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1. Investigating the effect of polygenic background on epilepsy phenotype in ‘monogenic’ familiesResearch in context

Author

Karen L. Oliver, Ingrid E. Scheffer, Colin A. Ellis, Bronwyn E. Grinton, Samuel F. Berkovic, Melanie Bahlo, Zaid Afawi, Dina Amrom, Eva Andermann, Jocelyn F. Bautista, Susannah T. Bellows, Judith Bluvstein, Gregory D. Cascino, Seo-Kyung Chung, Patrick Cossette, Sarah W. Curtis, Norman Delanty, Orrin Devinsky, Dennis Dlugos, Michael P. Epstein, Catharine Freyer, Micheline Gravel, Rebekah V. Harris, Erin L. Heinzen, Olivia J. Henry, Heidi E. Kirsch, Robert C. Knowlton, Eric H. Kossoff, Rebecca Loeb, Daniel H. Lowenstein, Anthony G. Marson, Heather C. Mefford, Paul V. Motika, Terence J. O'Brien, Ruth Ottman, Juliann M. Paolicchi, Slave Petrovski, William O. Pickrell, Mark I. Rees, Lynette G. Sadleir, Jerry J. Shih, Rani K. Singh, Michael C. Smith, Philip E.M. Smith, Rhys H. Thomas, Judith Weisenberg, Peter Widdess-Walsh, and Melodie R. Winawer

Subjects
Epilepsy genetics, Familial epilepsies, Genetic modifiers, Polygenic risk, GEFS+, GABRG2, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Phenotypic variability within families with epilepsy is often observed, even when relatives share the same monogenic cause. We aimed to investigate whether common polygenic risk for epilepsy could explain the penetrance and phenotypic expression of rare pathogenic variants in familial epilepsies. Methods: We studied 58 clinically heterogeneous families with genetic epilepsy with febrile seizures plus (GEFS+). Relatives were coded as either unaffected or affected with epilepsy, and graded according to phenotype severity: no seizures, febrile seizures (FS) only, febrile seizures plus (FS+), generalised/focal epilepsy, or developmental and epileptic encephalopathy (DEE). Epilepsy polygenic risk scores (PRSs) were tested for association with epilepsy phenotype. Within families, the mean PRS difference was compared between pairs concordant versus discordant for phenotype severity. Statistical analyses were performed using mixed-effect regression models. Findings: 304 individuals segregating a known, or presumed, rare variant of large effect, were studied. Within families, higher epilepsy polygenic risk was associated with an epilepsy diagnosis (OR = 1.39, 95% CI 1.08, 1.80, padj = 0.040). Relatives with a more severe phenotype had a mean pairwise PRS difference of +0.19 higher than relatives with a milder phenotype (padj = 0.010). The difference increased with greater phenotype discordance between relatives. As the cohort included two rare variants with >30 relatives each, variant-specific genotype–phenotype associations could also be analysed. Whilst the epilepsy PRS effect was strong for relatives segregating the GABRG2 p.Arg82Gln pathogenic variant (padj = 0.0010), the effect was not significant for SCN1B p.Cys121Trp. Interpretation: We provide support for genetic background modifying the penetrance and phenotypic expression of rare variants associated with ‘monogenic’ epilepsies. In GEFS+ families, relatives with higher epilepsy PRSs were more likely to show penetrance (epilepsy diagnosis) and a more severe phenotype. Variant-specific analyses suggest that some rare variants may be more susceptible to PRS modification, carrying important genetic counselling and disease prognostication implications for patients. Funding: National Health and Medical Research Council of Australia, Medical Research Future Fund of Australia.

Published
2024
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2. LGG-38. Dose-dependent seizure control for an NF1 patient treated via MEK-inhibition for optic pathway glioma

Author

Evan Cantor, Ashley Meyer, Andrea Ogle, Margaret Shatara, Andrew Cluster, Mohamed S Abdelbaki, Stephanie Morris, Judith Weisenberg, and Nicole M Brossier

Subjects
Cancer Research, Oncology, Neurology (clinical)
Abstract

BACKGROUND: Low-grade gliomas (LGG) are the most common solid tumor of childhood and can result in neurologic complications, including seizures, focal neurologic deficits, and learning difficulties. Molecularly targeted agents are increasingly being utilized to treat LGG, but the effect of these agents on accompanying neurologic complications are poorly understood. CASE: An 8-years old male with Neurofibromatosis Type 1 (NF1), medically refractory epilepsy and deep extensive glioma (extending from the optic pathway and involving the basal ganglia and corpus collosum) began selumetinib therapy due to radiographic and symptomatic tumor progression. Radiographic response (resolution of enhancement) was observed at 12 weeks of therapy, accompanied by improvement in seizure frequency, hemiparesis, and academic performance. Due to cardiotoxicity observed at that time (asymptomatic decreased ejection fraction and shortening fraction on echocardiogram), selumetinib was reduced to 50% dosing. On this reduced dose of selumetinib, seizures increased in frequency with subsequent worsening hemiparesis and recurrence of learning difficulties. One month later, dosing was escalated back to 100% due to interval resolution of cardiotoxicity, resulting in resolution of seizures and improvement in focal neurologic deficits and cognition. DISCUSSION: Dose-dependent response to MEK inhibition was observed without concurrent changes in anti-epileptic medications. The tumor was stable in size despite improved enhancement with treatment, suggesting that objective response by RANO criteria is not necessary for improved seizure control in LGG. Recent work has implicated the RAS/MEK/ERK pathway in neuronal precursor cells as a cause for epilepsy, suggesting that MEK inhibition of NF1-heterozygous neurons could be contributing to treatment response in this patient. Improvements in weakness and academic performance may have been due to improved seizure control or a direct effect of MEK inhibition on NF1-heterozygous neurons. CONCLUSION: MEK inhibition may have a clinically relevant anti-seizure effect for patients with pediatric LGG or NF1.

Published
2022
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3. Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Author

Schijven, D., Stevelink, R., Mccormack, M., van Rheenen, W., Luykx, J. J., Koeleman, B. P. C., Veldink, J. H., Aleksey, Shatunov, Mclaughlin, Russell L., van der Spek, Rick A. A., Alfredo, Iacoangeli, Kenna, Kevin P., van Eijk, Kristel R., Nicola, Ticozzi, Boris, Rogelj, Katarina, Vrabec, Metka, Ravnik-Glavač, Blaž, Koritnik, Janez, Zidar, Lea, Leonardis, Leja Dolenc Grošelj, Stéphanie, Millecamps, François, Salachas, Vincent, Meininger, Mamede de Carvalho, Susana, Pinto, Marta, Gromicho, Ana, Pronto-Laborinho, Mora, Jesus S., Ricardo, Rojas-García, Meraida, Polak, Siddharthan, Chandran, Shuna, Colville, Robert, Swingler, Morrison, Karen E., Shaw, Pamela J., John, Hardy, Orrell, Richard W., Alan, Pittman, Katie, Sidle, Pietro, Fratta, Andrea, Malaspina, Simon, Topp, Susanne, Petri, Susanna, Abdulla, Carsten, Drepper, Michael, Sendtner, Thomas, Meyer, Ophoff, Roel A., Staats, Kim A., Martina, Wiedau-Pazos, Catherine, Lomen-Hoerth, Van Deerlin, Vivianna M., Trojanowski, John Q., Lauren, Elman, Leo, Mccluskey, Nazli Basak, A., Thomas, Meitinger, Peter, Lichtner, Milena, Blagojevic-Radivojkov, Andres, Christian R., Gilbert, Bensimon, Bernhard, Landwehrmeyer, Alexis, Brice, Payan, Christine A. M., Safaa, Saker-Delye, Alexandra, Dürr, Wood, Nicholas W., Lukas, Tittmann, Wolfgang, Lieb, Andre, Franke, Marcella, Rietschel, Sven, Cichon, Nöthen, Markus M., Philippe, Amouyel, Christophe, Tzourio, Jean-François, Dartigues, Uitterlinden, Andre G., Fernando, Rivadeneira, Karol, Estrada, Albert, Hofman, Charles, Curtis, van der Kooi, Anneke J., Markus, Weber, Shaw, Christopher E., Smith, Bradley N., Daisy, Sproviero, Cristina, Cereda, Mauro, Ceroni, Luca, Diamanti, Roberto Del Bo, Stefania, Corti, Comi, Giacomo P., Sandra, D'Alfonso, Lucia, Corrado, Bertolin, Cinzia, Soraru', Gianni, Letizia, Mazzini, Viviana, Pensato, Cinzia, Gellera, Cinzia, Tiloca, Antonia, Ratti, Andrea, Calvo, Cristina, Moglia, Maura, Brunetti, Simona, Arcuti, Rosa, Capozzo, Chiara, Zecca, Christian, Lunetta, Silvana, Penco, Nilo, Riva, Alessandro, Padovani, Massimiliano, Filosto, Ian, Blair, Nicholson, Garth A., Rowe, Dominic B., Roger, Pamphlett, Kiernan, Matthew C., Julian, Grosskreutz, Witte, Otto W., Robert, Steinbach, Tino, Prell, Beatrice, Stubendorff, Ingo, Kurth, Hübner, Christian A., Nigel Leigh, P., Federico, Casale, Adriano, Chio, Ettore, Beghi, Elisabetta, Pupillo, Rosanna, Tortelli, Giancarlo, Logroscino, John, Powell, Ludolph, Albert C., Weishaupt, Jochen H., Wim, Robberecht, Philip Van Damme, Brown, Robert H., Glass, Jonathan D., Landers, John E., Orla, Hardiman, Andersen, Peter M., Philippe, Corcia, Patrick, Vourc'H, Vincenzo, Silani, van Es, Michael A., Jeroen Pasterkamp, R., Lewis, Cathryn M., Gerome, Breen, Ammar, Al-Chalabi, van den Berg, Leonard H., Veldink, Jan H., Daniela, Calini, Isabella, Fogh, Barbara, Castellotti, Franco, Taroni, Stella, Gagliardi, Giacomo, Comi, Sandra, D’Alfonso, Pegoraro, Elena, Giorgia, Querin, Francesca, Gerardi, Fabrizio, Rinaldi, Maria Sofia Cotelli, Luca, Chiveri, Maria Cristina Guaita, Patrizia, Perrone, Giancarlo, Comi, Carlo, Ferrarese, Lucio, Tremolizzo, Marialuisa, Delodovici, Giorgio, Bono, Stefania, Cammarosano, Antonio, Canosa, Dario, Cocito, Leonardo, Lopiano, Luca, Durelli, Bruno, Ferrero, Antonio, Bertolotto, Alessandro, Mauro, Luca, Pradotto, Roberto, Cantello, Enrica, Bersano, Dario, Giobbe, Maurizio, Gionco, Daniela, Leotta, Lucia, Appendino, Cavallo, Cavallo, Enrico, Odddenino, Claudio, Geda, Fabio, Poglio, Paola, Santimaria, Umberto, Massazza, Antonio, Villani, Roberto, Conti, Fabrizio, Pisano, Mario, Palermo, Franco, Vergnano, Paolo, Provera, Maria Teresa Penza, Marco, Aguggia, Nicoletta Di Vito, Piero, Meineri, Ilaria, Pastore, Paolo, Ghiglione, Danilo, Seliak, Nicola, Launaro, Giovanni, Astegiano, Bottacchi, Edo, Isabella Laura Simone, Stefano, Zoccolella, Michele, Zarrelli, Franco, Apollo, William, Camu, Jean Sebastien Hulot, Francois, Viallet, Philippe, Couratier, David, Maltete, Christine, Tranchant, Marie, Vidailhet, Bassel, Abou-Khalil, Pauls, Auce, Andreja, Avbersek, Melanie, Bahlo, David, J Balding, Thomas, Bast, Larry, Baum, Albert, J Becker, Felicitas, Becker, Bianca, Berghuis, Samuel, F Berkovic, Katja, E Boysen, Jonathan, P Bradfield, Lawrence, C Brody, Russell, J Buono, Ellen, Campbell, Gregory, D Cascino, Claudia, B Catarino, Gianpiero, L Cavalleri, Stacey, S Cherny, Krishna, Chinthapalli, Alison, J Coffey, Alastair, Compston, Antonietta, Coppola, Patrick, Cossette, John, J Craig, Gerrit-Jan de Haan, Peter De Jonghe, Carolien G, F de Kovel, Norman, Delanty, Chantal, Depondt, Orrin, Devinsky, Dennis, J Dlugos, Colin, P Doherty, Christian, E Elger, Johan, G Eriksson, Thomas, N Ferraro, Martha, Feucht, Ben, Francis, Jacqueline, A French, Saskia, Freytag, Verena, Gaus, Eric, B Geller, Christian, Gieger, Tracy, Glauser, Simon, Glynn, David, B Goldstein, Hongsheng, Gui, Youling, Guo, Kevin, F Haas, Hakon, Hakonarson, Kerstin, Hallmann, Sheryl, Haut, Erin, L Heinzen, Ingo, Helbig, Christian, Hengsbach, Helle, Hjalgrim, Michele, Iacomino, Andrés, Ingason, Michael, R Johnson, Reetta, Kälviäinen, Anne-Mari, Kantanen, Dalia, Kasperavičiūte, Dorothee Kasteleijn-Nolst Trenite, Heidi, E Kirsch, Robert, C Knowlton, Bobby P, C Koeleman, Roland, Krause, Martin, Krenn, Wolfram, S Kunz, Ruben, Kuzniecky, Patrick, Kwan, Dennis, Lal, Yu-Lung, Lau, Anna-Elina, Lehesjoki, Holger, Lerche, Costin, Leu, Dick, Lindhout, Warren, D Lo, Iscia, Lopes-Cendes, Daniel, H Lowenstein, Alberto, Malovini, Anthony, G Marson, Thomas, Mayer, Mark, Mccormack, James, L Mills, Nasir, Mirza, Martina, Moerzinger, Rikke, S Møller, Anne, M Molloy, Hiltrud, Muhle, Mark, Newton, Ping-Wing, Ng, Markus, M Nöthen, Peter, Nürnberg, Terence, J O’Brien, Karen, L Oliver, Aarno, Palotie, Faith, Pangilinan, Sarah, Peter, Slavé, Petrovski, Annapurna, Poduri, Michael, Privitera, Rodney, Radtke, Sarah, Rau, Philipp, S Reif, Eva, M Reinthaler, Felix, Rosenow, Josemir, W Sander, Thomas, Sander, Theresa, Scattergood, Steven, C Schachter, Christoph, J Schankin, Ingrid, E Scheffer, Bettina, Schmitz, Susanne, Schoch, Pak, C Sham, Jerry, J Shih, Graeme, J Sills, Sanjay, M Sisodiya, Lisa, Slattery, Alexander, Smith, David, F Smith, Michael, C Smith, Philip, E Smith, Anja C, M Sonsma, Doug, Speed, Michael, R Sperling, Bernhard, J Steinhoff, Ulrich, Stephani, Remi, Stevelink, Konstantin, Strauch, Pasquale, Striano, Hans, Stroink, Rainer, Surges, K Meng Tan, Liu Lin Thio, G Neil Thomas, Marian, Todaro, Rossana, Tozzi, Maria, S Vari, Eileen P, G Vining, Frank, Visscher, Sarah von Spiczak, Nicole, M Walley, Yvonne, G Weber, Zhi, Wei, Judith, Weisenberg, Christopher, D Whelan, Peter, Widdess-Walsh, Markus, Wolff, Stefan, Wolking, Wanling, Yang, Federico, Zara, Fritz, Zimprich, Project MinE ALS GWAS Consortium, International League Against Epilepsy Consortium on Complex Epilepsies, Department of Medical and Clinical Genetics, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, and HUS Helsinki and Uusimaa Hospital District

Subjects
Risk, 0301 basic medicine, Aging, Genetic correlation, Geriatrics & Gerontology, education, Genome-wide association study, Biology, ALS, Epilepsy, Amyotrophic Lateral Sclerosis, Gene Frequency, Humans, Genetic Variation, Genome-Wide Association Study, Negative Results, Article, 3124 Neurology and psychiatry, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, medicine, Amyotrophic lateral sclerosis, Allele frequency, Genetics, Science & Technology, Mechanism (biology), General Neuroscience, 3112 Neurosciences, Neurosciences, medicine.disease, 3. Good health, Minor allele frequency, 030104 developmental biology, Neurology (clinical), Neurosciences & Neurology, Geriatrics and Gerontology, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins. ispartof: NEUROBIOLOGY OF AGING vol:92 ispartof: location:United States status: published

Published
2020
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4. The epilepsy phenome/genome project

Author

Bassel, Abou-Khalil, Brian, Alldredge, Jocelyn, Bautista, Sam, Berkovic, Judith, Bluvstein, Alex, Boro, Gregory, Cascino, Damian, Consalvo, Sabrina, Cristofaro, Patricia, Crumrine, Orrin, Devinsky, Dennis, Dlugos, Michael, Epstein, Robyn, Fahlstrom, Miguel, Fiol, Nathan, Fountain, Kristen, Fox, Jacqueline, French, Catharine, Freyer Karn, Daniel, Friedman, Eric, Geller, Tracy, Glauser, Simon, Glynn, Kevin, Haas, Sheryl, Haut, Jean, Hayward, Sandra, Helmers, Sucheta, Joshi, Andres, Kanner, Heidi, Kirsch, Robert, Knowlton, Eric, Kossoff, Rachel, Kuperman, Ruben, Kuzniecky, Daniel, Lowenstein, Shannon, McGuire, Paul, Motika, Gerard, Nesbitt, Edward, Novotny, Ruth, Ottman, Juliann, Paolicchi, Jack, Parent, Kristen, Park, Annapurna, Poduri, Neil, Risch, Lynette, Sadleir, Ingrid, Scheffer, Renee, Shellhaas, Elliott, Sherr, Jerry J, Shih, Shlomo, Shinnar, Rani, Singh, Joseph, Sirven, Michael, Smith, Joe, Sullivan, Liu Lin, Thio, Anu, Venkat, Eileen, Vining, Gretchen, von Allmen, Judith, Weisenberg, Peter, Widdess-Walsh, and Andrew, Yourich

Subjects
Pharmacology, Research design, Genetic Research, Epilepsy, Genotype, business.industry, Information Management, Retrospective cohort study, General Medicine, Genome project, Phenome, medicine.disease, Article, Phenotype, Epilepsy Phenome/Genome Project, Research Design, Informatics, Medicine, Humans, Identification (biology), business, Clinical psychology, Oligonucleotide Array Sequence Analysis, Retrospective Studies
Abstract

Background Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype–genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy. Results EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants. Conclusions EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.

Published
2013

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