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1. Genetische Diagnostik der Epilepsien: Empfehlung der Kommission Epilepsie und Genetik der Deutschen Gesellschaft für Epileptologie (DGfE)

Author: Boßelmann, Christian, Borggräfe, Ingo, Fazeli, Walid, Klein, Karl-Martin, Kluger, Gerhard J., Müller-Schlüter, Karen, Neubauer, Bernd A., von Spiczak, Sarah, Steinbeis von Stülpnagel, Celina, Weber, Yvonne, Lemke, Johannes R., Wolking, Stefan, and Krey, Ilona
Published: 2023
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2. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author: Collaborative, Epi25, Feng, Yen-Chen Anne, Howrigan, Daniel P, Abbott, Liam E, Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L, Dhindsa, Ryan S, Stanley, Kate E, Cavalleri, Gianpiero L, Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M, Cossette, Patrick, Cotsapas, Chris, De Jonghe, Peter, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G, Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J, Scheffer, Ingrid E, Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M, Bellows, Susannah T, Leu, Costin, Bennett, Caitlin A, Johns, Esther MC, Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J, Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M, Sadoway, Tara R, Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S, Kousiappa, Ioanna, Tanteles, George A, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S, Knake, Susanne, Kunz, Wolfram S, Zsurka, Gábor, Elger, Christian E, Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, van Baalen, Andreas, von Spiczak, Sarah, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D, Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R, Krey, Ilona, Weber, Yvonne G, Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F, Steinhoff, Bernhard J, Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, and Schreiber, Herbert
Subjects: Clinical Research, Human Genome, Neurosciences, Epilepsy, Biotechnology, Genetics, Neurodegenerative, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Case-Control Studies, DNA Mutational Analysis, Exome, Genetic Markers, Genetic Predisposition to Disease, Genetic Variation, Humans, Phenotype, Exome Sequencing, Epi25 Collaborative. Electronic address: s.berkovic@unimelb.edu.au, Epi25 Collaborative, burden analysis, epilepsy, epileptic encephalopathy, exome, seizures, sequencing, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.
Published: 2019

3. Health-related quality of life in children and adolescents with tuberous sclerosis complex and their caregivers: A multicentre cohort study from Germany

Author: Willems, Laurent M., Schubert-Bast, Susanne, Grau, Janina, Hertzberg, Christoph, Kurlemann, Gerhard, Wiemer-Kruel, Adelheid, Bast, Thomas, Bertsche, Astrid, Bettendorf, Ulrich, Fiedler, Barbara, Hahn, Andreas, Hartmann, Hans, Hornemann, Frauke, Immisch, Ilka, Jacobs, Julia, Kieslich, Matthias, Klein, Karl Martin, Klotz, Kerstin A., Kluger, Gerhard, Knuf, Markus, Mayer, Thomas, Marquard, Klaus, Meyer, Sascha, Muhle, Hiltrud, Müller-Schlüter, Karen, Noda, Anna H., Ruf, Susanne, Sauter, Matthias, Schlump, Jan-Ulrich, Syrbe, Steffen, Thiels, Charlotte, Trollmann, Regina, Wilken, Bernd, Zöllner, Johann Philipp, Rosenow, Felix, and Strzelczyk, Adam
Published: 2021
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4. Efficacy, Retention and Tolerability of Everolimus in Patients with Tuberous Sclerosis Complex: A Survey-Based Study on Patients’ Perspectives

Author: Willems, Laurent M., Rosenow, Felix, Schubert-Bast, Susanne, Kurlemann, Gerhard, Zöllner, Johann Philipp, Bast, Thomas, Bertsche, Astrid, Bettendorf, Ulrich, Ebrahimi-Fakhari, Daniel, Grau, Janina, Hahn, Andreas, Hartmann, Hans, Hertzberg, Christoph, Hornemann, Frauke, Immisch, Ilka, Jacobs, Julia, Klein, Karl Martin, Klotz, Kerstin A., Kluger, Gerhard, Knake, Susanne, Knuf, Markus, Marquard, Klaus, Mayer, Thomas, Meyer, Sascha, Muhle, Hiltrud, Müller-Schlüter, Karen, von Podewils, Felix, Ruf, Susanne, Sauter, Matthias, Schäfer, Hannah, Schlump, Jan-Ulrich, Syrbe, Steffen, Thiels, Charlotte, Trollmann, Regina, Wiemer-Kruel, Adelheid, Wilken, Bernd, Zukunft, Bianca, and Strzelczyk, Adam
Published: 2021
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5. Direct and indirect costs and cost-driving factors of Tuberous sclerosis complex in children, adolescents, and caregivers: a multicenter cohort study

Author: Grau, Janina, Zöllner, Johann Philipp, Schubert-Bast, Susanne, Kurlemann, Gerhard, Hertzberg, Christoph, Wiemer-Kruel, Adelheid, Bast, Thomas, Bertsche, Astrid, Bettendorf, Ulrich, Fiedler, Barbara, Hahn, Andreas, Hartmann, Hans, Hornemann, Frauke, Immisch, Ilka, Jacobs, Julia, Kieslich, Matthias, Klein, Karl Martin, Klotz, Kerstin A., Kluger, Gerhard, Knuf, Markus, Mayer, Thomas, Marquard, Klaus, Meyer, Sascha, Muhle, Hiltrud, Müller-Schlüter, Karen, Noda, Anna H., Ruf, Susanne, Sauter, Matthias, Schlump, Jan-Ulrich, Syrbe, Steffen, Thiels, Charlotte, Trollmann, Regina, Wilken, Bernd, Willems, Laurent M., Rosenow, Felix, and Strzelczyk, Adam
Published: 2021
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6. Stiripentol fails to lower plasma oxalate in a dialysis-dependent PH1 patient

Author: Kempf, Caroline, Pfau, Anja, Holle, Johannes, Müller-Schlüter, Karen, Bufler, Philip, Knauf, Felix, and Müller, Dominik
Published: 2020
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7. The landscape of epilepsy-related GATOR1 variants

Author: Baldassari, Sara, Picard, Fabienne, Verbeek, Nienke E., van Kempen, Marjan, Brilstra, Eva H., Lesca, Gaetan, Conti, Valerio, Guerrini, Renzo, Bisulli, Francesca, Licchetta, Laura, Pippucci, Tommaso, Tinuper, Paolo, Hirsch, Edouard, de Saint Martin, Anne, Chelly, Jamel, Rudolf, Gabrielle, Chipaux, Mathilde, Ferrand-Sorbets, Sarah, Dorfmüller, Georg, Sisodiya, Sanjay, Balestrini, Simona, Schoeler, Natasha, Hernandez-Hernandez, Laura, Krithika, S., Oegema, Renske, Hagebeuk, Eveline, Gunning, Boudewijn, Deckers, Charles, Berghuis, Bianca, Wegner, Ilse, Niks, Erik, Jansen, Floor E., Braun, Kees, de Jong, Daniëlle, Rubboli, Guido, Talvik, Inga, Sander, Valentin, Uldall, Peter, Jacquemont, Marie-Line, Nava, Caroline, Leguern, Eric, Julia, Sophie, Gambardella, Antonio, d’Orsi, Giuseppe, Crichiutti, Giovanni, Faivre, Laurence, Darmency, Veronique, Benova, Barbora, Krsek, Pavel, Biraben, Arnaud, Lebre, Anne-Sophie, Jennesson, Mélanie, Sattar, Shifteh, Marchal, Cécile, Nordli, Jr, Douglas R, Lindstrom, Kristin, Striano, Pasquale, Lomax, Lysa Boissé, Kiss, Courtney, Bartolomei, Fabrice, Lepine, Anne Fabienne, Schoonjans, An-Sofie, Stouffs, Katrien, Jansen, Anna, Panagiotakaki, Eleni, Ricard-Mousnier, Brigitte, Thevenon, Julien, de Bellescize, Julitta, Catenoix, Hélène, Dorn, Thomas, Zenker, Martin, Müller-Schlüter, Karen, Brandt, Christian, Krey, Ilona, Polster, Tilman, Wolff, Markus, Balci, Meral, Rostasy, Kevin, Achaz, Guillaume, Zacher, Pia, Becher, Thomas, Cloppenborg, Thomas, Yuskaitis, Christopher J., Weckhuysen, Sarah, Poduri, Annapurna, Lemke, Johannes R., Møller, Rikke S., and Baulac, Stéphanie
Published: 2019
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8. Genetic diagnostics in epilepsies: recommendations of the Commission Epilepsy and Genetics of German Society of Epileptology (German ILAE Chapter)

Author: Boßelmann, Christian, primary, Borggräfe, Ingo, additional, Fazeli, Walid, additional, Klein, Karl-Martin, additional, Kluger, Gerhard J., additional, Müller-Schlüter, Karen, additional, Neubauer, Bernd A., additional, von Spiczak, Sarah, additional, Steinbeis von Stülpnagel, Celina, additional, Weber, Yvonne, additional, Lemke, Johannes R., additional, Wolking, Stefan, additional, and Krey, Ilona, additional
Published: 2023
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9. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], BMBF, Treat-ION, 01GM1907 [sponsor], Johannesen, Katrine M., Liu, Yuanyuan, Koko, Mahmoud, Gjerulfsen, Cathrine E., Sonnenberg, Lukas, Schubert, Julian, Fenger, Christina D., Eltokhi, Ahmed, Rannap, Maert, Koch, Nils A., Lauxmann, Stephan, Krüger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthová, Petra, Vlckova, Marketa, Lemke, Johannes R., Platzer, Konrad, Krey, Ilona, Heine, Constanze, Wieczorek, Dagmar, Kroell-Seger, Judith, Lund, Caroline, Klein, Karl Martin, Billie Au, P. Y., Rho, Jong M., Ho, Alice W., Masnada, Silvia, Veggiotti, Pierangelo, Giordano, Lucio, Accorsi, Patrizia, Hoei-Hansen, Christina E., Striano, Pasquale, Zara, Federico, Verhelst, Helene, Verhoeven, Judith S., van der Zwaag, Bert, Harder, Aster V. E., Brilstra, Eva, Pendziwiat, Manuela, Lebon, Sebastian, Vaccarezza, Maria, Minh Le, Ngoc, Christensen, Jakob, Grønborg, Sabine, Scherer, Stephen W., Howe, Jennifer, Fazeli, Walid, Howell, Katherine B., Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Bénédicte, Matricardi, Sara, Bonardi, Claudia M., Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vøllo, Arve, Motazacker, M. Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gélisse, Philippe, Marini, Carla, Guerrini, Renzo, Bilan, Frederic, Tibussek, Daniel, Koch-Hogrebe, Margarete, Perry, M. Scott, Ichikawa, Shoji, Dadali, Elena, Sharkov, Artem, Mishina, Irina, Abramov, Mikhail, Kanivets, Ilya, Korostelev, Sergey, Kutsev, Sergey, Wain, Karen E., Eisenhauer, Nancy, Wagner, Monisa, Savatt, Juliann M., Müller-Schlüter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie-Cecile, Destrée, Anne, Schoonjans, An-Sofie, Meuwissen, Marije, Buzatu, Marga, Jansen, Anna, Scalais, Emmanuel, Srivastava, Siddharth, Tan, Wen-Hann, Olson, Heather E., Loddenkemper, Tobias, Poduri, Annapurna, Helbig, Katherine L., Helbig, Ingo, Fitzgerald, Mark P., Goldberg, Ethan M., Roser, Timo, Borggraefe, Ingo, Brünger, Tobias, May, Patrick, Lal, Dennis, Lederer, Damien, Rubboli, Guido, Heyne, Henrike O., Lesca, Gaetan, Hedrich, Ulrike B. S., Benda, Jan, Gardella, Elena, Lerche, Holger, Møller, Rikke S., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], BMBF, Treat-ION, 01GM1907 [sponsor], Johannesen, Katrine M., Liu, Yuanyuan, Koko, Mahmoud, Gjerulfsen, Cathrine E., Sonnenberg, Lukas, Schubert, Julian, Fenger, Christina D., Eltokhi, Ahmed, Rannap, Maert, Koch, Nils A., Lauxmann, Stephan, Krüger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthová, Petra, Vlckova, Marketa, Lemke, Johannes R., Platzer, Konrad, Krey, Ilona, Heine, Constanze, Wieczorek, Dagmar, Kroell-Seger, Judith, Lund, Caroline, Klein, Karl Martin, Billie Au, P. Y., Rho, Jong M., Ho, Alice W., Masnada, Silvia, Veggiotti, Pierangelo, Giordano, Lucio, Accorsi, Patrizia, Hoei-Hansen, Christina E., Striano, Pasquale, Zara, Federico, Verhelst, Helene, Verhoeven, Judith S., van der Zwaag, Bert, Harder, Aster V. E., Brilstra, Eva, Pendziwiat, Manuela, Lebon, Sebastian, Vaccarezza, Maria, Minh Le, Ngoc, Christensen, Jakob, Grønborg, Sabine, Scherer, Stephen W., Howe, Jennifer, Fazeli, Walid, Howell, Katherine B., Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Bénédicte, Matricardi, Sara, Bonardi, Claudia M., Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vøllo, Arve, Motazacker, M. Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gélisse, Philippe, Marini, Carla, Guerrini, Renzo, Bilan, Frederic, Tibussek, Daniel, Koch-Hogrebe, Margarete, Perry, M. Scott, Ichikawa, Shoji, Dadali, Elena, Sharkov, Artem, Mishina, Irina, Abramov, Mikhail, Kanivets, Ilya, Korostelev, Sergey, Kutsev, Sergey, Wain, Karen E., Eisenhauer, Nancy, Wagner, Monisa, Savatt, Juliann M., Müller-Schlüter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie-Cecile, Destrée, Anne, Schoonjans, An-Sofie, Meuwissen, Marije, Buzatu, Marga, Jansen, Anna, Scalais, Emmanuel, Srivastava, Siddharth, Tan, Wen-Hann, Olson, Heather E., Loddenkemper, Tobias, Poduri, Annapurna, Helbig, Katherine L., Helbig, Ingo, Fitzgerald, Mark P., Goldberg, Ethan M., Roser, Timo, Borggraefe, Ingo, Brünger, Tobias, May, Patrick, Lal, Dennis, Lederer, Damien, Rubboli, Guido, Heyne, Henrike O., Lesca, Gaetan, Hedrich, Ulrike B. S., Benda, Jan, Gardella, Elena, Lerche, Holger, and Møller, Rikke S.
Abstract: We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n = 15, normal cognition, treatable seizures), 2) intermediate epilepsy (n = 33, mild ID, partially pharmaco-responsive), 3) developmental and epileptic encephalopathy (DEE, n = 177, severe ID, majority pharmaco-resistant), 4) generalized epilepsy (n = 20, mild to moderate ID, frequently with absence seizures), 5) unclassifiable epilepsy (n = 127), and 6) neurodevelopmental disorder without epilepsy (n = 20, mild to moderate ID). Groups 1–3 presented with focal or multifocal seizures (median age of onset: four months) and focal epileptiform discharges, whereas the onset of seizures in group 4 was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human NaV1.6 channels and whole-cell patch-clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested GOF variant had either focal (97, groups 1–3), or unclassifiable epilepsy (39), whereas 34 with a LOF variant had either generalized (14), no
Published: 2022

10. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

Author: Johannesen, Katrine M., Liu, Yuanyuan, Koko, Mahmoud, Gjerulfsen, Cathrine E., Sonnenberg, Lukas, Schubert, Julian, Fenger, Christina D., Eltokhi, Ahmed, Rannap, Maert, Koch, Nils A., Lauxmann, Stephan, Krüger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthová, Petra, Vlckova, Marketa, Lemke, Johannes R., Platzer, Konrad, Krey, Ilona, Heine, Constanze, Wieczorek, Dagmar, Kroell-Seger, Judith, Lund, Caroline, Klein, Karl Martin, Au, P. Y.Billie, Rho, Jong M., Ho, Alice W., Masnada, Silvia, Veggiotti, Pierangelo, Giordano, Lucio, Accorsi, Patrizia, Hoei-Hansen, Christina E., Striano, Pasquale, Zara, Federico, Verhelst, Helene, Verhoeven, Judith S., Braakman, Hilde M.H., van der Zwaag, Bert, Harder, Aster V.E., Brilstra, Eva, Pendziwiat, Manuela, Lebon, Sebastian, Vaccarezza, Maria, Le, Ngoc Minh, Christensen, Jakob, Grønborg, Sabine, Scherer, Stephen W., Howe, Jennifer, Fazeli, Walid, Howell, Katherine B., Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Bénédicte, Matricardi, Sara, Bonardi, Claudia M., Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vøllo, Arve, Motazacker, M. Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gélisse, Philippe, Marini, Carla, Guerrini, Renzo, Bilan, Frederic, Tibussek, Daniel, Koch-Hogrebe, Margarete, Perry, M. Scott, Ichikawa, Shoji, Dadali, Elena, Sharkov, Artem, Mishina, Irina, Abramov, Mikhail, Kanivets, Ilya, Korostelev, Sergey, Kutsev, Sergey, Wain, Karen E., Eisenhauer, Nancy, Wagner, Monisa, Savatt, Juliann M., Müller-Schlüter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie Cecile, Destrée, Anne, Schoonjans, An Sofie, Meuwissen, Marije, Buzatu, Marga, Jansen, Anna, Scalais, Emmanuel, Srivastava, Siddharth, Tan, Wen Hann, Olson, Heather E., Loddenkemper, Tobias, Poduri, Annapurna, Helbig, Katherine L., Helbig, Ingo, Fitzgerald, Mark P., Goldberg, Ethan M., Roser, Timo, Borggraefe, Ingo, Brünger, Tobias, May, Patrick, Lal, Dennis, Lederer, Damien, Rubboli, Guido, Heyne, Henrike O., Lesca, Gaetan, Hedrich, Ulrike B.S., Benda, Jan, Gardella, Elena, Lerche, Holger, Møller, Rikke S., Johannesen, Katrine M., Liu, Yuanyuan, Koko, Mahmoud, Gjerulfsen, Cathrine E., Sonnenberg, Lukas, Schubert, Julian, Fenger, Christina D., Eltokhi, Ahmed, Rannap, Maert, Koch, Nils A., Lauxmann, Stephan, Krüger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthová, Petra, Vlckova, Marketa, Lemke, Johannes R., Platzer, Konrad, Krey, Ilona, Heine, Constanze, Wieczorek, Dagmar, Kroell-Seger, Judith, Lund, Caroline, Klein, Karl Martin, Au, P. Y.Billie, Rho, Jong M., Ho, Alice W., Masnada, Silvia, Veggiotti, Pierangelo, Giordano, Lucio, Accorsi, Patrizia, Hoei-Hansen, Christina E., Striano, Pasquale, Zara, Federico, Verhelst, Helene, Verhoeven, Judith S., Braakman, Hilde M.H., van der Zwaag, Bert, Harder, Aster V.E., Brilstra, Eva, Pendziwiat, Manuela, Lebon, Sebastian, Vaccarezza, Maria, Le, Ngoc Minh, Christensen, Jakob, Grønborg, Sabine, Scherer, Stephen W., Howe, Jennifer, Fazeli, Walid, Howell, Katherine B., Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Bénédicte, Matricardi, Sara, Bonardi, Claudia M., Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vøllo, Arve, Motazacker, M. Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gélisse, Philippe, Marini, Carla, Guerrini, Renzo, Bilan, Frederic, Tibussek, Daniel, Koch-Hogrebe, Margarete, Perry, M. Scott, Ichikawa, Shoji, Dadali, Elena, Sharkov, Artem, Mishina, Irina, Abramov, Mikhail, Kanivets, Ilya, Korostelev, Sergey, Kutsev, Sergey, Wain, Karen E., Eisenhauer, Nancy, Wagner, Monisa, Savatt, Juliann M., Müller-Schlüter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie Cecile, Destrée, Anne, Schoonjans, An Sofie, Meuwissen, Marije, Buzatu, Marga, Jansen, Anna, Scalais, Emmanuel, Srivastava, Siddharth, Tan, Wen Hann, Olson, Heather E., Loddenkemper, Tobias, Poduri, Annapurna, Helbig, Katherine L., Helbig, Ingo, Fitzgerald, Mark P., Goldberg, Ethan M., Roser, Timo, Borggraefe, Ingo, Brünger, Tobias, May, Patrick, Lal, Dennis, Lederer, Damien, Rubboli, Guido, Heyne, Henrike O., Lesca, Gaetan, Hedrich, Ulrike B.S., Benda, Jan, Gardella, Elena, Lerche, Holger, and Møller, Rikke S.
Abstract: We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 i
Published: 2022

11. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

Author: Genetica Sectie Genoomdiagnostiek, Child Health, Genetica Klinische Genetica, Brain, Johannesen, Katrine M, Liu, Yuanyuan, Koko, Mahmoud, Gjerulfsen, Cathrine E, Sonnenberg, Lukas, Schubert, Julian, Fenger, Christina D, Eltokhi, Ahmed, Rannap, Maert, Koch, Nils A, Lauxmann, Stephan, Krüger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthová, Petra, Vlckova, Marketa, Lemke, Johannes R, Platzer, Konrad, Krey, Ilona, Heine, Constanze, Wieczorek, Dagmar, Kroell-Seger, Judith, Lund, Caroline, Klein, Karl Martin, Billie Au, P Y, Rho, Jong M, Ho, Alice W, Masnada, Silvia, Veggiotti, Pierangelo, Giordano, Lucio, Accorsi, Patrizia, Hoei-Hansen, Christina E, Striano, Pasquale, Zara, Federico, Verhelst, Helene, Verhoeven, Judith S, van der Zwaag, Bert, Harder, Aster V E, Brilstra, Eva, Pendziwiat, Manuela, Lebon, Sebastian, Vaccarezza, Maria, Minh Le, Ngoc, Christensen, Jakob, Grønborg, Sabine, Scherer, Stephen W, Howe, Jennifer, Fazeli, Walid, Howell, Katherine B, Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Bénédicte, Matricardi, Sara, Bonardi, Claudia M, Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vøllo, Arve, Motazacker, M Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gélisse, Philippe, Marini, Carla, Guerrini, Renzo, Bilan, Frederic, Tibussek, Daniel, Koch-Hogrebe, Margarete, Perry, M Scott, Ichikawa, Shoji, Dadali, Elena, Sharkov, Artem, Mishina, Irina, Abramov, Mikhail, Kanivets, Ilya, Korostelev, Sergey, Kutsev, Sergey, Wain, Karen E, Eisenhauer, Nancy, Wagner, Monisa, Savatt, Juliann M, Müller-Schlüter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie-Cecile, Destrée, Anne, Schoonjans, An-Sofie, Meuwissen, Marije, Buzatu, Marga, Jansen, Anna, Scalais, Emmanuel, Srivastava, Siddharth, Tan, Wen-Hann, Olson, Heather E, Loddenkemper, Tobias, Poduri, Annapurna, Helbig, Katherine L, Helbig, Ingo, Fitzgerald, Mark P, Goldberg, Ethan M, Roser, Timo, Borggraefe, Ingo, Brünger, Tobias, May, Patrick, Lal, Dennis, Lederer, Damien, Rubboli, Guido, Heyne, Henrike O, Lesca, Gaetan, Hedrich, Ulrike B S, Benda, Jan, Gardella, Elena, Lerche, Holger, Møller, Rikke S, Genetica Sectie Genoomdiagnostiek, Child Health, Genetica Klinische Genetica, Brain, Johannesen, Katrine M, Liu, Yuanyuan, Koko, Mahmoud, Gjerulfsen, Cathrine E, Sonnenberg, Lukas, Schubert, Julian, Fenger, Christina D, Eltokhi, Ahmed, Rannap, Maert, Koch, Nils A, Lauxmann, Stephan, Krüger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthová, Petra, Vlckova, Marketa, Lemke, Johannes R, Platzer, Konrad, Krey, Ilona, Heine, Constanze, Wieczorek, Dagmar, Kroell-Seger, Judith, Lund, Caroline, Klein, Karl Martin, Billie Au, P Y, Rho, Jong M, Ho, Alice W, Masnada, Silvia, Veggiotti, Pierangelo, Giordano, Lucio, Accorsi, Patrizia, Hoei-Hansen, Christina E, Striano, Pasquale, Zara, Federico, Verhelst, Helene, Verhoeven, Judith S, van der Zwaag, Bert, Harder, Aster V E, Brilstra, Eva, Pendziwiat, Manuela, Lebon, Sebastian, Vaccarezza, Maria, Minh Le, Ngoc, Christensen, Jakob, Grønborg, Sabine, Scherer, Stephen W, Howe, Jennifer, Fazeli, Walid, Howell, Katherine B, Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Bénédicte, Matricardi, Sara, Bonardi, Claudia M, Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vøllo, Arve, Motazacker, M Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gélisse, Philippe, Marini, Carla, Guerrini, Renzo, Bilan, Frederic, Tibussek, Daniel, Koch-Hogrebe, Margarete, Perry, M Scott, Ichikawa, Shoji, Dadali, Elena, Sharkov, Artem, Mishina, Irina, Abramov, Mikhail, Kanivets, Ilya, Korostelev, Sergey, Kutsev, Sergey, Wain, Karen E, Eisenhauer, Nancy, Wagner, Monisa, Savatt, Juliann M, Müller-Schlüter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie-Cecile, Destrée, Anne, Schoonjans, An-Sofie, Meuwissen, Marije, Buzatu, Marga, Jansen, Anna, Scalais, Emmanuel, Srivastava, Siddharth, Tan, Wen-Hann, Olson, Heather E, Loddenkemper, Tobias, Poduri, Annapurna, Helbig, Katherine L, Helbig, Ingo, Fitzgerald, Mark P, Goldberg, Ethan M, Roser, Timo, Borggraefe, Ingo, Brünger, Tobias, May, Patrick, Lal, Dennis, Lederer, Damien, Rubboli, Guido, Heyne, Henrike O, Lesca, Gaetan, Hedrich, Ulrike B S, Benda, Jan, Gardella, Elena, Lerche, Holger, and Møller, Rikke S
Published: 2022

12. Correction: The landscape of epilepsy-related GATOR1 variants

Author: Baldassari, Sara, Picard, Fabienne, Verbeek, Nienke E., van Kempen, Marjan, Brilstra, Eva H., Lesca, Gaetan, Conti, Valerio, Guerrini, Renzo, Bisulli, Francesca, Licchetta, Laura, Pippucci, Tommaso, Tinuper, Paolo, Hirsch, Edouard, de Saint Martin, Anne, Chelly, Jamel, Rudolf, Gabrielle, Chipaux, Mathilde, Ferrand-Sorbets, Sarah, Dorfmüller, Georg, Sisodiya, Sanjay, Balestrini, Simona, Schoeler, Natasha, Hernandez-Hernandez, Laura, Krithika, S., Oegema, Renske, Hagebeuk, Eveline, Gunning, Boudewijn, Deckers, Charles, Berghuis, Bianca, Wegner, Ilse, Niks, Erik H., Jansen, Floor E., Braun, Kees, de Jong, Daniëlle, Rubboli, Guido, Talvik, Inga, Sander, Valentin, Uldall, Peter, Jacquemont, Marie-Line, Nava, Caroline, Leguern, Eric, Julia, Sophie, Gambardella, Antonio, d’Orsi, Giuseppe, Crichiutti, Giovanni, Faivre, Laurence, Darmency, Veronique, Benova, Barbora, Krsek, Pavel, Biraben, Arnaud, Lebre, Anne-Sophie, Jennesson, Mélanie, Sattar, Shifteh, Marchal, Cécile, NordliJr, Douglas R, Lindstrom, Kristin, Striano, Pasquale, Lomax, Lysa Boissé, Kiss, Courtney, Bartolomei, Fabrice, Lepine, Anne Fabienne, Schoonjans, An-Sofie, Stouffs, Katrien, Jansen, Anna, Panagiotakaki, Eleni, Ricard-Mousnier, Brigitte, Thevenon, Julien, de Bellescize, Julitta, Catenoix, Hélène, Dorn, Thomas, Zenker, Martin, Müller-Schlüter, Karen, Brandt, Christian, Krey, Ilona, Polster, Tilman, Wolff, Markus, Balci, Meral, Rostasy, Kevin, Achaz, Guillaume, Zacher, Pia, Becher, Thomas, Cloppenborg, Thomas, Yuskaitis, Christopher J., Weckhuysen, Sarah, Poduri, Annapurna, Lemke, Johannes R., Møller, Rikke S., and Baulac, Stéphanie
Published: 2019
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13. Correction to: The landscape of epilepsy-related GATOR1 variants

Author: Baldassari, Sara, Picard, Fabienne, Verbeek, Nienke E., van Kempen, Marjan, Brilstra, Eva H., Lesca, Gaetan, Conti, Valerio, Guerrini, Renzo, Bisulli, Francesca, Licchetta, Laura, Pippucci, Tommaso, Tinuper, Paolo, Hirsch, Edouard, Martin, Anne de Saint, Chelly, Jamel, Rudolf, Gabrielle, Chipaux, Mathilde, Ferrand-Sorbets, Sarah, Dorfmüller, Georg, Sisodiya, Sanjay, Balestrini, Simona, Schoeler, Natasha, Hernandez-Hernandez, Laura, Krithika, S., Oegema, Renske, Hagebeuk, Eveline, Gunning, Boudewijn, Deckers, Charles, Berghuis, Bianca, Wegner, Ilse, Niks, Erik, Jansen, Floor, Braun, Kees, Jong, Daniëlle de, Rubboli, Guido, Talvik, Inga, Sander, Valentin, Uldall, Peter, Jacquemont, Marie-Line, Nava, Caroline, Leguern, Eric, Julia, Sophie, Gambardella, Antonio, d’Orsi, Giuseppe, Crichiutti, Giovanni, Faivre, Laurence, Darmency, Veronique, Benova, Barbora, Krsek, Pavel, Biraben, Arnaud, Lebre, Anne-Sophie, Jennesson, Mélanie, Sattar, Shifteh, Marchal, Cécile, NordliJr, Douglas R., Lindstrom, Kristin, Striano, Pasquale, Lomax, Lysa Boissé, Kiss, Courtney, Bartolomei, Fabrice, Lepine, Anne Fabienne, Schoonjans, An-Sofie, Stouffs, Katrien, Jansen, Anna, Panagiotakaki, Eleni, Ricard-Mousnier, Brigitte, Thevenon, Julien, Bellescize, Julitta de, Catenoix, Hélène, Dorn, Thomas, Zenker, Martin, Müller-Schlüter, Karen, Brandt, Christian, Krey, Ilona, Polster, Tilman, Wolff, Markus, Balci, Meral, Rostasy, Kevin, Achaz, Guillaume, Zacher, Pia, Becher, Thomas, Cloppenborg, Thomas, Yuskaitis, Christopher J., Weckhuysen, Sarah, Poduri, Annapurna, Lemke, Johannes R., Møller, Rikke S., and Baulac, Stéphanie
Published: 2019
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14. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author: Motelow, Joshua E., primary, Povysil, Gundula, additional, Dhindsa, Ryan S., additional, Stanley, Kate E., additional, Allen, Andrew S., additional, Feng, Yen-Chen Anne, additional, Howrigan, Daniel P., additional, Abbott, Liam E., additional, Tashman, Katherine, additional, Cerrato, Felecia, additional, Cusick, Caroline, additional, Singh, Tarjinder, additional, Heyne, Henrike, additional, Byrnes, Andrea E., additional, Churchhouse, Claire, additional, Watts, Nick, additional, Solomonson, Matthew, additional, Lal, Dennis, additional, Gupta, Namrata, additional, Neale, Benjamin M., additional, Cavalleri, Gianpiero L., additional, Cossette, Patrick, additional, Cotsapas, Chris, additional, De Jonghe, Peter, additional, Dixon-Salazar, Tracy, additional, Guerrini, Renzo, additional, Hakonarson, Hakon, additional, Heinzen, Erin L., additional, Helbig, Ingo, additional, Kwan, Patrick, additional, Marson, Anthony G., additional, Petrovski, Slavé, additional, Kamalakaran, Sitharthan, additional, Sisodiya, Sanjay M., additional, Stewart, Randy, additional, Weckhuysen, Sarah, additional, Depondt, Chantal, additional, Dlugos, Dennis J., additional, Scheffer, Ingrid E., additional, Striano, Pasquale, additional, Freyer, Catharine, additional, Krause, Roland, additional, May, Patrick, additional, McKenna, Kevin, additional, Regan, Brigid M., additional, Bennett, Caitlin A., additional, Leu, Costin, additional, Leech, Stephanie L., additional, O’Brien, Terence J., additional, Todaro, Marian, additional, Stamberger, Hannah, additional, Andrade, Danielle M., additional, Ali, Quratulain Zulfiqar, additional, Sadoway, Tara R., additional, Krestel, Heinz, additional, Schaller, André, additional, Papacostas, Savvas S., additional, Kousiappa, Ioanna, additional, Tanteles, George A., additional, Christou, Yiolanda, additional, Štěrbová, Katalin, additional, Vlčková, Markéta, additional, Sedláčková, Lucie, additional, Laššuthová, Petra, additional, Klein, Karl Martin, additional, Rosenow, Felix, additional, Reif, Philipp S., additional, Knake, Susanne, additional, Neubauer, Bernd A., additional, Zimprich, Friedrich, additional, Feucht, Martha, additional, Reinthaler, Eva M., additional, Kunz, Wolfram S., additional, Zsurka, Gábor, additional, Surges, Rainer, additional, Baumgartner, Tobias, additional, von Wrede, Randi, additional, Pendziwiat, Manuela, additional, Muhle, Hiltrud, additional, Rademacher, Annika, additional, van Baalen, Andreas, additional, von Spiczak, Sarah, additional, Stephani, Ulrich, additional, Afawi, Zaid, additional, Korczyn, Amos D., additional, Kanaan, Moien, additional, Canavati, Christina, additional, Kurlemann, Gerhard, additional, Müller-Schlüter, Karen, additional, Kluger, Gerhard, additional, Häusler, Martin, additional, Blatt, Ilan, additional, Lemke, Johannes R., additional, Krey, Ilona, additional, Weber, Yvonne G., additional, Wolking, Stefan, additional, Becker, Felicitas, additional, Lauxmann, Stephan, additional, Boßelmann, Christian, additional, Kegele, Josua, additional, Hengsbach, Christian, additional, Rau, Sarah, additional, Steinhoff, Bernhard J., additional, Schulze-Bonhage, Andreas, additional, Borggräfe, Ingo, additional, Schankin, Christoph J., additional, Schubert-Bast, Susanne, additional, Schreiber, Herbert, additional, Mayer, Thomas, additional, Korinthenberg, Rudolf, additional, Brockmann, Knut, additional, Wolff, Markus, additional, Dennig, Dieter, additional, Madeleyn, Rene, additional, Kälviäinen, Reetta, additional, Saarela, Anni, additional, Timonen, Oskari, additional, Linnankivi, Tarja, additional, Lehesjoki, Anna-Elina, additional, Rheims, Sylvain, additional, Lesca, Gaetan, additional, Ryvlin, Philippe, additional, Maillard, Louis, additional, Valton, Luc, additional, Derambure, Philippe, additional, Bartolomei, Fabrice, additional, Hirsch, Edouard, additional, Michel, Véronique, additional, Chassoux, Francine, additional, Rees, Mark I., additional, Chung, Seo-Kyung, additional, Pickrell, William O., additional, Powell, Robert, additional, Baker, Mark D., additional, Fonferko-Shadrach, Beata, additional, Lawthom, Charlotte, additional, Anderson, Joseph, additional, Schneider, Natascha, additional, Balestrini, Simona, additional, Zagaglia, Sara, additional, Braatz, Vera, additional, Johnson, Michael R., additional, Auce, Pauls, additional, Sills, Graeme J., additional, Baum, Larry W., additional, Sham, Pak C., additional, Cherny, Stacey S., additional, Lui, Colin H.T., additional, Delanty, Norman, additional, Doherty, Colin P., additional, Shukralla, Arif, additional, El-Naggar, Hany, additional, Widdess-Walsh, Peter, additional, Barišić, Nina, additional, Canafoglia, Laura, additional, Franceschetti, Silvana, additional, Castellotti, Barbara, additional, Granata, Tiziana, additional, Ragona, Francesca, additional, Zara, Federico, additional, Iacomino, Michele, additional, Riva, Antonella, additional, Madia, Francesca, additional, Vari, Maria Stella, additional, Salpietro, Vincenzo, additional, Scala, Marcello, additional, Mancardi, Maria Margherita, additional, Nobili, Lino, additional, Amadori, Elisabetta, additional, Giacomini, Thea, additional, Bisulli, Francesca, additional, Pippucci, Tommaso, additional, Licchetta, Laura, additional, Minardi, Raffaella, additional, Tinuper, Paolo, additional, Muccioli, Lorenzo, additional, Mostacci, Barbara, additional, Gambardella, Antonio, additional, Labate, Angelo, additional, Annesi, Grazia, additional, Manna, Lorella, additional, Gagliardi, Monica, additional, Parrini, Elena, additional, Mei, Davide, additional, Vetro, Annalisa, additional, Bianchini, Claudia, additional, Montomoli, Martino, additional, Doccini, Viola, additional, Barba, Carmen, additional, Hirose, Shinichi, additional, Ishii, Atsushi, additional, Suzuki, Toshimitsu, additional, Inoue, Yushi, additional, Yamakawa, Kazuhiro, additional, Beydoun, Ahmad, additional, Nasreddine, Wassim, additional, Khoueiry Zgheib, Nathalie, additional, Tumiene, Birute, additional, Utkus, Algirdas, additional, Sadleir, Lynette G., additional, King, Chontelle, additional, Caglayan, S. Hande, additional, Arslan, Mutluay, additional, Yapıcı, Zuhal, additional, Topaloglu, Pınar, additional, Kara, Bulent, additional, Yis, Uluc, additional, Turkdogan, Dilsad, additional, Gundogdu-Eken, Aslı, additional, Bebek, Nerses, additional, Uğur-İşeri, Sibel, additional, Baykan, Betül, additional, Salman, Barış, additional, Haryanyan, Garen, additional, Yücesan, Emrah, additional, Kesim, Yeşim, additional, Özkara, Çiğdem, additional, Tsai, Meng-Han, additional, Ho, Chen-Jui, additional, Lin, Chih-Hsiang, additional, Lin, Kuang-Lin, additional, Chou, I-Jun, additional, Poduri, Annapurna, additional, Shiedley, Beth R., additional, Shain, Catherine, additional, Noebels, Jeffrey L., additional, Goldman, Alicia, additional, Busch, Robyn M., additional, Jehi, Lara, additional, Najm, Imad M., additional, Ferguson, Lisa, additional, Khoury, Jean, additional, Glauser, Tracy A., additional, Clark, Peggy O., additional, Buono, Russell J., additional, Ferraro, Thomas N., additional, Sperling, Michael R., additional, Lo, Warren, additional, Privitera, Michael, additional, French, Jacqueline A., additional, Schachter, Steven, additional, Kuzniecky, Ruben I., additional, Devinsky, Orrin, additional, Hegde, Manu, additional, Greenberg, David A., additional, Ellis, Colin A., additional, Goldberg, Ethan, additional, Helbig, Katherine L., additional, Cosico, Mahgenn, additional, Vaidiswaran, Priya, additional, Fitch, Eryn, additional, Berkovic, Samuel F., additional, Lerche, Holger, additional, Lowenstein, Daniel H., additional, and Goldstein, David B., additional
Published: 2021
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15. Distinct gene-set burden patterns underlie common generalized and focal epilepsies

Author: Koko, Mahmoud, primary, Krause, Roland, additional, Sander, Thomas, additional, Bobbili, Dheeraj Reddy, additional, Nothnagel, Michael, additional, May, Patrick, additional, Lerche, Holger, additional, Feng, Yen-Chen Anne, additional, Howrigan, Daniel P, additional, Abbott, Liam E, additional, Tashman, Katherine, additional, Cerrato, Felecia, additional, Singh, Tarjinder, additional, Heyne, Henrike, additional, Byrnes, Andrea, additional, Churchhouse, Claire, additional, Watts, Nick, additional, Solomonson, Matthew, additional, Lal, Dennis, additional, Heinzen, Erin L, additional, Dhindsa, Ryan S, additional, Stanley, Kate E, additional, Cavalleri, Gianpiero L, additional, Hakonarson, Hakon, additional, Helbig, Ingo, additional, Weckhuysen, Sarah, additional, Petrovski, Slavé, additional, Kamalakaran, Sitharthan, additional, Sisodiya, Sanjay M, additional, Cossette, Patrick, additional, Cotsapas, Chris, additional, DeJonghe, Peter, additional, Dixon-Salazar, Tracy, additional, Guerrini, Renzo, additional, Kwan, Patrick, additional, Marson, Anthony G, additional, Stewart, Randy, additional, Depondt, Chantal, additional, Dlugos, Dennis J, additional, Scheffer, Ingrid E, additional, Striano, Pasquale, additional, Freyer, Catharine, additional, McKenna, Kevin, additional, Regan, Brigid M, additional, Bellows, Susannah T, additional, Leu, Costin, additional, Bennett, Caitlin A, additional, Johns, Esther M C, additional, Macdonald, Alexandra, additional, Shilling, Hannah, additional, Burgess, Rosemary, additional, Weckhuysen, Dorien, additional, Bahlo, Melanie, additional, O'Brien, Terence J, additional, Todaro, Marian, additional, Stamberger, Hannah, additional, Andrade, Danielle M, additional, Sadoway, Tara R, additional, Mo, Kelly, additional, Krestel, Heinz, additional, Gallati, Sabina, additional, Papacostas, Savvas S, additional, Kousiappa, Ioanna, additional, Tanteles, George A, additional, Štěrbová, Katalin, additional, Vlčková, Markéta, additional, Sedláčková, Lucie, additional, Laššuthová, Petra, additional, Klein, Karl Martin, additional, Rosenow, Felix, additional, Reif, Philipp S, additional, Knake, Susanne, additional, Kunz, Wolfram S, additional, Zsurka, Gábor, additional, Elger, Christian E, additional, Bauer, Jürgen, additional, Rademacher, Michael, additional, Pendziwiat, Manuela, additional, Muhle, Hiltrud, additional, Rademacher, Annika, additional, vanBaalen, Andreas, additional, vonSpiczak, Sarah, additional, Stephani, Ulrich, additional, Afawi, Zaid, additional, Korczyn, Amos D, additional, Kanaan, Moien, additional, Canavati, Christina, additional, Kurlemann, Gerhard, additional, Müller-Schlüter, Karen, additional, Kluger, Gerhard, additional, Häusler, Martin, additional, Blatt, Ilan, additional, Lemke, Johannes R, additional, Krey, Ilona, additional, Weber, Yvonne G, additional, Wolking, Stefan, additional, Becker, Felicitas, additional, Hengsbach, Christian, additional, Rau, Sarah, additional, Maisch, Ana F, additional, Steinhoff, Bernhard J, additional, Schulze-Bonhage, Andreas, additional, Schubert-Bast, Susanne, additional, Schreiber, Herbert, additional, Borggräfe, Ingo, additional, Schankin, Christoph J, additional, Mayer, Thomas, additional, Korinthenberg, Rudolf, additional, Brockmann, Knut, additional, Dennig, Dieter, additional, Madeleyn, Rene, additional, Kälviäinen, Reetta, additional, Auvinen, Pia, additional, Saarela, Anni, additional, Linnankivi, Tarja, additional, Lehesjoki, Anna-Elina, additional, Rees, Mark I, additional, Chung, Seo-Kyung, additional, Pickrell, William O, additional, Powell, Robert, additional, Schneider, Natascha, additional, Balestrini, Simona, additional, Zagaglia, Sara, additional, Braatz, Vera, additional, Johnson, Michael R, additional, Auce, Pauls, additional, Sills, Graeme J, additional, Baum, Larry W, additional, Sham, Pak C, additional, Cherny, Stacey S, additional, Lui, Colin H T, additional, Barišić, Nina, additional, Delanty, Norman, additional, Doherty, Colin P, additional, Shukralla, Arif, additional, McCormack, Mark, additional, El-Naggar, Hany, additional, Canafoglia, Laura, additional, Franceschetti, Silvana, additional, Castellotti, Barbara, additional, Granata, Tiziana, additional, Zara, Federico, additional, Iacomino, Michele, additional, Madia, Francesca, additional, Vari, Maria Stella, additional, Mancardi, Maria Margherita, additional, Salpietro, Vincenzo, additional, Bisulli, Francesca, additional, Tinuper, Paolo, additional, Licchetta, Laura, additional, Pippucci, Tommaso, additional, Stipa, Carlotta, additional, Minardi, Raffaella, additional, Gambardella, Antonio, additional, Labate, Angelo, additional, Annesi, Grazia, additional, Manna, Lorella, additional, Gagliardi, Monica, additional, Parrini, Elena, additional, Mei, Davide, additional, Vetro, Annalisa, additional, Bianchini, Claudia, additional, Montomoli, Martino, additional, Doccini, Viola, additional, Marini, Carla, additional, Suzuki, Toshimitsu, additional, Inoue, Yushi, additional, Yamakawa, Kazuhiro, additional, Tumiene, Birute, additional, Sadleir, Lynette G, additional, King, Chontelle, additional, Mountier, Emily, additional, Caglayan, Hande S, additional, Arslan, Mutluay, additional, Yapıcı, Zuhal, additional, Yis, Uluc, additional, Topaloglu, Pınar, additional, Kara, Bulent, additional, Turkdogan, Dilsad, additional, Gundogdu-Eken, Aslı, additional, Bebek, Nerses, additional, Uğur-İşeri, Sibel, additional, Baykan, Betül, additional, Salman, Barış, additional, Haryanyan, Garen, additional, Yücesan, Emrah, additional, Kesim, Yeşim, additional, Özkara, Çiğdem, additional, Poduri, Annapurna, additional, Shiedley, Beth R, additional, Shain, Catherine, additional, Buono, Russell J, additional, Ferraro, Thomas N, additional, Sperling, Michael R, additional, Lo, Warren, additional, Privitera, Michael, additional, French, Jacqueline A, additional, Schachter, Steven, additional, Kuzniecky, Ruben I, additional, Devinsky, Orrin, additional, Hegde, Manu, additional, Khankhanian, Pouya, additional, Helbig, Katherine L, additional, Ellis, Colin A, additional, Spalletta, Gianfranco, additional, Piras, Fabrizio, additional, Piras, Federica, additional, Gili, Tommaso, additional, Ciullo, Valentina, additional, Reif, Andreas, additional, McQuillin, Andrew, additional, Bass, Nick, additional, McIntosh, Andrew, additional, Blackwood, Douglas, additional, Johnstone, Mandy, additional, Palotie, Aarno, additional, Pato, Michele T, additional, Pato, Carlos N, additional, Bromet, Evelyn J, additional, Carvalho, Celia Barreto, additional, Achtyes, Eric D, additional, Azevedo, Maria Helena, additional, Kotov, Roman, additional, Lehrer, Douglas S, additional, Malaspina, Dolores, additional, Marder, Stephen R, additional, Medeiros, Helena, additional, Morley, Christopher P, additional, Perkins, Diana O, additional, Sobell, Janet L, additional, Buckley, Peter F, additional, Macciardi, Fabio, additional, Rapaport, Mark H, additional, Knowles, James A, additional, Cohort, Genomic Psychiatry, additional, Fanous, Ayman H, additional, McCarroll, Steven A, additional, Gupta, Namrata, additional, Gabriel, Stacey B, additional, Daly, Mark J, additional, Lander, Eric S, additional, Lowenstein, Daniel H, additional, Goldstein, David B, additional, Berkovic, Samuel F, additional, and Neale, Benjamin M, additional
Published: 2021
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16. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

Author: Johannesen, Katrine M., Liu, Yuanyuan, Gjerulfsen, Cathrine E., Koko, Mahmoud, Sonnenberg, Lukas, Schubert, Julian, Fenger, Christina D., Eltokhi, Ahmed, Rannap, Maert, Koch, Nils A., Lauxmann, Stephan, Krüger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthová, Petra, Vlckova, Marketa, Lemke, Johannes R., Krey, Ilona, Heine, Constanze, Wieczorek, Dagmar, Kroell-Seger, Judith, Lund, Caroline, Klein, Karl Martin, Au, P. Y. Billie, Rho, Jong M., Ho, Alice W., Masnada, Silvia, Veggiotti, Pierangelo, Giordano, Lucio, Accorsi, Patrizia, Hoei-Hansen, Christina E., Striano, Pasquale, Zara, Federico, Verhelst, Helene, S.Verhoeven, Judith, van der Zwaag, Bert, Harder, Aster V. E., Brilstra, Eva, Pendziwiat, Manuela, Lebon, Sebastian, Vaccarezza, Maria, Le, Ngoc Minh, Christensen, Jakob, Schmidt-Petersen, Mette U., Grønborg, Sabine, Scherer, Stephen W., Howe, Jennifer, Fazeli, Walid, Howell, Katherine B., Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Bénédicte, Matricardi, Sara, Bonardi, Claudia M., Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vøllo, Arve, Motazacker, M. Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gélisse, Philippe, Marini, Carla, Guerrini, Renzo, Bilan, Frederic, Tibussek, Daniel, Koch-Hogrebe, Margarete, Perry, M. Scott, Ichikawa, Shoji, Dadali, Elena, Sharkov, Artem, Mishina, Irina, Abramov, Mikhail, Kanivets, Ilya, Korostelev, Sergey, Kutsev, Sergey, Wain, Karen E., Eisenhauer, Nancy, Wagner, Monisa, Savatt, Juliann M., Müller-Schlüter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie-Cecile, Destrée, Anne, Schoonjans, An-Sofie, Meuwissen, Marije, Buzatu, Marga, Jansen, Anna, Scalais, Emmanuel, Srivastava, Siddharth, Tan, Wen-Hann, Olson, Heather E., Loddenkemper, Tobias, Poduri, Annapurna, Helbig, Katherine L., Helbig, Ingo, Fitzgerald, Mark P., Goldberg, Ethan M., Roser, Timo, Borggraefe, Ingo, Brünger, Tobias, May, Patrick, Lal, Dennis, Lederer, Damien, Rubboli, Guido, Lesca, Gaetan, Hedrich, Ulrike B. S., Benda, Jan, Gardella, Elena, Lerche, Holger, Møller, Rikke S., and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]
Subjects: Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant]
Abstract: We report detailed functional analyses and genotype-phenotype correlations in 433 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6. Five different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n=17, normal cognition, treatable seizures), 2) intermediate epilepsy (n=36, mild ID, partially pharmacoresponsive), 3) developmental and epileptic encephalopathy (DEE, n=191, severe ID, majority pharmacoresistant), 4) generalized epilepsy (n=21, mild to moderate ID, frequently with absence seizures), and 5) affected individuals without epilepsy (n=25, mild to moderate ID). Groups 1-3 presented with early-onset (median: four months) focal or multifocal seizures and epileptic discharges, whereas the onset of seizures in group 4 was later (median: 39 months) with generalized epileptic discharges. The epilepsy was not classifiable in 143 individuals. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin insensitive human NaV1.6 channels and whole-cell patch clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 165 individuals. All 133 individuals carrying GOF variants had either focal (76, groups 1-3), or unclassifiable epilepsy (37), whereas 32 with LOF variants had either generalized (14), no (11) or unclassifiable (5) epilepsy; only two had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of groups 1-3.In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a therapeutic treatment option in early onset SCN8A-related focal epilepsy.
Published: 2021

17. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

Author: Johannesen, Katrine M, primary, Liu, Yuanyuan, additional, Koko, Mahmoud, additional, Gjerulfsen, Cathrine E, additional, Sonnenberg, Lukas, additional, Schubert, Julian, additional, Fenger, Christina D, additional, Eltokhi, Ahmed, additional, Rannap, Maert, additional, Koch, Nils A, additional, Lauxmann, Stephan, additional, Krüger, Johanna, additional, Kegele, Josua, additional, Canafoglia, Laura, additional, Franceschetti, Silvana, additional, Mayer, Thomas, additional, Rebstock, Johannes, additional, Zacher, Pia, additional, Ruf, Susanne, additional, Alber, Michael, additional, Sterbova, Katalin, additional, Lassuthová, Petra, additional, Vlckova, Marketa, additional, Lemke, Johannes R, additional, Platzer, Konrad, additional, Krey, Ilona, additional, Heine, Constanze, additional, Wieczorek, Dagmar, additional, Kroell-Seger, Judith, additional, Lund, Caroline, additional, Klein, Karl Martin, additional, Au, P Y Billie, additional, Rho, Jong M, additional, Ho, Alice W, additional, Masnada, Silvia, additional, Veggiotti, Pierangelo, additional, Giordano, Lucio, additional, Accorsi, Patrizia, additional, Hoei-Hansen, Christina E, additional, Striano, Pasquale, additional, Zara, Federico, additional, Verhelst, Helene, additional, Verhoeven, Judith S, additional, Braakman, Hilde M H, additional, van der Zwaag, Bert, additional, Harder, Aster V E, additional, Brilstra, Eva, additional, Pendziwiat, Manuela, additional, Lebon, Sebastian, additional, Vaccarezza, Maria, additional, Le, Ngoc Minh, additional, Christensen, Jakob, additional, Grønborg, Sabine, additional, Scherer, Stephen W, additional, Howe, Jennifer, additional, Fazeli, Walid, additional, Howell, Katherine B, additional, Leventer, Richard, additional, Stutterd, Chloe, additional, Walsh, Sonja, additional, Gerard, Marion, additional, Gerard, Bénédicte, additional, Matricardi, Sara, additional, Bonardi, Claudia M, additional, Sartori, Stefano, additional, Berger, Andrea, additional, Hoffman-Zacharska, Dorota, additional, Mastrangelo, Massimo, additional, Darra, Francesca, additional, Vøllo, Arve, additional, Motazacker, M Mahdi, additional, Lakeman, Phillis, additional, Nizon, Mathilde, additional, Betzler, Cornelia, additional, Altuzarra, Cecilia, additional, Caume, Roseline, additional, Roubertie, Agathe, additional, Gélisse, Philippe, additional, Marini, Carla, additional, Guerrini, Renzo, additional, Bilan, Frederic, additional, Tibussek, Daniel, additional, Koch-Hogrebe, Margarete, additional, Perry, M Scott, additional, Ichikawa, Shoji, additional, Dadali, Elena, additional, Sharkov, Artem, additional, Mishina, Irina, additional, Abramov, Mikhail, additional, Kanivets, Ilya, additional, Korostelev, Sergey, additional, Kutsev, Sergey, additional, Wain, Karen E, additional, Eisenhauer, Nancy, additional, Wagner, Monisa, additional, Savatt, Juliann M, additional, Müller-Schlüter, Karen, additional, Bassan, Haim, additional, Borovikov, Artem, additional, Nassogne, Marie Cecile, additional, Destrée, Anne, additional, Schoonjans, An Sofie, additional, Meuwissen, Marije, additional, Buzatu, Marga, additional, Jansen, Anna, additional, Scalais, Emmanuel, additional, Srivastava, Siddharth, additional, Tan, Wen Hann, additional, Olson, Heather E, additional, Loddenkemper, Tobias, additional, Poduri, Annapurna, additional, Helbig, Katherine L, additional, Helbig, Ingo, additional, Fitzgerald, Mark P, additional, Goldberg, Ethan M, additional, Roser, Timo, additional, Borggraefe, Ingo, additional, Brünger, Tobias, additional, May, Patrick, additional, Lal, Dennis, additional, Lederer, Damien, additional, Rubboli, Guido, additional, Heyne, Henrike O, additional, Lesca, Gaetan, additional, Hedrich, Ulrike B S, additional, Benda, Jan, additional, Gardella, Elena, additional, Lerche, Holger, additional, and Møller, Rikke S, additional
Published: 2021
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18. Additional file 1 of Direct and indirect costs and cost-driving factors of Tuberous sclerosis complex in children, adolescents, and caregivers: a multicenter cohort study

Author: Grau, Janina, Zöllner, Johann Philipp, Schubert-Bast, Susanne, Kurlemann, Gerhard, Hertzberg, Christoph, Wiemer-Kruel, Adelheid, Bast, Thomas, Bertsche, Astrid, Bettendorf, Ulrich, Fiedler, Barbara, Hahn, Andreas, Hartmann, Hans, Hornemann, Frauke, Immisch, Ilka, Jacobs, Julia, Kieslich, Matthias, Klein, Karl Martin, Klotz, Kerstin A., Kluger, Gerhard, Knuf, Markus, Mayer, Thomas, Marquard, Klaus, Meyer, Sascha, Muhle, Hiltrud, Müller-Schlüter, Karen, Noda, Anna H., Ruf, Susanne, Sauter, Matthias, Schlump, Jan-Ulrich, Syrbe, Steffen, Thiels, Charlotte, Trollmann, Regina, Wilken, Bernd, Willems, Laurent M., Rosenow, Felix, and Strzelczyk, Adam
Abstract: Additional file 1. Supplementary Table 1. Direct costs related to TSC manifestations.
Published: 2021
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19. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., Goldstein, David B., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., and Goldstein, David B.
Abstract: Summary 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

20. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Johannesen, Katrine M., Liu, Yuanyuan, Gjerulfsen, Cathrine E., Koko, Mahmoud, Sonnenberg, Lukas, Schubert, Julian, Fenger, Christina D., Eltokhi, Ahmed, Rannap, Maert, Koch, Nils A., Lauxmann, Stephan, Krüger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthová, Petra, Vlckova, Marketa, Lemke, Johannes R., Krey, Ilona, Heine, Constanze, Wieczorek, Dagmar, Kroell-Seger, Judith, Lund, Caroline, Klein, Karl Martin, Au, P. Y. Billie, Rho, Jong M., Ho, Alice W., Masnada, Silvia, Veggiotti, Pierangelo, Giordano, Lucio, Accorsi, Patrizia, Hoei-Hansen, Christina E., Striano, Pasquale, Zara, Federico, Verhelst, Helene, S.Verhoeven, Judith, van der Zwaag, Bert, Harder, Aster V. E., Brilstra, Eva, Pendziwiat, Manuela, Lebon, Sebastian, Vaccarezza, Maria, Le, Ngoc Minh, Christensen, Jakob, Schmidt-Petersen, Mette U., Grønborg, Sabine, Scherer, Stephen W., Howe, Jennifer, Fazeli, Walid, Howell, Katherine B., Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Bénédicte, Matricardi, Sara, Bonardi, Claudia M., Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vøllo, Arve, Motazacker, M. Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gélisse, Philippe, Marini, Carla, Guerrini, Renzo, Bilan, Frederic, Tibussek, Daniel, Koch-Hogrebe, Margarete, Perry, M. Scott, Ichikawa, Shoji, Dadali, Elena, Sharkov, Artem, Mishina, Irina, Abramov, Mikhail, Kanivets, Ilya, Korostelev, Sergey, Kutsev, Sergey, Wain, Karen E., Eisenhauer, Nancy, Wagner, Monisa, Savatt, Juliann M., Müller-Schlüter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie-Cecile, Destrée, Anne, Schoonjans, An-Sofie, Meuwissen, Marije, Buzatu, Marga, Jansen, Anna, Scalais, Emmanuel, Srivastava, Siddharth, Tan, Wen-Hann, Olson, Heather E., Loddenkemper, Tobias, Poduri, Annapurna, Helbig, Katherine L., Helbig, Ingo, Fitzgerald, Mark P., Goldberg, Ethan M., Roser, Timo, Borggraefe, Ingo, Brünger, Tobias, May, Patrick, Lal, Dennis, Lederer, Damien, Rubboli, Guido, Lesca, Gaetan, Hedrich, Ulrike B. S., Benda, Jan, Gardella, Elena, Lerche, Holger, Møller, Rikke S., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Johannesen, Katrine M., Liu, Yuanyuan, Gjerulfsen, Cathrine E., Koko, Mahmoud, Sonnenberg, Lukas, Schubert, Julian, Fenger, Christina D., Eltokhi, Ahmed, Rannap, Maert, Koch, Nils A., Lauxmann, Stephan, Krüger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthová, Petra, Vlckova, Marketa, Lemke, Johannes R., Krey, Ilona, Heine, Constanze, Wieczorek, Dagmar, Kroell-Seger, Judith, Lund, Caroline, Klein, Karl Martin, Au, P. Y. Billie, Rho, Jong M., Ho, Alice W., Masnada, Silvia, Veggiotti, Pierangelo, Giordano, Lucio, Accorsi, Patrizia, Hoei-Hansen, Christina E., Striano, Pasquale, Zara, Federico, Verhelst, Helene, S.Verhoeven, Judith, van der Zwaag, Bert, Harder, Aster V. E., Brilstra, Eva, Pendziwiat, Manuela, Lebon, Sebastian, Vaccarezza, Maria, Le, Ngoc Minh, Christensen, Jakob, Schmidt-Petersen, Mette U., Grønborg, Sabine, Scherer, Stephen W., Howe, Jennifer, Fazeli, Walid, Howell, Katherine B., Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Bénédicte, Matricardi, Sara, Bonardi, Claudia M., Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vøllo, Arve, Motazacker, M. Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gélisse, Philippe, Marini, Carla, Guerrini, Renzo, Bilan, Frederic, Tibussek, Daniel, Koch-Hogrebe, Margarete, Perry, M. Scott, Ichikawa, Shoji, Dadali, Elena, Sharkov, Artem, Mishina, Irina, Abramov, Mikhail, Kanivets, Ilya, Korostelev, Sergey, Kutsev, Sergey, Wain, Karen E., Eisenhauer, Nancy, Wagner, Monisa, Savatt, Juliann M., Müller-Schlüter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie-Cecile, Destrée, Anne, Schoonjans, An-Sofie, Meuwissen, Marije, Buzatu, Marga, Jansen, Anna, Scalais, Emmanuel, Srivastava, Siddharth, Tan, Wen-Hann, Olson, Heather E., Loddenkemper, Tobias, Poduri, Annapurna, Helbig, Katherine L., Helbig, Ingo, Fitzgerald, Mark P., Goldberg, Ethan M., Roser, Timo, Borggraefe, Ingo, Brünger, Tobias, May, Patrick, Lal, Dennis, Lederer, Damien, Rubboli, Guido, Lesca, Gaetan, Hedrich, Ulrike B. S., Benda, Jan, Gardella, Elena, Lerche, Holger, and Møller, Rikke S.
Abstract: We report detailed functional analyses and genotype-phenotype correlations in 433 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6. Five different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n=17, normal cognition, treatable seizures), 2) intermediate epilepsy (n=36, mild ID, partially pharmacoresponsive), 3) developmental and epileptic encephalopathy (DEE, n=191, severe ID, majority pharmacoresistant), 4) generalized epilepsy (n=21, mild to moderate ID, frequently with absence seizures), and 5) affected individuals without epilepsy (n=25, mild to moderate ID). Groups 1-3 presented with early-onset (median: four months) focal or multifocal seizures and epileptic discharges, whereas the onset of seizures in group 4 was later (median: 39 months) with generalized epileptic discharges. The epilepsy was not classifiable in 143 individuals. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin insensitive human NaV1.6 channels and whole-cell patch clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 165 individuals. All 133 individuals carrying GOF variants had either focal (76, groups 1-3), or unclassifiable epilepsy (37), whereas 32 with LOF variants had either generalized (14), no (11) or unclassifiable (5) epilepsy; only two had DEE. Computational modeling in the GOF group revealed a signific
Published: 2021

21. Efficacy, retention and tolerability of everolimus in patients with tuberous sclerosis complex: a survey-based study on patients’ perspectives

Author: Willems, Laurent Maximilian, Rosenow, Felix, Schubert-Bast, Susanne, Kurlemann, Gerhard, Zöllner, Johann Philipp, Bast, Thomas, Bertsche, Astrid, Bettendorf, Ulrich, Ebrahimi-Fakhari, Daniel, Grau, Janina, Hahn, Andreas, Hartmann, Hans, Hertzberg, Christoph, Hornemann, Frauke, Immisch, Ilka, Jacobs-LeVan, Julia, Klein, Karl Martin, Klotz, Kerstin Alexandra, Kluger, Gerhard, Knake, Susanne, Knuf, Markus, Marquard, Klaus, Mayer, Thomas, Meyer, Sascha, Muhle, Hiltrud, Müller-Schlüter, Karen, Podewils, Felix von, Ruf, Susanne, Sauter, Matthias, Schäfer, Hannah, Schlump, Jan-Ulrich, Syrbe, Steffen, Thiels, Charlotte, Trollmann, Regina, Wiemer-Kruel, Adelheid, Wilken, Bernd, Zukunft, Bianca, Strzelczyk, Adam, Willems, Laurent Maximilian, Rosenow, Felix, Schubert-Bast, Susanne, Kurlemann, Gerhard, Zöllner, Johann Philipp, Bast, Thomas, Bertsche, Astrid, Bettendorf, Ulrich, Ebrahimi-Fakhari, Daniel, Grau, Janina, Hahn, Andreas, Hartmann, Hans, Hertzberg, Christoph, Hornemann, Frauke, Immisch, Ilka, Jacobs-LeVan, Julia, Klein, Karl Martin, Klotz, Kerstin Alexandra, Kluger, Gerhard, Knake, Susanne, Knuf, Markus, Marquard, Klaus, Mayer, Thomas, Meyer, Sascha, Muhle, Hiltrud, Müller-Schlüter, Karen, Podewils, Felix von, Ruf, Susanne, Sauter, Matthias, Schäfer, Hannah, Schlump, Jan-Ulrich, Syrbe, Steffen, Thiels, Charlotte, Trollmann, Regina, Wiemer-Kruel, Adelheid, Wilken, Bernd, Zukunft, Bianca, and Strzelczyk, Adam
Abstract: Background: The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. Objective: The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective. Methods: A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. Results: Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0–15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8–10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most f
Published: 2021

22. Prescription patterns of antiseizure drugs in tuberous sclerosis complex (TSC)-associated epilepsy: a multicenter cohort study from Germany and review of the literature

Author: Strzelczyk, Adam, primary, Grau, Janina, additional, Bast, Thomas, additional, Bertsche, Astrid, additional, Bettendorf, Ulrich, additional, Hahn, Andreas, additional, Hartmann, Hans, additional, Hertzberg, Christoph, additional, Hornemann, Frauke, additional, Immisch, Ilka, additional, Jacobs, Julia, additional, Klotz, Kerstin A., additional, Kluger, Gerhard, additional, Knake, Susanne, additional, Knuf, Markus, additional, Kurlemann, Gerhard, additional, Marquard, Klaus, additional, Mayer, Thomas, additional, Meyer, Sascha, additional, Muhle, Hiltrud, additional, Müller-Schlüter, Karen, additional, von Podewils, Felix, additional, Rosenow, Felix, additional, Ruf, Susanne, additional, Sauter, Matthias, additional, Schäfer, Hannah, additional, Schlump, Jan-Ulrich, additional, Schubert-Bast, Susanne, additional, Syrbe, Steffen, additional, Thiels, Charlotte, additional, Trollmann, Regina, additional, Wiemer-Kruel, Adelheid, additional, Wilken, Bernd, additional, Zukunft, Bianca, additional, and Zöllner, Johann Philipp, additional
Published: 2021
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23. Epilepsy Subtype-Specific Copy Number Burden Observed in a Genome-Wide Study of 17 458 Subjects

Author: Niestroj, Lisa-Marie, Perez-Palma, Eduardo, Howrigan, Daniel P., Zhou, Yadi, Cheng, Feixiong, Saarentaus, Elmo, Nürnberg, Peter, Stevelink, Remi, Daly, Mark J., Palotie, Aarno, Lal, Dennis, Feng, Yen-Chen Anne, Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Churchhouse, Claire, Gupta, Namrata, Neale, Benjamin M., Berkovic, Samuel F., Lerche, Holger, Goldstein, David B., Lowenstein, Daniel H., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J., Todaro, Marian, Weckhuysen, Sarah, Stamberger, Hannah, De Jonghe, Peter, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Šterbová, Katalin, Vlcková, Markéta, Sedlácková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, van Baalen, Andreas, von Spiczak, Sarah, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišic, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Muccioli, Lorenzo, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Mameniskiene, Ruta, Utkus, Algirdas, Praninskiene, Ruta, Grikiniene, Jurgita, Samaitiene, Ruta, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapici, Zuhal, Yis, Uluc, Topaloglu, Pinar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Asli, Bebek, Nerses, Ugur-Iseri, Sibel, Baykan, Betül, Salman, Baris, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yesim, Özkara, Çigdem, Sheidley, Beth R., Shain, Catherine, Poduri, Annapurna, Buono, Russell J, Ferraro, Thomas N, Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Piras, Federica, Gili, Tommaso, Ciullo, Valentina, YÜCESAN, EMRAH, Niestroj L.-M., Perez-Palma E., Howrigan D.P., Zhou Y., Cheng F., Saarentaus E., Nurnberg P., Stevelink R., Daly M.J., Palotie A., Lal D, Epi 25 Collaborative, Bisulli F., Tinuper P., Licchetta L., and Epi25 Collaborative
Subjects: Developmental and epileptic encephalopathy, Male, 0301 basic medicine, DNA Copy Number Variations, Disease, Bioinformatics, Genome, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, copy number variation, developmental and epileptic encephalopathy, epilepsy, focal epilepsy, genetic generalized epilepsy, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Generalized epilepsy, DNA Copy Number Variation, Copy number variation, business.industry, Breakpoint, Focal epilepsy, Original Articles, medicine.disease, 3. Good health, Genetic generalized epilepsy, 030104 developmental biology, Female, Human medicine, Neurology (clinical), Personalized medicine, business, 030217 neurology & neurosurgery, Genome-Wide Association Study, Human
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 characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.
Published: 2020

24. Erratum:Correction: The landscape of epilepsy-related GATOR1 variants (Genetics in medicine : official journal of the American College of Medical Genetics (2019) 21 2 (398-408))

Author: Baldassari, Sara, Picard, Fabienne, Verbeek, Nienke E., van Kempen, Marjan, Brilstra, Eva H., Lesca, Gaetan, Conti, Valerio, Guerrini, Renzo, Bisulli, Francesca, Licchetta, Laura, Pippucci, Tommaso, Tinuper, Paolo, Hirsch, Edouard, de Saint Martin, Anne, Chelly, Jamel, Rudolf, Gabrielle, Chipaux, Mathilde, Ferrand-Sorbets, Sarah, Dorfmüller, Georg, Sisodiya, Sanjay, Balestrini, Simona, Schoeler, Natasha, Hernandez-Hernandez, Laura, Krithika, S., Oegema, Renske, Hagebeuk, Eveline, Gunning, Boudewijn, Deckers, Charles, Berghuis, Bianca, Wegner, Ilse, Niks, Erik H., Jansen, Floor E., Braun, Kees, de Jong, Daniëlle, Rubboli, Guido, Talvik, Inga, Sander, Valentin, Uldall, Peter, Jacquemont, Marie Line, Nava, Caroline, Leguern, Eric, Julia, Sophie, Gambardella, Antonio, d'Orsi, Giuseppe, Crichiutti, Giovanni, Faivre, Laurence, Darmency, Veronique, Benova, Barbora, Krsek, Pavel, Biraben, Arnaud, Lebre, Anne Sophie, Jennesson, Mélanie, Sattar, Shifteh, Marchal, Cécile, NordliJr, Douglas R., Lindstrom, Kristin, Striano, Pasquale, Lomax, Lysa Boissé, Kiss, Courtney, Bartolomei, Fabrice, Lepine, Anne Fabienne, Schoonjans, An Sofie, Stouffs, Katrien, Jansen, Anna, Panagiotakaki, Eleni, Ricard-Mousnier, Brigitte, Thevenon, Julien, de Bellescize, Julitta, Catenoix, Hélène, Dorn, Thomas, Zenker, Martin, Müller-Schlüter, Karen, Brandt, Christian, Krey, Ilona, Polster, Tilman, Wolff, Markus, Balci, Meral, Rostasy, Kevin, Achaz, Guillaume, Zacher, Pia, Becher, Thomas, Cloppenborg, Thomas, Yuskaitis, Christopher J., Weckhuysen, Sarah, Poduri, Annapurna, Lemke, Johannes R., Møller, Rikke S., and Baulac, Stéphanie
Abstract: The original version of this article contained an error in the spelling of the author Erik H. Niks, which was incorrectly given as Erik Niks. This has now been corrected in both the PDF and HTML versions of the article.
Published: 2019

25. Correction to:The landscape of epilepsy-related GATOR1 variants (Genetics in Medicine, (2019), 21, 2, (398-408), 10.1038/s41436-018-0060-2)

Author: Baldassari, Sara, Picard, Fabienne, Verbeek, Nienke E., van Kempen, Marjan, Brilstra, Eva H., Lesca, Gaetan, Conti, Valerio, Guerrini, Renzo, Bisulli, Francesca, Licchetta, Laura, Pippucci, Tommaso, Tinuper, Paolo, Hirsch, Edouard, Martin, Anne de Saint, Chelly, Jamel, Rudolf, Gabrielle, Chipaux, Mathilde, Ferrand-Sorbets, Sarah, Dorfmüller, Georg, Sisodiya, Sanjay, Balestrini, Simona, Schoeler, Natasha, Hernandez-Hernandez, Laura, Krithika, S., Oegema, Renske, Hagebeuk, Eveline, Gunning, Boudewijn, Deckers, Charles, Berghuis, Bianca, Wegner, Ilse, Niks, Erik, Jansen, Floor, Braun, Kees, Jong, Daniëlle de, Rubboli, Guido, Talvik, Inga, Sander, Valentin, Uldall, Peter, Jacquemont, Marie Line, Nava, Caroline, Leguern, Eric, Julia, Sophie, Gambardella, Antonio, d’Orsi, Giuseppe, Crichiutti, Giovanni, Faivre, Laurence, Darmency, Veronique, Benova, Barbora, Krsek, Pavel, Biraben, Arnaud, Lebre, Anne Sophie, Jennesson, Mélanie, Sattar, Shifteh, Marchal, Cécile, NordliJr, Douglas R., Lindstrom, Kristin, Striano, Pasquale, Lomax, Lysa Boissé, Kiss, Courtney, Bartolomei, Fabrice, Lepine, Anne Fabienne, Schoonjans, An Sofie, Stouffs, Katrien, Jansen, Anna, Panagiotakaki, Eleni, Ricard-Mousnier, Brigitte, Thevenon, Julien, Bellescize, Julitta de, Catenoix, Hélène, Dorn, Thomas, Zenker, Martin, Müller-Schlüter, Karen, Brandt, Christian, Krey, Ilona, Polster, Tilman, Wolff, Markus, Balci, Meral, Rostasy, Kevin, Achaz, Guillaume, Zacher, Pia, Becher, Thomas, Cloppenborg, Thomas, Yuskaitis, Christopher J., Weckhuysen, Sarah, Poduri, Annapurna, Lemke, Johannes R., Møller, Rikke S., and Baulac, Stéphanie
Subjects: ComputingMethodologies_DOCUMENTANDTEXTPROCESSING
Abstract: The original version of this Article contained an error in the author list where the corresponding author Stéphanie Baulac was repeated twice. This has now been corrected in the HTML, the PDF was correct at the time of publication.
Published: 2019

26. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L., Dhindsa, Ryan S., Stanley, Kate E., Cavalleri, Gianpiero L., Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišić, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Yis, Uluc, Topaloglu, Pınar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Uğur-İşeri, Sibel, Baykan, Betül, Salman, Barış, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yeşim, Özkara, Çiğdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Fanous, Ayman H., McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., Neale, Benjamin M., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L., Dhindsa, Ryan S., Stanley, Kate E., Cavalleri, Gianpiero L., Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, Baalen, Andreas Van, Spiczak, Sarah Von, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišić, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Yis, Uluc, Topaloglu, Pınar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Uğur-İşeri, Sibel, Baykan, Betül, Salman, Barış, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yeşim, Özkara, Çiğdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Fanous, Ayman H., McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., and Neale, Benjamin M.
Abstract: Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.
Published: 2019

27. The landscape of epilepsy-related GATOR1 variants

Author: Genetica, Genetica Klinische Genetica, Genetica Oper. Mangt Genoom Diagnostiek, Brain, Child Health, ZL Kinder Ner en Nec Medisch, Baldassari, Sara, Picard, Fabienne, Verbeek, Nienke E., van Kempen, Marjan, Brilstra, Eva H., Lesca, Gaetan, Conti, Valerio, Guerrini, Renzo, Bisulli, Francesca, Licchetta, Laura, Pippucci, Tommaso, Tinuper, Paolo, Hirsch, Edouard, de Saint Martin, Anne, Chelly, Jamel, Rudolf, Gabrielle, Chipaux, Mathilde, Ferrand-Sorbets, Sarah, Dorfmüller, Georg, Sisodiya, Sanjay, Balestrini, Simona, Schoeler, Natasha, Hernandez-Hernandez, Laura, Krithika, S., Oegema, Renske, Hagebeuk, Eveline, Gunning, Boudewijn, Deckers, Charles, Berghuis, Bianca, Wegner, Ilse, Niks, Erik, Jansen, Floor E., Braun, Kees, de Jong, Daniëlle, Rubboli, Guido, Talvik, Inga, Sander, Valentin, Uldall, Peter, Jacquemont, Marie Line, Nava, Caroline, Leguern, Eric, Julia, Sophie, Gambardella, Antonio, d’Orsi, Giuseppe, Crichiutti, Giovanni, Faivre, Laurence, Darmency, Veronique, Benova, Barbora, Krsek, Pavel, Biraben, Arnaud, Lebre, Anne Sophie, Jennesson, Mélanie, Sattar, Shifteh, Marchal, Cécile, Nordli, Douglas R., Lindstrom, Kristin, Striano, Pasquale, Lomax, Lysa Boissé, Kiss, Courtney, Bartolomei, Fabrice, Lepine, Anne Fabienne, Schoonjans, An Sofie, Stouffs, Katrien, Jansen, Anna, Panagiotakaki, Eleni, Ricard-Mousnier, Brigitte, Thevenon, Julien, de Bellescize, Julitta, Catenoix, Hélène, Dorn, Thomas, Zenker, Martin, Müller-Schlüter, Karen, Brandt, Christian, Krey, Ilona, Polster, Tilman, Wolff, Markus, Balci, Meral, Rostasy, Kevin, Achaz, Guillaume, Zacher, Pia, Becher, Thomas, Cloppenborg, Thomas, Yuskaitis, Christopher J., Weckhuysen, Sarah, Poduri, Annapurna, Lemke, Johannes R., Møller, Rikke S., Baulac, Stéphanie, Genetica, Genetica Klinische Genetica, Genetica Oper. Mangt Genoom Diagnostiek, Brain, Child Health, ZL Kinder Ner en Nec Medisch, Baldassari, Sara, Picard, Fabienne, Verbeek, Nienke E., van Kempen, Marjan, Brilstra, Eva H., Lesca, Gaetan, Conti, Valerio, Guerrini, Renzo, Bisulli, Francesca, Licchetta, Laura, Pippucci, Tommaso, Tinuper, Paolo, Hirsch, Edouard, de Saint Martin, Anne, Chelly, Jamel, Rudolf, Gabrielle, Chipaux, Mathilde, Ferrand-Sorbets, Sarah, Dorfmüller, Georg, Sisodiya, Sanjay, Balestrini, Simona, Schoeler, Natasha, Hernandez-Hernandez, Laura, Krithika, S., Oegema, Renske, Hagebeuk, Eveline, Gunning, Boudewijn, Deckers, Charles, Berghuis, Bianca, Wegner, Ilse, Niks, Erik, Jansen, Floor E., Braun, Kees, de Jong, Daniëlle, Rubboli, Guido, Talvik, Inga, Sander, Valentin, Uldall, Peter, Jacquemont, Marie Line, Nava, Caroline, Leguern, Eric, Julia, Sophie, Gambardella, Antonio, d’Orsi, Giuseppe, Crichiutti, Giovanni, Faivre, Laurence, Darmency, Veronique, Benova, Barbora, Krsek, Pavel, Biraben, Arnaud, Lebre, Anne Sophie, Jennesson, Mélanie, Sattar, Shifteh, Marchal, Cécile, Nordli, Douglas R., Lindstrom, Kristin, Striano, Pasquale, Lomax, Lysa Boissé, Kiss, Courtney, Bartolomei, Fabrice, Lepine, Anne Fabienne, Schoonjans, An Sofie, Stouffs, Katrien, Jansen, Anna, Panagiotakaki, Eleni, Ricard-Mousnier, Brigitte, Thevenon, Julien, de Bellescize, Julitta, Catenoix, Hélène, Dorn, Thomas, Zenker, Martin, Müller-Schlüter, Karen, Brandt, Christian, Krey, Ilona, Polster, Tilman, Wolff, Markus, Balci, Meral, Rostasy, Kevin, Achaz, Guillaume, Zacher, Pia, Becher, Thomas, Cloppenborg, Thomas, Yuskaitis, Christopher J., Weckhuysen, Sarah, Poduri, Annapurna, Lemke, Johannes R., Møller, Rikke S., and Baulac, Stéphanie
Published: 2019

28. Efficacy, retention, and tolerability of Brivaracetam in patients with epileptic encephalopathies : a multicenter cohort study from Germany

Author: Willems, Laurent M., Bertsche, Astrid, Bösebeck, Frank, Hornemann, Frauke, Immisch, Ilka, Klein, Karl M., Knake, Susanne, Kunz, Rhina, Kurlemann, Gerhard, Langenbruch, Lisa, Möddel, Gabriel, Müller-Schlüter, Karen, von Podewils, Felix, Reif, Philipp S., Steinhoff, Bernhard J., Steinig, Isabel, Rosenow, Felix, Schubert-Bast, Susanne, Strzelczyk, Adam, and Cendes, Fernando
Subjects: Neurology, levetiracetam, seizure, epileptic encephalopathies, anticonvulsants, epilepsy, ddc:610, Original Research
Abstract: Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE). Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017. Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%. Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam.
Published: 2018

29. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author: Feng, Yen-Chen Anne, primary, Howrigan, Daniel P., additional, Abbott, Liam E., additional, Tashman, Katherine, additional, Cerrato, Felecia, additional, Singh, Tarjinder, additional, Heyne, Henrike, additional, Byrnes, Andrea, additional, Churchhouse, Claire, additional, Watts, Nick, additional, Solomonson, Matthew, additional, Lal, Dennis, additional, Heinzen, Erin L., additional, Dhindsa, Ryan S., additional, Stanley, Kate E., additional, Cavalleri, Gianpiero L., additional, Hakonarson, Hakon, additional, Helbig, Ingo, additional, Krause, Roland, additional, May, Patrick, additional, Weckhuysen, Sarah, additional, Petrovski, Slavé, additional, Kamalakaran, Sitharthan, additional, Sisodiya, Sanjay M., additional, Cossette, Patrick, additional, Cotsapas, Chris, additional, De Jonghe, Peter, additional, Dixon-Salazar, Tracy, additional, Guerrini, Renzo, additional, Kwan, Patrick, additional, Marson, Anthony G., additional, Stewart, Randy, additional, Depondt, Chantal, additional, Dlugos, Dennis J., additional, Scheffer, Ingrid E., additional, Striano, Pasquale, additional, Freyer, Catharine, additional, McKenna, Kevin, additional, Regan, Brigid M., additional, Bellows, Susannah T., additional, Leu, Costin, additional, Bennett, Caitlin A., additional, Johns, Esther M.C., additional, Macdonald, Alexandra, additional, Shilling, Hannah, additional, Burgess, Rosemary, additional, Weckhuysen, Dorien, additional, Bahlo, Melanie, additional, O’Brien, Terence J., additional, Todaro, Marian, additional, Stamberger, Hannah, additional, Andrade, Danielle M., additional, Sadoway, Tara R., additional, Mo, Kelly, additional, Krestel, Heinz, additional, Gallati, Sabina, additional, Papacostas, Savvas S., additional, Kousiappa, Ioanna, additional, Tanteles, George A., additional, Štěrbová, Katalin, additional, Vlčková, Markéta, additional, Sedláčková, Lucie, additional, Laššuthová, Petra, additional, Klein, Karl Martin, additional, Rosenow, Felix, additional, Reif, Philipp S., additional, Knake, Susanne, additional, Kunz, Wolfram S., additional, Zsurka, Gábor, additional, Elger, Christian E., additional, Bauer, Jürgen, additional, Rademacher, Michael, additional, Pendziwiat, Manuela, additional, Muhle, Hiltrud, additional, Rademacher, Annika, additional, van Baalen, Andreas, additional, von Spiczak, Sarah, additional, Stephani, Ulrich, additional, Afawi, Zaid, additional, Korczyn, Amos D., additional, Kanaan, Moien, additional, Canavati, Christina, additional, Kurlemann, Gerhard, additional, Müller-Schlüter, Karen, additional, Kluger, Gerhard, additional, Häusler, Martin, additional, Blatt, Ilan, additional, Lemke, Johannes R., additional, Krey, Ilona, additional, Weber, Yvonne G., additional, Wolking, Stefan, additional, Becker, Felicitas, additional, Hengsbach, Christian, additional, Rau, Sarah, additional, Maisch, Ana F., additional, Steinhoff, Bernhard J., additional, Schulze-Bonhage, Andreas, additional, Schubert-Bast, Susanne, additional, Schreiber, Herbert, additional, Borggräfe, Ingo, additional, Schankin, Christoph J., additional, Mayer, Thomas, additional, Korinthenberg, Rudolf, additional, Brockmann, Knut, additional, Dennig, Dieter, additional, Madeleyn, Rene, additional, Kälviäinen, Reetta, additional, Auvinen, Pia, additional, Saarela, Anni, additional, Linnankivi, Tarja, additional, Lehesjoki, Anna-Elina, additional, Rees, Mark I., additional, Chung, Seo-Kyung, additional, Pickrell, William O., additional, Powell, Robert, additional, Schneider, Natascha, additional, Balestrini, Simona, additional, Zagaglia, Sara, additional, Braatz, Vera, additional, Johnson, Michael R., additional, Auce, Pauls, additional, Sills, Graeme J., additional, Baum, Larry W., additional, Sham, Pak C., additional, Cherny, Stacey S., additional, Lui, Colin H.T., additional, Barišić, Nina, additional, Delanty, Norman, additional, Doherty, Colin P., additional, Shukralla, Arif, additional, McCormack, Mark, additional, El-Naggar, Hany, additional, Canafoglia, Laura, additional, Franceschetti, Silvana, additional, Castellotti, Barbara, additional, Granata, Tiziana, additional, Zara, Federico, additional, Iacomino, Michele, additional, Madia, Francesca, additional, Vari, Maria Stella, additional, Mancardi, Maria Margherita, additional, Salpietro, Vincenzo, additional, Bisulli, Francesca, additional, Tinuper, Paolo, additional, Licchetta, Laura, additional, Pippucci, Tommaso, additional, Stipa, Carlotta, additional, Minardi, Raffaella, additional, Gambardella, Antonio, additional, Labate, Angelo, additional, Annesi, Grazia, additional, Manna, Lorella, additional, Gagliardi, Monica, additional, Parrini, Elena, additional, Mei, Davide, additional, Vetro, Annalisa, additional, Bianchini, Claudia, additional, Montomoli, Martino, additional, Doccini, Viola, additional, Marini, Carla, additional, Suzuki, Toshimitsu, additional, Inoue, Yushi, additional, Yamakawa, Kazuhiro, additional, Tumiene, Birute, additional, Sadleir, Lynette G., additional, King, Chontelle, additional, Mountier, Emily, additional, Caglayan, S. Hande, additional, Arslan, Mutluay, additional, Yapıcı, Zuhal, additional, Yis, Uluc, additional, Topaloglu, Pınar, additional, Kara, Bulent, additional, Turkdogan, Dilsad, additional, Gundogdu-Eken, Aslı, additional, Bebek, Nerses, additional, Uğur-İşeri, Sibel, additional, Baykan, Betül, additional, Salman, Barış, additional, Haryanyan, Garen, additional, Yücesan, Emrah, additional, Kesim, Yeşim, additional, Özkara, Çiğdem, additional, Poduri, Annapurna, additional, Shiedley, Beth R., additional, Shain, Catherine, additional, Buono, Russell J., additional, Ferraro, Thomas N., additional, Sperling, Michael R., additional, Lo, Warren, additional, Privitera, Michael, additional, French, Jacqueline A., additional, Schachter, Steven, additional, Kuzniecky, Ruben I., additional, Devinsky, Orrin, additional, Hegde, Manu, additional, Khankhanian, Pouya, additional, Helbig, Katherine L., additional, Ellis, Colin A., additional, Spalletta, Gianfranco, additional, Piras, Fabrizio, additional, Piras, Federica, additional, Gili, Tommaso, additional, Ciullo, Valentina, additional, Reif, Andreas, additional, McQuillin, Andrew, additional, Bass, Nick, additional, McIntosh, Andrew, additional, Blackwood, Douglas, additional, Johnstone, Mandy, additional, Palotie, Aarno, additional, Pato, Michele T., additional, Pato, Carlos N., additional, Bromet, Evelyn J., additional, Carvalho, Celia Barreto, additional, Achtyes, Eric D., additional, Azevedo, Maria Helena, additional, Kotov, Roman, additional, Lehrer, Douglas S., additional, Malaspina, Dolores, additional, Marder, Stephen R., additional, Medeiros, Helena, additional, Morley, Christopher P., additional, Perkins, Diana O., additional, Sobell, Janet L., additional, Buckley, Peter F., additional, Macciardi, Fabio, additional, Rapaport, Mark H., additional, Knowles, James A., additional, Fanous, Ayman H., additional, McCarroll, Steven A., additional, Gupta, Namrata, additional, Gabriel, Stacey B., additional, Daly, Mark J., additional, Lander, Eric S., additional, Lowenstein, Daniel H., additional, Goldstein, David B., additional, Lerche, Holger, additional, Berkovic, Samuel F., additional, and Neale, Benjamin M., additional
Published: 2019
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30. Postmarketing experience with brivaracetam in the treatment of focal epilepsy in children and adolescents

Author: Schubert-Bast, Susanne, primary, Willems, Laurent M., additional, Kurlemann, Gerhard, additional, Knake, Susanne, additional, Müller-Schlüter, Karen, additional, Rosenow, Felix, additional, and Strzelczyk, Adam, additional
Published: 2018
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31. Efficacy, retention, and tolerability of Brivaracetam in patients with epileptic encephalopathies : a multicenter cohort study from Germany

Author: Cendes, Fernando, Willems, Laurent Maximilian, Bertsche, Astrid, Bösebeck, Frank, Hornemann, Frauke, Immisch, Ilka, Klein, Karl Martin, Knake, Susanne, Kunz, Rhina, Kurlemann, Gerhard, Langenbruch, Lisa Marie, Möddel, Gabriel, Müller-Schlüter, Karen, Podewils, Felix von, Reif, Philipp Sebastian, Steinhoff, Bernhard J., Steinig, Isabel, Rosenow, Felix, Schubert-Bast, Susanne, Strzelczyk, Adam, Cendes, Fernando, Willems, Laurent Maximilian, Bertsche, Astrid, Bösebeck, Frank, Hornemann, Frauke, Immisch, Ilka, Klein, Karl Martin, Knake, Susanne, Kunz, Rhina, Kurlemann, Gerhard, Langenbruch, Lisa Marie, Möddel, Gabriel, Müller-Schlüter, Karen, Podewils, Felix von, Reif, Philipp Sebastian, Steinhoff, Bernhard J., Steinig, Isabel, Rosenow, Felix, Schubert-Bast, Susanne, and Strzelczyk, Adam
Abstract: Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE). Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017. Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%. Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam.
Published: 2018

32. Efficacy, Retention, and Tolerability of Brivaracetam in Patients With Epileptic Encephalopathies: A Multicenter Cohort Study From Germany

Author: Willems, Laurent M., primary, Bertsche, Astrid, additional, Bösebeck, Frank, additional, Hornemann, Frauke, additional, Immisch, Ilka, additional, Klein, Karl M., additional, Knake, Susanne, additional, Kunz, Rhina, additional, Kurlemann, Gerhard, additional, Langenbruch, Lisa, additional, Möddel, Gabriel, additional, Müller-Schlüter, Karen, additional, von Podewils, Felix, additional, Reif, Philipp S., additional, Steinhoff, Bernhard J., additional, Steinig, Isabel, additional, Rosenow, Felix, additional, Schubert-Bast, Susanne, additional, and Strzelczyk, Adam, additional
Published: 2018
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33. Use of brivaracetam in genetic generalized epilepsies and for acute, intravenous treatment of absence status epilepticus

Author: Strzelczyk, Adam, primary, Kay, Lara, additional, Bauer, Sebastian, additional, Immisch, Ilka, additional, Klein, Karl Martin, additional, Knake, Susanne, additional, Kowski, Alexander, additional, Kunz, Rhina, additional, Kurlemann, Gerhard, additional, Langenbruch, Lisa, additional, Möddel, Gabriel, additional, Müller-Schlüter, Karen, additional, Reif, Philipp S., additional, Schubert-Bast, Susanne, additional, Steinhoff, Bernhard J., additional, Steinig, Isabel, additional, Willems, Laurent M., additional, von Podewils, Felix, additional, and Rosenow, Felix, additional
Published: 2018
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34. Regulation of Arginine Vasopressin in Enuretic Children Under Fluid Restriction

Author: Eggert, Paul, primary, Müller-Schlüter, Karen, additional, and Müller, Dominik, additional
Published: 1999
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35. Distinct gene-set burden patterns underlie common generalized and focal epilepsies

Author: Mahmoud Koko, Roland Krause, Thomas Sander, Dheeraj Reddy Bobbili, Michael Nothnagel, Patrick May, Holger Lerche, Yen-Chen Anne Feng, Daniel P Howrigan, Liam E Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L Heinzen, Ryan S Dhindsa, Kate E Stanley, Gianpiero L Cavalleri, Hakon Hakonarson, Ingo Helbig, Sarah Weckhuysen, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M Sisodiya, Patrick Cossette, Chris Cotsapas, Peter DeJonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G Marson, Randy Stewart, Chantal Depondt, Dennis J Dlugos, Ingrid E Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M Regan, Susannah T Bellows, Costin Leu, Caitlin A Bennett, Esther M C Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J O'Brien, Marian Todaro, Hannah Stamberger, Danielle M Andrade, Tara R Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S Papacostas, Ioanna Kousiappa, George A Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S Reif, Susanne Knake, Wolfram S Kunz, Gábor Zsurka, Christian E Elger, Jürgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas vanBaalen, Sarah vonSpiczak, Ulrich Stephani, Zaid Afawi, Amos D Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R Lemke, Ilona Krey, Yvonne G Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F Maisch, Bernhard J Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I Rees, Seo-Kyung Chung, William O Pickrell, Robert Powell, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R Johnson, Pauls Auce, Graeme J Sills, Larry W Baum, Pak C Sham, Stacey S Cherny, Colin H T Lui, Nina Barišić, Norman Delanty, Colin P Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G Sadleir, Chontelle King, Emily Mountier, Hande S Caglayan, Mutluay Arslan, Zuhal Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, Annapurna Poduri, Beth R Shiedley, Catherine Shain, Russell J Buono, Thomas N Ferraro, Michael R Sperling, Warren Lo, Michael Privitera, Jacqueline A French, Steven Schachter, Ruben I Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L Helbig, Colin A Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T Pato, Carlos N Pato, Evelyn J Bromet, Celia Barreto Carvalho, Eric D Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S Lehrer, Dolores Malaspina, Stephen R Marder, Helena Medeiros, Christopher P Morley, Diana O Perkins, Janet L Sobell, Peter F Buckley, Fabio Macciardi, Mark H Rapaport, James A Knowles, Genomic Psychiatry Cohort, Ayman H Fanous, Steven A McCarroll, Namrata Gupta, Stacey B Gabriel, Mark J Daly, Eric S Lander, Daniel H Lowenstein, David B Goldstein, Samuel F Berkovic, Benjamin M Neale, Epi25 Collaborative, Koko M., Krause R., Sander T., Bobbili D.R., Nothnagel M., May P., Lerche H., Bisulli F., Tinuper P., Pippucci T., Abbott, Liam E., Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Tashman, Katherine, Korinthenberg, Rudolf, Brockmann, Knut, Kurlemann, Gerhard, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Cerrato, Felecia, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Singh, Tarjinder, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišic, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, Heyne, Henrike, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Byrnes, Andrea, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Churchhouse, Claire, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Watts, Nick, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, Hande S., Arslan, Mutluay, Yapici, Zuhal, Yis, Uluc, Solomonson, Matthew, Topaloglu, Pinar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Asli, Bebek, Nerses, Ugur-Iseri, Sibel, Baykan, Betül, Salman, Baris, Haryanyan, Garen, Yücesan, Emrah, Lal, Dennis, Kesim, Yesim, Özkara, Çigdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, Heinzen, Erin L., French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Dhindsa, Ryan S., Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Stanley, Kate E., Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Cavalleri, Gianpiero L., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Cohort, Genomic Psychiatry, Fanous, Ayman H., Hakonarson, Hakon, McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., Neale, Benjamin M., Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, DeJonghe, Peter, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O'Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Šterbová, Katalin, Vlcková, Markéta, Sedlácková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Feng, Yen-Chen Anne, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, van Baalen, Andreas, von Spiczak, Sarah, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Howrigan, Daniel P., Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany). [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]
Subjects: Exome sequencing, Male, Medicine (General), Neurology [D14] [Human health sciences], Gene-set, Genome-wide association study, Disease, Biology, Epileptogenesis, General Biochemistry, Genetics and Molecular Biology, Whole Exome Sequencing, Epilepsy, R5-920, medicine, Missense mutation, Humans, Exome, Genetic Predisposition to Disease, Gene, Genetic association, Ultra-rare variant, Genetics, Neurologie [D14] [Sciences de la santé humaine], Burden analysis, Genetic Variation, General Medicine, medicine.disease, Ultra-rare variants, Gene-sets, Case-Control Studies, Medicine, epilepsy, Epilepsy, Generalized, Female, Genetics & genetic processes [F10] [Life sciences], Epilepsies, Partial, Human medicine, Burden analysi, Génétique & processus génétiques [F10] [Sciences du vivant], Case-Control Studie, Research Paper, Genome-Wide Association Study, Human
Abstract: EBioMedicine 72, 103588 (2021). doi:10.1016/j.ebiom.2021.103588, Published by Elsevier, Amsterdam [u.a.]
Published: 2021

36. Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

Author: Chen S, Abou-Khalil BW, Afawi Z, Ali QZ, Amadori E, Anderson A, Anderson J, Andrade DM, Annesi G, Arslan M, Auce P, Bahlo M, Baker MD, Balagura G, Balestrini S, Banks E, Barba C, Barboza K, Bartolomei F, Bass N, Baum LW, Baumgartner TH, Baykan B, Bebek N, Becker F, Bennett CA, Beydoun A, Bianchini C, Bisulli F, Blackwood D, Blatt I, Borggräfe I, Bosselmann C, Braatz V, Brand H, Brockmann K, Buono RJ, Busch RM, Caglayan SH, Canafoglia L, Canavati C, Castellotti B, Cavalleri GL, Cerrato F, Chassoux F, Cherian C, Cherny SS, Cheung CL, Chou IJ, Chung SK, Churchhouse C, Ciullo V, Clark PO, Cole AJ, Cosico M, Cossette P, Cotsapas C, Cusick C, Daly MJ, Davis LK, Jonghe P, Delanty N, Dennig D, Depondt C, Derambure P, Devinsky O, Di Vito L, Dickerson F, Dlugos DJ, Doccini V, Doherty CP, El-Naggar H, Ellis CA, Epstein L, Evans M, Faucon A, Feng YA, Ferguson L, Ferraro TN, Da Silva IF, Ferri L, Feucht M, Fields MC, Fitzgerald M, Fonferko-Shadrach B, Fortunato F, Franceschetti S, French JA, Freri E, Fu JM, Gabriel S, Gagliardi M, Gambardella A, Gauthier L, Giangregorio T, Gili T, Glauser TA, Goldberg E, Goldman A, Goldstein DB, Granata T, Grant R, Greenberg DA, Guerrini R, Gundogdu-Eken A, Gupta N, Haas K, Hakonarson H, Haryanyan G, Häusler M, Hegde M, Heinzen EL, Helbig I, Hengsbach C, Heyne H, Hirose S, Hirsch E, Ho CJ, Hoeper O, Howrigan DP, Hucks D, Hung PC, Iacomino M, Inoue Y, Inuzuka LM, Ishii A, Jehi L, Johnson MR, Johnstone M, Kälviäinen R, Kanaan M, Kara B, Kariuki SM, Kegele J, Kesim Y, Khoueiry-Zgheib N, Khoury J, King C, Klein KM, Kluger G, Knake S, Kok F, Korczyn AD, Korinthenberg R, Koupparis A, Kousiappa I, Krause R, Krenn M, Krestel H, Krey I, Kunz WS, Kurlemann G, Kuzniecky RI, Kwan P, La Vega-Talbott M, Labate A, Lacey A, Lal D, Laššuthová P, Lauxmann S, Lawthom C, Leech SL, Lehesjoki AE, Lemke JR, Lerche H, Lesca G, Leu C, Lewin N, Lewis-Smith D, Li GH, Liao C, Licchetta L, Lin CH, Lin KL, Linnankivi T, Lo W, Lowenstein DH, Lowther C, Lubbers L, Lui CHT, Macedo-Souza LI, Madeleyn R, Madia F, Magri S, Maillard L, Marcuse L, Marques P, Marson AG, Matthews AG, May P, Mayer T, McArdle W, McCarroll SM, McGoldrick P, McGraw CM, McIntosh A, McQuillan A, Meador KJ, Mei D, Michel V, Millichap JJ, Minardi R, Montomoli M, Mostacci B, Muccioli L, Muhle H, Müller-Schlüter K, Najm IM, Nasreddine W, Neaves S, Neubauer BA, Newton CRJC, Noebels JL, Northstone K, Novod S, O'Brien TJ, Owusu-Agyei S, Özkara Ç, Palotie A, Papacostas SS, Parrini E, Pato C, Pato M, Pendziwiat M, Pennell PB, Petrovski S, Pickrell WO, Pinsky R, Pinto D, Pippucci T, Piras F, Piras F, Poduri A, Pondrelli F, Posthuma D, Powell RHW, Privitera M, Rademacher A, Ragona F, Ramirez-Hamouz B, Rau S, Raynes HR, Rees MI, Regan BM, Reif A, Reinthaler E, Rheims S, Ring SM, Riva A, Rojas E, Rosenow F, Ryvlin P, Saarela A, Sadleir LG, Salman B, Salmon A, Salpietro V, Sammarra I, Scala M, Schachter S, Schaller A, Schankin CJ, Scheffer IE, Schneider N, Schubert-Bast S, Schulze-Bonhage A, Scudieri P, Sedláčková L, Shain C, Sham PC, Shiedley BR, Siena SA, Sills GJ, Sisodiya SM, Smoller JW, Solomonson M, Spalletta G, Sparks KR, Sperling MR, Stamberger H, Steinhoff BJ, Stephani U, Štěrbová K, Stewart WC, Stipa C, Striano P, Strzelczyk A, Surges R, Suzuki T, Talarico M, Talkowski ME, Taneja RS, Tanteles GA, Timonen O, Timpson NJ, Tinuper P, Todaro M, Topaloglu P, Tsai MH, Tumiene B, Turkdogan D, Uğur-İşeri S, Utkus A, Vaidiswaran P, Valton L, van Baalen A, Vari MS, Vetro A, Vlčková M, von Brauchitsch S, von Spiczak S, Wagner RG, Watts N, Weber YG, Weckhuysen S, Widdess-Walsh P, Wiebe S, Wolf SM, Wolff M, Wolking S, Wong I, von Wrede R, Wu D, Yamakawa K, Yapıcı Z, Yis U, Yolken R, Yücesan E, Zagaglia S, Zahnert F, Zara F, Zimprich F, Zizovic M, Zsurka G, Neale BM, and Berkovic SF
Abstract: Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies., Competing Interests: Competing Interests B.M.N is a member of the scientific advisory board at Deep Genomics and Neumora. No other authors have competing interests to declare
Published: 2024
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37. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications.

Author: Johannesen KM, Liu Y, Koko M, Gjerulfsen CE, Sonnenberg L, Schubert J, Fenger CD, Eltokhi A, Rannap M, Koch NA, Lauxmann S, Krüger J, Kegele J, Canafoglia L, Franceschetti S, Mayer T, Rebstock J, Zacher P, Ruf S, Alber M, Sterbova K, Lassuthová P, Vlckova M, Lemke JR, Platzer K, Krey I, Heine C, Wieczorek D, Kroell-Seger J, Lund C, Klein KM, Au PYB, Rho JM, Ho AW, Masnada S, Veggiotti P, Giordano L, Accorsi P, Hoei-Hansen CE, Striano P, Zara F, Verhelst H, Verhoeven JS, Braakman HMH, van der Zwaag B, Harder AVE, Brilstra E, Pendziwiat M, Lebon S, Vaccarezza M, Le NM, Christensen J, Grønborg S, Scherer SW, Howe J, Fazeli W, Howell KB, Leventer R, Stutterd C, Walsh S, Gerard M, Gerard B, Matricardi S, Bonardi CM, Sartori S, Berger A, Hoffman-Zacharska D, Mastrangelo M, Darra F, Vøllo A, Motazacker MM, Lakeman P, Nizon M, Betzler C, Altuzarra C, Caume R, Roubertie A, Gélisse P, Marini C, Guerrini R, Bilan F, Tibussek D, Koch-Hogrebe M, Perry MS, Ichikawa S, Dadali E, Sharkov A, Mishina I, Abramov M, Kanivets I, Korostelev S, Kutsev S, Wain KE, Eisenhauer N, Wagner M, Savatt JM, Müller-Schlüter K, Bassan H, Borovikov A, Nassogne MC, Destrée A, Schoonjans AS, Meuwissen M, Buzatu M, Jansen A, Scalais E, Srivastava S, Tan WH, Olson HE, Loddenkemper T, Poduri A, Helbig KL, Helbig I, Fitzgerald MP, Goldberg EM, Roser T, Borggraefe I, Brünger T, May P, Lal D, Lederer D, Rubboli G, Heyne HO, Lesca G, Hedrich UBS, Benda J, Gardella E, Lerche H, and Møller RS
Subjects: Genetic Association Studies, Humans, Infant, Mutation, Prognosis, Seizures drug therapy, Seizures genetics, Sodium Channel Blockers therapeutic use, Epilepsy, Generalized drug therapy, Epilepsy, Generalized genetics, Epileptic Syndromes drug therapy, Epileptic Syndromes genetics, Intellectual Disability genetics, NAV1.6 Voltage-Gated Sodium Channel genetics
Abstract: We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Published: 2022
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37 results on '"Müller-Schlüter, Karen"'

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