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172 results on '"Muhle, H"'

1. mGlu3 metabotropic glutamate receptors as a target for the treatment of absence epilepsy: Preclinical and human genetics data

Author: Celli, R., Striano, P., Citraro, R., Di Menna, L., Cannella, M., Imbriglio, T., Koko, M., De Sarro, G., Monn, J. A., Battaglia, G., van Luijtelaar, G., Nicoletti, F., Russo, E., Leo, A., Palotie, A., Folkhalsan, A. -E. L., Ruppert, A. -K., Lal, D., Thiele, H., Altmuller, J., Jabbari, K., Nurnberg, P., Sander, T., Siren, A., Becker, F., Lerche, H., Weber, Y., Koeleman, B., Caglayan, H., Hjalgrim, H., Moller, R., Muhle, H., Helbig, I., Everett, K., May, P., Krause, R., Balling, R., Nabbout, R., Zara, F., Scala, M., Iacomino, M., Scudieri, P., Bocciardi, R., Balagura, G., Minetti, C., Riva, A., Vari, M. S., Amadori, E., Perinelli, M., Verrotti, A., Baulac, S., and Kunz, W.
Subjects: gaba, Pharmacology, cortico-thalamo-cortical network, Action, intention, and motor control, human genetics, glutamate, General Medicine, absence epilepsy, eeg, mglu3 receptors, Psychiatry and Mental health, Neurology, Pharmacology (medical), Neurology (clinical)
Abstract: Background: Previous studies suggest that different metabotropic glutamate (mGlu) receptor subtypes are potential drug targets for the treatment of absence epilepsy. However, no information is available on mGlu3 receptors. Objective: To examine whether (i) abnormalities changes of mGlu3 receptor expression/signaling are found in the somatosensory cortex and thalamus of WAG/Rij rats developing spontaneous absence seizures; (ii) selective activation of mGlu3 receptors with LY2794193 affects the number and duration of spike-wave discharges (SWDs) in WAG/Rij rats; and (iii) a genetic variant of GRM3 (encoding the mGlu3 receptor) is associated with absence epilepsy. Methods: Animals: immunoblot analysis of mGlu3 receptors, GAT-1, GLAST, and GLT-1; real-time PCR analysis of mGlu3 mRNA levels; assessment of mGlu3 receptor signaling; EEG analysis of SWDs; assessment of depressive-like behavior. Humans: search for GRM3 and GRM5 missense variants in 196 patients with absence epilepsy or other IGE/GGE Idiopathic Generalized Epilepsy (IGE)/ Genetic Generalized Epilepsy (GGE) and 125,748 controls. Results: mGlu3 protein levels and mGlu3-mediated inhibition of cAMP formation were reduced in the thalamus and somatosensory cortex of pre-symptomatic (25-27 days old) and symptomatic (6-7 months old) WAG/Rij rats compared to age-matched controls. Treatment with LY2794193 (1 or 10 mg/kg, i.p.) reduced absence seizures and depressive-like behavior in WAG/Rij rats. LY2794193 also enhanced GAT1, GLAST, and GLT-1 protein levels in the thalamus and somatosensory cortex. GRM3 and GRM5 gene variants did not differ between epileptic patients and controls. Conclusions: We suggest that mGlu3 receptors modulate the activity of the cortico-thalamo-cortical circuit underlying SWDs and that selective mGlu3 receptor agonists are promising candidate drugs for absence epilepsy treatment.
Published: 2023

2. KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties

Author: Cioclu, M.C., Mosca, I., Ambrosino, P., Puzo, D., Bayat, A., Wortmann, S.B., Koch, J., Strehlow, V., Shirai, K., Matsumoto, N., Sanders, S.J., Michaud, V., Legendre, M., Riva, A., Striano, P., Muhle, H., Pendziwiat, M., Lesca, G., Mangano, G.D., Nardello, R., Lemke, J.R., Møller, R.S., Soldovieri, M.V., Kamsteeg, E.J., Rubboli, G., Taglialatela, M., Cioclu, M.C., Mosca, I., Ambrosino, P., Puzo, D., Bayat, A., Wortmann, S.B., Koch, J., Strehlow, V., Shirai, K., Matsumoto, N., Sanders, S.J., Michaud, V., Legendre, M., Riva, A., Striano, P., Muhle, H., Pendziwiat, M., Lesca, G., Mangano, G.D., Nardello, R., Lemke, J.R., Møller, R.S., Soldovieri, M.V., Kamsteeg, E.J., Rubboli, G., and Taglialatela, M.
Abstract: Item does not contain fulltext, OBJECTIVE: Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2-related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying 14 novel or previously untested variants. METHODS: Twenty-five patients harboring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole-cell electrophysiology in HEK-293 and SH-SY5Y cells. RESULTS: The phenotypic spectrum encompassed: (a) intellectual disability/developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; (b) epilepsy (15/25); (c) neurological impairment, with altered muscle tone (14/22); (d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (9 new, 10 reported previously): 16 missense, 1 in-frame deletion of a single amino acid, 1 nonsense, and 1 frameshift. Among tested variants, 8 showed gain-of-function (GoF), and 6 loss-of-function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others. INTERPRETATION: We expanded the phenotypic and genotypic spectrum of KCNT2-related disorders, highlighting novel genotype-phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. ANN NEUROL 2023;94:332-349.
Published: 2023

3. Association of ultra-rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study

Author: Koko, M, Motelow, JE, Stanley, KE, Bobbili, DR, Dhindsa, RS, May, P, Alldredge, BK, Allen, AS, Altmüller, J, Amrom, D, Andermann, E, Auce, P, Avbersek, A, Baulac, S, Bautista, JF, Becker, F, Bellows, Susannah, Berghuis, B, Berkovic, SF, Bluvstein, J, Boro, A, Bridgers, J, Burgess, R, Caglayan, H, Cascino, GD, Cavalleri, GL, Chung, SK, Cieuta-Walti, C, Cloutier, V, Consalvo, D, Cossette, P, Crumrine, P, Delanty, N, Depondt, C, Desbiens, R, Devinsky, O, Dlugos, D, Epstein, MP, Everett, K, Fiol, M, Fountain, NB, Francis, B, French, J, Freyer, C, Friedman, D, Gambardella, A, Geller, EB, Girard, S, Glauser, T, Glynn, S, Goldstein, DB, Gravel, M, Haas, K, Haut, SR, Heinzen, EL, Helbig, I, Hildebrand, MS, Johnson, MR, Jorgensen, A, Joshi, S, Kanner, A, Kirsch, HE, Klein, KM, Knowlton, RC, Koeleman, BPC, Kossoff, EH, Krause, R, Krenn, M, Kunz, WS, Kuzniecky, R, Langley, SR, LeGuern, E, Lehesjoki, AE, Lerche, H, Leu, C, Lortie, A, Lowenstein, DH, Marson, AG, Mebane, C, Mefford, HC, Meloche, C, Moreau, C, Motika, PV, Muhle, H, Møller, RS, Nabbout, R, Nguyen, DK, Nikanorova, M, Novotny, EJ, Nürnberg, P, Ottman, R, O’Brien, TJ, Paolicchi, JM, Parent, JM, Park, K, Peter, S, Petrou, S, Petrovski, S, Pickrell, WO, Poduri, A, Koko, M, Motelow, JE, Stanley, KE, Bobbili, DR, Dhindsa, RS, May, P, Alldredge, BK, Allen, AS, Altmüller, J, Amrom, D, Andermann, E, Auce, P, Avbersek, A, Baulac, S, Bautista, JF, Becker, F, Bellows, Susannah, Berghuis, B, Berkovic, SF, Bluvstein, J, Boro, A, Bridgers, J, Burgess, R, Caglayan, H, Cascino, GD, Cavalleri, GL, Chung, SK, Cieuta-Walti, C, Cloutier, V, Consalvo, D, Cossette, P, Crumrine, P, Delanty, N, Depondt, C, Desbiens, R, Devinsky, O, Dlugos, D, Epstein, MP, Everett, K, Fiol, M, Fountain, NB, Francis, B, French, J, Freyer, C, Friedman, D, Gambardella, A, Geller, EB, Girard, S, Glauser, T, Glynn, S, Goldstein, DB, Gravel, M, Haas, K, Haut, SR, Heinzen, EL, Helbig, I, Hildebrand, MS, Johnson, MR, Jorgensen, A, Joshi, S, Kanner, A, Kirsch, HE, Klein, KM, Knowlton, RC, Koeleman, BPC, Kossoff, EH, Krause, R, Krenn, M, Kunz, WS, Kuzniecky, R, Langley, SR, LeGuern, E, Lehesjoki, AE, Lerche, H, Leu, C, Lortie, A, Lowenstein, DH, Marson, AG, Mebane, C, Mefford, HC, Meloche, C, Moreau, C, Motika, PV, Muhle, H, Møller, RS, Nabbout, R, Nguyen, DK, Nikanorova, M, Novotny, EJ, Nürnberg, P, Ottman, R, O’Brien, TJ, Paolicchi, JM, Parent, JM, Park, K, Peter, S, Petrou, S, Petrovski, S, Pickrell, WO, and Poduri, A
Published: 2022

4. Association of ultra-rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study

Author: Koko, M., Motelow, J. E., Stanley, K. E., Bobbili, D. R., Dhindsa, R. S., May, P., Alldredge, B. K., Allen, A. S., Altmuller, J., Amrom, D., Andermann, E., Auce, P., Avbersek, A., Baulac, S., Bautista, J. F., Becker, F., Bellows, S. T., Berghuis, B., Berkovic, S. F., Bluvstein, J., Boro, A., Bridgers, J., Burgess, R., Caglayan, H., Cascino, G. D., Cavalleri, G. L., Chung, S. -K., Cieuta-Walti, C., Cloutier, V., Consalvo, D., Cossette, P., Crumrine, P., Delanty, N., Depondt, C., Desbiens, R., Devinsky, O., Dlugos, D., Epstein, M. P., Everett, K., Fiol, M., Fountain, N. B., Francis, B., French, J., Freyer, C., Friedman, D., Gambardella, A., Geller, E. B., Girard, S., Glauser, T., Glynn, S., Goldstein, D. B., Gravel, M., Haas, K., Haut, S. R., Heinzen, E. L., Helbig, I., Hildebrand, M. S., Johnson, M. R., Jorgensen, A., Joshi, S., Kanner, A., Kirsch, H. E., Klein, K. M., Knowlton, R. C., Koeleman, B. P. C., Kossoff, E. H., Krause, R., Krenn, M., Kunz, W. S., Kuzniecky, R., Langley, S. R., Leguern, E., Lehesjoki, A. -E., Lerche, H., Leu, C., Lortie, A., Lowenstein, D. H., Marson, A. G., Mebane, C., Mefford, H. C., Meloche, C., Moreau, C., Motika, P. V., Muhle, H., Moller, R. S., Nabbout, R., Nguyen, D. K., Nikanorova, M., Novotny, E. J., Nurnberg, P., Ottman, R., O'Brien, T. J., Paolicchi, J. M., Parent, J. M., Park, K., Peter, S., Petrou, S., Petrovski, S., Pickrell, W. O., Poduri, A., Radtke, R. A., Rees, M. I., Regan, B. M., Ren, Z., Sadleir, L. G., Sander, J. W., Sander, T., Scheffer, I. E., Schubert, J., Shellhaas, R. A., Sherr, E. H., Shih, J. J., Shinnar, S., Sills, G. J., Singh, R. K., Siren, A., Sirven, J., Sisodiya, S. M., Smith, M. C., Sonsma, A. C. M., Striano, P., Sullivan, J., Thio, L. L., Thomas, R. H., Venkat, A., Vining, E. P. G., Von Allmen, G. K., Wang, Q., Weber, Y. G., Weckhuysen, S., Weisenberg, J. L., Widdess-Walsh, P., Winawer, M. R., Wolking, S., Zara, F., Zimprich, F., Canadian Epilepsy Network, Epi4K Consortium, Epilepsy Phenome/Genome Project, EpiPGX Consortium, EuroEPINOMICS-CoGIE Consortium, Department of Medical and Clinical Genetics, Medicum, Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Peter, Sarah, Petrou, Steven, Petrovski, Slavé, Pickrell, William O., Poduri, Annapurna, Radtke, Rodney A., Rees, Mark I., Regan, Brigid M., Ren, Zhong, Sadleir, Lynette G., Alldredge, Brian K., Sander, Josemir W., Sander, Thomas, Scheffer, Ingrid E., Schubert, Julian, Shellhaas, Renée A., Sherr, Elliott H., Shih, Jerry J., Shinnar, Shlomo, Sills, Graeme J., Singh, Rani K., Allen, Andrew S., Siren, Auli, Sirven, Joseph, Sisodiya, Sanjay M., Smith, Michael C., Sonsma, Anja C. M., Striano, Pasquale, Sullivan, Joseph, Thio, Liu Lin, Thomas, Rhys H., Venkat, Anu, Altmüller, Janine, Vining, Eileen P. G., Von Allmen, Gretchen K., Wang, Quanli, Weber, Yvonne G., Weckhuysen, Sarah, Weisenberg, Judith L., Widdess-Walsh, Peter, Winawer, Melodie R., Wolking, Stefan, Zara, Federico, Amrom, Dina, Zimprich, Fritz, Andermann, Eva, Auce, Pauls, Avbersek, Andreja, Baulac, Stéphanie, Bautista, Jocelyn F., Becker, Felicitas, Bellows, Susannah T., Berghuis, Bianca, Berkovic, Samuel F., Bluvstein, Judith, Boro, Alex, Bridgers, Joshua, Burgess, Rosemary, Caglayan, Hande, Cascino, Gregory D., Cavalleri, Gianpiero L., Chung, Seo-Kyung, Cieuta-Walti, Cécile, Cloutier, Véronique, Consalvo, Damian, Cossette, Patrick, Crumrine, Patricia, Delanty, Norman, Depondt, Chantal, Desbiens, Richard, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael P., Everett, Kate, Fiol, Miguel, Fountain, Nathan B., Francis, Ben, French, Jacqueline, Freyer, Catharine, Friedman, Daniel, Gambardella, Antonio, Geller, Eric B., Girard, Simon, Glauser, Tracy, Glynn, Simon, Goldstein, David B., Gravel, Micheline, Haas, Kevin, Haut, Sheryl R., Heinzen, Erin L., Helbig, Ingo, Hildebrand, Michael S., Johnson, Michael R., Jorgensen, Andrea, Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E., Klein, Karl M., Knowlton, Robert C., Koeleman, Bobby P. C., Kossoff, Eric H., Krause, Roland, Krenn, Martin, Kunz, Wolfram S., Kuzniecky, Ruben, Langley, Sarah R., LeGuern, Eric, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lortie, Anne, Lowenstein, Daniel H., Marson, Anthony G., Mebane, Caroline, Mefford, Heather C., Meloche, Caroline, Moreau, Claudia, Motika, Paul V., Muhle, Hiltrud, Møller, Rikke S., Nabbout, Rima, Nguyen, Dang K., Nikanorova, Marina, Novotny, Edward J., Nürnberg, Peter, Ottman, Ruth, O'Brien, Terence J., Paolicchi, Juliann M., Parent, Jack M., and Park, Kristen
Subjects: GABA receptors, Neurology [D14] [Human health sciences], Clinical Sciences, GABA(A) receptors, GABRG2, familial epilepsy, Article, Clinical Research, Receptors, Exome Sequencing, Genetics, 2.1 Biological and endogenous factors, Humans, GGE, Genetic Predisposition to Disease, sporadic epilepsy, EpiPGX Consortium, Aetiology, gamma-Aminobutyric Acid, GABAA receptors, Epi4K Consortium, Epilepsy, Neurology & Neurosurgery, Neurologie [D14] [Sciences de la santé humaine], Generalized, GABA-A, Prevention, Human Genome, Neurosciences, 1184 Genetics, developmental biology, physiology, 3112 Neurosciences, Receptors, GABA-A, EuroEPINOMICS-CoGIE Consortium, Neurology, Case-Control Studies, Epilepsy, Generalized, Canadian Epilepsy Network, Neurology (clinical), Genetics & genetic processes [F10] [Life sciences], 3111 Biomedicine, Human medicine, Génétique & processus génétiques [F10] [Sciences du vivant], Epilepsy Phenome/Genome Project
Abstract: ObjectiveWe aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE.MethodsWe performed a case-control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19genes encoding γ-aminobutyric acid type A [GABAA ] receptors, 113genes representing the GABAergic pathway).ResultsGABRG2 was associated with GGE (p=1.8×10-5 ), approaching study-wide significance in familial GGE (p=3.0×10-6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR]=3.9, 95% confidence interval [CI]=1.9-7.8, false discovery rate [FDR]-adjusted p=.0024), whereas their association with sporadic GGE had marginally lower odds (OR=3.1, 95% CI=1.3-6.7, FDR-adjusted p=.022). URVs in GABAergic pathway genes were associated with familial GGE (OR=1.8, 95% CI=1.3-2.5, FDR-adjusted p=.0024) but not with sporadic GGE (OR=1.3, 95% CI=.9-1.9, FDR-adjusted p=.19).SignificanceURVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.
Published: 2022

5. Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy

Author: Wolking, S., Moreau, C., Mccormack, M., Krause, R., Krenn, M., Berkovic, S., Cavalleri, G. L., Delanty, N., Depondt, C., Johnson, M. R., Koeleman, B. P. C., Kunz, W. S., Lerche, H., Marson, A. G., O'Brien, T. J., Petrovski, S., Sander, J. W., Sills, G. J., Striano, P., Zara, F., Zimprich, F., Sisodiya, S. M., Girard, S. L., Cossette, P., Avbersek, A., Leu, C., Heggeli, K., Demurtas, R., Willis, J., Speed, D., Sargsyan, N., Chinthapalli, K., Borghei, M., Coppola, A., Gambardella, A., Becker, F., Rau, S., Hengsbach, C., Weber, Y. G., Berghuis, B., Campbell, E., Gudmundsson, L. J., Ingason, A., Stefansson, K., Schneider, R., Balling, R., Auce, P., Francis, B., Jorgensen, A., Morris, A., Langley, S., Srivastava, P., Brodie, M., Todaro, M., Hutton, J., Muhle, H., Klein, K. M., Moller, R. S., Nikanorova, M., Weckhuysen, S., Rener-Primec, Z., Craig, J., and Stefansson, H.
Subjects: 0301 basic medicine, Male, Candidate gene, Drug Resistant Epilepsy, Neurology [D14] [Human health sciences], Neurosciences. Biological psychiatry. Neuropsychiatry, Drug resistance, Bioinformatics, Polymorphism, Single Nucleotide, Whole Exome Sequencing, Cohort Studies, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Exome Sequencing, medicine, Humans, Polymorphism, RC346-429, Gene, Exome sequencing, Research Articles, Genetic Association Studies, Neurologie [D14] [Sciences de la santé humaine], business.industry, General Neuroscience, Genetic variants, Genetic Variation, Single Nucleotide, medicine.disease, DEPDC5, Female, 030104 developmental biology, Cohort, Neurology (clinical), Neurology. Diseases of the nervous system, business, 030217 neurology & neurosurgery, RC321-571, Research Article
Abstract: Annals of Clinical and Translational Neurology 8(7), 1376-1387 (2021). doi:10.1002/acn3.51374, Published by Wiley, Chichester [u.a.]
Published: 2021

6. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author: Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, Goldstein, DB, Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, and Goldstein, DB
Abstract: Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
Published: 2021

7. Polygenic burden in focal and generalized epilepsies

Author: Leu C., Stevelink R., Smith A. W., Goleva S. B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S. M., Cavalleri G. L., Koeleman B. P. C., Lerche H., Jehi L., Davis L. K., Najm I. M., Palotie A., Daly M. J., Busch R. M., Lal D., Feng Y. -C. A., Howrigan D. P., Abbott L. E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B. M., Berkovic S. F., Goldstein D. B., Lowenstein D. H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E. L., Helbig I., Kwan P., Marson A. G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D. J., Scheffer I. E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B. M., Bellows S. T., Bennett C. A., Johns E. M. C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T. J., Todaro M., Stamberger H., Andrade D. M., Sadoway T. R., Mo K., Krestel H., Gallati S., Papacostas S. S., Kousiappa I., Tanteles G. A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K. M., Rosenow F., Reif P. S., Knake S., Kunz W. S., Zsurka G., Elger C. E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A. D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J. R., Krey I., Weber Y. G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A. F., Steinhoff B. J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C. J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A. -E., Rees M. I., Chung S. -K., Pickrell W. O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M. R., Auce P., Sills G. J., Baum L. W., Sham P. C., Cherny S. S., Lui C. H. T., Barisic N., Delanty N., Doherty C. P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M. S., Mancardi M. M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L. G., King C., Mountier E., Caglayan S. H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B. R., Shain C., Poduri A., Buono R. J., Ferraro T. N., Sperling M. R., Lo W., Privitera M., French J. A., Schachter S., Kuzniecky R. I., Devinsky O., Hegde M., Khankhanian P., Helbig K. L., Ellis C. A., Spalletta G., Piras F., Gili T., Ciullo V., Leu C., Stevelink R., Smith A.W., Goleva S.B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S.M., Cavalleri G.L., Koeleman B.P.C., Lerche H., Jehi L., Davis L.K., Najm I.M., Palotie A., Daly M.J., Busch R.M., Lal D., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B.M., Berkovic S.F., Goldstein D.B., Lowenstein D.H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bellows S.T., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B.R., Shain C., Poduri A., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Commission of the European Communities, Medical Research Council (MRC), Tumienė, Birutė, Mameniškienė, Rūta, Utkus, Algirdas, Praninskienė, Rūta, Grikinienė, Jurgita, Samaitienė-Aleknienė, Rūta, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Helsinki Institute of Life Science HiLIFE, and Department of Medical and Clinical Genetics
Subjects: 0301 basic medicine, Male, Multifactorial Inheritance, Epi25 Consortium, Databases, Factual, FEATURES, Genome-wide association study, Epilepsies, 3124 Neurology and psychiatry, Cohort Studies, Epilepsy, 0302 clinical medicine, Cost of Illness, 1ST SEIZURE, HISTORY, genetics, POPULATION, 11 Medical and Health Sciences, education.field_of_study, medicine.diagnostic_test, SCORES, Single Nucleotide, Biobank, 3. Good health, 17 Psychology and Cognitive Sciences, Genetic generalized epilepsy, Epilepsy, Generalized, Female, Partial, Cohort study, Human, medicine.medical_specialty, Population, European Continental Ancestry Group, Clinical Neurology, BIOBANK, Polymorphism, Single Nucleotide, epilepsy, genetic generalized epilepsy, common variant risk, Databases, 03 medical and health sciences, Genetic, Internal medicine, medicine, Journal Article, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, Generalized epilepsy, education, SEIZURE RECURRENCE, Factual, METAANALYSIS, Genetic testing, Neurology & Neurosurgery, RISK PREDICTION, Generalized, business.industry, 3112 Neurosciences, Common variant risk, Genetic Variation, Original Articles, medicine.disease, Comorbidity, Cost of Illne, Epilepsies, Partial, Genome-Wide Association Study, 030104 developmental biology, Neurology (clinical), Cohort Studie, business, 030217 neurology & neurosurgery
Abstract: See Hansen and Møller (doi:10.1093/brain/awz318) for a scientific commentary on this article. Using polygenic risk scores from a genome-wide association study in generalized and focal epilepsy, Leu et al. reveal a significantly higher genetic burden for epilepsy in multiple cohorts of people with epilepsy compared to population controls. Quantification of common variant burden may be valuable for epilepsy prognosis and treatment., Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10−15; Cleveland: P = 2.85×10−4; Finnish-ancestry Epi25: P = 1.80×10−4) or population controls (Epi25: P = 2.35×10−70; Cleveland: P = 1.43×10−7; Finnish-ancestry Epi25: P = 3.11×10−4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10−4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10−19; Cleveland: P = 1.69×10−6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10−15; Cleveland: P = 1.39×10−2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls—in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.
Published: 2019

8. Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

Author: Lal, D., May, P., Perez-Palma, E., Samocha, K. E., Kosmicki, J. A., Robinson, E. B., Moller, R. S., Krause, R., Nurnberg, P., Weckhuysen, S., De Jonghe, P., Guerrini, R., Niestroj, L. M., Du, J., Marini, C., Balling, R., Barisic, N., Baulac, S., Caglayan, H., Craiu, D. C., Depienne, C., Helbig, I., Hjalgrim, H., Hoffman-Zacharska, D., Jahn, J., Klein, K. M., Koeleman, B. P. C., Komarek, V., Leguern, E., Lehesjoki, A. -E., Lemke, J. R., Lerche, H., Linnankivi, T., Muhle, H., Pal, D. K., Palotie, A., Rosenow, F., Schubert-Bast, S., Selmer, K., Serratosa, J. M., Stephani, U., Sterbova, K., Striano, P., Suls, A., Talvik, T., Von Spiczak, S., Weber, Y. G., Zara, F., Ware, J. S., Kurki, M., Gormley, P., Tang, S., Wu, S., Biskup, S., Poduri, A., Neubauer, B. A., Helbig, K. L., Majithia, A. R., Daly, M. J., EuroEPINOMICS-RES Consortium, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Department of Medical and Clinical Genetics, Medicum, HUS Helsinki and Uusimaa Hospital District, and Wellcome Trust
Subjects: Candidate gene, lcsh:QH426-470, Developmental Disabilities, Mutation, Missense, Sequence Homology, lcsh:Medicine, ORTHOLOGS, Computational biology, Conservation, Gene family, Missense variants, Neurodevelopmental disorders, Paralogs, Biology, 03 medical and health sciences, MULTIPLE SEQUENCE ALIGNMENT, PHYLOGENETIC TREES, Genetics, Missense mutation, Ensembl, Molecular Biology, Gene, Genetics (clinical), Phylogeny, 030304 developmental biology, 0303 health sciences, 0604 Genetics, Phylogenetic tree, Research, 030305 genetics & heredity, lcsh:R, 1184 Genetics, developmental biology, physiology, 1103 Clinical Sciences, EuroEPINOMICS-RES Consortium, Human genetics, lcsh:Genetics, Genetic Loci, DE-NOVO MUTATIONS, Multigene Family, Molecular Medicine, Human medicine, Orthologous Gene, Genome-Wide Association Study
Abstract: Background Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Methods Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. Results We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint. Conclusion This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes.
Published: 2020

9. Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load

Author: Perucca, P., Anderson, A., Jazayeri, D., Hitchcock, A., Graham, J., Todaro, M., Tomson, T., Battino, D., Perucca, E., Ferri, M. M., Rochtus, A., Lagae, L., Canevini, M. P., Zambrelli, E., Campbell, E., Koeleman, B. P. C., Scheffer, I. E., Berkovic, S. F., Kwan, P., Sisodiya, S. M., Goldstein, D. B., Petrovski, S., Craig, J., Vajda, F. J. E., O'Brien, T. J., Leu, C., Wolking, S., Peter, S., Weber, Y. G., Weckhuysen, S., Moller, R. S., Nikanorova, M., Muhle, H., Avbersek, A., Heggeli, K., Striano, P., Gambardella, A., Langley, S. R., Krenn, M., Klein, K. M., Mccormack, M., Borghei, M., Willis, J., Berghuis, B., Jorgensen, A., Auce, P., Francis, B., Srivastava, P., Sonsma, A. C. M., Sander, Jw., Zimprich, F., Depondt, C., Johnson, M. M., Marson, A. G., Sills, G. J., Kunz, W. S., Cavalleri, G. L., Delanty, N., Zara, F., Krause, R., Lerche, H., Andrade, D., Sen, A., Bazil, C. W., Boland, M., Cavalleri, G., Choi, H., Colombo, S., Costello, D., Devinsky, O., Doherty, C. P., Dugan, P., Frankel, W., Heinzen, E., Johnson, M., Marson, T., Mikati, M., Ottman, R., Pandolfo, M., Radtke, R., Rees, M., Sadoway, T., Valley, N., Walley, N., Wood, N., and Zuberi, S.
Subjects: Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, DNA Copy Number Variations, Polymorphism, Single Nucleotide, Paternal Age, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Pregnancy, Polymorphism (computer science), medicine, Humans, Exome, Copy-number variation, Indel, business.industry, Confounding, Infant, Newborn, Abnormalities, Drug-Induced, Genetic Variation, DNA, medicine.disease, Genetic load, Exact test, Teratogens, 030104 developmental biology, Neurology, Anticonvulsants, Female, Neurology (clinical), Genetic Load, business, 030217 neurology & neurosurgery
Abstract: OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism which we investigated. METHODS: Whole-exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in: children exposed prenatally to AEDs (AED-exposed children) vs children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs vs those without BDs, adjusting for confounders. Fisher's exact test was used to compare categorical data. RESULTS: 67 child-parent trios were included: 10 with AED-exposed children with BDs; 46 with AED-exposed unaffected children; 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children [median dnSNV/indel number/child (range): 3 (0-7) vs 3 (1-5), p = 0.50]. Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9/67 (13%) children, none of whom had BDs. The proportion of cases harbouring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counselling. This article is protected by copyright. All rights reserved.
Published: 2020

10. Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17458 subjects

Author: Niestroj, LM, Perez-Palma, E, Howrigan, DP, Zhou, Y, Cheng, F, Saarentaus, E, Nürnberg, P, Stevelink, R, Daly, MJ, Palotie, A, Lal, D, Feng, YCA, Abbott, LE, Tashman, K, Cerrato, F, Churchhouse, C, Gupta, N, Neale, BM, Berkovic, SF, Lerche, H, Goldstein, DB, Lowenstein, DH, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Leu, C, Bennett, CA, Bellows, Susannah, Johns, EMC, MacDonald, A, Shilling, H, Burgess, R, Weckhuysen, D, Bahlo, M, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Sadoway, TR, Mo, K, Krestel, H, Gallati, S, Papacostas, SS, Kousiappa, I, Tanteles, GA, Šterbová, K, Vlcková, M, Sedlácková, L, Laššuthová, P, Martin, K, Rosenow, F, Reif, PS, Knake, S, Kunz, WS, Zsurka, G, Elger, CE, Bauer, J, Rademacher, M, Pendziwiat, M, Muhle, H, Rademacher, A, Van Baalen, A, Von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Müller-Schlüter, K, Kluger, G, Häusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Niestroj, LM, Perez-Palma, E, Howrigan, DP, Zhou, Y, Cheng, F, Saarentaus, E, Nürnberg, P, Stevelink, R, Daly, MJ, Palotie, A, Lal, D, Feng, YCA, Abbott, LE, Tashman, K, Cerrato, F, Churchhouse, C, Gupta, N, Neale, BM, Berkovic, SF, Lerche, H, Goldstein, DB, Lowenstein, DH, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Leu, C, Bennett, CA, Bellows, Susannah, Johns, EMC, MacDonald, A, Shilling, H, Burgess, R, Weckhuysen, D, Bahlo, M, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Sadoway, TR, Mo, K, Krestel, H, Gallati, S, Papacostas, SS, Kousiappa, I, Tanteles, GA, Šterbová, K, Vlcková, M, Sedlácková, L, Laššuthová, P, Martin, K, Rosenow, F, Reif, PS, Knake, S, Kunz, WS, Zsurka, G, Elger, CE, Bauer, J, Rademacher, M, Pendziwiat, M, Muhle, H, Rademacher, A, Van Baalen, A, Von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Müller-Schlüter, K, Kluger, G, Häusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, and Becker, F
Abstract: Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5-3% of patients carry epilepsy-associated CNVs. The character
Published: 2020

11. Semantic Similarity Analysis Reveals Robust Gene-Disease Relationships in Developmental and Epileptic Encephalopathies

Author: Galer, PD, Ganesan, S, Lewis-Smith, D, McKeown, SE, Pendziwiat, M, Helbig, KL, Ellis, CA, Rademacher, A, Smith, L, Poduri, A, Seiffert, S, von Spiczak, S, Muhle, H, van Baalen, A, Thomas, RH, Krause, R, Weber, Y, Helbig, I, Galer, PD, Ganesan, S, Lewis-Smith, D, McKeown, SE, Pendziwiat, M, Helbig, KL, Ellis, CA, Rademacher, A, Smith, L, Poduri, A, Seiffert, S, von Spiczak, S, Muhle, H, van Baalen, A, Thomas, RH, Krause, R, Weber, Y, and Helbig, I
Abstract: More than 100 genetic etiologies have been identified in developmental and epileptic encephalopathies (DEEs), but correlating genetic findings with clinical features at scale has remained a hurdle because of a lack of frameworks for analyzing heterogenous clinical data. Here, we analyzed 31,742 Human Phenotype Ontology (HPO) terms in 846 individuals with existing whole-exome trio data and assessed associated clinical features and phenotypic relatedness by using HPO-based semantic similarity analysis for individuals with de novo variants in the same gene. Gene-specific phenotypic signatures included associations of SCN1A with "complex febrile seizures" (HP: 0011172; p = 2.1 × 10-5) and "focal clonic seizures" (HP: 0002266; p = 8.9 × 10-6), STXBP1 with "absent speech" (HP: 0001344; p = 1.3 × 10-11), and SLC6A1 with "EEG with generalized slow activity" (HP: 0010845; p = 0.018). Of 41 genes with de novo variants in two or more individuals, 11 genes showed significant phenotypic similarity, including SCN1A (n = 16, p < 0.0001), STXBP1 (n = 14, p = 0.0021), and KCNB1 (n = 6, p = 0.011). Including genetic and phenotypic data of control subjects increased phenotypic similarity for all genetic etiologies, whereas the probability of observing de novo variants decreased, emphasizing the conceptual differences between semantic similarity analysis and approaches based on the expected number of de novo events. We demonstrate that HPO-based phenotype analysis captures unique profiles for distinct genetic etiologies, reflecting the breadth of the phenotypic spectrum in genetic epilepsies. Semantic similarity can be used to generate statistical evidence for disease causation analogous to the traditional approach of primarily defining disease entities through similar clinical features.
Published: 2020

12. De novo variants in neurodevelopmental disorders with epilepsy

Author: Heyne, H. O., Singh, T., Stamberger, H., Abou Jamra, R., Caglayan, H., Craiu, D., De Jonghe, P., Guerrini, R., Helbig, K. L., Koeleman, B. P. C., Kosmicki, J. A., Linnankivi, T., May, P., Muhle, H., Moller, R. S., Neubauer, B. A., Palotie, A., Pendziwiat, M., Striano, P., Tang, S., Wu, S., Afawi, Z., De Kovel, C., Dimova, P., Djemie, T., Endziniene, M., Hoffman-Zacharska, D., Jahn, J., Korff, C., Lehesjoki, A. -E., Marini, C., Muller, S. H., Pal, D., Schwarz, N., Selmer, K., Serratosa, J., Stephani, U., Sterbova, K., Suls, A., Syrbe, S., Talvik, I., Von Spiczak, S., Zara, F., Poduri, A., Weber, Y. G., Weckhuysen, S., Sisodiya, S. M., Daly, M. J., Helbig, I., Lal, D., Lemke, J. R., Children's Hospital, Lastenneurologian yksikkö, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Research Programme for Molecular Neurology, Neuroscience Center, HUS Children and Adolescents, Genomics of Neurological and Neuropsychiatric Disorders, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], University of Luxembourg: High Performance Computing - ULHPC [research center], Korff, Christian, and EuroEPINOMICS RES Consortium
Subjects: Exome/genetics, Male, 0301 basic medicine, ILAE COMMISSION, Joint analysis, Neurodevelopmental Disorders/genetics, Bioinformatics, Epilepsy/genetics, Epilepsy, 0302 clinical medicine, Intellectual disability, SEQUENCE VARIANTS, Missense mutation, Epilepsy is a frequent feature, Exome, TERMINOLOGY, Disease gene, 0303 health sciences, ddc:618, medicine.diagnostic_test, Genetic Predisposition to Disease/genetics, Neurodevelopmental disorders, 1184 Genetics, developmental biology, physiology, HUMAN-DISEASE, PREVALENCE, 3. Good health, Genetic Variation/genetics, De novo variants, Female, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Genetic Testing/methods, Disease Association, Biology, CLASSIFICATION, 03 medical and health sciences, Intellectual Disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Limited evidence, 030304 developmental biology, Genetic testing, business.industry, MUTATIONS, AUTISM SPECTRUM DISORDER, Genetic Variation, medicine.disease, Intellectual Disability/genetics, 030104 developmental biology, Neurodevelopmental Disorders, epilepsy, KCNQ2 ENCEPHALOPATHY, Human medicine, 3111 Biomedicine, business, Genetic diagnosis, 030217 neurology & neurosurgery
Abstract: Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant excess of DNV, of which SNAP25 and GABRB2 had previously only limited evidence for disease association. Joint analysis of all individuals with NDD also implicated CACNA1E as a novel disease gene. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be associated with epilepsy. We further demonstrate to what extent our results impact current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDD with epilepsy.
Published: 2018

13. A SLC2A1 MUTATION IN A BOY WITH CHILDHOOD ABSENCE EPILEPSY, ALTERNATING HEMIPLEGIA AND ATAXIA: p818

Author: Muhle, H., Möller, F., Stephani, U., and Helbig, I.
Published: 2012

14. Clinical spectrum of STX1B-related epileptic disorders

Author: Wolking, S, May, P, Mei, D, Møller, RS, Balestrini, S, Helbig, KL, Altuzarra, CD, Chatron, N, Kaiwar, C, Stöhr, K, Widdess-Walsh, P, Mendelsohn, BA, Numis, A, Cilio, MR, Van Paesschen, W, Svendsen, LL, Oates, S, Hughes, E, Goyal, S, Brown, K, Saenz, M, Dorn, T, Muhle, H, Pagnamenta, AT, Vavoulis, DV, Knight, SJL, Taylor, JC, Canevini, MP, Darra, F, Gavrilova, RH, Powis, Z, Tang, S, Marquetand, J, Armstrong, M, McHale, D, Klee, EW, Kluger, GJ, Lowenstein, DH, Weckhuysen, S, Pal, DK, Helbig, I, Guerrini, R, Thomas, RH, Rees, MI, Lesca, G, Sisodiya, SM, Weber, YG, Lal, D, Marini, C, Lerche, H, and Schubert, J
Subjects: Male, Drug Resistant Epilepsy, Adolescent, Developmental Disabilities, Mutation, Missense, Clinical Neurology, FEBRILE SEIZURES PLUS, GENERALIZED EPILEPSY, Syntaxin 1, PROTEIN, Article, Seizures, Febrile, Young Adult, Loss of Function Mutation, Humans, HETEROGENEITY, SCN1A, Child, Epilepstic disorders, Science & Technology, Learning Disabilities, Infant, Newborn, High-Throughput Nucleotide Sequencing, Infant, GENETIC-VARIATION, Electroencephalography, Sequence Analysis, DNA, SODIUM-CHANNEL, Epilepstic disorders, STX1B, Phenotype, DE-NOVO MUTATIONS, Child, Preschool, ONSET, STXBP1, STX1B, Anticonvulsants, Female, Human medicine, Epilepsies, Partial, Neurosciences & Neurology, Epileptic Syndromes, Life Sciences & Biomedicine
Abstract: OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies. ispartof: NEUROLOGY vol:92 issue:11 pages:E1238-E1249 ispartof: location:United States status: published
Published: 2019

15. A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

Author: Berghuis, B., Stapleton, C., Sonsma, A. C. M., Hulst, J., de Haan, G. -J., Lindhout, D., Demurtas, R., Krause, R., Depondt, C., Kunz, W. S., Zara, F., Striano, P., Craig, J., Auce, P., Marson, A. G., Stefansson, H., O'Brien, T. J., Johnson, M. R., Sills, G. J., Wolking, S., Lerche, H., Sisodiya, S. M., Sander, J. W., Cavalleri, G. L., Koeleman, B. P. C., Mccormack, M., Avbersek, A., Leu, C., Heggeli, K., Willis, J., Speed, D., Sargsyan, N., Chinthapalli, K., Borghei, M., Coppola, A., Gambardella, A., Becker, F., Rau, S., Hengsbach, C., Weber, Y. G., Delanty, N., Campbell, E., Gudmundsson, L. J., Ingason, A., Stefansson, K., Schneider, R., Balling, R., Francis, B., Jorgensen, A., Morris, A., Langley, S., Srivastava, P., Brodie, M., Todaro, M., Petrovski, S., Hutton, J., Zimprich, F., Krenn, M., Muhle, H., Martin Klein, K., Moller, R., Nikanorova, M., Weckhuysen, S., Rener-Primec, Z., Berghuis, Bianca, Stapleton, Caragh, Sonsma, Anja C. M., Hulst, Janic, de Haan, Gerrit-Jan, Lindhout, Dick, Demurtas, Rita, Krause, Roland, Depondt, Chantal, Kunz, Wolfram S., Zara, Federico, Striano, Pasquale, Craig, John, Auce, Paul, Marson, Anthony G., Stefansson, Hreinn, O'Brien, Terence J., Johnson, Michael R., Sills, Graeme J., Wolking, Stefan, Lerche, Holger, Sisodiya, Sanjay M., Sander, Josemir W., Cavalleri, Gianpiero L., Koeleman, Bobby P. C., Mccormack, Mark, Weckhuysen, Sarah, EpiPGX Consortium, Imperial College Healthcare NHS Trust- BRC Funding, and Commission of the European Communities
Subjects: medicine.medical_specialty, hyponatremia, Clinical Neurology, Gastroenterology, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, adverse effects, antiepileptic drugs, EpiPGX Consortium, GWAS, antiepileptic drug, Internal medicine, adverse effect, medicine, Oxcarbazepine, Adverse effect, 030304 developmental biology, 0303 health sciences, business.industry, Généralités, Carbamazepine, medicine.disease, 3. Good health, Neurology, Cohort, Full‐length Original Research, Phenobarbital, Human medicine, Neurology (clinical), Hyponatremia, business, 030217 neurology & neurosurgery, Drug metabolism, medicine.drug
Abstract: Objective: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy. Methods: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum. Results: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found. Significance: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2019

16. EXCITATORY AND INHIBITORY MECHANISMS OF PHOTOSENSITIVITY: 071

Author: Siniatchkin, M., Groppa, S., Jerosch, B., Muhle, H., Shepherd, A., Siebner, H., and Stephani, U.
Published: 2006

17. NEW SUSCEPTIBILITY LOCUS AT 13Q13·2 FOR EPILEPSY-RELATED PHOTOSENSITIVITY IN A COMBINED EUROPEAN GENOMEWIDE LINKAGE SCAN: 041

Author: Pinto, D., Tauer, U., Lorenz, S., Muhle, H., Neubauer, B., Waltz, S., Lenzen, K., Rudolf, G., de Haan, G., Lindhout, D., Koeleman, B., Sander, T., Trenité, D. Kasteleijn-Nolst, and Stephani, U.
Published: 2006

18. Nonparalytic poliomyelitis in Lyme borreliosis

Author: van Baalen, A, Muhle, H, Straube, T, Jansen, O, and Stephani, U
Published: 2006

19. Survey of the Biological Effects of Refractory Ceramic Fibres: Overload and Its Possible Consequences

Author: Brown, R. C., Bellmann, B., Muhle, H., DAVIS, J. M. G., and Maxim, L. D.
Published: 2005

20. SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals

Author: Ng, BG, Sosicka, P, Agadi, S, Almannai, M, Bacino, CA, Barone, R, Botto, LD, Burton, JE, Carlston, C, Chung, BH-Y, Cohen, JS, Coman, D, Dipple, KM, Dorrani, N, Dobyns, WB, Elias, AF, Epstein, L, Gahl, WA, Garozzo, D, Hammer, TB, Haven, J, Heron, D, Herzog, M, Hoganson, GE, Hunter, JM, Jain, M, Juusola, J, Lakhani, S, Lee, H, Lee, J, Lewis, K, Longo, N, Lourenco, CM, Mak, CCY, McKnight, D, Mendelsohn, BA, Mignot, C, Mirzaa, G, Mitchell, W, Muhle, H, Nelson, SF, Olczak, M, Palmer, CGS, Partikian, A, Patterson, MC, Pierson, TM, Quinonez, SC, Regan, BM, Ross, ME, Guillen Sacoto, MJ, Scaglia, F, Scheffer, IE, Segal, D, Singhal, NS, Striano, P, Sturiale, L, Symonds, JD, Tang, S, Vilain, E, Willis, M, Wolfe, LA, Yang, H, Yano, S, Powis, Z, Suchy, SF, Rosenfeld, JA, Edmondson, AC, Grunewald, S, Freeze, HH, Ng, BG, Sosicka, P, Agadi, S, Almannai, M, Bacino, CA, Barone, R, Botto, LD, Burton, JE, Carlston, C, Chung, BH-Y, Cohen, JS, Coman, D, Dipple, KM, Dorrani, N, Dobyns, WB, Elias, AF, Epstein, L, Gahl, WA, Garozzo, D, Hammer, TB, Haven, J, Heron, D, Herzog, M, Hoganson, GE, Hunter, JM, Jain, M, Juusola, J, Lakhani, S, Lee, H, Lee, J, Lewis, K, Longo, N, Lourenco, CM, Mak, CCY, McKnight, D, Mendelsohn, BA, Mignot, C, Mirzaa, G, Mitchell, W, Muhle, H, Nelson, SF, Olczak, M, Palmer, CGS, Partikian, A, Patterson, MC, Pierson, TM, Quinonez, SC, Regan, BM, Ross, ME, Guillen Sacoto, MJ, Scaglia, F, Scheffer, IE, Segal, D, Singhal, NS, Striano, P, Sturiale, L, Symonds, JD, Tang, S, Vilain, E, Willis, M, Wolfe, LA, Yang, H, Yano, S, Powis, Z, Suchy, SF, Rosenfeld, JA, Edmondson, AC, Grunewald, S, and Freeze, HH
Abstract: Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.
Published: 2019

21. 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

22. Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis

Author: Knaus, A. (Alexej), Pantel, J.T. (Jean Tori), Pendziwiat, M. (Manuela), Hajjir, N. (Nurulhuda), Zhao, M. (Max), Hsieh, T.-C. (Tzung-Chien), Schubach, M. (Max), Gurovich, Y. (Yaron), Fleischer, N. (Nicole), Jäger, M. (Marten), Köhler, S. (Sebastian), Muhle, H. (Hiltrud), Korff, C. (Christian), Møller, R.S. (Rikke S.), Bayat, A. (Allan), Calvas, P. (Patrick), Chassaing, N. (Nicolas), Warren, H. (Hannah), Skinner, S. (Steven), Louie, R. (Raymond), Evers, C. (Christina), Bohn, M. (Marc), Christen, H.-J. (Hans-Jürgen), Born, M. (Myrthe) van den, Obersztyn, E. (Ewa), Charzewska, A. (Agnieszka), Endziniene, M. (Milda), Kortüm, F. (Fanny), Brown, N. (Natasha), Robinson, P.N. (Peter N.), Schelhaas, H.J. (Helenius), Weber, Y. (Yvonne), Helbig, I. (Ingo), Mundlos, S. (Stefan), Horn, D. (Denise), Krawitz, P., Knaus, A. (Alexej), Pantel, J.T. (Jean Tori), Pendziwiat, M. (Manuela), Hajjir, N. (Nurulhuda), Zhao, M. (Max), Hsieh, T.-C. (Tzung-Chien), Schubach, M. (Max), Gurovich, Y. (Yaron), Fleischer, N. (Nicole), Jäger, M. (Marten), Köhler, S. (Sebastian), Muhle, H. (Hiltrud), Korff, C. (Christian), Møller, R.S. (Rikke S.), Bayat, A. (Allan), Calvas, P. (Patrick), Chassaing, N. (Nicolas), Warren, H. (Hannah), Skinner, S. (Steven), Louie, R. (Raymond), Evers, C. (Christina), Bohn, M. (Marc), Christen, H.-J. (Hans-Jürgen), Born, M. (Myrthe) van den, Obersztyn, E. (Ewa), Charzewska, A. (Agnieszka), Endziniene, M. (Milda), Kortüm, F. (Fanny), Brown, N. (Natasha), Robinson, P.N. (Peter N.), Schelhaas, H.J. (Helenius), Weber, Y. (Yvonne), Helbig, I. (Ingo), Mundlos, S. (Stefan), Horn, D. (Denise), and Krawitz, P.
Abstract: Background: Glycosylphosphatidylinositol biosynthesis defects (GPIBDs) cause a group of phenotypically overlapping recessive syndromes with intellectual disability, for which pathogenic mutations have been described in 16 genes of the corresponding molecular pathway. An elevated serum activity of alkaline phosphatase (AP), a GPI-linked enzyme, has been used to assign GPIBDs to the phenotypic series of hyperphosphatasia with mental retardation syndrome (HPMRS) and to distinguish them from another subset of GPIBDs, termed multiple congenital anomalies hypotonia seizures syndrome (MCAHS). However, the increasing number of individuals with a GPIBD shows that hyperphosphatasia is a variable feature that is not ideal for a clinical classification. Methods: We studied the discriminatory power of multiple GPI-linked substrates that were assessed by flow cytometry in blood cells and fibroblasts of 39 and 14 individuals with a GPIBD, respectively. On the phenotypic level, we evaluated the frequency of occurrence of clinical symptoms and analyzed the performance of computer-assisted image analysis of the facial gestalt in 91 individuals. Results: We found that certain malformations such as Morbus Hirschsprung and diaphragmatic defects are more likely to be associated with particular gene defects (PIGV, PGAP3, PIGN). However, especially at the severe end of the clinical spectrum of HPMRS, there is a high phenotypic overlap with MCAHS. Elevation of AP has also been documented in some of the individuals with MCAHS, namely those with PIGA mutations. Although the impairment of GPI-linked substrates is supposed to play the key role in the pathophysiology of GPIBDs, we could not observe gene-specific profiles for flow cytometric markers or a correlation between their cell surface levels and the severity of the phenotype. In contrast, it was facial recognition software that achieved the highest accuracy in predicting the disease-causing gene in a GPIBD. Conclusions: Due to the overlap
Published: 2018
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23. Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis

Author: Knaus, A, Pantel, JT, Pendziwiat, M, Hajjir, N, Zhao, M, Hsieh, T-C, Schubach, M, Gurovich, Y, Fleischer, N, Jaeger, M, Koehler, S, Muhle, H, Korff, C, Moller, RS, Bayat, A, Calvas, P, Chassaing, N, Warren, H, Skinner, S, Louie, R, Evers, C, Bohn, M, Christen, H-J, van den Born, M, Obersztyn, E, Charzewska, A, Endziniene, M, Kortuem, F, Brown, N, Robinson, PN, Schelhaas, HJ, Weber, Y, Helbig, I, Mundlos, S, Horn, D, Krawitz, PM, Knaus, A, Pantel, JT, Pendziwiat, M, Hajjir, N, Zhao, M, Hsieh, T-C, Schubach, M, Gurovich, Y, Fleischer, N, Jaeger, M, Koehler, S, Muhle, H, Korff, C, Moller, RS, Bayat, A, Calvas, P, Chassaing, N, Warren, H, Skinner, S, Louie, R, Evers, C, Bohn, M, Christen, H-J, van den Born, M, Obersztyn, E, Charzewska, A, Endziniene, M, Kortuem, F, Brown, N, Robinson, PN, Schelhaas, HJ, Weber, Y, Helbig, I, Mundlos, S, Horn, D, and Krawitz, PM
Abstract: BACKGROUND: Glycosylphosphatidylinositol biosynthesis defects (GPIBDs) cause a group of phenotypically overlapping recessive syndromes with intellectual disability, for which pathogenic mutations have been described in 16 genes of the corresponding molecular pathway. An elevated serum activity of alkaline phosphatase (AP), a GPI-linked enzyme, has been used to assign GPIBDs to the phenotypic series of hyperphosphatasia with mental retardation syndrome (HPMRS) and to distinguish them from another subset of GPIBDs, termed multiple congenital anomalies hypotonia seizures syndrome (MCAHS). However, the increasing number of individuals with a GPIBD shows that hyperphosphatasia is a variable feature that is not ideal for a clinical classification. METHODS: We studied the discriminatory power of multiple GPI-linked substrates that were assessed by flow cytometry in blood cells and fibroblasts of 39 and 14 individuals with a GPIBD, respectively. On the phenotypic level, we evaluated the frequency of occurrence of clinical symptoms and analyzed the performance of computer-assisted image analysis of the facial gestalt in 91 individuals. RESULTS: We found that certain malformations such as Morbus Hirschsprung and diaphragmatic defects are more likely to be associated with particular gene defects (PIGV, PGAP3, PIGN). However, especially at the severe end of the clinical spectrum of HPMRS, there is a high phenotypic overlap with MCAHS. Elevation of AP has also been documented in some of the individuals with MCAHS, namely those with PIGA mutations. Although the impairment of GPI-linked substrates is supposed to play the key role in the pathophysiology of GPIBDs, we could not observe gene-specific profiles for flow cytometric markers or a correlation between their cell surface levels and the severity of the phenotype. In contrast, it was facial recognition software that achieved the highest accuracy in predicting the disease-causing gene in a GPIBD. CONCLUSIONS: Due to the overlap
Published: 2018

24. 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

25. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders

Author: Wolff, M. (Markus), Johannesen, K.M. (Katrine M.), Hedrich, U.B.S. (Ulrike B. S.), Masnada, S. (Silvia), Rubboli, G. (Guido), Gardella, E. (Elena), Lesca, G. (Gaetan), Ville, D. (Dorothée), Milh, M. (Mathieu), Villard, L. (Laurent), Afenjar, A. (Alexandra), Chantot-Bastaraud, S. (Sandra), Mignot, A., Lardennois, C. (Caroline), Nava, C. (Caroline), Schwarz, N. (Niklas), Gérard, M. (Marion), Perrin, L. (Laurence), Doummar, D. (Diane), Auvin, S. (Stéphane), Miranda, M.J. (Maria J.), Hempel, M. (Maja), Brilstra, E. (Eva), Knoers, N.V.A.M. (Nine), Verbeek, N.E. (Nienke), Kempen, M.J.A. (M. J A) van, Braun, K.P. (Kees P.), Mancini, G.M.S. (Grazia), Biskup, S. (Saskia), Hörtnagel, K. (Konstanze), Döcker, M. (Miriam), Bast, T. (Thomas), Loddenkemper, T. (Tobias), Wong-Kisiel, L. (Lily), Baumeister, F.M. (Friedrich M.), Fazeli, W. (Walid), Striano, P. (Pasquale), Dilena, R. (Robertino), Fontana, E. (Elena), Zara, F. (Federico), Kurlemann, G. (Gerhard), Klepper, J. (Joerg), Thoene, J.G. (Jess G.), Arndt, D.H. (Daniel H.), Deconinck, N. (Nicolas), Schmitt-Mechelke, T. (Thomas), Maier, O. (Oliver), Muhle, H. (Hiltrud), Wical, B. (Beverly), Finetti, C. (Claudio), Brückner, R. (Reinhard), Pietz, J. (Joachim), Golla, G. (Günther), Jillella, D. (Dinesh), Linnet, K.M. (Karen M.), Charles, P. (Perrine), Moog, U. (Ute), Õiglane-Shlik, E. (Eve), Mantovani, J.F. (John F.), Park, K. (Kristen), Deprez, M. (Marie), Lederer, D. (Damien), Mary, S. (Sandrine), Scalais, E. (Emmanuel), Selim, L. (Laila), Coster, R.N.A. (R. N A) van, Lagae, L. (Lieven), Nikanorova, M. (Marina), Hjalgrim, H. (Helle), Korenke, G.C. (Christoph), Trivisano, M. (Marina), Specchio, N. (Nicola), Ceulemans, B. (Berten), Dorn, T. (Thomas), Helbig, K.L. (Katherine L.), Hardies, K. (K.), Stamberger, H. (Hannah), Jonghe, P. (P.) de, Weckhuysen, S. (Sarah), Lemke, J.R. (Johannes R.), Krägeloh-Mann, I. (Ingeborg), Helbig, I. (Ingo), Kluger, G. (Gerhard), Lerche, H. (Holger), Møller, R.S. (Rikke), Wolff, M. (Markus), Johannesen, K.M. (Katrine M.), Hedrich, U.B.S. (Ulrike B. S.), Masnada, S. (Silvia), Rubboli, G. (Guido), Gardella, E. (Elena), Lesca, G. (Gaetan), Ville, D. (Dorothée), Milh, M. (Mathieu), Villard, L. (Laurent), Afenjar, A. (Alexandra), Chantot-Bastaraud, S. (Sandra), Mignot, A., Lardennois, C. (Caroline), Nava, C. (Caroline), Schwarz, N. (Niklas), Gérard, M. (Marion), Perrin, L. (Laurence), Doummar, D. (Diane), Auvin, S. (Stéphane), Miranda, M.J. (Maria J.), Hempel, M. (Maja), Brilstra, E. (Eva), Knoers, N.V.A.M. (Nine), Verbeek, N.E. (Nienke), Kempen, M.J.A. (M. J A) van, Braun, K.P. (Kees P.), Mancini, G.M.S. (Grazia), Biskup, S. (Saskia), Hörtnagel, K. (Konstanze), Döcker, M. (Miriam), Bast, T. (Thomas), Loddenkemper, T. (Tobias), Wong-Kisiel, L. (Lily), Baumeister, F.M. (Friedrich M.), Fazeli, W. (Walid), Striano, P. (Pasquale), Dilena, R. (Robertino), Fontana, E. (Elena), Zara, F. (Federico), Kurlemann, G. (Gerhard), Klepper, J. (Joerg), Thoene, J.G. (Jess G.), Arndt, D.H. (Daniel H.), Deconinck, N. (Nicolas), Schmitt-Mechelke, T. (Thomas), Maier, O. (Oliver), Muhle, H. (Hiltrud), Wical, B. (Beverly), Finetti, C. (Claudio), Brückner, R. (Reinhard), Pietz, J. (Joachim), Golla, G. (Günther), Jillella, D. (Dinesh), Linnet, K.M. (Karen M.), Charles, P. (Perrine), Moog, U. (Ute), Õiglane-Shlik, E. (Eve), Mantovani, J.F. (John F.), Park, K. (Kristen), Deprez, M. (Marie), Lederer, D. (Damien), Mary, S. (Sandrine), Scalais, E. (Emmanuel), Selim, L. (Laila), Coster, R.N.A. (R. N A) van, Lagae, L. (Lieven), Nikanorova, M. (Marina), Hjalgrim, H. (Helle), Korenke, G.C. (Christoph), Trivisano, M. (Marina), Specchio, N. (Nicola), Ceulemans, B. (Berten), Dorn, T. (Thomas), Helbig, K.L. (Katherine L.), Hardies, K. (K.), Stamberger, H. (Hannah), Jonghe, P. (P.) de, Weckhuysen, S. (Sarah), Lemke, J.R. (Johannes R.), Krägeloh-Mann, I. (Ingeborg), Helbig, I. (Ingo), Kluger, G. (Gerhard), Lerche, H. (Holger), and Møller, R.S. (Rikke)
Abstract: Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatme
Published: 2017
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26. DNM1 encephalopathy

Author: Von Spiczak, S, Helbig, KL, Shinde, DN, Huether, R, Pendziwiat, M, Lourenço, C, Nunes, ME, Sarco, DP, Kaplan, RA, Dlugos, DJ, Kirsch, H, Slavotinek, A, Cilio, MR, Cervenka, MC, Cohen, JS, McClellan, R, Fatemi, A, Yuen, A, Sagawa, Y, Littlejohn, R, McLean, SD, Hernandez-Hernandez, L, Maher, B, Møller, RS, Palmer, E, Lawson, JA, Campbell, CA, Joshi, CN, Kolbe, DL, Hollingsworth, G, Neubauer, BA, Muhle, H, Stephani, U, Scheffer, IE, Pena, SDJ, Sisodiya, SM, Helbig, I, Von Spiczak, S, Helbig, KL, Shinde, DN, Huether, R, Pendziwiat, M, Lourenço, C, Nunes, ME, Sarco, DP, Kaplan, RA, Dlugos, DJ, Kirsch, H, Slavotinek, A, Cilio, MR, Cervenka, MC, Cohen, JS, McClellan, R, Fatemi, A, Yuen, A, Sagawa, Y, Littlejohn, R, McLean, SD, Hernandez-Hernandez, L, Maher, B, Møller, RS, Palmer, E, Lawson, JA, Campbell, CA, Joshi, CN, Kolbe, DL, Hollingsworth, G, Neubauer, BA, Muhle, H, Stephani, U, Scheffer, IE, Pena, SDJ, Sisodiya, SM, and Helbig, I
Abstract: Objective: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. Methods: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. Results: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. Conclusions: The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.
Published: 2017

27. DNM1 encephalopathy A new disease of vesicle fission

Author: von Spiczak, S, Helbig, KL, Shinde, DN, Huether, R, Pendziwiat, M, Lourenco, C, Nunes, ME, Sarco, DP, Kaplan, RA, Dlugos, DJ, Kirsch, H, Slavotinek, A, Cilio, MR, Cervenka, MC, Cohen, JS, McClellan, R, Fatemi, A, Yuen, A, Sagawa, Y, Littlejohn, R, McLean, SD, Hernandez-Hernandez, L, Maher, B, Moller, RS, Palmer, E, Lawson, JA, Campbell, CA, Joshi, CN, Kolbe, DL, Hollingsworth, G, Neubauer, BA, Muhle, H, Stephani, U, Scheffer, IE, Pena, SDJ, Sisodiya, SM, Helbig, I, von Spiczak, S, Helbig, KL, Shinde, DN, Huether, R, Pendziwiat, M, Lourenco, C, Nunes, ME, Sarco, DP, Kaplan, RA, Dlugos, DJ, Kirsch, H, Slavotinek, A, Cilio, MR, Cervenka, MC, Cohen, JS, McClellan, R, Fatemi, A, Yuen, A, Sagawa, Y, Littlejohn, R, McLean, SD, Hernandez-Hernandez, L, Maher, B, Moller, RS, Palmer, E, Lawson, JA, Campbell, CA, Joshi, CN, Kolbe, DL, Hollingsworth, G, Neubauer, BA, Muhle, H, Stephani, U, Scheffer, IE, Pena, SDJ, Sisodiya, SM, and Helbig, I
Abstract: OBJECTIVE: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. METHODS: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. RESULTS: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. CONCLUSIONS: The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.
Published: 2017

28. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes

Author: Lal, D., Reinthaler, E. M., Dejanovic, B., May, P., Thiele, H., Lehesjoki, A. . E., Schwarz, G., Riesch, E., Ikram, M. A., Van Duijn, C. M., Uitterlinden, A. G., Hofman, A., Steinböck, H., Gruber sedlmayr, U., Neophytou, B., Zara, F., Hahn, A., Gormley, P., Becker, F., Weber, Y. G., Cilio, M. R., Kunz, W. S., Krause, R., Zimprich, F., Lemke, J. R., Nürnberg, P., Sander, T., Lerche, H., Neubauer, B. A., Palotie, A., Ruppert, A. K., Suls, A., Siren, A., Koeleman, B., Haberlandt, E., Ronen, G. M., Caglayan, H., Hjalgrim, H., Muhle, H., Schulz, H., Helbig, I., Altmüller, J., Geldner, J., Schubert, J., Jabbari, K., Everett, K., Feucht, M., Balestri, M., Nothnagel, M., Striano, Pasquale, Møller, R. S., Nabbout, R., Balling, R., Baulac, S., Bianchi, A., La Neve, A., Minetti, Carlo, Giuseppe, C., Neuroscience Center, Research Programs Unit, Anna-Elina Lehesjoki / Principal Investigator, Research Programme for Molecular Neurology, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], and Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center]
Subjects: 0301 basic medicine, Male, Genetics and Molecular Biology (all), FEBRILE SEIZURES PLUS, Disease, Pathogenesis, Bioinformatics, Pathology and Laboratory Medicine, Biochemistry, Epilepsy, Database and Informatics Methods, 0302 clinical medicine, Risk Factors, Medicine and Health Sciences, Medicine, SCN1A, Myoclonic Seizures, NEURONAL SODIUM-CHANNEL, MUTATION, Multidisciplinary, SEVERE MYOCLONIC EPILEPSY, Research Support, Non-U.S. Gov't, Medicine (all), Syndrome, Clinical Trial, 3. Good health, PREVALENCE, Multicenter Study, Neurology, Cohort, Female, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Sequence Analysis, DRAVET SYNDROME, Research Article, Science, Mutation, Missense, Amino Acid Substitution, Case-Control Studies, Humans, NAV1.1 Voltage-Gated Sodium Channel, Agricultural and Biological Sciences (all), Biochemistry, Genetics and Molecular Biology (all), GENERALIZED EPILEPSY, Sequence Databases, Research and Analysis Methods, ITALIAN PATIENTS, 03 medical and health sciences, Dravet syndrome, Journal Article, Genetics, HEMIPLEGIC MIGRAINE, Tonic-Clonic Seizures, Generalized epilepsy, Molecular Biology Techniques, Sequencing Techniques, Molecular Biology, business.industry, Case-control study, 3112 Neurosciences, Biology and Life Sciences, Human Genetics, Epileptic Seizures, medicine.disease, GENE, Human genetics, 030104 developmental biology, Biological Databases, Epilepsy syndromes, Mutation Databases, Genetics of Disease, 3111 Biomedicine, Missense, business, 030217 neurology & neurosurgery
Abstract: A. Palotie on työryhmän jäsen. Objective The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p. T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10(-4); OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.
Published: 2016

29. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy

Author: Mignot, C., von Stulpnage, C., Nava, C., Ville, D., Sanlaville, D., Lesca, G., Rastetter, A., Gachet, B., Marie, Y., Korenke, G. C., Borggraefe, I., Hoffmann-Zacharska, D., Szczepanik, E., Rudzka-Dybala, M., Uluc, Yis, Caglayan, H., Isapof, A., Marey, I., Panagiotakaki, E., Korff, C., Rossier, E., Riess, A., Beck-Woedl, S., Rauch, A., Zweier, C., Hoyer, J., Reis, A., Mironov, M., Bobylova, M., Mukhin, K., Hernandez-Hernandez, L., Maher, B., Sisodiya, S., Kuhn, M., Glaeser, D., Wechuysen, S., Myers, C. T., Mefford, H. C., Hortnagel, K., Biskup, S., Lemke, J. R., Heron, D., Kluger, G., Depienne, C., Craiu, D., De Jonghe, P., Helbig, I., Guerrini, R., Lehesjoki, A. -E., Marini, C., Muhle, H., Moller, R. S., Neubauer, B., Pal, D., Selmer, K., Stephani, U., Sterbova, K., Striano, P., Talvik, T., von Spiczak, S., Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie Pédiatrique [CHU Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, Université de Lyon, Klinikum Oldenburg [Oldenburg], Zentrum für Kinder- und Jugendmedizin, Dpt of Pediatric Neurology and Developmental Medicine and Epilepsy Center [Munich], University of Munich, Department of Medical Genetics, Institute of Mother and Child, Division of Child Neurology, Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Dpt of Molecular Biology and Genetics Istanbul, Boǧaziçi üniversitesi = Boğaziçi University [Istanbul], Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hôpital Femme Mère Enfant, Dpt de l'Enfant et de l'Adolescent, Neuropédiatrie [Genève], Hôpitaux Universitaires de Genève (HUG), Institute of Human Genetics [Tuebingen], University of Tuebingen, Institute of Medical Genetics and Applied Genomics [Tübingen], University of Tübingen, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Svt. Luka's Institute of Child Neurology and Epilepsy, Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Genetikum, Neurogenetics Group, Division of Genetic Medicine [Seattle], University of Washington [Seattle], CeGaT GmbH, Institut für Humangenetik, Universität Heidelberg [Heidelberg], Mignot, Cyril, von Stülpnagel, Celina, Korff, Christian, EuroEPINOMICS-RES MAE Working Grp, HAL-UPMC, Gestionnaire, Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Lyon-Est (GHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Boğaziçi University [Istanbul], CHU Trousseau [APHP], and Universität Heidelberg [Heidelberg] = Heidelberg University
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, Encephalopathy, Myoclonic Jerk, SYNGAP1, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, fluids and secretions, Medizinische Fakultät, Intellectual disability, mental disorders, Genetics, medicine, ddc:610, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Exome, Genetics (clinical), reproductive and urinary physiology, ddc:618, business.industry, medicine.disease, Hypotonia, 3. Good health, 030104 developmental biology, Autism, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Mae Euroepinomics-Res Mae; International audience; Objective We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype–phenotype correlations.Methods We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed.Results We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3′ and 5′ exons. Seizures in patients with mutations in exons 4–5 were more pharmacoresponsive than in patients with mutations in exons 8–15.Conclusions SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.
Published: 2016

30. Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline

Author: Hardies, K, Cai, Y, Jardel, C, Jansen, Ac, Cao, M, May, P, Djémié, T, Hachon Le Camus, C, Keymolen, K, Deconinck, T, Bhambhani, V, Long, C, Sajan, Sa, Helbig, Kl, Suls, A, Balling, R, Helbig, I, De Jonghe, P, Depienne, C, De Camilli, P, Weckhuysen, S, Afawi, Z, Baulac, S, Barisic, N, Caglayan, H, Craiu, D, De Kovel CG, Lopez, Rg, Guerrini, R, Hjalgrim, H, Lerche, H, Jahn, J, Klein, Km, Koeleman, Bc, Leguern, E, Lemke, J, Marini, C, Muhle, H, Rosenow, F, Serratosa, Jm, Štěrbová, Ks, Møller, Rs, Palotie, A, Striano, P, Weber, Y, Zara, F., Mental Health and Wellbeing research group, Public Health Sciences, Neurogenetics, Clinical sciences, AR Working Grp, and EuroEPINOMICS RES Consortium
Subjects: Male, 0301 basic medicine, Drug Resistant Epilepsy, medicine.medical_specialty, Phosphatase, Nerve Tissue Proteins, Biology, Compound heterozygosity, SYNJ1, Cohort Studies, Consanguinity, 03 medical and health sciences, Epilepsy, Arts and Humanities (miscellaneous), SYNJ1 dual phosphatase activity, Polyphosphoinositide Phosphatase, Internal medicine, early onset epilepsy, medicine, Journal Article, Humans, Missense mutation, Exome, Age of Onset, Child, neurodegenerative disorder, recessive disorder, Medicine (all), Neurology (clinical), Exome sequencing, Synaptic vesicle endocytosis, Genetics, Neurodegenerative Diseases, Heterozygote advantage, Original Articles, Neurodegenerative disorder, medicine.disease, Phosphoric Monoester Hydrolases, Pedigree, Phenotype, 030104 developmental biology, Endocrinology, Child, Preschool, Female, Human medicine
Abstract: SYNJ1 encodes a polyphosphoinositide phosphatase (Synaptojanin 1) with a prominent role in synaptic vesicle dynamics. Hardies et al. report three families (six patients) with autosomal recessive SYNJ1 variants, who display early-onset refractory seizures and progressive neurological decline. The pathogenic variants entail loss of the dual phosphatase activity of Synaptojanin 1.SYNJ1 encodes a polyphosphoinositide phosphatase (Synaptojanin 1) with a prominent role in synaptic vesicle dynamics. Hardies et al. report three families (six patients) with autosomal recessive SYNJ1 variants, who display early-onset refractory seizures and progressive neurological decline. The pathogenic variants entail loss of the dual phosphatase activity of Synaptojanin 1.SYNJ1 encodes a polyphosphoinositide phosphatase, synaptojanin 1, which contains two consecutive phosphatase domains and plays a prominent role in synaptic vesicle dynamics. Autosomal recessive inherited variants in SYNJ1 have previously been associated with two different neurological diseases: a recurrent homozygous missense variant (p.Arg258Gln) that abolishes Sac1 phosphatase activity was identified in three independent families with early onset parkinsonism, whereas a homozygous nonsense variant (p.Arg136*) causing a severe decrease of mRNA transcript was found in a single patient with intractable epilepsy and tau pathology. We performed whole exome or genome sequencing in three independent sib pairs with early onset refractory seizures and progressive neurological decline, and identified novel segregating recessive SYNJ1 defects. A homozygous missense variant resulting in an amino acid substitution (p.Tyr888Cys) was found to impair, but not abolish, the dual phosphatase activity of SYNJ1, whereas three premature stop variants (homozygote p.Trp843* and compound heterozygote p.Gln647Argfs*6/p.Ser1122Thrfs*3) almost completely abolished mRNA transcript production. A genetic follow-up screening in a large cohort of 543 patients with a wide phenotypical range of epilepsies and intellectual disability revealed no additional pathogenic variants, showing that SYNJ1 deficiency is rare and probably linked to a specific phenotype. While variants leading to early onset parkinsonism selectively abolish Sac1 function, our results provide evidence that a critical reduction of the dual phosphatase activity of SYNJ1 underlies a severe disorder with neonatal refractory epilepsy and a neurodegenerative disease course. These findings further expand the clinical spectrum of synaptic dysregulation in patients with severe epilepsy, and emphasize the importance of this biological pathway in seizure pathophysiology.
Published: 2016

31. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia

Author: Hardies, K., De Kovel, C. G. F., Weckhuysen, S., Asselbergh, B., Geuens, T., Deconinck, T., Azmi, A., May, P., Brilstra, E., Becker, F., Barisic, N., Craiu, D., Braun, K. P. J., Lal, D., Thiele, H., Schubert, J., Weber, Y., Van 'T Slot, R., Nurnberg, P., Balling, R., Timmerman, V., Lerche, H., Maudsley, S., Helbig, I., Suls, A., Koeleman, B. P. C., De Jonghe, P., Afawi, Z., Baulac, S., Caglayan, H., Lopez, R. G., Guerrini, R., Hjalgrim, H., Jahn, J., Klein, K. M., Leguern, E., Lemke, J., Marini, C., Muhle, H., Rosenow, F., Serratosa, J., Sterbova, K., Moller, R. S., Striano, P., Zara, F., and EuroEPINOMICS RES Consortium
Subjects: Male, medicine.medical_specialty, Adolescent, anaplerosis, epileptic encephalopathy, NaCT, recessive disorder, SLC13A5, teeth hypoplasia, medicine.medical_treatment, Developmental Disabilities, Mutant, Genes, Recessive, Biology, medicine.disease_cause, Citric Acid, Epilepsy, Internal medicine, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Child, Gene, Anodontia, Genetics, Mutation, Brain Diseases, Symporters, Citrate transport, medicine.disease, Hypoplasia, Pedigree, Endocrinology, HEK293 Cells, Epilepsy syndromes, Female, Neurology (clinical), Human medicine, Ketogenic diet
Abstract: The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry a heterozygous de novo mutation in one of the genes associated with the disease entity. Occasionally recessive mutations are identified: a recent publication described a distinct neonatal epileptic encephalopathy (MIM 615905) caused by autosomal recessive mutations in the SLC13A5 gene. Here, we report eight additional patients belonging to four different families with autosomal recessive mutations in SLC13A5. SLC13A5 encodes a high affinity sodium-dependent citrate transporter, which is expressed in the brain. Neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates; therefore they rely on the uptake of intermediates, such as citrate, to maintain their energy status and neurotransmitter production. The effect of all seven identified mutations (two premature stops and five amino acid substitutions) was studied in vitro, using immunocytochemistry, selective western blot and mass spectrometry. We hereby demonstrate that cells expressing mutant sodium-dependent citrate transporter have a complete loss of citrate uptake due to various cellular loss-of-function mechanisms. In addition, we provide independent proof of the involvement of autosomal recessive SLC13A5 mutations in the development of neonatal epileptic encephalopathies, and highlight teeth hypoplasia as a possible indicator for SLC13A5 screening. All three patients who tried the ketogenic diet responded well to this treatment, and future studies will allow us to ascertain whether this is a recurrent feature in this severe disorder.
Published: 2015

32. The Phenotypic Spectrum Associated with Gabrb3 Mutations:From Febrile Seizures to Severe Epileptic Encephalopathies

Author: Moller, R. S., Nikanorova, M., Brilstra, E. H., Vaher, U., Talvik, I., Talvik, T., Kluger, G., Lemke, J. R., Myers, C., Larsen, L. H. G., Pendziwiat, M., Mang, Y., van Gassen, K. L., Dahl, H. A., Rubboli, G., Tommerup, N., Helbig, I., Mefford, H. C., and Muhle, H.
Published: 2015

33. Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures

Author: Carvill, Gl, Mcmahon, Jm, Schneider, Andrea, Zemel, M, Myers, Ct, Saykally, J, Nguyen, J, Robbiano, A, Zara, F, Specchio, N, Mecarelli, O, Smith, Rl, Leventer, Rj, Møller, Rs, Nikanorova, M, Dimova, P, Jordanova, A, Petrou, S, Helbig, I, Striano, P, Weckhuysen, S, Berkovic, Sf, Scheffer, Ie, Mefford, Hc, von Spiczak, S, Muhle, H, Caglayan, H, Sterbova, K, Craiu, D, Hoffman, D, Lehesjoki, Ae, Selmer, K, Depienne, C, Lemke, J, Marini, Carla, Guerrini, Renzo, Neubauer, B, Talvik, T, Suls, A, and Leguern, E.
Subjects: GABA, Transporter SLC6A1, Epilepsy, Myoclonic-Atonic Seizures
Published: 2015

34. Stxbp1:Clinical and Genetic Description of 39 New Patients with an Stxbp1 Mutation and Review of Literature

Author: Stamberger, H., Nikanorova, M., Willemsen, M., Fjaer, R., Ramsey, K., Viri, M., Sterbova, K., Wolf, M., Verhelst, H., Benkel, I., Fannemel, M., Muhle, H., Casara, G., Van Coster, R., Angriman, M., Lederer, D., De Jonghe, P., Striano, P., Lemke, J., Moller, R. S., and Weckhuysen, S.
Published: 2015

35. 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

36. Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes

Author: Lal, D. (Dennis), Reinthaler, E.M. (Eva M.), Dejanovic, B. (Borislav), May, P. (Patrick), Thiele, H. (Holger), Lehesjoki, A.E., Schwarz, G. (Günter), Riesch, E. (Erik), Ikram, M.A. (Arfan), Duijn, C.M. (Cornelia) van, Uitterlinden, A.G. (André), Hofman, A. (Albert), Steinböck, H. (Hannelore), Gruber-Sedlmayr, U. (Ursula), Neophytou, B. (Birgit), Zara, F. (Federico), Hahn, A. (Andreas), Gormley, A.M., Becker, F. (Felicitas), Weber, Y.G. (Yvonne G.), Cilio, M.R. (Maria Roberta), Kunz, W.S. (Wolfram S.), Krause, R. (Roland), Zimprich, F. (Fritz), Lemke, J.R. (Johannes R.), Nürnberg, P. (Peter), Sander, T. (Thomas), Lerche, H. (Holger), Neubauer, B.A. (Bernd A.), Palotie, A. (Aarno), Ruppert, A.-K. (Ann-Kathrin), Suls, A. (A.), Siren, A. (Auli), Koeleman, B.P.C. (Bobby), Haberlandt, E. (Edda), Ronen, G.M. (Gabriel M.), Caglayan, H. (Hande), Hjalgrim, H. (Helle), Muhle, H. (Hiltrud), Schulz, H. (Herbert), Helbig, I. (Ingo), Altmüller, J. (Janine), Geldner, J. (Julia), Schubert, J. (Julian), Jabbari, K. (Kamel), Everett, K. (Kate), Feucht, M. (Martha), Balestri, M. (Martina), Nothnagel, M. (Michael), Striano, P. (Pasquale), Møller, R.S. (Rikke), Nabbout, R. (Rima), Balling, R. (Rudi), Baulac, S. (Stephanie), Kunz, W. (Wolfram), Bianchi, A. (Amedeo), La Neve, A. (Angela), Minetti, C., Giuseppe, C. (Capovilla), Lal, D. (Dennis), Reinthaler, E.M. (Eva M.), Dejanovic, B. (Borislav), May, P. (Patrick), Thiele, H. (Holger), Lehesjoki, A.E., Schwarz, G. (Günter), Riesch, E. (Erik), Ikram, M.A. (Arfan), Duijn, C.M. (Cornelia) van, Uitterlinden, A.G. (André), Hofman, A. (Albert), Steinböck, H. (Hannelore), Gruber-Sedlmayr, U. (Ursula), Neophytou, B. (Birgit), Zara, F. (Federico), Hahn, A. (Andreas), Gormley, A.M., Becker, F. (Felicitas), Weber, Y.G. (Yvonne G.), Cilio, M.R. (Maria Roberta), Kunz, W.S. (Wolfram S.), Krause, R. (Roland), Zimprich, F. (Fritz), Lemke, J.R. (Johannes R.), Nürnberg, P. (Peter), Sander, T. (Thomas), Lerche, H. (Holger), Neubauer, B.A. (Bernd A.), Palotie, A. (Aarno), Ruppert, A.-K. (Ann-Kathrin), Suls, A. (A.), Siren, A. (Auli), Koeleman, B.P.C. (Bobby), Haberlandt, E. (Edda), Ronen, G.M. (Gabriel M.), Caglayan, H. (Hande), Hjalgrim, H. (Helle), Muhle, H. (Hiltrud), Schulz, H. (Herbert), Helbig, I. (Ingo), Altmüller, J. (Janine), Geldner, J. (Julia), Schubert, J. (Julian), Jabbari, K. (Kamel), Everett, K. (Kate), Feucht, M. (Martha), Balestri, M. (Martina), Nothnagel, M. (Michael), Striano, P. (Pasquale), Møller, R.S. (Rikke), Nabbout, R. (Rima), Balling, R. (Rudi), Baulac, S. (Stephanie), Kunz, W. (Wolfram), Bianchi, A. (Amedeo), La Neve, A. (Angela), Minetti, C., and Giuseppe, C. (Capovilla)
Abstract: Objective: The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods: We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation: We identified 8 known missense mutations, previously reported as patho
Published: 2016
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37. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy

Author: Stamberger, H., Nikanorova, M., Willemsen, M.H., Accorsi, P., Angriman, M., Baier, H., Benkel-Herrenbrueck, I., Benoit, V., Budetta, M., Caliebe, A., Cantalupo, G., Capovilla, G., Casara, G., Courage, C., Deprez, M., Destree, A., Dilena, R., Erasmus, C.E., Fannemel, M., Fjaer, R., Giordano, L., Helbig, K.L., Heyne, H.O., Klepper, J., Kluger, G.J., Lederer, D., Lodi, M., Maier, O., Merkenschlager, A., Michelberger, N., Minetti, C., Muhle, H., Phalin, J., Ramsey, K., Romeo, A., Schallner, J., Schanze, I., Shinawi, M., Sleegers, K., Sterbova, K., Syrbe, S., Traverso, M., Tzschach, A., Uldall, P., Coster, R. van, Verhelst, H., Viri, M., Winter, S., Wolff, M., Zenker, M., Zoccante, L., Jonghe, P. De, Helbig, I., Striano, P., Lemke, J.R., Moller, R.S., Weckhuysen, S., Stamberger, H., Nikanorova, M., Willemsen, M.H., Accorsi, P., Angriman, M., Baier, H., Benkel-Herrenbrueck, I., Benoit, V., Budetta, M., Caliebe, A., Cantalupo, G., Capovilla, G., Casara, G., Courage, C., Deprez, M., Destree, A., Dilena, R., Erasmus, C.E., Fannemel, M., Fjaer, R., Giordano, L., Helbig, K.L., Heyne, H.O., Klepper, J., Kluger, G.J., Lederer, D., Lodi, M., Maier, O., Merkenschlager, A., Michelberger, N., Minetti, C., Muhle, H., Phalin, J., Ramsey, K., Romeo, A., Schallner, J., Schanze, I., Shinawi, M., Sleegers, K., Sterbova, K., Syrbe, S., Traverso, M., Tzschach, A., Uldall, P., Coster, R. van, Verhelst, H., Viri, M., Winter, S., Wolff, M., Zenker, M., Zoccante, L., Jonghe, P. De, Helbig, I., Striano, P., Lemke, J.R., Moller, R.S., and Weckhuysen, S.
Abstract: Contains fulltext : 168130.pdf (publisher's version ) (Closed access), OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. CONCLUSION: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.
Published: 2016

38. Pitfalls in genetic testing: the story of missed SCN1A mutations

Author: Djemie, T, Weckhuysen, S, von Spiczak, S, Carvill, GL, Jaehn, J, Anttonen, A-K, Brilstra, E, Caglayan, HS, de Kovel, CG, Depienne, C, Gaily, E, Hamalainen, E, Giraldez, BG, Gormley, P, Guerrero-Lopez, R, Guerrini, R, Hartmann, C, Hernandez-Hernandez, L, Hjalgrim, H, Koeleman, BPC, Leguern, E, Lehesjoki, A-E, Lemke, JR, Leu, C, Marini, C, McMahon, JM, Mei, D, Moller, RS, Muhle, H, Myers, CT, Nava, C, Serratosa, JM, Sisodiya, SM, Stephani, U, Striano, P, van Kempen, MJA, Verbeek, NE, Usluer, S, Zara, F, Palotie, A, Mefford, HC, Scheffer, IE, De Jonghe, P, Helbig, I, Suls, A, Djemie, T, Weckhuysen, S, von Spiczak, S, Carvill, GL, Jaehn, J, Anttonen, A-K, Brilstra, E, Caglayan, HS, de Kovel, CG, Depienne, C, Gaily, E, Hamalainen, E, Giraldez, BG, Gormley, P, Guerrero-Lopez, R, Guerrini, R, Hartmann, C, Hernandez-Hernandez, L, Hjalgrim, H, Koeleman, BPC, Leguern, E, Lehesjoki, A-E, Lemke, JR, Leu, C, Marini, C, McMahon, JM, Mei, D, Moller, RS, Muhle, H, Myers, CT, Nava, C, Serratosa, JM, Sisodiya, SM, Stephani, U, Striano, P, van Kempen, MJA, Verbeek, NE, Usluer, S, Zara, F, Palotie, A, Mefford, HC, Scheffer, IE, De Jonghe, P, Helbig, I, and Suls, A
Abstract: BACKGROUND: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations. METHODS: We sent out a survey to 16 genetic centers performing SCN1A testing. RESULTS: We collected data on 28 mutations initially missed using Sanger sequencing. All patients were falsely reported as SCN1A mutation-negative, both due to technical limitations and human errors. CONCLUSION: We illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A mutations are an even more frequent cause of DS than already anticipated.
Published: 2016

39. MODELING OF FEVER-ASSOCIATED EPILEPSY SYNDROMES CAUSED BY MUTATIONS IN STX1B IN ZEBRAFISH

Author: Siekierska, A., Schubert, J., Langlois, M., May, P., Huneau, C., Becker, F., Muhle, H., Suls, A., Lemke, J. R., De Kovel, C. G. F., Thiele, H., Kecskes, A., Jacmin, M., Koeleman, B., Martin, B., de Witte, P. A. M., Biskup, S., De Jonghe, P., Helbig, I., Balling, R., Nuernberg, P., Crawford, A. D., Weber, Y. G., Lerche, H., Esguerra, C. V., Siekierska, A., Schubert, J., Langlois, M., May, P., Huneau, C., Becker, F., Muhle, H., Suls, A., Lemke, J. R., De Kovel, C. G. F., Thiele, H., Kecskes, A., Jacmin, M., Koeleman, B., Martin, B., de Witte, P. A. M., Biskup, S., De Jonghe, P., Helbig, I., Balling, R., Nuernberg, P., Crawford, A. D., Weber, Y. G., Lerche, H., and Esguerra, C. V.
Published: 2015

40. CHD2 variants are a risk factor for photosensitivity in epilepsy

Author: Galizia, EC, Myers, CT, Leu, C, de Kovel, CGF, Afrikanova, T, Cordero-Maldonado, ML, Martins, TG, Jacmin, M, Drury, S, Chinthapalli, VK, Muhle, H, Pendziwiat, M, Sander, T, Ruppert, A-K, Moller, RS, Thiele, H, Krause, R, Schubert, J, Lehesjoki, A-E, Nuernberg, P, Lerche, H, Palotie, A, Coppola, A, Striano, S, Del Gaudio, L, Boustred, C, Schneider, AL, Lench, N, Jocic-Jakubi, B, Covanis, A, Capovilla, G, Veggiotti, P, Piccioli, M, Parisi, P, Cantonetti, L, Sadleir, LG, Mullen, SA, Berkovic, SF, Stephani, U, Helbig, I, Crawford, AD, Esguerra, CV, Trenite, DGAK-N, Koeleman, BPC, Mefford, HC, Scheffer, IE, Sisodiya, SM, Galizia, EC, Myers, CT, Leu, C, de Kovel, CGF, Afrikanova, T, Cordero-Maldonado, ML, Martins, TG, Jacmin, M, Drury, S, Chinthapalli, VK, Muhle, H, Pendziwiat, M, Sander, T, Ruppert, A-K, Moller, RS, Thiele, H, Krause, R, Schubert, J, Lehesjoki, A-E, Nuernberg, P, Lerche, H, Palotie, A, Coppola, A, Striano, S, Del Gaudio, L, Boustred, C, Schneider, AL, Lench, N, Jocic-Jakubi, B, Covanis, A, Capovilla, G, Veggiotti, P, Piccioli, M, Parisi, P, Cantonetti, L, Sadleir, LG, Mullen, SA, Berkovic, SF, Stephani, U, Helbig, I, Crawford, AD, Esguerra, CV, Trenite, DGAK-N, Koeleman, BPC, Mefford, HC, Scheffer, IE, and Sisodiya, SM
Abstract: Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into hum
Published: 2015

41. Chronische Neuroborreliose als Ursache bilateraler Basalganglieninfarkte bei 16-jähriger Patientin mit unspezifischen neurologischen und psychischen Symptomen

Author: Albers, J, Muhle, H, van Baalen, A, Ostertag, P, Rohr, A, and Stephani, U
Subjects: ddc: 610, 610 Medical sciences, Medicine
Abstract: Hintergrund: Die chronische Neuroborreliose ist eine seltene Komplikation der Lyme-Borreliose mit vielfältiger Symptomatik, ihre möglichst frühzeitige Erkennung ist entscheidend für den weiteren Krankheitsverlauf. Methodik: Beschreibung des klinischen Verlauf einer Patientin [for full text, please go to the a.m. URL], 61. Jahrestagung der Norddeutschen Gesellschaft für Kinder- und Jugendmedizin (NDGKJ)
Published: 2012
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42. 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

43. Research recommendations for selected IARC-classified agents

Author: Ward, E.M., Schulte, P.A., Straif, K., Hopf, Nancy B., Caldwell, J.C., Carreón, T., DeMarini, D.M., Fowler, B.A., Goldstein, B.D., Hemminki, K., Hines, C.J., Pursiainen, K.H., Kuempel, E., Lewtas, J., Lunn, R.M., Lynge, E., McElvenny, D.M., Muhle, H., Nakajima, T., Robertson, L.W., Rothman, N., Ruder, A.M., Schubauer-Berigan, M.K., Siemiatycki, J., Silverman, D., Smith, M.T., Sorahan, T., Steenland, K., Stevens, R.G., Vineis, P., Zahm, S.H., Zeise, L., and Cogliano, V.J.
Subjects: Animals, Carcinogenicity Tests, Evidence-Based Medicine, Humans
Abstract: OBJECTIVES: There are some common occupational agents and exposure circumstances where evidence of carcinogenicity is substantial but not yet conclusive for humans. The objectives are to identify research gaps and needs for twenty agents prioritized for review based on evidence of widespread human exposures and potential carcinogenicity in animals or humans. DATA SOURCES: A systematic review was conducted of new data published since the most recent pertinent IARC monograph meeting. DATA EXTRACTION: Reviewers were charged with identifying data gaps and general and specific approaches to address them, focusing on research that would be important in resolving classification uncertainties. An expert meeting brought reviewers together to discuss each agent and the identified data gaps and approaches. DATA SYNTHESIS: Several overarching issues were identified that pertained to multiple agents; these included the importance of recognizing that carcinogenic agents can act through multiple toxicity pathways and mechanisms, including epigenetic mechanisms, oxidative stress and immuno- and hormonal modulation. CONCLUSIONS: Studies in occupational populations provide important opportunities to understand the mechanisms through which exogenous agents cause cancer and intervene to prevent human exposure and/or prevent or detect cancer among those already exposed. Scientific developments are likely to increase the challenges and complexities of carcinogen testing and evaluation in the future, and epidemiologic studies will be particularly critical to inform carcinogen classification and risk assessment processes.[Authors]
Published: 2010

44. Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region

Author: Reutlinger, C., Helbig, I., Gawelczyk, B., Subero, J.I., Tonnies, H., Muhle, H., Finsterwalder, K., Vermeer, S., Pfundt, R., Sperner, J., Stefanova, I., Gillessen-Kaesbach, G., Spiczak, S. von, Baalen, A. van, Boor, R., Siebert, R., Stephani, U., and Caliebe, A.
Subjects: Genomic disorders and inherited multi-system disorders [IGMD 3], nervous system diseases
Abstract: Contains fulltext : 88225.pdf (Publisher’s version ) (Closed access) Seizure disorders of the rolandic region comprise a spectrum of different epilepsy syndromes ranging from benign rolandic epilepsy to more severe seizure disorders including atypical benign partial epilepsy/pseudo-Lennox syndrome,electrical status epilepticus during sleep, and Landau-Kleffner syndrome. Centrotemporal spikes are the unifying electroencephalographic hallmark of these benign focal epilepsies, indicating a pathophysiologic relationship between the various epilepsies arising from the rolandic region. The etiology of these epilepsies is elusive, but a genetic component is assumed given the heritability of the characteristic electrographic trait. Herein we report on three patients with intellectual disability, various dysmorphic features, and epilepsies involving the rolandic region, carrying previously undescribed deletions in 16p13. The only gene located in the critical region shared by all three patients is GRIN2A coding for the alpha-2 subunit of the neuronal N-methyl-D-aspartate(NMDA) receptor. 01 september 2010
Published: 2010

45. 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

46. Identifying and managing the conflicts between agriculture and biodiversity conservation in Europe–A review

Author: Henle, K., Alard, D., Clitherow, J., Cobb, P., Firbank, L. G., Kull, T., Mccracken, D., Moritz, R., Muhle, H., Niemela, J., Nowicki, P., Rebane, M., Wascher, D., Watt, A., Young, J., Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), Biodiversité, Gènes & Communautés (BioGeCo), Institut National de la Recherche Agronomique (INRA)-Université de Bordeaux (UB), Natural England, Farming and Wildlife Advisory Group, Partenaires INRAE, North Wyke Research Station, Institute of Agricultural and Environmental Sciences, Estonian University of Life Sciences (EMU), Scottish Agricultural College, Martin-Luther-University Halle-Wittenberg, University of Helsinki, Wageningen University and Research Centre (WUR), and NERC
Subjects: 0106 biological sciences, restoration, countryside, Biodiversity, CONFLICT RECONCILIATION, INTÉRÊTS PRIVES, 010501 environmental sciences, promoting biodiversity, 010603 evolutionary biology, 01 natural sciences, GESTION DES EXPLOITATIONS AGRICOLES, ABANDONMENT, Landscape Centre, landscapes, DIVERSITÉ BIOLOGIQUE, farmland biodiversity, land-use, media_common.cataloged_instance, Wageningen Environmental Research, MONITORING, European union, 0105 earth and related environmental sciences, media_common, [SDV.EE]Life Sciences [q-bio]/Ecology, environment, 2. Zero hunger, STAKEHOLDERS, agri-environment schemes, Ecology, Land use, AGRICULTURAL POLICIES, business.industry, INTENSIFICATION, Environmental resource management, Alterra - Centrum Landschap, Stakeholder, 15. Life on land, BIODIVERSITY CONSERVATION, 13. Climate action, Agriculture, quality, Scale (social sciences), Conflict management, Animal Science and Zoology, Science policy, AGRICULTURAL LANDSCAPES, business, Agronomy and Crop Science, management, policy
Abstract: International audience; This paper reviews conflicts between biodiversity conservation and agricultural activities in agricultural landscapes and evaluates strategies to reconcile such conflicts. Firstly, a historical perspective on the development of conflicts related to biodiversity in agricultural landscapes is presented. Secondly, recent trends in agricultural policies of the European Union that contribute to biodiversity decline in agricultural landscapes are considered. Three major processes responsible for creating biodiversity-related conflicts are described: the intensification of agriculture, the abandonment of marginally productive but High Nature Value Farmland, and the changing scale of agricultural operations. Conflicts created by these processes and approaches to their reconciliation are identified, emphasizing the need for monitoring as an integral part of conflict reconciliation strategies. A generic approach comprising three types of monitoring is developed for measuring success of reconciliation strategies: monitoring of the intensity of the conflict between stakeholders, of the social and economic effects on farmers, and of the status and trends in biodiversity. Surprisingly, we found no evidence in the literature that the first type of monitoring has ever been undertaken for biodiversity-related conflicts in agricultural landscapes. For each type of monitoring, suitable indicators are outlined. Finally, challenges for conflict management in agricultural landscapes are summarized.
Published: 2008

47. 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

48. Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies.

Author: Mefford, H.C., Muhle, H., Ostertag, P., Spiczak, S. von, Buysse, K., Baker, C., Franke, A., Malafosse, A., Genton, P., Thomas, P., Gurnett, C.A., Schreiber, S., Bassuk, A.G., Guipponi, M., Stephani, U., Helbig, I., Eichler, E.E., Mefford, H.C., Muhle, H., Ostertag, P., Spiczak, S. von, Buysse, K., Baker, C., Franke, A., Malafosse, A., Genton, P., Thomas, P., Gurnett, C.A., Schreiber, S., Bassuk, A.G., Guipponi, M., Stephani, U., Helbig, I., and Eichler, E.E.
Abstract: Contains fulltext : 88500.pdf (publisher's version ) (Open Access), Epilepsy is one of the most common neurological disorders in humans with a prevalence of 1% and a lifetime incidence of 3%. Several genes have been identified in rare autosomal dominant and severe sporadic forms of epilepsy, but the genetic cause is unknown in the vast majority of cases. Copy number variants (CNVs) are known to play an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID), autism, and schizophrenia. Genome-wide studies of copy number variation in epilepsy have not been performed. We have applied whole-genome oligonucleotide array comparative genomic hybridization to a cohort of 517 individuals with various idiopathic, non-lesional epilepsies. We detected one or more rare genic CNVs in 8.9% of affected individuals that are not present in 2,493 controls; five individuals had two rare CNVs. We identified CNVs in genes previously implicated in other neurodevelopmental disorders, including two deletions in AUTS2 and one deletion in CNTNAP2. Therefore, our findings indicate that rare CNVs are likely to contribute to a broad range of generalized and focal epilepsies. In addition, we find that 2.9% of patients carry deletions at 15q11.2, 15q13.3, or 16p13.11, genomic hotspots previously associated with ID, autism, or schizophrenia. In summary, our findings suggest common etiological factors for seemingly diverse diseases such as ID, autism, schizophrenia, and epilepsy.
Published: 2010

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

Author: Neubauer, Bernd A., Waldegger, S., Heinzinger, J., Hahn, A., Kurlemann, G., Fiedler, B., Eberhard, F., Muhle, H., Stephani, U., Garkisch, S., Eeg-Olofsson, Orvar, Müller, U., Sander, T., Neubauer, Bernd A., Waldegger, S., Heinzinger, J., Hahn, A., Kurlemann, G., Fiedler, B., Eberhard, F., Muhle, H., Stephani, U., Garkisch, S., Eeg-Olofsson, Orvar, Müller, U., and Sander, T.
Abstract: OBJECTIVE: To explore the involvement of M-type potassium channels KCNQ2, Q3, and Q5 in the pathogenesis of common idiopathic epilepsies. METHODS: Sequence analysis of the KCNQ2, Q3, and Q5 coding regions was performed in a screening sample consisting of 58 nuclear families with rolandic epilepsy. Subsequently, an association study was conducted for all discovered variants in a case-control sample comprising 459 German patients with idiopathic generalized epilepsy (IGE) and 462 population controls. RESULTS: An in-frame deletion of codon 116 in KCNQ2 (p.Lys116del) and a missense mutation in KCNQ3 (p.Glu299Lys) were detected in two index cases exhibiting rolandic epilepsy and benign neonatal convulsions. Both mutations resulted in reduced potassium current amplitude in Xenopus oocytes. Mutation analysis of families with rolandic epilepsy without neonatal seizures discovered three novel missense variations (KCNQ2 p.Ile592Met, KCNQ3 p.Ala381Val, KCNQ3 p.Pro574Ser). The KCNQ2 p.Ile592Met variant displayed a significant reduction of potassium current amplitude in Xenopus oocytes and was present only once in 552 controls. Both missense variants identified in KCNQ3 (p.Ala381Val and p.Pro574Ser) were present in all affected family members and did not occur in controls, but did not show obvious functional abnormalities. The KCNQ3 missense variant p.Pro574Ser was also detected in 8 of 455 IGE patients but not in 454 controls (p = 0.008). In KCNQ2, a silent single nucleotide polymorphism (rs1801545) was found overrepresented in both epilepsy samples (IGE, p = 0.004). CONCLUSION: Sequence variations of the KCNQ2 and KCNQ3 genes may contribute to the etiology of common idiopathic epilepsy syndromes.
Published: 2008
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50. 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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