaglia L, Barbagli D, Gaus V, Kretz R, Tota MG, Israel H, Reuter U, Martus P, Cantello R, Schmitz B, Monaco F, Viana, M, Mula, M, Jauch, R, Cavanna, A, Strigaro, G, Collimedaglia, L, Barbagli, D, Gaus, V, Kretz, R, Tota, M, Israel, H, Reuter, U, Martus, P, Cantello, R, Schmitz, B, Monaco, F, Viana M, Mula M, Jauch R, Cavanna A, Strigaro G, Collimedaglia L, Barbagli D, Gaus V, Kretz R, Tota MG, Israel H, Reuter U, Martus P, Cantello R, Schmitz B, and Monaco F

Published
2008

11. Clinical and psychopathological definition of the interictal dysphoric disorder of epilepsy

Author

Mula, M, Jauch, R, Cavanna, A, Collimedaglia, L, Barbagli, D, Gaus, V, Kretz, R, Viana, M, Tota, G, Israel, H, Reuter, U, Martus, P, Cantello, R, Monaco, F, Schmitz, B, Mula M, Jauch R, Cavanna A, Collimedaglia L, Barbagli D, Gaus V, Kretz R, Viana M, Tota G, Israel H, Reuter U, Martus P, Cantello R, Monaco F, Schmitz B., Mula, M, Jauch, R, Cavanna, A, Collimedaglia, L, Barbagli, D, Gaus, V, Kretz, R, Viana, M, Tota, G, Israel, H, Reuter, U, Martus, P, Cantello, R, Monaco, F, Schmitz, B, Mula M, Jauch R, Cavanna A, Collimedaglia L, Barbagli D, Gaus V, Kretz R, Viana M, Tota G, Israel H, Reuter U, Martus P, Cantello R, Monaco F, and Schmitz B.

Abstract

Purpose: Different authors suggested the occurrence of a pleomorphic affective syndrome in patients with epilepsy named interictal dysphoric disorder (IDD). We sought to investigate whether IDD occurs only in patients with epilepsy and to validate IDD features against DSM-IV criteria. Methods: Consecutive patients with a diagnosis of epilepsy (E) or migraine (M) have been assessed using the BDI, MDQ, and the Interictal Dysphoric Disorder Inventory (IDDI), a questionnaire specifically created to evaluate IDD symptoms. Diagnosis of current and lifetime DSM-IV Axis I disorders was established using the MINI Plus version 5.0.0. Results: A total of 229 patients (E = 117; M = 112) were evaluated. Females were significantly more represented in the migraine group (E = 46.5% vs. M = 73.3% p = 0.009), but there was no difference in age, duration of the disease, or education level. Patients with epilepsy were more likely to screen positively at MDQ (E = 17% vs. M = 5.3% p = 0.006) and to have a diagnosis of bipolar disorder (E = 14.5% vs. M = 4.5% p = 0.013) as compared to migraine patients. There was no between-groups difference in IDD prevalence (E = 17%; M = 18.7%) and IDDI total scores (E = 4.1 ± 2.0 vs. M = 3.8 ± 2.0). Validation of IDD against DSM-IV categories showed current major depression being the foremost diagnostic category correlated with IDD in both epilepsy (OR = 0.32-0.12-0.88, p = 0.028) and migraine (OR = 0.10, 95% CI = 0.02-0.49, p = 0.004) samples. Current anxiety disorder correlated with IDD only in migraine patients (OR = 0.19, 95% CI = 0.05-0.77, p = 0.02). Conclusion: IDD represents a homogenous construct that can be diagnosed in a relevant proportion of patients but it is not typical only of epilepsy, occurring in other central nervous system disorders such as migraine.

Published
2008

12. Contribution of anxiety disorders comorbidity to quality of life of patients with epilepsy

Author

Tota, G, Mula, M, Jauch, R, Cavanna, A, Collimedaglia, L, Barbagli, D, Gaus, V, Kretz, R, Viana, M, Israel, H, Reuter, U, Martus, P, Cantello, R, Schmitz, B, Monaco, F, Tota G, Mula M, Jauch R, Cavanna A, Collimedaglia L, Barbagli D, Gaus V, Kretz R, Viana M, Israel H, Reuter U, Martus P, Cantello R, Schmitz B, Monaco F, Tota, G, Mula, M, Jauch, R, Cavanna, A, Collimedaglia, L, Barbagli, D, Gaus, V, Kretz, R, Viana, M, Israel, H, Reuter, U, Martus, P, Cantello, R, Schmitz, B, Monaco, F, Tota G, Mula M, Jauch R, Cavanna A, Collimedaglia L, Barbagli D, Gaus V, Kretz R, Viana M, Israel H, Reuter U, Martus P, Cantello R, Schmitz B, and Monaco F

Published
2007

13. Contribution of psychiatric comorbidity to quality of life of patients with migraine

Author

Viana, M, Mula, M, Jauch, R, Cavanna, A, Strigaro, G, Collimedaglia, L, Barbagli, D, Gaus, V, Kretz, R, Tota, M, Israel, H, Reuter, U, Martus, P, Cantello, R, Schmitz, B, Monaco, F, Viana M, Mula M, Jauch R, Cavanna A, Strigaro G, Collimedaglia L, Barbagli D, Gaus V, Kretz R, Tota MG, Israel H, Reuter U, Martus P, Cantello R, Schmitz B, Monaco F, Viana, M, Mula, M, Jauch, R, Cavanna, A, Strigaro, G, Collimedaglia, L, Barbagli, D, Gaus, V, Kretz, R, Tota, M, Israel, H, Reuter, U, Martus, P, Cantello, R, Schmitz, B, Monaco, F, Viana M, Mula M, Jauch R, Cavanna A, Strigaro G, Collimedaglia L, Barbagli D, Gaus V, Kretz R, Tota MG, Israel H, Reuter U, Martus P, Cantello R, Schmitz B, and Monaco F

Published
2007

14. Bipolar disorder is more prevalent in epilepsy than in migraine: a clinical replication

Author

Collimedaglia, L, Mula, M, Jauch, R, Cavanna, A, Servo, S, Barbagli, D, Gaus, V, Kretz, R, Viana, M, Tota, M, Israel, H, Reuter, U, Martus, P, Cantello, R, Schmitz, B, Monaco, F, Collimedaglia L, Mula M, Jauch R, Cavanna A, Servo S, Barbagli D, Gaus V, Kretz R, Viana M, Tota MG, Israel H, Reuter U, Martus P, Cantello R, Schmitz B, Monaco F, Collimedaglia, L, Mula, M, Jauch, R, Cavanna, A, Servo, S, Barbagli, D, Gaus, V, Kretz, R, Viana, M, Tota, M, Israel, H, Reuter, U, Martus, P, Cantello, R, Schmitz, B, Monaco, F, Collimedaglia L, Mula M, Jauch R, Cavanna A, Servo S, Barbagli D, Gaus V, Kretz R, Viana M, Tota MG, Israel H, Reuter U, Martus P, Cantello R, Schmitz B, and Monaco F

Published
2007

15. Contribution of bipolar disorder comorbidity to quality of life of patients with epilepsy

Author

Barbagli, D, Mula, M, Jauch, R, Cavanna, A, Collimedaglia, L, Gaus, V, Kretz, R, Viana, M, Tota, M, Israel, H, Reuter, U, Martus, P, Cantello, R, Schmitz, B, Monaco, F, Barbagli D, Mula M, Jauch R, Cavanna A, Collimedaglia L, Gaus V, Kretz R, Viana M, Tota MG, Israel H, Reuter U, Martus P, Cantello R, Schmitz B, Monaco F, Barbagli, D, Mula, M, Jauch, R, Cavanna, A, Collimedaglia, L, Gaus, V, Kretz, R, Viana, M, Tota, M, Israel, H, Reuter, U, Martus, P, Cantello, R, Schmitz, B, Monaco, F, Barbagli D, Mula M, Jauch R, Cavanna A, Collimedaglia L, Gaus V, Kretz R, Viana M, Tota MG, Israel H, Reuter U, Martus P, Cantello R, Schmitz B, and Monaco F

Published
2007

16. Contribution of psychiatric comorbidity to quality of life of patients with migraine

Author

Viana M, Mula M, Jauch R, Cavanna A, Strigaro G, Collimedaglia L, Barbagli D, Gaus V, Kretz R, Tota MG, Israel H, Reuter U, Martus P, Cantello R, Schmitz B, Monaco F, Viana, M, Mula, M, Jauch, R, Cavanna, A, Strigaro, G, Collimedaglia, L, Barbagli, D, Gaus, V, Kretz, R, Tota, M, Israel, H, Reuter, U, Martus, P, Cantello, R, Schmitz, B, and Monaco, F

Subjects
migraine
Published
2007

17. Bipolar disorder is more prevalent in epilepsy than in migraine: a clinical replication

Author

Collimedaglia L, Mula M, Jauch R, Cavanna A, Servo S, Barbagli D, Gaus V, Kretz R, Viana M, Tota MG, Israel H, Reuter U, Martus P, Cantello R, Schmitz B, Monaco F, Collimedaglia, L, Mula, M, Jauch, R, Cavanna, A, Servo, S, Barbagli, D, Gaus, V, Kretz, R, Viana, M, Tota, M, Israel, H, Reuter, U, Martus, P, Cantello, R, Schmitz, B, and Monaco, F

Subjects
Bipolar disorder
Published
2007

18. Contribution of anxiety disorders comorbidity to quality of life of patients with epilepsy

Author

Tota G, Mula M, Jauch R, Cavanna A, Collimedaglia L, Barbagli D, Gaus V, Kretz R, Viana M, Israel H, Reuter U, Martus P, Cantello R, Schmitz B, Monaco F, Tota, G, Mula, M, Jauch, R, Cavanna, A, Collimedaglia, L, Barbagli, D, Gaus, V, Kretz, R, Viana, M, Israel, H, Reuter, U, Martus, P, Cantello, R, Schmitz, B, and Monaco, F

Subjects
epilepsy
Published
2007

19. Contribution of bipolar disorder comorbidity to quality of life of patients with epilepsy

Author

Barbagli D, Mula M, Jauch R, Cavanna A, Collimedaglia L, Gaus V, Kretz R, Viana M, Tota MG, Israel H, Reuter U, Martus P, Cantello R, Schmitz B, Monaco F, Barbagli, D, Mula, M, Jauch, R, Cavanna, A, Collimedaglia, L, Gaus, V, Kretz, R, Viana, M, Tota, M, Israel, H, Reuter, U, Martus, P, Cantello, R, Schmitz, B, and Monaco, F

Subjects
epilepsy
Published
2007

20. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1,2q22.3 and 17q21.32

Author

Steffens, M., Leu, C., Ruppert, A., Zara, F., Striano, P., Robbiano, A., Capovilla, G., Tinuper, P., Gambardella, A., Bianchi, A., La neve, A., Crichiutti, G., de kovel, C. G., Trenité, D. K. -N., de haan, G., Lindhout, D., Gaus, V., Schmitz, B., Janz, D., Weber, Y. G., Becker, F., Lerche, H., Steinhoff, B. J., Kleefuß-Lie, A. A., Kunz, W. S., Surges, R., Elger, C. E., Muhle, H., Von spiczak, S., Ostertag, P., Helbig, I., Stephani, U., Møller, R. S., Hjalgrim, H., Dibbens, L. M., Bellows, S., Oliver, K., Mullen, S., Scheffer, I. E., Berkovic, S. F., Everett, K. V., Gardiner, M. R., Marini, Chiara, Guerrini, R., Lehesjoki, A., Siren, A., Guipponi, M., Malafosse, A., Thomas, P., Nabbout, R., Baulac, S., Leguern, E., Guerrero, R., Serratosa, J. M., Reif, P. S., Rosenow, F., Mörzinger, M., Feucht, M., Zimprich, F., Kapser, C., Schankin, C. J., Suls, A., Smets, K., De jonghe, P., Jordanova, A., Caglayan, H., Yapici, Z., Yalcin, D. A., Baykan, B., Bebek, N., Ozbek, U., Gieger, C., Wichmann, H., Balschun, T., Ellinghaus, D., Franke, A., Meesters, C., Becker, T., Wienker, T. F., Hempelmann, A., Schulz, H., Rüschendorf, F., Leber, M., Pauck, S. M., Trucks, H., Toliat, M. R., Nürnberg, P., Avanzini, G., Koeleman, B. P., Sander, T., Weckhuysen, S., Claes, L., Deprez, L., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Lehesjoki, A. -E., von Spiczak, S., Martin Klein, K., Oertel, W. H., Hamer, H. M., Marini, C., Mei, D., Norci, V., Pezzella, M., La Neve, A., Vigliano, P., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Egeo, G., Teresa Giallonardo, M., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., de Haan, G. -J., Giraldez, B. G., Ozbeck, U., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Ozkara, C., Yalcin, O., Turkdogan, D., Dizdarer, G., Agan, K., Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Frederico, Dibbens, Leanne Michelle, Sander, Thomas, EPICURE Consortium, Epicure, Consortium, DEL GIUDICE, Ennio, Steffens, M, Leu, C, Ruppert, Ak, Zara, F, Striano, P, Robbiano, A., Coppola, Antonietta, E. P. I. C. U. R. E. Consortium, E. M. I.Net Consortium, M. Steffen, C. Leu, A. Ruppert, F. Zara, P. Striano, A. Robbiano, G. Capovilla, P. Tinuper, A. Gambardella, A. Bianchi, A. L. Neve, G. Crichiutti, C. G. F, D. K. Trenité, G. d. Haan, D. Lindhout, V. Gau, B. Schmitz, D. Janz, Y. G. Weber, F. Becker, H. Lerche, B. J. Steinhoff, A. A. Kleefuß-Lie, W. S. Kunz, R. Surge, C. E. Elger, H. Muhle, S. v. Spiczak, P. Ostertag, I. Helbig, U. Stephani, R. S. Møller, H. Hjalgrim, L. M. Dibben, S. Bellow, K. Oliver, S. Mullen, I. E. Scheffer, S. F. Berkovic, K. V. Everett, M. R. Gardiner, C. Marini, R. Guerrini, A. Lehesjoki, A. Siren, M. Guipponi, A. Malafosse, P. Thoma, R. Nabbout, S. Baulac, E. Leguern, R. Guerrero, J. M. Serratosa, P. S. Reif, F. Rosenow, M. Mörzinger, M. Feucht, F. Zimprich, C. Kapser, C. J. Schankin, A. Sul, K. Smet, P. D. Jonghe, A. Jordanova, H. Caglayan, Z. Yapici, D. A. Yalcin, B. Baykan, N. Bebek, U. Ozbek, C. Gieger, H. Wichmann, T. Balschun, D. Ellinghau, A. Franke, C. Meester, T. Becker, T. F. Wienker, A. Hempelmann, H. Schulz, F. Rüschendorf, M. Leber, S. M. Pauck, H. Truck, M. R. Toliat, P. Nürnberg, G. Avanzini, B. P. C, and T. Sander

Subjects
Candidate gene, Juvenile, Genome-wide association study, Alleles, Epilepsy, ZEB2 protein, human, VRK2 protein, human, 0302 clinical medicine, genetics [Genetic Predisposition to Disease], genetics, Humans, Myoclonic Epilepsy, genetics [Epilepsy, Generalized], SCN1A protein, human, Genetics (clinical), Genetics, 0303 health sciences, genetics [Epilepsy, Absence], Myoclonic Epilepsy, Juvenile, genetics, Genetic Predisposition to Disease, General Medicine, Protein-Serine-Threonine Kinases, 3. Good health, Chemistry, Absence, genetics, Epilepsy, genetics [Myoclonic Epilepsy, Juvenile], Epilepsy, Generalized, genetics [Receptor, Muscarinic M3], genetics, NAV1.1 Voltage-Gated Sodium Channel, genetics [Homeodomain Proteins], Single-nucleotide polymorphism, genetics [NAV1.1 Voltage-Gated Sodium Channel], Protein Serine-Threonine Kinases, Biology, genetics [Protein-Serine-Threonine Kinases], 03 medical and health sciences, ddc:570, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, genetics, Repressor Protein, Allele, Molecular Biology, Alleles, Zinc Finger E-box Binding Homeobox 2, 030304 developmental biology, Homeodomain Proteins, Receptor, Muscarinic M3, genetics, Protein-Serine-Threonine Kinase, genetics, Receptor, Generalized, genetics, Genome-Wide Association Study, Homeodomain Protein, Heritability, medicine.disease, NAV1.1 Voltage-Gated Sodium Channel, Repressor Proteins, genetics [Repressor Proteins], Muscarinic M3, Epilepsy, Absence, Myoclonic epilepsy, Human medicine, Juvenile myoclonic epilepsy, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3\% and account for 20-30\% of all epilepsies. Despite their high heritability of 80\%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Published
2012
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24. Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance

Author

Dibbens, Lm, Mullen, S, Helbig, I, Mefford, Hc, Bayly, Ma, Bellows, S, Leu, C, Trucks, H, Obermeier, T, Wittig, M, Franke, A, Caglayan, H, Yapici, Z, Sander, T, Eichler, Ee, Scheffer, Ie, Mulley, Jc, Berkovic, Sf, De Jonghe, P, Suls, A, Hjalgrim, H, Madsen, Jm, Møller, Rs, Lehesjoki, Ae, Siren, A, Gaus, V, Janz, D, Schmitz, B, Elger, Ce, Hallmann, K, Kleefuß-Lie, Aa, Kunz, Ws, Raabe, A, Muhle, H, Ostertag, P, von Spiczak, S, Stephani, U, Lerche, H, Weber, Yg, Striano, P, Zara, F, Marini, C, Brilstra, Eh, Kastelijn-Nolst, Trenité, Koeleman, D, Bpc, de Kovel, Cgf, Lindhout, D, Swinkels, Mem, Yalcin, O, Baykan, B, Turkdogan, D, Dizdarer, G, Ozkara, C, Lee, Y, Müller-Quernheim, J, Fölster-Holst, R, Hofmann, S, Nebel, A., Schreiber, S, Schürmann, M, Rodriguez, E, Weidinger, S, Baurecht, H, Lie, Ba, Boberg, Km, Karlsen, Th., De Jonghe, Peter, Suls, Arvid, Dibbens, Leanne M, Mullen, Saul, Helbig, Ingo, Mefford, Heather C, Bayly, Marta A, Bellows, Susannah, Leu, Costin, Trucks, Holger, Obermeier, Tanja, Wittig, Michael, Franke, Andre, Caglayan, Hande, Yapici, Zuhal, Sander, Thomas, Eichler, Evan E, Scheffer, Ingrid E, Mulley, John C, and Berkovic, Samuel F

Subjects
Male, Proband, Clinical Sciences, idiopathic generalized epilepsy, European Continental Ancestry Group, Single-nucleotide polymorphism, Pedigree chart, family studies, Biology, White People, Cohort Studies, Idiopathic generalized epilepsy, Epilepsy, single nucleotide polymorphism, genetic inheritance, Genetics, medicine, inheritance, Humans, SNP, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), seizures, Chromosomes, Human, Pair 15, Articles, General Medicine, 5q13.3 deletions, medicine.disease, Penetrance, Pedigree, Female, Human medicine, microdeletion, Chromosome Deletion, Comparative genomic hybridization
Abstract

Microdeletion at chromosomal position 15q13.3 has been described in intellectual disability, autism spectrum disorders, schizophrenia and recently in idiopathic generalized epilepsy (IGE). Using independent IGE cohorts, we first aimed to confirm the association of 15q13.3 deletions and IGE. We then set out to determine the relative occurrence of sporadic and familial cases and to examine the likelihood of having seizures for individuals with the microdeletion in familial cases. The 15q13.3 microdeletion was identified in 7 of 539 (1.3%) unrelated cases of IGE using quantitative PCR or SNP arrays and confirmed by array comparative genomic hybridization analysis using probes specific to the 15q13.3 region. The inheritance of this lesion was tracked using family studies. Of the seven microdeletions identified in probands, three were de novo, two were transmitted from an unaffected parent and in two cases the parents were unavailable. Non-penetrance of the microdeletion was identified in 4/7 pedigrees and three pedigrees included other family members with IGE who lacked the 15q13.3 deletion. The odds ratio is 68 (95% confidence interval 29-181), indicating a pathogenic lesion predisposing to epilepsy with complex inheritance and incomplete penetrance for the IGE component of the phenotype in multiplex families. Refereed/Peer-reviewed

Published
2009
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25. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Author

Steffens, M, Leu, C, Ruppert, A-K, Zara, F, Striano, P, Robbiano, A, Capovilla, G, Tinuper, P, Gambardella, A, Bianchi, A, La Neve, A, Crichiutti, G, de Kovel, CGF, Trenite, DK-N, de Haan, G-J, Lindhout, D, Gaus, V, Schmitz, B, Janz, D, Weber, YG, Becker, F, Lerche, H, Steinhoff, BJ, Kleefuss-Lie, AA, Kunz, WS, Surges, R, Elger, CE, Muhle, H, von Spiczak, S, Ostertag, P, Helbig, I, Stephani, U, Moller, RS, Hjalgrim, H, Dibbens, LM, Bellows, S, Oliver, K, Mullen, S, Scheffer, IE, Berkovic, SF, Everett, KV, Gardiner, MR, Marini, C, Guerrini, R, Lehesjoki, A-E, Siren, A, Guipponi, M, Malafosse, A, Thomas, P, Nabbout, R, Baulac, S, Leguern, E, Guerrero, R, Serratosa, JM, Reif, PS, Rosenow, F, Moerzinger, M, Feucht, M, Zimprich, F, Kapser, C, Schankin, CJ, Suls, A, Smets, K, De Jonghe, P, Jordanova, A, Caglayan, H, Yapici, Z, Yalcin, DA, Baykan, B, Bebek, N, Ozbek, U, Gieger, C, Wichmann, H-E, Balschun, T, Ellinghaus, D, Franke, A, Meesters, C, Becker, T, Wienker, TF, Hempelmann, A, Schulz, H, Rueschendorf, F, Leber, M, Pauck, SM, Trucks, H, Toliat, MR, Nuernberg, P, Avanzini, G, Koeleman, BPC, Sander, T, Steffens, M, Leu, C, Ruppert, A-K, Zara, F, Striano, P, Robbiano, A, Capovilla, G, Tinuper, P, Gambardella, A, Bianchi, A, La Neve, A, Crichiutti, G, de Kovel, CGF, Trenite, DK-N, de Haan, G-J, Lindhout, D, Gaus, V, Schmitz, B, Janz, D, Weber, YG, Becker, F, Lerche, H, Steinhoff, BJ, Kleefuss-Lie, AA, Kunz, WS, Surges, R, Elger, CE, Muhle, H, von Spiczak, S, Ostertag, P, Helbig, I, Stephani, U, Moller, RS, Hjalgrim, H, Dibbens, LM, Bellows, S, Oliver, K, Mullen, S, Scheffer, IE, Berkovic, SF, Everett, KV, Gardiner, MR, Marini, C, Guerrini, R, Lehesjoki, A-E, Siren, A, Guipponi, M, Malafosse, A, Thomas, P, Nabbout, R, Baulac, S, Leguern, E, Guerrero, R, Serratosa, JM, Reif, PS, Rosenow, F, Moerzinger, M, Feucht, M, Zimprich, F, Kapser, C, Schankin, CJ, Suls, A, Smets, K, De Jonghe, P, Jordanova, A, Caglayan, H, Yapici, Z, Yalcin, DA, Baykan, B, Bebek, N, Ozbek, U, Gieger, C, Wichmann, H-E, Balschun, T, Ellinghaus, D, Franke, A, Meesters, C, Becker, T, Wienker, TF, Hempelmann, A, Schulz, H, Rueschendorf, F, Leber, M, Pauck, SM, Trucks, H, Toliat, MR, Nuernberg, P, Avanzini, G, Koeleman, BPC, and Sander, T

Abstract

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Published
2012

27. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies

Author

de Kovel, C. G. F., primary, Trucks, H., additional, Helbig, I., additional, Mefford, H. C., additional, Baker, C., additional, Leu, C., additional, Kluck, C., additional, Muhle, H., additional, von Spiczak, S., additional, Ostertag, P., additional, Obermeier, T., additional, Kleefuss-Lie, A. A., additional, Hallmann, K., additional, Steffens, M., additional, Gaus, V., additional, Klein, K. M., additional, Hamer, H. M., additional, Rosenow, F., additional, Brilstra, E. H., additional, Kasteleijn-Nolst Trenite, D., additional, Swinkels, M. E. M., additional, Weber, Y. G., additional, Unterberger, I., additional, Zimprich, F., additional, Urak, L., additional, Feucht, M., additional, Fuchs, K., additional, Moller, R. S., additional, Hjalgrim, H., additional, De Jonghe, P., additional, Suls, A., additional, Ruckert, I.-M., additional, Wichmann, H.-E., additional, Franke, A., additional, Schreiber, S., additional, Nurnberg, P., additional, Elger, C. E., additional, Lerche, H., additional, Stephani, U., additional, Koeleman, B. P. C., additional, Lindhout, D., additional, Eichler, E. E., additional, and Sander, T., additional

Published
2009
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31. EURAP

Author

Kretz, R., primary, Coban, I., additional, Gaus, V., additional, and Schmitz, B., additional

Published
2006
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35. 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Author

Eva M. Reinthaler, Dennis Lal, Sebastien Lebon, Michael S. Hildebrand, Hans-Henrik M. Dahl, Brigid M. Regan, Martha Feucht, Hannelore Steinböck, Birgit Neophytou, Gabriel M. Ronen, Laurian Roche, Ursula Gruber-Sedlmayr, Julia Geldner, Edda Haberlandt, Per Hoffmann, Stefan Herms, Christian Gieger, Melanie Waldenberger, Andre Franke, Michael Wittig, Susanne Schoch, Albert J. Becker, Andreas Hahn, Katrin Männik, Mohammad R. Toliat, Georg Winterer, Holger Lerche, Peter Nürnberg, Heather Mefford, Ingrid E. Scheffer, Samuel F. Berkovic, Jacques S. Beckmann, Thomas Sander, Sebastien Jacquemont, Alexandre Reymond, Fritz Zimprich, Bernd A. Neubauer, Bernd Neubauer, Martina Mörzinger, Arvid Suls, Sarah Weckhuysen, Lieve Claes, Liesbet Deprez, Katrien Smets, Tine Van Dyck, Tine Deconinck, Peter De Jonghe, Rikke S Møller, Laura L. Klitten, Helle Hjalgrim, Kiel Campus, Ingo Helbig, Hiltrud Muhle, Philipp Ostertag, Sarah von Spiczak, Ulrich Stephani, Holger Trucks, Christian E. Elger, Ailing A. Kleefuß-Lie, Wolfram S. Kunz, Rainer Surges, Verena Gaus, Dieter Janz, Bettina Schmitz, Felix Rosenow, Karl Martin Klein, Philipp S. Reif, Wolfgang H. Oertel, Hajo M. Hamer, Felicitas Becker, Yvonne Weber, Bobby P.C. Koeleman, Carolien de Kovel, Dick Lindhout, Agnès Ameil, Joris Andrieux, Sonia Bouquillon, Odile Boute, Jeanne de Flandre, Jean Marie Cuisset, Jean-Christophe Cuvellier, Roger Salengro, Albert David, Bert de Vries, Marie-Ange Delrue, Martine Doco-Fenzy, Bridget A. Fernandez, Delphine Heron, Boris Keren, Robert Lebel, Bruno Leheup, Suzanne Lewis, Maria Antonietta Mencarelli, Cyril Mignot, Jean-Claude Minet, Alexandre Moerman, Fanny Morice-Picard, Mafalda Mucciolo, Katrin Ounap, Laurent Pasquier, Florence Petit, Francesca Ragona, Evica Rajcan-Separovic, Alessandra Renieri, Claudine Rieubland, Damien Sanlaville, Elisabeth Sarrazin, Yiping Shen, Mieke van Haelst, Anneke Vulto-van Silfhout, 16p11.2 European Consortium, EPICURE Consortium, EuroEPINOMICS Consortium, Reinthaler, EM., Zimprich, F., Feucht, M., Steinböck, H., Neophytou, B., Geldner, J., Gruber-Sedlmayr, U., Haberlandt, E., Ronen, GM., Roche, L., Lal, D., Nürnberg, P., Sander, T., Lerche, H., Neubauer, B., Mörzinger, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Møller, RS., Klitten, LL., Hjalgrim, H., Campus, K., Helbig, I., Muhle, H., Ostertag, P., von Spiczak, S., Stephani, U., Trucks, H., Elger, CE., Kleefuß-Lie, AA., Kunz, WS., Surges, R., Gaus, V., Janz, D., Schmitz, B., Rosenow, F., Klein, KM., Reif, PS., Oertel, WH., Hamer, HM., Becker, F., Weber, Y., Koeleman, BP., de Kovel, C., Lindhout, D., Ameil, A., Andrieux, J., Bouquillon, S., Boute, O., Cordier, MP., Cuisset, JM., Cuvellier, JC., David, A., de Vries, B., Delrue, MA., Doco-Fenzy, M., Fernandez, BA., Heron, D., Keren, B., Lebel, R., Leheup, B., Lewis, S., Mencarelli, MA., Mignot, C., Minet, JC., Moerman, A., Morice-Picard, F., Mucciolo, M., Ounap, K., Pasquier, L., Petit, F., Ragona, F., Rajcan-Separovic, E., Renieri, A., Rieubland, C., Sanlaville, D., Sarrazin, E., Shen, Y., van Haelst, M., Vulto-van Silfhout, A., and Other departments

Subjects
Male, DNA Copy Number Variations, Chromosomes, Human, Pair 22, 610 Medicine & health, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Temporal lobe, Epilepsy, Gene duplication, Chromosome Duplication, Genetics, medicine, Humans, Copy-number variation, Child, Molecular Biology, Genetics (clinical), Chromosomes, Human, Pair 15, Infant, General Medicine, Odds ratio, medicine.disease, Epilepsy, Rolandic, Rolandic epilepsy, Exact test, Chromosomes, Human, Pair 1, Child, Preschool, Female, Chromosomes, Human, Pair 16
Abstract

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.

Published
2014
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36. Interictal dysphoric disorder and periictal dysphoric symptoms in patients with epilepsy

Author

Marco, Mula, Regina, Jauch, Andrea, Cavanna, Verena, Gaus, Rebekka, Kretz, Laura, Collimedaglia, Davide, Barbagli, Roberto, Cantello, Francesco, Monaco, Bettina, Schmitz, Mula, M, Jauch, R, Cavanna, A, Gaus, V, Kretz, R, Collimedaglia, L, Barbagli, D, Cantello, R, Monaco, F, and Schmitz, B

Subjects
Adult, Male, Cross-Sectional Studies, Epilepsy, Periictal dysphoria, Mood Disorders, Depression, Humans, Female, Affective Symptoms, Middle Aged, Interictal dysphoric disorder
Abstract

Purpose: The issue of phenomenology of mood disorders in epilepsy still remains controversial. It has been suggested that a subgroup of patients may develop an affective syndrome also known as interictal dysphoric disorder (IDD). However, the number of behavioral changes that may occur around the ictus needs to be taken into account for an accurate distinction between "true" psychiatric phenomenology and periictal phenomena. This study aimed at identifying clinical correlates of the IDD, with special attention to the relationship between symptoms and seizures. Methods: A sample of 142 consecutive adult outpatients with epilepsy were assessed using the Interictal Dysphoric Disorder Inventory (IDDI), a 38-item, self-report questionnaire specifically developed to evaluate presence and severity of IDD symptoms as well as their habitual association with seizures (coded as before, after, during, or when seizure-free) and their duration. Results: IDD was diagnosed in 31 subjects but symptoms showed a clear-cut relationship with epileptic seizures in 54.8% of cases, leading to an operative distinction between true IDD and periictal dysphoric symptoms (PDS). There was no significant difference among patients with IDD, PDS, or those without psychopathology. In the IDD group, symptoms were chronic and unremitting in one-third of cases, with labile affective symptoms being correlated with age at onset of seizures (rho = )0.612, p = 0.020) and duration of the epilepsy (rho = 0.833, p < 0.001). Discussion: An operative distinction between IDD and PDS bears the opportunity to identify different clinical endophenotypes that may have different prognoses and require different treatment strategies.

Published
2010

37. Manic/hypomanic symptoms and quality of life measures in patients with epilepsy

Author

Laura Collimedaglia, Francesco Monaco, Bettina Schmitz, R. Kretz, Regina Jauch, Roberto Cantello, Michele Viana, Andrea E. Cavanna, Marco Mula, Verena Gaus, Davide Barbagli, Mula, M, Jauch, R, Cavanna, A, Collimedaglia, L, Barbagli, D, Gaus, V, Kretz, R, Viana, M, Cantello, R, Monaco, F, and Schmitz, B

Subjects
Quality of life, Adult, Employment, Male, medicine.medical_specialty, Bipolar Disorder, Personality Inventory, Clinical Neurology, Comorbidity, Neuropsychological Tests, Severity of Illness Index, Epilepsy, Surveys and Questionnaires, medicine, Humans, In patient, Bipolar disorder, Psychiatry, Depression (differential diagnoses), Psychiatric Status Rating Scales, General Medicine, Hypomania, Middle Aged, medicine.disease, Mania, Neurology, Socioeconomic Factors, Female, Neurology (clinical), medicine.symptom, Psychology, Independent living, Clinical psychology
Abstract

Purpose Although several studies pointed out an association between depression and quality of life (QoL) of patients with epilepsy, data about manic/hypomanic symptoms (MHS) remain scanty. In this study, we sought to investigate their relationship with social and health-related QoL measures in patients with epilepsy. Methods Consecutive adult outpatients with epilepsy were assessed using the M.I.N.I. Plus version 5.0.0 and the QOLIE-31. Results Among 117 evaluated patients, 17 fulfilled DSM-IV criteria for manic/hypomanic episodes. Patients with MHS, as compared to those without, showed lower scores in emotional well-being, energy and fatigue, medication effects, social function and total QOLIE score. However, there was no between-groups difference in educational achievements, employment status, living situation, comorbid psychiatric disorders, history of suicide or abuse of illicit drugs. Conclusions MHS are associated with poor QoL measures in patients with epilepsy, though without differences in educational achievements, employment status and independent living.

Published
2009

38. Clinical and psychopathological definition of the interictal dysphoric disorder of epilepsy

Author

R. Kretz, Michele Viana, Uwe Reuter, Laura Collimedaglia, Bettina Schmitz, Marco Mula, Andrea E. Cavanna, Davide Barbagli, Grazia Tota, Francesco Monaco, H. Israel, Peter Martus, Verena Gaus, Roberto Cantello, Regina Jauch, Mula, M, Jauch, R, Cavanna, A, Collimedaglia, L, Barbagli, D, Gaus, V, Kretz, R, Viana, M, Tota, G, Israel, H, Reuter, U, Martus, P, Cantello, R, Monaco, F, and Schmitz, B

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Bipolar Disorder, Personality Inventory, Migraine Disorders, Central nervous system disease, Epilepsy, Surveys and Questionnaires, Terminology as Topic, medicine, Prevalence, Humans, Bipolar disorder, Age of Onset, Psychiatry, Migraine, Depression (differential diagnoses), Psychiatric Status Rating Scales, Depressive Disorder, Depression, Syndrome, Interictal dysphoric disorder, medicine.disease, Anxiety Disorders, Diagnostic and Statistical Manual of Mental Disorders, Cross-Sectional Studies, Neurology, Female, Neurology (clinical), Age of onset, medicine.symptom, Psychology, Anxiety disorder
Abstract

Summary Purpose: Different authors suggested the occurrence of a pleomorphic affective syndrome in patients with epilepsy named interictal dysphoric disorder (IDD). We sought to investigate whether IDD occurs only in patients with epilepsy and to validate IDD features against DSM-IV criteria. Methods: Consecutive patients with a diagnosis of epilepsy (E) or migraine (M) have been assessed using the BDI, MDQ, and the Interictal Dysphoric Disorder Inventory (IDDI), a questionnaire specifically created to evaluate IDD symptoms. Diagnosis of current and lifetime DSM-IV Axis I disorders was established using the MINI Plus version 5.0.0. Results: A total of 229 patients (E = 117; M = 112) were evaluated. Females were significantly more represented in the migraine group (E = 46.5% vs. M = 73.3% p = 0.009), but there was no difference in age, duration of the disease, or education level. Patients with epilepsy were more likely to screen positively at MDQ (E = 17% vs. M = 5.3% p = 0.006) and to have a diagnosis of bipolar disorder (E = 14.5% vs. M = 4.5% p = 0.013) as compared to migraine patients. There was no between-groups difference in IDD prevalence (E = 17%; M = 18.7%) and IDDI total scores (E = 4.1 ± 2.0 vs. M = 3.8 ± 2.0). Validation of IDD against DSM-IV categories showed current major depression being the foremost diagnostic category correlated with IDD in both epilepsy (OR = 0.32–0.12–0.88, p = 0.028) and migraine (OR = 0.10, 95% CI = 0.02–0.49, p = 0.004) samples. Current anxiety disorder correlated with IDD only in migraine patients (OR = 0.19, 95% CI = 0.05–0.77, p = 0.02). Conclusion: IDD represents a homogenous construct that can be diagnosed in a relevant proportion of patients but it is not typical only of epilepsy, occurring in other central nervous system disorders such as migraine.

Published
2007

39. [Epilepsy and pregnancy].

Author

Gaus V, Ilyas-Feldmann M, and Schmitz B

Subjects
Child, Pregnancy, Female, Humans, Seizures, Child Development, Mothers, Referral and Consultation, Anticonvulsants therapeutic use, Epilepsy diagnosis, Epilepsy drug therapy
Abstract

Background: Regarding treatment of women of childbearing potential with epilepsy, several aspects of family planning and desire to have children have to be taken into account., Objective: Overview of current data on mutual implications of epileptic seizures, antiseizure medication (ASM), pregnancy and child development., Method: Review of the current literature, discussion and presentation of resulting treatment recommendations., Results: Many ASMs bear the potential for clinically relevant interactions with both contraceptives and altered concentrations of sexual hormones and modified pharmacokinetics during pregnancy. All ASMs show an increased risk for congenital malformations; however, due to seizure-related risks for the mother and child effective ASM treatment during pregnancy is crucial., Conclusion: When considering the special aspects of consultation and treatment of women of childbearing potential with epilepsy most pregnancies are uncomplicated., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Published
2024
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40. Clinical Course and Ophthalmologic Findings in Idiopathic Intracranial Hypertension and Pregnancy.

Author

Knoche T, Danyel LA, Varlet L, Haffner P, Alzureiqi MS, Kowski A, and Gaus V

Abstract

Idiopathic intracranial hypertension (IIH) has its highest prevalence among women of childbearing age and therefore frequently coincides with pregnancy. This retrospective cohort study aimed to explore the impact of pregnancy on the clinical course, ophthalmologic findings and on the therapeutic management of IIH patients. Individual patient records were reviewed for neuro-ophthalmologic findings, treatment strategy, adherence to therapy and pregnancy complications. Sixteen patients with 19 documented pregnancies were identified. The visual acuity, visual field defects and the grade of papilledema at baseline and after pregnancy were compared. The visual acuity and visual field mean deviation at baseline and at follow-up after pregnancy did not significantly differ. Papilledema at baseline was more pronounced in patients who had been diagnosed with IIH during pregnancy than in patients with established IIH. In this cohort, the visual acuity and the visual field were not lastingly impacted by pregnancy. The adherence to therapy was low, with 69% discontinuing treatment or medication.

Published
2023
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41. Neurofilament light chain marks severity of papilledema in idiopathic intracranial hypertension.

Author

Knoche T, Gaus V, Haffner P, and Kowski A

Subjects
Humans, Intermediate Filaments, Retrospective Studies, Intracranial Hypertension complications, Intracranial Hypertension diagnosis, Papilledema complications, Papilledema diagnosis, Pseudotumor Cerebri complications, Pseudotumor Cerebri diagnosis
Abstract

Background: Neurofilament light chain (NfL) reflects axonal damage in neurological disorders. It has recently been evaluated in idiopathic intracranial hypertension (IIH). A biomarker indicating the severity of optic nerve damage in IIH could support diagnostic accuracy and therapeutic decisions., Methods: We retrospectively reviewed NfL concentrations in the cerebrospinal fluid (CSF) of 35 IIH patients and 12 healthy controls, who had received diagnostic workup for IIH in our clinic. The diagnosis of IIH was made according to the modified Friedman criteria for IIH and for IIH without papilledema Friedman DI et al Neurol 81:1159-1165 (2013) [1]. NfL in the CSF (CSF-NfL) was correlated with the severity of papilledema and with CSF opening pressure., Results: CSF-NfL correlated with CSF opening pressure at the time of collection. In patients with IIH and moderate or severe papilledema, CSF-NfL was significantly increased compared to patients with mild or no papilledema. Healthy controls with raised intracranial pressure showed no relevant elevation of CSF-NfL., Conclusion: CSF-NfL appears to correlate with the severity of papilledema in IIH and with CSF opening pressure and may therefore be a predictor of optic nerve damage in IIH patients., (© 2023. The Author(s).)

Published
2023
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43. Gender-specific outcomes of deep brain stimulation for Parkinson's disease - results from a single movement disorder center.

Author

Kübler D, Astalosch M, Gaus V, Krause P, de Almeida Marcelino AL, Schneider GH, and Kühn A

Subjects
Humans, Female, Male, Treatment Outcome, Mental Status and Dementia Tests, Parkinson Disease diagnosis, Deep Brain Stimulation, Subthalamic Nucleus surgery
Abstract

Introduction and Goal: The investigation of gender differences in treatment response is crucial for effective personalized therapies. With only 30%, women are underrepresented in trials for deep brain stimulation (DBS) in Parkinson's disease (PD). It is therefore important to evaluate gender-specific outcomes of DBS in PD in order to improve therapeutic counseling., Methods: We analyzed clinical outcome parameters of 203 patients with PD that underwent DBS surgery targeting the subthalamic nucleus (STN) at our movement disorder center. A total of 27.6% of patients were female and 72.4% male. Motor and non-motor scores were compared before and 1 year after DBS surgery (1y FU) using Wilcoxon signed-rank tests and gender specific outcomes were analyzed with chi-square tests., Results: At 1y FU, we found significant improvement in UPDRS II, UPDRS III (35.78 ± 36.14% MedOFF vs. StimON-MedOFF), UPDRS IV, depression (BDI-II), and health-related disability as (ADL) that showed no gender-specific differences. No significant change was revealed for UPDRS I, QUIP, and DemTect for the entire cohort. However, when analyzing both groups separately, only women improved in general cognition (plus 1.26 ± 3.03 DemTect points, p = 0.014*), whereas only men ameliorated in depression (minus 1.97 ± 6.92 BDI-II points, p = 0.002**) and impulsivity (minus 2.80 ± 7.27 QUIP points, p = 0.004**). Chi-square tests, however, revealed no significant differences between genders., Conclusion and Outlook: STN-DBS is a highly effective treatment for motor and non-motor symptoms of PD for both women and men but our study hints towards gender-specific outcomes in non-motor-domains like cognition, depressive symptoms, and impulsivity. To explore this in more detail, larger cohorts need to be investigated in multicenter trials., (© 2023. The Author(s).)

Published
2023
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44. Valproic acid use in fertile women with genetic generalized epilepsies.

Author

Steinbart D, Gaus V, Kowski AB, and Holtkamp M

Subjects
Anticonvulsants adverse effects, Female, Humans, Infant, Newborn, Male, Retrospective Studies, Epilepsy drug therapy, Epilepsy genetics, Epilepsy, Generalized drug therapy, Epilepsy, Generalized genetics, Valproic Acid adverse effects
Abstract

Objectives: In genetic generalized epilepsies (GGE), valproic acid (VPA) is the most efficacious compound. However, due to teratogenicity and increased risk for impaired cognitive development after intrauterine exposure, its use in women of fertile age is strictly regulated but sometimes unavoidable., Methods: All patients with GGE treated at the outpatient clinic of a tertiary epilepsy center with at least one visit between January 2015 and April 2020 were included in this retrospective study. The rate of women aged 18 to 49 years taking VPA was compared to that of men of the same age group and to women > 49 years. Furthermore, in each group, clinical variables associated with VPA use were sought., Results: Twenty-eight out of 125 women of fertile age (22%) were treated with VPA, compared to 28 out of 56 men ≤ 49 years (50%; p = .002) and to 22 out of 40 female patients > 49 years (55%; p < .001). VPA dose was lower in fertile women compared to men, with no difference in seizure freedom rates. In women ≤ 49 years, multivariate analysis demonstrated age as the only variable independently associated with VPA use (OR 1.095; 95% CI 1.036-1.159). In the other two groups, no associated variables were identified., Conclusions: Despite warnings with respect to teratogenicity and impaired cognitive development with VPA, from 2015 to 2020, almost every fourth women of fertile age with GGE received this compound. Inevitably lower VPA doses in these women seem sufficient for favorable seizure freedom rates., (© 2021 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Published
2021
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45. Specific adverse effects of antiepileptic drugs--A true-to-life monotherapy study.

Author

Kowski AB, Weissinger F, Gaus V, Fidzinski P, Losch F, and Holtkamp M

Subjects
Adult, Aged, Anticonvulsants therapeutic use, Anxiety chemically induced, Carbamazepine adverse effects, Carbamazepine therapeutic use, Depression chemically induced, Drug-Related Side Effects and Adverse Reactions diagnosis, Drug-Related Side Effects and Adverse Reactions epidemiology, Epilepsy epidemiology, Fatigue chemically induced, Female, Humans, Lamotrigine, Levetiracetam, Male, Middle Aged, Piracetam adverse effects, Piracetam analogs & derivatives, Quality of Life, Triazines adverse effects, Valproic Acid adverse effects, Young Adult, Anticonvulsants adverse effects, Epilepsy diagnosis, Epilepsy drug therapy
Abstract

Background: In patients taking antiepileptic drugs (AEDs) for epilepsy, adverse effects (AEs) often lead to unfavorable quality of life, impaired adherence, and, eventually, discontinuation of pharmacological treatment. In a true-to-life sample of subjects from our academic epilepsy outpatient clinic, we aimed to identify predictors for overall high AE burden and for specific AEs focusing on patients on monotherapy., Methods: All patients ≥16years of age with epilepsy for ≥12months were routinely asked to complete the Liverpool Adverse Event Profile (LAEP) just before their appointment. Demographic, epilepsy, and treatment variables were derived from our comprehensive outpatient database., Results: Out of 841 patients, 438 (61% female, mean age: 44.7±17.1years) on monotherapy were included in this study. Levetiracetam (n=151), lamotrigine (n=167), valproic acid (n=73), or controlled-release carbamazepine (n=47) were the most commonly used antiepileptic drugs (AEDs). Independent predictors for general high AE burden (LAEP score≥45) were duration of epilepsy, lack of 12-month seizure freedom, and partial epilepsy, but none of the four individual AEDs. The most frequent LAEP-defined specific AEs were sleepiness, difficulty concentrating, tiredness, and memory problems. The three most frequent independent predictors for each of the 19 AEs were lack of 12-month seizure freedom (13/19 AEs), individual AED (7/19 AEs), and partial epilepsy (6/19 AEs). Levetiracetam was independently associated with anger/aggression, nervousness/agitation, upset stomach, depression, and sleep disturbance; lamotrigine with nervousness/agitation, upset stomach, and difficulty concentrating; and valproic acid with upset stomach and shaky hands., Conclusion: Individual AEDs independently predicted some specific AEs, but not overall high AE burden. Our findings may help to characterize patients with epilepsy who are at high risk for specific AEs. Dose reduction or change to another AED may reduce LAEP score and potential nonadherence., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2016
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46. Gender differences in depression, but not in anxiety in people with epilepsy.

Author

Gaus V, Kiep H, Holtkamp M, Burkert S, and Kendel F

Subjects
Adult, Anticonvulsants adverse effects, Anticonvulsants therapeutic use, Comorbidity, Epilepsy drug therapy, Female, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, Seizures drug therapy, Seizures epidemiology, Seizures psychology, Self Report, Sex Factors, Anxiety epidemiology, Depression epidemiology, Epilepsy epidemiology, Epilepsy psychology
Abstract

Purpose: Anxiety and depression are frequent comorbidities in people with epilepsy (PWE), but possible gender differences are often neglected. The aim of the present study was to analyze if men and women with epilepsy differ with regard to anxiety and depressive symptoms and to identify possible predictors., Methods: Adult consecutive PWE (N=302; 53% women) completed self-report questionnaires, including the depression module of the Patient Health Questionnaire (PHQ-9), the anxiety module of the Hospital Anxiety and Depression Scale (HADS-A) and the subscales "medication effects" and "seizure worry" of the Patient-weighted Quality of Life in Epilepsy Inventory-31-P (QOLIE-31-P)., Results: There was no gender difference in extent of anxiety (p=.532), which was mainly due to higher anxiety levels in men compared to the general population. The gender difference in depressive symptoms was significant (p=.009), with female patients being more affected. The most important predictors for anxiety and depressive symptoms were detrimental effects of medication (QOL medication effects) and of seizure worry (QOL seizure worry). Moreover, these predictors were more closely associated with anxiety and depressive symptoms in men., Conclusion: Future intervention studies could show whether providing more information about the illness and medication effects may improve anxiety and depression. Our results suggest that such interventions should be tailored to the different needs of men and women., (Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Published
2015
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47. Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies.

Author

Lal D, Ruppert AK, Trucks H, Schulz H, de Kovel CG, Kasteleijn-Nolst Trenité D, Sonsma AC, Koeleman BP, Lindhout D, Weber YG, Lerche H, Kapser C, Schankin CJ, Kunz WS, Surges R, Elger CE, Gaus V, Schmitz B, Helbig I, Muhle H, Stephani U, Klein KM, Rosenow F, Neubauer BA, Reinthaler EM, Zimprich F, Feucht M, Møller RS, Hjalgrim H, De Jonghe P, Suls A, Lieb W, Franke A, Strauch K, Gieger C, Schurmann C, Schminke U, Nürnberg P, and Sander T

Subjects
Adolescent, Adult, Case-Control Studies, Child, Cohort Studies, DNA Copy Number Variations, Female, Gene Rearrangement, Genetic Association Studies, Genome, Human, Humans, Male, Polymorphism, Single Nucleotide, Protein Interaction Domains and Motifs, Young Adult, Epilepsy, Generalized genetics, Neurodevelopmental Disorders genetics, Sequence Deletion
Abstract

Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.

Published
2015
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48. Gender differences in social support in persons with epilepsy.

Author

Burkert S, Kendel F, Kiep H, Holtkamp M, and Gaus V

Subjects
Adult, Aged, Epilepsy epidemiology, Female, Germany epidemiology, Humans, Male, Middle Aged, Sex Factors, Epilepsy psychology, Social Support
Abstract

The present study focused on social support as a key feature of the enhancement and maintenance of mental health. So far, literature on gender differences in social support and its effects on the experience of stress in individuals with epilepsy is scarce. We hypothesized that in individuals with epilepsy, social support buffers detrimental effects of stressors (e.g., unpredictable occurrence of seizures) on mental health. Additionally, we explored the role of gender in this process. In 299 individuals with epilepsy, data from validated questionnaires on seizures in the last 3months, perceived support, social network size, and depressive symptoms were analyzed. Women reported higher depressive symptoms (t=2.51, p<.01) and higher perceived support (t=2.50, p<.01) than men. Women and men did not differ in social network size (t=-0.46, p=64), nor in experiencing seizures (χ(2)=0.07, p=.82). Regression analyses revealed no buffer effects. Perceived support was negatively associated with depressive symptoms (B=-0.49, p<.001, 95% CI [-0.67; -0.32]). With regard to depressive symptoms, social integration was slightly more beneficial for women (Bcond.=-0.06, p<.001; 95% CI [-0.09; -0.03]) than for men (Bcond.=-0.02, p=.09; 95% CI [-0.04; 0.01]). Findings present perceived support and social integration as general health resources in individuals with epilepsy regardless of previously experienced seizures. They also encourage further research on gender-specific effects in individuals with epilepsy and move towards recommendations for practitioners and gender-specific interventions. Future aims will be to enhance social integration in order to support adjustment to the chronic condition of epilepsy and to improve individuals' confidence in support interactions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2015
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49. Association study of TRPC4 as a candidate gene for generalized epilepsy with photosensitivity.

Author

von Spiczak S, Muhle H, Helbig I, de Kovel CG, Hampe J, Gaus V, Koeleman BP, Lindhout D, Schreiber S, Sander T, and Stephani U

Subjects
Base Sequence, Genotype, Haplotypes, Photic Stimulation, Polymorphism, Single Nucleotide, Epilepsy, Generalized genetics, Epilepsy, Reflex genetics, Genetic Predisposition to Disease, TRPC Cation Channels genetics
Abstract

Photoparoxysmal response (PPR) is characterized by abnormal visual sensitivity of the brain to photic stimulation. Frequently associated with idiopathic generalized epilepsies (IGEs), it might be an endophenotype for cortical excitability. Transient receptor potential cation (TRPC) channels are involved in the generation of epileptiform discharges, and TRPC4 constitutes the main TRPC channel in the central nervous system. The present study investigated an association of PPR with sequence variations of the TRPC4 gene. Thirty-five single nucleotide polymorphisms (SNP) within TRPC4 were genotyped in 273 PPR probands and 599 population controls. Association analyses were performed for the broad PPR endophenotype (PPR types I-IV; n = 273), a narrow model of affectedness (PPR types III and IV; n = 214) and PPR associated with IGE (PPR/IGE; n = 106) for each SNP and for corresponding haplotypes. Association was found between the intron 5 SNP rs10507456 and PPR/IGE both for single markers (P = 0.005) and haplotype level (P = 0.01). Three additional SNPs (rs1535775, rs10161932 and rs7338118) within the same haplotype block were associated with PPR/IGE at P < 0.05 (uncorrected) as well as two more markers (rs10507457, rs7329459) located in intron 3. Again, the corresponding haplotype also showed association with PPR/IGE. Results were not significant following correction for multiple comparisons by permutation analysis for single markers and Bonferroni-Holm for haplotypes. No association was found between variants in TRPC4 and other phenotypes. Our results showed a trend toward association of TRPC4 variants and PPR/IGE. Further studies including larger samples of photosensitive probands are required to clarify the relevance of TRPC4 for PPR and IGE.

Published
2010
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50. Interictal dysphoric disorder and periictal dysphoric symptoms in patients with epilepsy.

Author

Mula M, Jauch R, Cavanna A, Gaus V, Kretz R, Collimedaglia L, Barbagli D, Cantello R, Monaco F, and Schmitz B

Subjects
Adult, Affective Symptoms complications, Cross-Sectional Studies, Epilepsy complications, Female, Humans, Male, Middle Aged, Mood Disorders complications, Affective Symptoms physiopathology, Affective Symptoms psychology, Epilepsy physiopathology, Epilepsy psychology, Mood Disorders physiopathology, Mood Disorders psychology
Abstract

Purpose: The issue of phenomenology of mood disorders in epilepsy still remains controversial. It has been suggested that a subgroup of patients may develop an affective syndrome also known as interictal dysphoric disorder (IDD). However, the number of behavioral changes that may occur around the ictus needs to be taken into account for an accurate distinction between "true" psychiatric phenomenology and periictal phenomena. This study aimed at identifying clinical correlates of the IDD, with special attention to the relationship between symptoms and seizures., Methods: A sample of 142 consecutive adult outpatients with epilepsy were assessed using the Interictal Dysphoric Disorder Inventory (IDDI), a 38-item, self-report questionnaire specifically developed to evaluate presence and severity of IDD symptoms as well as their habitual association with seizures (coded as before, after, during, or when seizure-free) and their duration., Results: IDD was diagnosed in 31 subjects but symptoms showed a clear-cut relationship with epileptic seizures in 54.8% of cases, leading to an operative distinction between true IDD and periictal dysphoric symptoms (PDS). There was no significant difference among patients with IDD, PDS, or those without psychopathology. In the IDD group, symptoms were chronic and unremitting in one-third of cases, with labile affective symptoms being correlated with age at onset of seizures (rho = -0.612, p = 0.020) and duration of the epilepsy (rho = 0.833, p < 0.001)., Discussion: An operative distinction between IDD and PDS bears the opportunity to identify different clinical endophenotypes that may have different prognoses and require different treatment strategies.

Published
2010
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