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1. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.

Author

Chen, Yuyang, Dawes, Ruebena, Kim, Hyung, Ljungdahl, Alicia, Stenton, Sarah, Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra, Ganesh, Vijay, Ma, Jialan, Ellingford, Jamie, Delage, Erwan, DSouza, Elston, Dong, Shan, Adams, David, Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin, Berger, Seth, Bernstein, Jonathan, Bhatnagar, Ishita, Blair, Ed, Brown, Natasha, Burrage, Lindsay, Chapman, Kimberly, Coman, David, Compton, Alison, Cunningham, Chloe, DSouza, Precilla, Danecek, Petr, Délot, Emmanuèle, Dias, Kerith-Rae, Elias, Ellen, Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie, Gallacher, Lyndon, Genetti, Casie, Goriely, Anne, Grant, Christina, Haack, Tobias, Higgs, Jenny, Hinch, Anjali, Hurles, Matthew, Kuechler, Alma, Lachlan, Katherine, Lalani, Seema, Lecoquierre, François, Leitão, Elsa, Fevre, Anna, Leventer, Richard, Liebelt, Jan, Lindsay, Sarah, Lockhart, Paul, Ma, Alan, Macnamara, Ellen, Mansour, Sahar, Maurer, Taylor, Mendez, Hector, Metcalfe, Kay, Montgomery, Stephen, Moosajee, Mariya, Nassogne, Marie-Cécile, Neumann, Serena, ODonoghue, Michael, OLeary, Melanie, Palmer, Elizabeth, Pattani, Nikhil, Phillips, John, Pitsava, Georgia, Pysar, Ryan, Rehm, Heidi, Reuter, Chloe, Revencu, Nicole, Riess, Angelika, Rius, Rocio, Rodan, Lance, Roscioli, Tony, Rosenfeld, Jill, Sachdev, Rani, Shaw-Smith, Charles, Simons, Cas, Sisodiya, Sanjay, Snell, Penny, St Clair, Laura, Stark, Zornitza, Stewart, Helen, Tan, Tiong, Tan, Natalie, Temple, Suzanna, Thorburn, David, Tifft, Cynthia, Uebergang, Eloise, VanNoy, Grace, Vasudevan, Pradeep, Vilain, Eric, and Viskochil, David

Subjects
Humans, RNA, Small Nuclear, Neurodevelopmental Disorders, Female, Male, Brain, Heterozygote, Alleles, Syndrome, Spliceosomes, Animals
Abstract

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5 splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

Published
2024

2. Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries

Author

García-Marín, Luis M., Campos, Adrian I., Diaz-Torres, Santiago, Rabinowitz, Jill A., Ceja, Zuriel, Mitchell, Brittany L., Grasby, Katrina L., Thorp, Jackson G., Agartz, Ingrid, Alhusaini, Saud, Ames, David, Amouyel, Philippe, Andreassen, Ole A., Arfanakis, Konstantinos, Arias-Vasquez, Alejandro, Armstrong, Nicola J., Athanasiu, Lavinia, Bastin, Mark E., Beiser, Alexa S., Bennett, David A., Bis, Joshua C., Boks, Marco P. M., Boomsma, Dorret I., Brodaty, Henry, Brouwer, Rachel M., Buitelaar, Jan K., Burkhardt, Ralph, Cahn, Wiepke, Calhoun, Vince D., Carmichael, Owen T., Chakravarty, Mallar, Chen, Qiang, Ching, Christopher R. K., Cichon, Sven, Crespo-Facorro, Benedicto, Crivello, Fabrice, Dale, Anders M., Smith, George Davey, de Geus, Eco J. C., De Jager, Philip L., de Zubicaray, Greig I., Debette, Stéphanie, DeCarli, Charles, Depondt, Chantal, Desrivières, Sylvane, Djurovic, Srdjan, Ehrlich, Stefan, Erk, Susanne, Espeseth, Thomas, Fernández, Guillén, Filippi, Irina, Fisher, Simon E., Fleischman, Debra A., Fletcher, Evan, Fornage, Myriam, Forstner, Andreas J., Francks, Clyde, Franke, Barbara, Ge, Tian, Goldman, Aaron L., Grabe, Hans J., Green, Robert C., Grimm, Oliver, Groenewold, Nynke A., Gruber, Oliver, Gudnason, Vilmundur, Håberg, Asta K., Haukvik, Unn K., Heinz, Andreas, Hibar, Derrek P., Hilal, Saima, Himali, Jayandra J., Ho, Beng-Choon, Hoehn, David F., Hoekstra, Pieter J., Hofer, Edith, Hoffmann, Wolfgang, Holmes, Avram J., Homuth, Georg, Hosten, Norbert, Ikram, M. Kamran, Ipser, Jonathan C., Jack Jr, Clifford R., Jahanshad, Neda, Jönsson, Erik G., Kahn, Rene S., Kanai, Ryota, Klein, Marieke, Knol, Maria J., Launer, Lenore J., Lawrie, Stephen M., Hellard, Stephanie Le, Lee, Phil H., Lemaître, Hervé, Li, Shuo, Liewald, David C. M., Lin, Honghuang, Longstreth, Jr, W. T., Lopez, Oscar L., Luciano, Michelle, Maillard, Pauline, Marquand, Andre F., Martin, Nicholas G., Martinot, Jean-Luc, Mather, Karen A., Mattay, Venkata S., McMahon, Katie L., Mecocci, Patrizia, Melle, Ingrid, Meyer-Lindenberg, Andreas, Mirza-Schreiber, Nazanin, Milaneschi, Yuri, Mosley, Thomas H., Mühleisen, Thomas W., Müller-Myhsok, Bertram, Maniega, Susana Muñoz, Nauck, Matthias, Nho, Kwangsik, Niessen, Wiro J., Nöthen, Markus M., Nyquist, Paul A., Oosterlaan, Jaap, Pandolfo, Massimo, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W. J. H., Pike, G. Bruce, Psaty, Bruce M., Pütz, Benno, Reppermund, Simone, Rietschel, Marcella D., Risacher, Shannon L., Romanczuk-Seiferth, Nina, Romero-Garcia, Rafael, Roshchupkin, Gennady V., Rotter, Jerome I., Sachdev, Perminder S., Sämann, Philipp G., Saremi, Arvin, Sargurupremraj, Muralidharan, Saykin, Andrew J., Schmaal, Lianne, Schmidt, Helena, Schmidt, Reinhold, Schofield, Peter R., Scholz, Markus, Schumann, Gunter, Schwarz, Emanuel, Shen, Li, Shin, Jean, Sisodiya, Sanjay M., Smith, Albert V., Smoller, Jordan W., Soininen, Hilkka S., Steen, Vidar M., Stein, Dan J., Stein, Jason L., Thomopoulos, Sophia I., Toga, Arthur W., Tordesillas-Gutiérrez, Diana, Trollor, Julian N., Valdes-Hernandez, Maria C., van ′t Ent, Dennis, van Bokhoven, Hans, van der Meer, Dennis, van der Wee, Nic J. A., Vázquez-Bourgon, Javier, Veltman, Dick J., Vernooij, Meike W., Villringer, Arno, Vinke, Louis N., Völzke, Henry, Walter, Henrik, Wardlaw, Joanna M., Weinberger, Daniel R., Weiner, Michael W., Wen, Wei, Westlye, Lars T., Westman, Eric, White, Tonya, Witte, A. Veronica, Wolf, Christiane, Yang, Jingyun, Zwiers, Marcel P., Ikram, M. Arfan, Seshadri, Sudha, Thompson, Paul M., Satizabal, Claudia L., Medland, Sarah E., and Rentería, Miguel E.

Published
2024
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3. Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers.

Author

Boen, Rune, Kaufmann, Tobias, van der Meer, Dennis, Frei, Oleksandr, Agartz, Ingrid, Ames, David, Andersson, Micael, Armstrong, Nicola, Artiges, Eric, Atkins, Joshua, Bauer, Jochen, Benedetti, Francesco, Boomsma, Dorret, Brodaty, Henry, Brosch, Katharina, Buckner, Randy, Cairns, Murray, Calhoun, Vince, Caspers, Svenja, Cichon, Sven, Corvin, Aiden, Crespo-Facorro, Benedicto, Dannlowski, Udo, David, Friederike, de Geus, Eco, de Zubicaray, Greig, Desrivières, Sylvane, Doherty, Joanne, Donohoe, Gary, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fisher, Simon, Forstner, Andreas, Fortaner-Uyà, Lidia, Frouin, Vincent, Fukunaga, Masaki, Ge, Tian, Glahn, David, Goltermann, Janik, Grabe, Hans, Green, Melissa, Groenewold, Nynke, Grotegerd, Dominik, Grøntvedt, Gøril, Hahn, Tim, Hashimoto, Ryota, Hehir-Kwa, Jayne, Henskens, Frans, Holmes, Avram, Håberg, Asta, Haavik, Jan, Jacquemont, Sebastien, Jansen, Andreas, Jockwitz, Christiane, Jönsson, Erik, Kikuchi, Masataka, Kircher, Tilo, Kumar, Kuldeep, Le Hellard, Stephanie, Leu, Costin, Linden, David, Liu, Jingyu, Loughnan, Robert, Mather, Karen, McMahon, Katie, McRae, Allan, Medland, Sarah, Meinert, Susanne, Moreau, Clara, Morris, Derek, Mowry, Bryan, Mühleisen, Thomas, Nenadić, Igor, Nöthen, Markus, Nyberg, Lars, Ophoff, Roel, Owen, Michael, Pantelis, Christos, Paolini, Marco, Paus, Tomas, Pausova, Zdenka, Persson, Karin, Quidé, Yann, Marques, Tiago, Sachdev, Perminder, Sando, Sigrid, Schall, Ulrich, Scott, Rodney, Selbæk, Geir, Shumskaya, Elena, Silva, Ana, Sisodiya, Sanjay, Stein, Frederike, Stein, Dan, Straube, Benjamin, Streit, Fabian, Strike, Lachlan, Teumer, Alexander, and Teutenberg, Lea

Subjects
15q11.2 BP1-BP2, 1q21.1 distal, Brain structure, Copy number variants, Intraindividual variability, Magnetic resonance imaging, Humans, Chromosome Deletion, Brain, Magnetic Resonance Imaging, Abnormalities, Multiple, Chromosomes, Human, Pair 15, DNA Copy Number Variations
Abstract

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individuals regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

Published
2024

4. Current practice in diagnostic genetic testing of the epilepsies.

Author

Krey, Ilona, Platzer, Konrad, Esterhuizen, Alina, Berkovic, Samuel, Helbig, Ingo, Hildebrand, Michael, Lerche, Holger, Møller, Rikke, Poduri, Annapurna, Sadleir, Lynette, Sisodiya, Sanjay, Weckhuysen, Sarah, Wilmshurst, Jo, Weber, Yvonne, Lemke, Johannes, Cross, J, Lowenstein, Daniel, Mefford, Heathea, Perucca, Piero, Tan, Nigel, Caglayan, Hande, Helbig, Katherine, and Singh, Gagandeep

Subjects
genetic epilepsy, next-generation sequencing, genetic counseling genetic testing, variant of uncertain significance, precision medicine, Diagnostic Techniques and Procedures, Epilepsy, Genetic Testing, Humans
Abstract

Epilepsy genetics is a rapidly developing field, in which novel disease-associated genes, novel mechanisms associated with epilepsy, and precision medicine approaches are continuously being identified. In the past decade, advances in genomic knowledge and analysis platforms have begun to make clinical genetic testing accessible for, in principle, people of all ages with epilepsy. For this reason, the Genetics Commission of the International League Against Epilepsy (ILAE) presents this update on clinical genetic testing practice, including current techniques, indications, yield of genetic testing, recommendations for pre- and post-test counseling, and follow-up after genetic testing is completed. We acknowledge that the resources vary across different settings but highlight that genetic diagnostic testing for epilepsy should be prioritized when the likelihood of an informative finding is high. Results of genetic testing, in particular the identification of causative genetic variants, are likely to improve individual care. We emphasize the importance of genetic testing for individuals with epilepsy as we enter the era of precision therapy.

Published
2022

5. Event‐based modeling in temporal lobe epilepsy demonstrates progressive atrophy from cross‐sectional data

Author

Lopez, Seymour M, Aksman, Leon M, Oxtoby, Neil P, Vos, Sjoerd B, Rao, Jun, Kaestner, Erik, Alhusaini, Saud, Alvim, Marina, Bender, Benjamin, Bernasconi, Andrea, Bernasconi, Neda, Bernhardt, Boris, Bonilha, Leonardo, Caciagli, Lorenzo, Caldairou, Benoit, Caligiuri, Maria Eugenia, Calvet, Angels, Cendes, Fernando, Concha, Luis, Conde‐Blanco, Estefania, Davoodi‐Bojd, Esmaeil, de Bézenac, Christophe, Delanty, Norman, Desmond, Patricia M, Devinsky, Orrin, Domin, Martin, Duncan, John S, Focke, Niels K, Foley, Sonya, Fortunato, Francesco, Galovic, Marian, Gambardella, Antonio, Gleichgerrcht, Ezequiel, Guerrini, Renzo, Hamandi, Khalid, Ives‐Deliperi, Victoria, Jackson, Graeme D, Jahanshad, Neda, Keller, Simon S, Kochunov, Peter, Kotikalapudi, Raviteja, Kreilkamp, Barbara AK, Labate, Angelo, Larivière, Sara, Lenge, Matteo, Lui, Elaine, Malpas, Charles, Martin, Pascal, Mascalchi, Mario, Medland, Sarah E, Meletti, Stefano, Morita‐Sherman, Marcia E, Owen, Thomas W, Richardson, Mark, Riva, Antonella, Rüber, Theodor, Sinclair, Ben, Soltanian‐Zadeh, Hamid, Stein, Dan J, Striano, Pasquale, Taylor, Peter N, Thomopoulos, Sophia I, Thompson, Paul M, Tondelli, Manuela, Vaudano, Anna Elisabetta, Vivash, Lucy, Wang, Yujiang, Weber, Bernd, Whelan, Christopher D, Wiest, Roland, Winston, Gavin P, Yasuda, Clarissa Lin, McDonald, Carrie R, Alexander, Daniel C, Sisodiya, Sanjay M, Altmann, Andre, Bargalló, Núria, Bartolini, Emanuele, O’Brien, Terence J, and Thomas, Rhys H

Subjects
Brain Disorders, Epilepsy, Neurodegenerative, Neurosciences, Clinical Research, Biomedical Imaging, Aetiology, 2.1 Biological and endogenous factors, Neurological, Good Health and Well Being, Atrophy, Biomarkers, Cross-Sectional Studies, Epilepsy, Temporal Lobe, Hippocampus, Humans, Magnetic Resonance Imaging, Sclerosis, disease progression, duration of illness, event-based model, MTLE, patient staging, ENIGMA-Epilepsy Working Group, Clinical Sciences, Neurology & Neurosurgery
Abstract

ObjectiveRecent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features.MethodsWe extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1-weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1625 healthy controls from 25 centers. Features with a moderate case-control effect size (Cohen d ≥ .5) were used to train an event-based model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance.ResultsIn MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10-16 ), age at onset (ρ = -.18, p = 9.82 × 10-7 ), and ASM resistance (area under the curve = .59, p = .043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE-HS with mild or nondetectable abnormality on T1W MRI.SignificanceFrom cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features.

Published
2022

7. Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy

Author

Park, Bo-yong, Larivière, Sara, Rodríguez-Cruces, Raul, Royer, Jessica, Tavakol, Shahin, Wang, Yezhou, Caciagli, Lorenzo, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simon S, Cendes, Fernando, Alvim, Marina KM, Yasuda, Clarissa, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K, Kreilkamp, Barbara AK, Domin, Martin, von Podewils, Felix, Langner, Soenke, Rummel, Christian, Rebsamen, Michael, Wiest, Roland, Martin, Pascal, Kotikalapudi, Raviteja, Bender, Benjamin, O’Brien, Terence J, Law, Meng, Sinclair, Benjamin, Vivash, Lucy, Kwan, Patrick, Desmond, Patricia M, Malpas, Charles B, Lui, Elaine, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Lenge, Matteo, Guerrini, Renzo, Bartolini, Emanuele, Hamandi, Khalid, Foley, Sonya, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah JA, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin, Severino, Mariasavina, Striano, Pasquale, Parodi, Costanza, Tortora, Domenico, Hatton, Sean N, Vos, Sjoerd B, Duncan, John S, Galovic, Marian, Whelan, Christopher D, Bargalló, Núria, Pariente, Jose, Conde-Blanco, Estefania, Vaudano, Anna Elisabetta, Tondelli, Manuela, Meletti, Stefano, Kong, Xiang‐Zhen, Francks, Clyde, Fisher, Simon E, Caldairou, Benoit, Ryten, Mina, Labate, Angelo, Sisodiya, Sanjay M, Thompson, Paul M, McDonald, Carrie R, Bernasconi, Andrea, Bernasconi, Neda, and Bernhardt, Boris C

Subjects
Epilepsy, Neurodegenerative, Clinical Research, Brain Disorders, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Atrophy, Connectome, Epilepsy, Temporal Lobe, Hippocampus, Humans, Magnetic Resonance Imaging, temporal lobe epilepsy, asymmetry, cortical thickness, multi-site, gradients, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy.

Published
2022

8. Mono-allelic KCNB2 variants lead to a neurodevelopmental syndrome caused by altered channel inactivation

Author

Bhat, Shreyas, Rousseau, Justine, Michaud, Coralie, Lourenço, Charles Marques, Stoler, Joan M., Louie, Raymond J., Clarkson, Lola K., Lichty, Angie, Koboldt, Daniel C., Reshmi, Shalini C., Sisodiya, Sanjay M., Hoytema van Konijnenburg, Eva M.M., Koop, Klaas, van Hasselt, Peter M., Démurger, Florence, Dubourg, Christèle, Sullivan, Bonnie R., Hughes, Susan S., Thiffault, Isabelle, Tremblay, Elisabeth Simard, Accogli, Andrea, Srour, Myriam, Blunck, Rikard, and Campeau, Philippe M.

Published
2024
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9. The ENIGMA‐Epilepsy working group: Mapping disease from large data sets

Author

Sisodiya, Sanjay M, Whelan, Christopher D, Hatton, Sean N, Huynh, Khoa, Altmann, Andre, Ryten, Mina, Vezzani, Annamaria, Caligiuri, Maria Eugenia, Labate, Angelo, Gambardella, Antonio, Ives‐Deliperi, Victoria, Meletti, Stefano, Munsell, Brent C, Bonilha, Leonardo, Tondelli, Manuela, Rebsamen, Michael, Rummel, Christian, Vaudano, Anna Elisabetta, Wiest, Roland, Balachandra, Akshara R, Bargalló, Núria, Bartolini, Emanuele, Bernasconi, Andrea, Bernasconi, Neda, Bernhardt, Boris, Caldairou, Benoit, Carr, Sarah JA, Cavalleri, Gianpiero L, Cendes, Fernando, Concha, Luis, Desmond, Patricia M, Domin, Martin, Duncan, John S, Focke, Niels K, Guerrini, Renzo, Hamandi, Khalid, Jackson, Graeme D, Jahanshad, Neda, Kälviäinen, Reetta, Keller, Simon S, Kochunov, Peter, Kowalczyk, Magdalena A, Kreilkamp, Barbara AK, Kwan, Patrick, Lariviere, Sara, Lenge, Matteo, Lopez, Seymour M, Martin, Pascal, Mascalchi, Mario, Moreira, José CV, Morita‐Sherman, Marcia E, Pardoe, Heath R, Pariente, Jose C, Raviteja, Kotikalapudi, Rocha, Cristiane S, Rodríguez‐Cruces, Raúl, Seeck, Margitta, Semmelroch, Mira KHG, Sinclair, Benjamin, Soltanian‐Zadeh, Hamid, Stein, Dan J, Striano, Pasquale, Taylor, Peter N, Thomas, Rhys H, Thomopoulos, Sophia I, Velakoulis, Dennis, Vivash, Lucy, Weber, Bernd, Yasuda, Clarissa Lin, Zhang, Junsong, Thompson, Paul M, McDonald, Carrie R, Abela, Eugenio, Absil, Julie, Adams, Sophia, Alhusaini, Saud, Alvim, Marina, Balestrini, Simona, Bender, Benjamin, Bergo, Felipe, Bernardes, Tauana, Calvo, Anna, Carreno, Mar, Cherubini, Andrea, David, Philippe, Davoodi‐Bojd, Esmaeil, Delanty, Norman, Depondt, Chantal, Devinsky, Orrin, Doherty, Colin, França, Wendy Caroline, Franceschet, Leticia, Hibar, Derrek P, Ishikawa, Akari, Kaestner, Erik, Langner, Soenke, Liu, Min, Mirandola, Laura, Naylor, Jillian, and Nazem‐Zadeh, Mohammad‐reza

Subjects
Brain Disorders, Biomedical Imaging, Neurosciences, Epilepsy, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, covariance, deep learning, DTI, event-based modeling, gene expression, genetics, imaging, MRI, quantitative, rsfMRI, ENIGMA Consortium Epilepsy Working Group, Cognitive Sciences, Experimental Psychology
Abstract

Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller-scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well-established by the ENIGMA Consortium, ENIGMA-Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural covariance, and event-based modeling analysis. We explore age of onset- and duration-related features, as well as phenomena-specific work focusing on particular epilepsy syndromes or phenotypes, multimodal analyses focused on understanding the biology of disease progression, and deep learning approaches. We encourage groups who may be interested in participating to make contact to further grow and develop ENIGMA-Epilepsy.

Published
2022

10. Structural network alterations in focal and generalized epilepsy assessed in a worldwide ENIGMA study follow axes of epilepsy risk gene expression

Author

Larivière, Sara, Royer, Jessica, Rodríguez-Cruces, Raúl, Paquola, Casey, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simon S, Cendes, Fernando, Yasuda, Clarissa L, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K, Domin, Martin, von Podewills, Felix, Langner, Soenke, Rummel, Christian, Wiest, Roland, Martin, Pascal, Kotikalapudi, Raviteja, O’Brien, Terence J, Sinclair, Benjamin, Vivash, Lucy, Desmond, Patricia M, Lui, Elaine, Vaudano, Anna Elisabetta, Meletti, Stefano, Tondelli, Manuela, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Winston, Gavin P, Griffin, Aoife, Singh, Aditi, Tiwari, Vijay K, Kreilkamp, Barbara AK, Lenge, Matteo, Guerrini, Renzo, Hamandi, Khalid, Foley, Sonya, Rüber, Theodor, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah JA, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin, Severino, Mariasavina, Striano, Pasquale, Tortora, Domenico, Kaestner, Erik, Hatton, Sean N, Vos, Sjoerd B, Caciagli, Lorenzo, Duncan, John S, Whelan, Christopher D, Thompson, Paul M, Sisodiya, Sanjay M, Bernasconi, Andrea, Labate, Angelo, McDonald, Carrie R, Bernasconi, Neda, and Bernhardt, Boris C

Subjects
Neurodegenerative, Genetics, Neurosciences, Brain Disorders, Epilepsy, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Connectome, Epilepsy, Generalized, Epilepsy, Temporal Lobe, Gene Expression, Humans, Immunoglobulin E, Magnetic Resonance Imaging, Nerve Net
Abstract

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes.

Published
2022

11. Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

Author

Hansen, Justine Y, Shafiei, Golia, Vogel, Jacob W, Smart, Kelly, Bearden, Carrie E, Hoogman, Martine, Franke, Barbara, van Rooij, Daan, Buitelaar, Jan, McDonald, Carrie R, Sisodiya, Sanjay M, Schmaal, Lianne, Veltman, Dick J, van den Heuvel, Odile A, Stein, Dan J, van Erp, Theo GM, Ching, Christopher RK, Andreassen, Ole A, Hajek, Tomas, Opel, Nils, Modinos, Gemma, Aleman, André, van der Werf, Ysbrand, Jahanshad, Neda, Thomopoulos, Sophia I, Thompson, Paul M, Carson, Richard E, Dagher, Alain, and Misic, Bratislav

Subjects
Neurosciences, Pediatric, Brain Disorders, Mental Health, Aetiology, Underpinning research, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Mental health, Neurological, Brain, Brain Diseases, Connectome, Humans, Magnetic Resonance Imaging, Neural Pathways
Abstract

Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morphometry from the ENIGMA consortium, we construct maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N = 21,000 participants and N = 26,000 controls, collected using a harmonised processing protocol. We systematically compare cortical maps to multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, and myelination (molecular vulnerability), as well as global connectomic measures including number of connections, centrality, and connection diversity (connectomic vulnerability). We find a relationship between molecular vulnerability and white-matter architecture that drives cortical disorder profiles. Local attributes, particularly neurotransmitter receptor profiles, constitute the best predictors of both disorder-specific cortical morphology and cross-disorder similarity. Finally, we find that cross-disorder abnormalities are consistently subtended by a small subset of network epicentres in bilateral sensory-motor, inferior temporal lobe, precuneus, and superior parietal cortex. Collectively, our results highlight how local molecular attributes and global connectivity jointly shape cross-disorder cortical abnormalities.

Published
2022

12. Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections

Author

Borras, Silvia, Clark, Caroline, Dean, John, Miedzybrodzka, Zosia, Ross, Alison, Tennant, Stephen, Dabir, Tabib, Donnelly, Deirdre, Humphreys, Mervyn, Magee, Alex, McConnell, Vivienne, McKee, Shane, McNerlan, Susan, Morrison, Patrick J., Rea, Gillian, Stewart, Fiona, Cole, Trevor, Cooper, Nicola, Cooper-Charles, Lisa, Cox, Helen, Islam, Lily, Jarvis, Joanna, Keelagher, Rebecca, Lim, Derek, McMullan, Dominic, Morton, Jenny, Naik, Swati, O’Driscoll, Mary, Ong, Kai-Ren, Osio, Deborah, Ragge, Nicola, Turton, Sarah, Vogt, Julie, Williams, Denise, Bodek, Simon, Donaldson, Alan, Hills, Alison, Low, Karen, Newbury-Ecob, Ruth, Norman, Andrew M., Roberts, Eileen, Scurr, Ingrid, Smithson, Sarah, Tooley, Madeleine, Abbs, Steve, Armstrong, Ruth, Dunn, Carolyn, Holden, Simon, Park, Soo-Mi, Paterson, Joan, Raymond, Lucy, Reid, Evan, Sandford, Richard, Simonic, Ingrid, Tischkowitz, Marc, Woods, Geoff, Bradley, Lisa, Comerford, Joanne, Green, Andrew, Lynch, Sally, McQuaid, Shirley, Mullaney, Brendan, Berg, Jonathan, Goudie, David, Mavrak, Eleni, McLean, Joanne, McWilliam, Catherine, Reavey, Eleanor, Azam, Tara, Cleary, Elaine, Jackson, Andrew, Lam, Wayne, Lampe, Anne, Moore, David, Porteous, Mary, Baple, Emma, Baptista, Júlia, Brewer, Carole, Castle, Bruce, Kivuva, Emma, Owens, Martina, Rankin, Julia, Shaw-Smith, Charles, Turner, Claire, Turnpenny, Peter, Tysoe, Carolyn, Bradley, Therese, Davidson, Rosemarie, Gardiner, Carol, Joss, Shelagh, Kinning, Esther, Longman, Cheryl, McGowan, Ruth, Murday, Victoria, Pilz, Daniela, Tobias, Edward, Whiteford, Margo, Williams, Nicola, Barnicoat, Angela, Clement, Emma, Faravelli, Francesca, Hurst, Jane, Jenkins, Lucy, Jones, Wendy, Ajith Kumar, V.K., Lees, Melissa, Loughlin, Sam, Male, Alison, Morrogh, Deborah, Rosser, Elisabeth, Scott, Richard, Wilson, Louise, Beleza, Ana, Deshpande, Charu, Flinter, Frances, Holder, Muriel, Irving, Melita, Izatt, Louise, Josifova, Dragana, Mohammed, Shehla, Molenda, Aneta, Robert, Leema, Roworth, Wendy, Ruddy, Deborah, Ryten, Mina, Yau, Shu, Bennett, Christopher, Blyth, Moira, Campbell, Jennifer, Coates, Andrea, Dobbie, Angus, Hewitt, Sarah, Hobson, Emma, Jackson, Eilidh, Jewell, Rosalyn, Kraus, Alison, Prescott, Katrina, Sheridan, Eamonn, Thomson, Jenny, Bradshaw, Kirsty, Dixit, Abhijit, Eason, Jacqueline, Haines, Rebecca, Harrison, Rachel, Mutch, Stacey, Sarkar, Ajoy, Searle, Claire, Shannon, Nora, Sharif, Abid, Suri, Mohnish, Vasudevan, Pradeep, Canham, Natalie, Ellis, Ian, Greenhalgh, Lynn, Howard, Emma, Stinton, Victoria, Swale, Andrew, Weber, Astrid, Banka, Siddharth, Breen, Catherine, Briggs, Tracy, Burkitt-Wright, Emma, Chandler, Kate, Clayton-Smith, Jill, Donnai, Dian, Douzgou, Sofia, Gaunt, Lorraine, Jones, Elizabeth, Kerr, Bronwyn, Langley, Claire, Metcalfe, Kay, Smith, Audrey, Wright, Ronnie, Bourn, David, Burn, John, Fisher, Richard, Hellens, Steve, Henderson, Alex, Montgomery, Tara, Splitt, Miranda, Straub, Volker, Wright, Michael, Zwolinski, Simon, Allen, Zoe, Bernhard, Birgitta, Brady, Angela, Brooks, Claire, Busby, Louise, Clowes, Virginia, Ghali, Neeti, Holder, Susan, Ibitoye, Rita, Wakeling, Emma, Blair, Edward, Carmichael, Jenny, Cilliers, Deirdre, Clasper, Susan, Gibbons, Richard, Kini, Usha, Lester, Tracy, Nemeth, Andrea, Poulton, Joanna, Price, Sue, Shears, Debbie, Stewart, Helen, Wilkie, Andrew, Albaba, Shadi, Baker, Duncan, Balasubramanian, Meena, Johnson, Diana, Parker, Michael, Quarrell, Oliver, Stewart, Alison, Willoughby, Josh, Crosby, Charlene, Elmslie, Frances, Homfray, Tessa, Jin, Huilin, Lahiri, Nayana, Mansour, Sahar, Marks, Karen, McEntagart, Meriel, Saggar, Anand, Tatton-Brown, Kate, Butler, Rachel, Clarke, Angus, Corrin, Sian, Fry, Andrew, Kamath, Arveen, McCann, Emma, Mugalaasi, Hood, Pottinger, Caroline, Procter, Annie, Sampson, Julian, Sansbury, Francis, Varghese, Vinod, Baralle, Diana, Callaway, Alison, Cassidy, Emma J., Daniels, Stacey, Douglas, Andrew, Foulds, Nicola, Hunt, David, Kharbanda, Mira, Lachlan, Katherine, Mercer, Catherine, Side, Lucy, Temple, I. Karen, Wellesley, Diana, Ambrose, J.C., Arumugam, P., Baple, E.L., Bleda, M., Boardman-Pretty, F., Boissiere, J.M., Boustred, C.R., Caulfield, M.J., Chan, G.C., Craig, C.E.H., Daugherty, L.C., de Burca, A., Devereau, A., Elgar, G., Foulger, R.E., Fowler, T., FurióTarí, P., Hackett, J.M., Halai, D., Hamblin, A., Henderson, S., Holman, J.E., Hubbard, T.J.P., Ibáñez, K., Jackson, R., Jones, L.J., Kasperaviciute, D., Kayikci, M., Lahnstein, L., Lawson, K., Leigh, S.E.A., Leong, I.U.S., Lopez, F.J., MaleadyCrowe, F., Mason, J., McDonagh, E.M., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A.C., Odhams, C.A., Patch, C., Perez-Gil, D., Polychronopoulos, D., Pullinger, J., Rahim, T., Rendon, A., Riesgo-Ferreiro, P., Rogers, T., Ryten, M., Savage, K., Sawant, K., Scott, R.H., Siddiq, A., Sieghart, A., Smedley, D., Smith, K.R., Sosinsky, A., Spooner, W., Stevens, H.E., Stuckey, A., Sultana, R., Thomas, E.R.A., Thompson, S.R., Tucci, A., Walsh, E., Watters, S.A., Welland, M.J., Williams, E., Witkowska, K., Acosta, Maria T., Adam, Margaret, Adams, David R., Agrawal, Pankaj B., Alejandro, Mercedes E., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bennet, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonnenmann, Carsten, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Peter Chang, Ta Chen, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D'Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davids, Mariska, Dayal, Jyoti G., Deardorff, Matthew, Dell'Angelica, Esteban C., Dhar, Shweta U., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Douine, Emilie D., Draper, David D., Duncan, Laura, Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Esteves, Cecilia, Estwick, Tyra, Falk, Marni, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L., Findley, Laurie C., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Fresard, Laure, Gahl, William A., Glass, Ian, Godfrey, Rena A., Golden-Grant, Katie, Goldman, Alica M., Goldstein, David B., Grajewski, Alana, Groden, Catherine A., Gropman, Andrea L., Gutierrez, Irma, Hahn, Sihoun, Hamid, Rizwan, Hanchard, Neil A., Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Huang, Yong, Isasi, Rosario, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Johnston, Jean M., Karaviti, Lefkothea, Kelley, Emily G., Kennedy, Jennifer, Kiley, Dana, Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Korrick, Susan, Koziura, Mary, Krier, Joel B., Lalani, Seema R., Lam, Byron, Lam, Christina, Lanpher, Brendan C., Lanza, Ian R., Lau, C. Christopher, LeBlanc, Kimberly, Lee, Brendan H., Lee, Hane, Levitt, Roy, Lewis, Richard A., Lincoln, Sharyn A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Mak, Bryan, Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Markello, Thomas C., Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McCormack, Colleen E., McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Merritt, J. Lawrence, Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo M., Morimoto, Marie, Mulvihill, John J., Murdock, David R., Nakano-Okuno, Mariko, Nath, Avi, Nelson, Stan F., Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Papp, Jeanette C., Parker, Neil H., Phillips, John A., Posey, Jennifer E., Potocki, Lorraine, Pusey, Barbara N., Quinlan, Aaron, Raskind, Wendy, Raja, Archana N., Rao, Deepak A., Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Samson, Susan L., Saporta, Mario, Scott, C. Ron, Schaechter, Judy, Schedl, Timothy, Scott, Daryl A., Sharma, Prashant, Shin, Jimann, Signer, Rebecca, Sillari, Catherine H., Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solem, Emily, Solnica-Krezel, Lilianna, Stoler, Joan M., Stong, Nicholas, Sullivan, Jennifer A., Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tamburro, Cecelia P., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Tucker, Brianna M., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Wallace, Stephanie, Walley, Nicole M., Walsh, Chris A., Walker, Melissa, Wambach, Jennifer, Wan, Jijun, Wang, Lee-Kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Wener, Mark, Wenger, Tara, Perry, Katherine Wesseling, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Woods, Jeremy D., Yamamoto, Shinya, Yang, John, Yu, Guoyun, Zastrow, Diane B., Zhao, Chunli, Zuchner, Stephan, Jeffries, Lauren, Mis, Emily K., McWalter, Kirsty, Donkervoort, Sandra, Brodsky, Nina N., Carpier, Jean-Marie, Ji, Weizhen, Ionita, Cristian, Roy, Bhaskar, Morrow, Jon S., Darbinyan, Armine, Iyer, Krishna, Aul, Ritu B., Chao, Katherine R., Cobbold, Laura, Cohen, Stacey, Custodio, Helena M., Drummond-Borg, Margaret, Finanger, Erika, Hainline, Bryan E., Helbig, Ingo, Hewson, Stacy, Hu, Ying, Jackson, Adam, Konstantino, Monica, Leach, Meganne E., McCormick, David, Nelson, Stanley, Nguyen, Joanne, Nugent, Kimberly, Ortega, Lucy, Goodkin, Howard P., Roeder, Elizabeth, Roy, Sani, Sapp, Katie, Saade, Dimah, Sisodiya, Sanjay M., Stals, Karen, Towner, Shelley, Wilson, William, Khokha, Mustafa K., Bönnemann, Carsten G., Lucas, Carrie L., and Lakhani, Saquib A.

Published
2024
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13. Structural brain imaging studies offer clues about the effects of the shared genetic etiology among neuropsychiatric disorders

Author

Radonjić, Nevena V, Hess, Jonathan L, Rovira, Paula, Andreassen, Ole, Buitelaar, Jan K, Ching, Christopher RK, Franke, Barbara, Hoogman, Martine, Jahanshad, Neda, McDonald, Carrie, Schmaal, Lianne, Sisodiya, Sanjay M, Stein, Dan J, van den Heuvel, Odile A, van Erp, Theo GM, van Rooij, Daan, Veltman, Dick J, Thompson, Paul, and Faraone, Stephen V

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Neurosciences, Serious Mental Illness, Genetics, Brain Disorders, Clinical Research, Autism, Intellectual and Developmental Disabilities (IDD), Schizophrenia, Mental Health, Prevention, Aetiology, 2.1 Biological and endogenous factors, Mental health, Attention Deficit Disorder with Hyperactivity, Autism Spectrum Disorder, Brain, Depressive Disorder, Major, Humans, Neuroimaging, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

Genomewide association studies have found significant genetic correlations among many neuropsychiatric disorders. In contrast, we know much less about the degree to which structural brain alterations are similar among disorders and, if so, the degree to which such similarities have a genetic etiology. From the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium, we acquired standardized mean differences (SMDs) in regional brain volume and cortical thickness between cases and controls. We had data on 41 brain regions for: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), epilepsy, major depressive disorder (MDD), obsessive compulsive disorder (OCD), and schizophrenia (SCZ). These data had been derived from 24,360 patients and 37,425 controls. The SMDs were significantly correlated between SCZ and BD, OCD, MDD, and ASD. MDD was positively correlated with BD and OCD. BD was positively correlated with OCD and negatively correlated with ADHD. These pairwise correlations among disorders were correlated with the corresponding pairwise correlations among disorders derived from genomewide association studies (r = 0.494). Our results show substantial similarities in sMRI phenotypes among neuropsychiatric disorders and suggest that these similarities are accounted for, in part, by corresponding similarities in common genetic variant architectures.

Published
2021

14. Climate change and epilepsy: Insights from clinical and basic science studies

Author

Gulcebi, Medine I, Bartolini, Emanuele, Lee, Omay, Lisgaras, Christos Panagiotis, Onat, Filiz, Mifsud, Janet, Striano, Pasquale, Vezzani, Annamaria, Hildebrand, Michael S, Jimenez-Jimenez, Diego, Junck, Larry, Lewis-Smith, David, Scheffer, Ingrid E, Thijs, Roland D, Zuberi, Sameer M, Blenkinsop, Stephen, Fowler, Hayley J, Foley, Aideen, Sisodiya, Sanjay M, Consortium, on behalf of the EpilepsyClimateChange, Balestrini, Simona, Berkovic, Samuel, Cavalleri, Gianpiero, Correa, Daniel José, Custodio, Helena Martins, Galovic, Marian, Guerrini, Renzo, Henshall, David, Howard, Olga, Hughes, Kelvin, Katsarou, Anna, Koeleman, Bobby PC, Krause, Roland, Lowenstein, Daniel, Mandelenaki, Despoina, Marini, Carla, O'Brien, Terence J, Pace, Adrian, De Palma, Luca, Perucca, Piero, Pitkänen, Asla, Quinn, Finola, Selmer, Kaja Kristine, Steward, Charles A, Swanborough, Nicola, Thijs, Roland, Tittensor, Phil, Trivisano, Marina, Weckhuysen, Sarah, and Zara, Federico

Subjects
Biomedical and Clinical Sciences, Neurosciences, Epilepsy, Climate-Related Exposures and Conditions, Global Warming Climate Change, Brain Disorders, Climate Change, Sleep Research, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, Climate Action, Animals, COVID-19, Death, Sudden, Global Health, Hot Temperature, Humans, Humidity, Public Health, Sleep Deprivation, Weather, Global warming, Emergency, Seizure, Temperature, Extreme weather events, Public health, Epilepsy Climate Change Consortium, Clinical Sciences, Neurology & Neurosurgery, Biological psychology, Clinical and health psychology
Abstract

Climate change is with us. As professionals who place value on evidence-based practice, climate change is something we cannot ignore. The current pandemic of the novel coronavirus, SARS-CoV-2, has demonstrated how global crises can arise suddenly and have a significant impact on public health. Global warming, a chronic process punctuated by acute episodes of extreme weather events, is an insidious global health crisis needing at least as much attention. Many neurological diseases are complex chronic conditions influenced at many levels by changes in the environment. This review aimed to collate and evaluate reports from clinical and basic science about the relationship between climate change and epilepsy. The keywords climate change, seasonal variation, temperature, humidity, thermoregulation, biorhythm, gene, circadian rhythm, heat, and weather were used to search the published evidence. A number of climatic variables are associated with increased seizure frequency in people with epilepsy. Climate change-induced increase in seizure precipitants such as fevers, stress, and sleep deprivation (e.g. as a result of more frequent extreme weather events) or vector-borne infections may trigger or exacerbate seizures, lead to deterioration of seizure control, and affect neurological, cerebrovascular, or cardiovascular comorbidities and risk of sudden unexpected death in epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. According to the results of the limited number of experimental studies with animal models of seizures or epilepsy, different seizure types appear to have distinct susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, has a critical role in seizure threshold and seizure-related brain damage. Links between climate change and epilepsy are likely to be multifactorial, complex, and often indirect, which makes predictions difficult. We need more data on possible climate-driven altered risks for seizures, epilepsy, and epileptogenesis, to identify underlying mechanisms at systems, cellular, and molecular levels for better understanding of the impact of climate change on epilepsy. Further focussed data would help us to develop evidence for mitigation methods to do more to protect people with epilepsy from the effects of climate change.

Published
2021

15. Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder

Author

Pavinato, Lisa, Stanic, Jennifer, Barzasi, Marta, Gurgone, Antonia, Chiantia, Giuseppe, Cipriani, Valentina, Eberini, Ivano, Palazzolo, Luca, Di Luca, Monica, Costa, Alex, Marcantoni, Andrea, Biamino, Elisa, Spada, Marco, Hiatt, Susan M., Kelley, Whitley V., Vestito, Letizia, Sisodiya, Sanjay M., Efthymiou, Stephanie, Chand, Prem, Kaiyrzhanov, Rauan, Bruselles, Alessandro, Cardaropoli, Simona, Tartaglia, Marco, De Rubeis, Silvia, Buxbaum, Joseph D., Smedley, Damian, Ferrero, Giovanni Battista, Giustetto, Maurizio, Gardoni, Fabrizio, and Brusco, Alfredo

Published
2023
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16. Artificial intelligence for classification of temporal lobe epilepsy with ROI-level MRI data: A worldwide ENIGMA-Epilepsy study

Author

Gleichgerrcht, Ezequiel, Munsell, Brent C, Alhusaini, Saud, Alvim, Marina KM, Bargalló, Núria, Bender, Benjamin, Bernasconi, Andrea, Bernasconi, Neda, Bernhardt, Boris, Blackmon, Karen, Caligiuri, Maria Eugenia, Cendes, Fernando, Concha, Luis, Desmond, Patricia M, Devinsky, Orrin, Doherty, Colin P, Domin, Martin, Duncan, John S, Focke, Niels K, Gambardella, Antonio, Gong, Bo, Guerrini, Renzo, Hatton, Sean N, Kälviäinen, Reetta, Keller, Simon S, Kochunov, Peter, Kotikalapudi, Raviteja, Kreilkamp, Barbara AK, Labate, Angelo, Langner, Soenke, Larivière, Sara, Lenge, Matteo, Lui, Elaine, Martin, Pascal, Mascalchi, Mario, Meletti, Stefano, O'Brien, Terence J, Pardoe, Heath R, Pariente, Jose C, Rao, Jun Xian, Richardson, Mark P, Rodríguez-Cruces, Raúl, Rüber, Theodor, Sinclair, Ben, Soltanian-Zadeh, Hamid, Stein, Dan J, Striano, Pasquale, Taylor, Peter N, Thomas, Rhys H, Vaudano, Anna Elisabetta, Vivash, Lucy, von Podewills, Felix, Vos, Sjoerd B, Weber, Bernd, Yao, Yi, Yasuda, Clarissa Lin, Zhang, Junsong, Thompson, Paul M, Sisodiya, Sanjay M, McDonald, Carrie R, Bonilha, Leonardo, Group, ENIGMA-Epilepsy Working, Altmann, Andre, Depondt, Chantal, Galovic, Marian, Thomopoulos, Sophia I, and Wiest, Roland

Subjects
Biomedical Imaging, Neurodegenerative, Neurosciences, Brain Disorders, Prevention, Epilepsy, 2.1 Biological and endogenous factors, Aetiology, Neurological, Artificial Intelligence, Brain, Epilepsy, Temporal Lobe, Hippocampus, Humans, Magnetic Resonance Imaging, Sclerosis, Support Vector Machine, Temporal lobe epilepsy, Machine learning, Artificial inteligence, ENIGMA-Epilepsy Working Group
Abstract

Artificial intelligence has recently gained popularity across different medical fields to aid in the detection of diseases based on pathology samples or medical imaging findings. Brain magnetic resonance imaging (MRI) is a key assessment tool for patients with temporal lobe epilepsy (TLE). The role of machine learning and artificial intelligence to increase detection of brain abnormalities in TLE remains inconclusive. We used support vector machine (SV) and deep learning (DL) models based on region of interest (ROI-based) structural (n = 336) and diffusion (n = 863) brain MRI data from patients with TLE with ("lesional") and without ("non-lesional") radiographic features suggestive of underlying hippocampal sclerosis from the multinational (multi-center) ENIGMA-Epilepsy consortium. Our data showed that models to identify TLE performed better or similar (68-75%) compared to models to lateralize the side of TLE (56-73%, except structural-based) based on diffusion data with the opposite pattern seen for structural data (67-75% to diagnose vs. 83% to lateralize). In other aspects, structural and diffusion-based models showed similar classification accuracies. Our classification models for patients with hippocampal sclerosis were more accurate (68-76%) than models that stratified non-lesional patients (53-62%). Overall, SV and DL models performed similarly with several instances in which SV mildly outperformed DL. We discuss the relative performance of these models with ROI-level data and the implications for future applications of machine learning and artificial intelligence in epilepsy care.

Published
2021

18. Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study

Author

Larivière, Sara, Rodríguez-Cruces, Raúl, Royer, Jessica, Caligiuri, Maria Eugenia, Gambardella, Antonio, Concha, Luis, Keller, Simon S, Cendes, Fernando, Yasuda, Clarissa, Bonilha, Leonardo, Gleichgerrcht, Ezequiel, Focke, Niels K, Domin, Martin, von Podewills, Felix, Langner, Soenke, Rummel, Christian, Wiest, Roland, Martin, Pascal, Kotikalapudi, Raviteja, O’Brien, Terence J, Sinclair, Benjamin, Vivash, Lucy, Desmond, Patricia M, Alhusaini, Saud, Doherty, Colin P, Cavalleri, Gianpiero L, Delanty, Norman, Kälviäinen, Reetta, Jackson, Graeme D, Kowalczyk, Magdalena, Mascalchi, Mario, Semmelroch, Mira, Thomas, Rhys H, Soltanian-Zadeh, Hamid, Davoodi-Bojd, Esmaeil, Zhang, Junsong, Lenge, Matteo, Guerrini, Renzo, Bartolini, Emanuele, Hamandi, Khalid, Foley, Sonya, Weber, Bernd, Depondt, Chantal, Absil, Julie, Carr, Sarah JA, Abela, Eugenio, Richardson, Mark P, Devinsky, Orrin, Severino, Mariasavina, Striano, Pasquale, Tortora, Domenico, Hatton, Sean N, Vos, Sjoerd B, Duncan, John S, Whelan, Christopher D, Thompson, Paul M, Sisodiya, Sanjay M, Bernasconi, Andrea, Labate, Angelo, McDonald, Carrie R, Bernasconi, Neda, and Bernhardt, Boris C

Subjects
Mental Health, Brain Disorders, Epilepsy, Clinical Research, Neurosciences, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological
Abstract

Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies.

Published
2020

19. White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA-Epilepsy study

Author

Hatton, Sean N, Huynh, Khoa H, Bonilha, Leonardo, Abela, Eugenio, Alhusaini, Saud, Altmann, Andre, Alvim, Marina KM, Balachandra, Akshara R, Bartolini, Emanuele, Bender, Benjamin, Bernasconi, Neda, Bernasconi, Andrea, Bernhardt, Boris, Bargallo, Núria, Caldairou, Benoit, Caligiuri, Maria E, Carr, Sarah JA, Cavalleri, Gianpiero L, Cendes, Fernando, Concha, Luis, Davoodi-bojd, Esmaeil, Desmond, Patricia M, Devinsky, Orrin, Doherty, Colin P, Domin, Martin, Duncan, John S, Focke, Niels K, Foley, Sonya F, Gambardella, Antonio, Gleichgerrcht, Ezequiel, Guerrini, Renzo, Hamandi, Khalid, Ishikawa, Akari, Keller, Simon S, Kochunov, Peter V, Kotikalapudi, Raviteja, Kreilkamp, Barbara AK, Kwan, Patrick, Labate, Angelo, Langner, Soenke, Lenge, Matteo, Liu, Min, Lui, Elaine, Martin, Pascal, Mascalchi, Mario, Moreira, José CV, Morita-Sherman, Marcia E, O’Brien, Terence J, Pardoe, Heath R, Pariente, José C, Ribeiro, Letícia F, Richardson, Mark P, Rocha, Cristiane S, Rodríguez-Cruces, Raúl, Rosenow, Felix, Severino, Mariasavina, Sinclair, Benjamin, Soltanian-Zadeh, Hamid, Striano, Pasquale, Taylor, Peter N, Thomas, Rhys H, Tortora, Domenico, Velakoulis, Dennis, Vezzani, Annamaria, Vivash, Lucy, von Podewils, Felix, Vos, Sjoerd B, Weber, Bernd, Winston, Gavin P, Yasuda, Clarissa L, Zhu, Alyssa H, Thompson, Paul M, Whelan, Christopher D, Jahanshad, Neda, Sisodiya, Sanjay M, and McDonald, Carrie R

Subjects
Genetics, Neurodegenerative, Epilepsy, Clinical Research, Brain Disorders, Neurosciences, Biomedical Imaging, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Brain, Diffusion Magnetic Resonance Imaging, Epileptic Syndromes, Female, Humans, Image Interpretation, Computer-Assisted, Male, Middle Aged, White Matter, epilepsy, diffusion tensor imaging, multisite analysis, white matter, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P

Published
2020

20. A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Author

Abbott, Kristin M., Banka, Siddharth, de Boer, Elke, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Denommé-Pichon, Anne-Sophie, Faivre, Laurence, Gilissen, Christian, Haack, Tobias B., Havlovicova, Marketa, Hoischen, Alexander, Jackson, Adam, Kerstjens, Mieke, Kleefstra, Tjitske, Martín, Estrella López, Macek, Milan, Jr., Matalonga, Leslie, Maystadt, Isabelle, Morleo, Manuela, Nigro, Vicenzo, Pinelli, Michele, Pizzi, Simone, Posada, Manuel, Radio, Francesca C., Renieri, Alessandra, Riess, Olaf, Rooryck, Caroline, Ryba, Lukas, Agathe, Jean-Madeleine de Sainte, Santen, Gijs W.E., Schwarz, Martin, Tartaglia, Marco, Thauvin, Christel, Torella, Annalaura, Trimouille, Aurélien, Verloes, Alain, Vissers, Lisenka, Vitobello, Antonio, Votypka, Pavel, Zguro, Kristina, Boer, Elke de, Cohen, Enzo, Danis, Daniel, Gao, Fei, Horvath, Rita, Johari, Mridul, Johanson, Lennart, Li, Shuang, Morsy, Heba, Nelson, Isabelle, Paramonov, Ida, te Paske, Iris B.A.W., Robinson, Peter, Savarese, Marco, Steyaert, Wouter, Töpf, Ana, van der Velde, Joeri K., Vandrovcova, Jana, Graessner, Holm, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Schüle, Rebecca, Xu, Jishu, Kessler, Christoph, Wayand, Melanie, Synofzik, Matthis, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Lerche, Holger, Kegele, Josua, Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, ‘t Hoen, Peter A.C., Vissers, Lisenka E.L.M., Sablauskas, Karolis, de Voer, Richarda M., Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, Paske, Iris te, Janssen, Erik, Steehouwer, Marloes, Yaldiz, Burcu, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Maddi, Vatsalya, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Bettolo, Chiara Marini, Manera, Jordi Diaz, Hambleton, Sophie, Engelhardt, Karin, Alexander, Elizabeth, Duffourd, Yannis, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Laurie, Steven, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Lagorce, David, Hongnat, Oscar, Chahdil, Maroua, Lebreton, Emeline, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Ben Yaou, Rabah, Metay, Corinne, Eymard, Bruno, Atalaia, Antonio, Stojkovic, Tanya, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Lišková, Petra, Doležalová, Pavla, Parkinson, Helen, Keane, Thomas, Freeberg, Mallory, Thomas, Coline, Spalding, Dylan, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Efthymiou, Stephanie, Cali, Elisa, Magrinelli, Francesca, Sisodiya, Sanjay M., Rohrer, Jonathan, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, de Vries, Geert, De Winter, Jonathan, Beijer, Danique, de Jonghe, Peter, Van de Vondel, Liedewei, De Ridder, Willem, Weckhuysen, Sarah, Nigro, Vincenzo, Mutarelli, Margherita, Varavallo, Alessandra, Banfi, Sandro, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Gualandi, Francesca, Bigoni, Stefania, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Vries, Gerben, Neerincx, Pieter B., Ruvolo, David, Kerstjens Frederikse, Wilhemina S., Zonneveld-Huijssoon, Eveline, Roelofs-Prins, Dieuwke, van Gijn, Marielle, Köhler, Sebastian, Metcalfe, Alison, Drunat, Séverine, Heron, Delphine, Mignot, Cyril, Keren, Boris, Lacombe, Didier, Trimouille, Aurelien, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Cilio, Maria-Roberta, Carpancea, Evelina, Depondt, Chantal, Lederer, Damien, Sznajer, Yves, Duerinckx, Sarah, Mary, Sandrine, Macaya, Alfons, Cazurro-Gutiérrez, Ana, Pérez-Dueñas, Belén, Munell, Francina, Jarava, Clara Franco, Masó, Laura Batlle, Marcé-Grau, Anna, Colobran, Roger, Hackman, Peter, Udd, Bjarne, Hemelsoet, Dimitri, Dermaut, Bart, Schuermans, Nika, Poppe, Bruce, Verdin, Hannah, Osorio, Andrés Nascimento, Depienne, Christel, Roos, Andreas, Cordts, Isabell, Deschauer, Marcus, Striano, Pasquale, Zara, Federico, Riva, Antonella, Iacomino, Michele, Uva, Paolo, Scala, Marcello, Scudieri, Paolo, Başak, Ayşe Nazlı, Claeys, Kristl, Boztug, Kaan, Haimel, Matthias, W.E, Gijs, Ruivenkamp, Claudia A.L., Natera de Benito, Daniel, Thompson, Rachel, Polavarapu, Kiran, Grimbacher, Bodo, Zaganas, Ioannis, Kokosali, Evgenia, Lambros, Mathioudakis, Evangeliou, Athanasios, Spilioti, Martha, Kapaki, Elisabeth, Bourbouli, Mara, Radio, Francesca Clementina, Balicza, Peter, Molnar, Maria Judit, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Delgado, Beatriz Martínez, Alonso García de la Rosa, F. Javier, Schröck, Evelin, Rump, Andreas, Mei, Davide, Vetro, Annalisa, Balestrini, Simona, Guerrini, Renzo, Chinnery, Patrick F., Ratnaike, Thiloka, Schon, Katherine, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, May, Patrick, Beeson, David, Cossins, Judith, Furini, Simone, Fallerini, Chiara, Benetti, Elisa, Afenjar, Alexandra, Goldenberg, Alice, Masurel, Alice, Phan, Alice, Dieux-Coeslier, Anne, Fargeot, Anne, Guerrot, Anne-Marie, Toutain, Annick, Molin, Arnaud, Sorlin, Arthur, Putoux, Audrey, Jouret, Béatrice, Laudier, Béatrice, Demeer, Bénédicte, Doray, Bérénice, Bonniaud, Bertille, Isidor, Bertrand, Gilbert-Dussardier, Brigitte, Leheup, Bruno, Reversade, Bruno, Paul, Carle, Vincent-Delorme, Catherine, Neiva, Cecilia, Poirsier, Céline, Quélin, Chloé, Chiaverini, Christine, Coubes, Christine, Francannet, Christine, Colson, Cindy, Desplantes, Claire, Wells, Constance, Goizet, Cyril, Sanlaville, Damien, Amram, Daniel, Lehalle, Daphné, Geneviève, David, Gaillard, Dominique, Zivi, Einat, Sarrazin, Elisabeth, Steichen, Elisabeth, Schaefer, Élise, Lacaze, Elodie, Jacquemin, Emmanuel, Bongers, Ernie, Kilic, Esra, Colin, Estelle, Giuliano, Fabienne, Prieur, Fabienne, Laffargue, Fanny, Morice-Picard, Fanny, Petit, Florence, Cartault, François, Feillet, François, Baujat, Geneviève, Morin, Gilles, Diene, Gwenaëlle, Journel, Hubert, Perthus, Isabelle, Lespinasse, James, Alessandri, Jean-Luc, Amiel, Jeanne, Martinovic, Jelena, Delanne, Julian, Albuisson, Juliette, Lambert, Laëtitia, Perrin, Laurence, Ousager, Lilian Bomme, Van Maldergem, Lionel, Pinson, Lucile, Ruaud, Lyse, Samimi, Mahtab, Bournez, Marie, Bonnet-Dupeyron, Marie Noëlle, Vincent, Marie, Jacquemont, Marie-Line, Cordier-Alex, Marie-Pierre, Gérard-Blanluet, Marion, Willems, Marjolaine, Spodenkiewicz, Marta, Doco-Fenzy, Martine, Rossi, Massimiliano, Renaud, Mathilde, Fradin, Mélanie, Mathieu, Michèle, Holder-Espinasse, Muriel H., Houcinat, Nada, Hanna, Nadine, Leperrier, Nathalie, Chassaing, Nicolas, Philip, Nicole, Boute, Odile, Van Kien, Philippe Khau, Parent, Philippe, Bitoun, Pierre, Sarda, Pierre, Vabres, Pierre, Jouk, Pierre-Simon, Touraine, Renaud, El Chehadeh, Salima, Whalen, Sandra, Marlin, Sandrine, Passemard, Sandrine, Grotto, Sarah, Bellanger, Séverine Audebert, Blesson, Sophie, Nambot, Sophie, Naudion, Sophie, Lyonnet, Stanislas, Odent, Sylvie, Attie-Bitach, Tania, Busa, Tiffany, Drouin-Garraud, Valérie, Layet, Valérie, Bizaoui, Varoona, Cusin, Véronica, Capri, Yline, Alembik, Yves, Jean-Marçais, Nolwenn, López-Martín, Estrella, Macek, Milan, Mencarelli, Maria Antonietta, Moutton, Sébastien, Pfundt, Rolph, Safraou, Hana, Thauvin-Robinet, Christel, Thevenon, Julien, Tran Mau-Them, Frédéric, de Vries, Bert B.A., Willemsen, Marjolein H., and Philippe, Christophe

Published
2023
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21. Climate change and disorders of the nervous system

Author

Sisodiya, Sanjay M, primary, Gulcebi, Medine I, additional, Fortunato, Francesco, additional, Mills, James D, additional, Haynes, Ethan, additional, Bramon, Elvira, additional, Chadwick, Paul, additional, Ciccarelli, Olga, additional, David, Anthony S, additional, De Meyer, Kris, additional, Fox, Nick C, additional, Davan Wetton, Joanna, additional, Koltzenburg, Martin, additional, Kullmann, Dimitri M, additional, Kurian, Manju A, additional, Manji, Hadi, additional, Maslin, Mark A, additional, Matharu, Manjit, additional, Montgomery, Hugh, additional, Romanello, Marina, additional, Werring, David J, additional, Zhang, Lisa, additional, Friston, Karl J, additional, and Hanna, Michael G, additional

Published
2024
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23. SCN1A overexpression, associated with a genomic region marked by a risk variant for a common epilepsy, raises seizure susceptibility

Author

Silvennoinen, Katri, Gawel, Kinga, Tsortouktzidis, Despina, Pitsch, Julika, Alhusaini, Saud, van Loo, Karen M. J., Picardo, Richard, Michalak, Zuzanna, Pagni, Susanna, Martins Custodio, Helena, Mills, James, Whelan, Christopher D., de Zubicaray, Greig I., McMahon, Katie L., van der Ent, Wietske, Kirstein-Smardzewska, Karolina J., Tiraboschi, Ettore, Mudge, Jonathan M., Frankish, Adam, Thom, Maria, Wright, Margaret J., Thompson, Paul M., Schoch, Susanne, Becker, Albert J., Esguerra, Camila V., and Sisodiya, Sanjay M.

Published
2022
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24. Polygenic burden in focal and generalized epilepsies

Author

Leu, Costin, Stevelink, Remi, Smith, Alexander W, Goleva, Slavina B, Kanai, Masahiro, Ferguson, Lisa, Campbell, Ciaran, Kamatani, Yoichiro, Okada, Yukinori, Sisodiya, Sanjay M, Cavalleri, Gianpiero L, Koeleman, Bobby PC, Lerche, Holger, Jehi, Lara, Davis, Lea K, Najm, Imad M, Palotie, Aarno, Daly, Mark J, Busch, Robyn M, Consortium, Epi25, and Lal, Dennis

Subjects
Biomedical and Clinical Sciences, Clinical Research, Neurosciences, Brain Disorders, Neurodegenerative, Epilepsy, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Cohort Studies, Cost of Illness, Databases, Factual, Epilepsies, Partial, Epilepsy, Generalized, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide, White People, Epi25 Consortium, common variant risk, epilepsy, genetic generalized epilepsy, genetics, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10-15; Cleveland: P = 2.85×10-4; Finnish-ancestry Epi25: P = 1.80×10-4) or population controls (Epi25: P = 2.35×10-70; Cleveland: P = 1.43×10-7; Finnish-ancestry Epi25: P = 3.11×10-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10-19; Cleveland: P = 1.69×10-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10-15; Cleveland: P = 1.39×10-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.

Published
2019

25. 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

26. Clinical spectrum of STX1B-related epileptic disorders.

Author

Cilio, Maria, Van Paesschen, Wim, Svendsen, Lene, Oates, Stephanie, Hughes, Elaine, Goyal, Sushma, Brown, Kathleen, Sifuentes Saenz, Margarita, Dorn, Thomas, Muhle, Hiltrud, Pagnamenta, Alistair, Vavoulis, Dimitris, Knight, Samantha, Taylor, Jenny, Canevini, Maria, Darra, Francesca, Gavrilova, Ralitza, Powis, Zöe, Tang, Shan, Marquetand, Justus, Armstrong, Martin, McHale, Duncan, Klee, Eric, Kluger, Gerhard, Lowenstein, Daniel, Weckhuysen, Sarah, Pal, Deb, Helbig, Ingo, Guerrini, Renzo, Thomas, Rhys, Rees, Mark, Lesca, Gaetan, Sisodiya, Sanjay, Weber, Yvonne, Lal, Dennis, Marini, Carla, Lerche, Holger, Schubert, Julian, Wolking, Stefan, May, Patrick, Mei, Davide, Møller, Rikke, Balestrini, Simona, Helbig, Katherine, Altuzarra, Cecilia, Chatron, Nicolas, Kaiwar, Charu, Stöhr, Katharina, Widdess-Walsh, Peter, Mendelsohn, Bryce, and Numis, Adam

Subjects
Adolescent, Anticonvulsants, Child, Child, Preschool, Developmental Disabilities, Drug Resistant Epilepsy, Electroencephalography, Epilepsies, Partial, Epileptic Syndromes, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Learning Disabilities, Loss of Function Mutation, Male, Mutation, Missense, Phenotype, Seizures, Febrile, Sequence Analysis, DNA, Syntaxin 1, Young Adult
Abstract

OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.

Published
2019

27. N‐of‐1 trials in epilepsy: A systematic review and lessons paving the way forward.

Author

Defelippe, Victoria M., Brilstra, Eva H., Otte, Willem M., Cross, Helen J., O'Callaghan, Finbar, De Giorgis, Valentina, Poduri, Annapurna, Lerche, Holger, Sisodiya, Sanjay, Braun, Kees P. J., Jansen, Floor E., and Perucca, Emilio

Subjects
SEIZURES (Medicine), INDIVIDUALIZED medicine, INFORMATION design, PEOPLE with epilepsy, CRIME & the press, EPILEPSY
Abstract

Objective: Defined as prospective single‐patient crossover studies with repeated paired cycles of active and control intervention, N‐of‐1 trials have gained attention as an option to obtain high‐quality evidence of efficacy, particularly for patients with rare epilepsies in whom conduction of well‐powered randomized controlled trials can be challenging. The objective of this systematic review is to provide an appraisal of the literature on N‐of‐1 trials in individuals with epilepsy. Methods: We searched PubMed and Embase on January 12, 2024, for studies meeting the following criteria: prospectively planned, within‐patient, multiple‐crossover design in individuals with epilepsy and outcomes related to comorbidities. Information on design, outcome measurements, intervention, and analyses was retrieved. Risk of bias assessment was performed using the Risk of Bias in N‐of‐1 Trials (RoBiNT) scale. We highlighted methodological aspects of the N‐of‐1 trials identified and discuss future recommendations. Results: Five studies met our inclusion criteria. An additional multiple‐crossover trial that evaluated treatment effects exclusively at group level was also included because of its relevance to N‐of‐1 study methodology. The studies enrolled individuals with focal seizures, absences or cognitive impairement and electrographic discharges. Treatments included established or investigational antiseizure medications, off‐label medications, neurostimulation or lifestyle intervention. Three of the five N‐of‐1 trials reported on individual cases. The studies' strengths were the use of individualized treatment dosages and symptom‐specific patient‐reported outcomes. Limitations were related to minimal reporting of baseline characteristics and seizure burden. Significance: The trials identified by our search exemplify how the N‐of‐1 design can be applied to assess interventions in individuals with epilepsy‐related disorders. Future N‐of‐1 trials of antiseizure interventions should take into account baseline seizure frequency, should apply statistical models suited to capture seizure frequency changes reliably and make predefined interim assessments. Non‐seizure outcome measures evaluable over short periods should be considered. Tailored N‐of‐1 methodology could pave the way to evidence‐based, treatment selection for patients with rare epilepsies. [ABSTRACT FROM AUTHOR]

Published
2024
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30. COVID‐19 response in a long‐term care facility for people with epilepsy

Author

Delazer, Luisa, primary, Pressler, Noah, additional, Balestrini, Simona, additional, Xiao, Fenglai, additional, Clayton, Lisa M., additional, Anders‐Cannon, Jonny, additional, Salvatierra, Rebecca, additional, Henry, Ian, additional, Sisodiya, Sanjay M., additional, Sander, Josemir W., additional, and Koepp, Matthias J., additional

Published
2024
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31. Epilepsy and Related Disorders

Author

Duncan, John, primary, Sander, Josemir, additional, Alim‐Marvasti, Ali, additional, Balestrini, Simona, additional, Baxendale, Sallie, additional, Bindman, Dorothea, additional, Chinthapalli, Krishna, additional, Chowdhury, Fahmida, additional, Diehl, Beate, additional, Eriksson, Sofia, additional, Foong, Jackie, additional, Heaney, Dominic, additional, Khan, Sofia, additional, Koepp, Matthias, additional, Kullmann, Dimitri, additional, Rajakulendran, Sanjeev, additional, Rugg‐Gunn, Fergus, additional, Sidhu, Meneka, additional, Sisodiya, Sanjay, additional, de Tisi, Jane, additional, Thom, Maria, additional, Walker, Matthew, additional, and Yogarajah, Mahinda, additional

Published
2024
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33. A worldwide ENIGMA study on epilepsy-related gray and white matter compromise across the adult lifespan

Author

Chen, Judy, primary, Ngo, Alexander, additional, Rodríguez-Cruces, Raúl, additional, Royer, Jessica, additional, Caligiuri, Maria Eugenia, additional, Gambardella, Antonio, additional, Concha, Luis, additional, Keller, Simon S., additional, Cendes, Fernando, additional, Yasuda, Clarissa L., additional, Alvim, Marina K. M., additional, Bonilha, Leonardo, additional, Gleichgerrcht, Ezequiel, additional, Focke, Niels K., additional, Kreilkamp, Barbara, additional, Domin, Martin, additional, von Podewils, Felix, additional, Langner, Soenke, additional, Rummel, Christian, additional, Wiest, Roland, additional, Martin, Pascal, additional, Kotikalapudi, Raviteja, additional, Bender, Benjamin, additional, O’Brien, Terence J., additional, Sinclair, Benjamin, additional, Vivash, Lucy, additional, Kwan, Patrick, additional, Desmond, Patricia M., additional, Lui, Elaine, additional, Duma, Gian Marco, additional, Bonanni, Paolo, additional, Ballerini, Alice, additional, Vaudano, Anna Elisabetta, additional, Meletti, Stefano, additional, Tondelli, Manuela, additional, Alhusaini, Saud, additional, Doherty, Colin P., additional, Cavalleri, Gianpiero L., additional, Delanty, Norman, additional, Kälviäinen, Reetta, additional, Jackson, Graeme D., additional, Kowalczyk, Magdalena, additional, Mascalchi, Mario, additional, Semmelroch, Mira, additional, Thomas, Rhys H., additional, Soltanian-Zadeh, Hamid, additional, Davoodi-Bojd, Esmaeil, additional, Zhang, Junsong, additional, Lenge, Matteo, additional, Guerrini, Renzo, additional, Bartolini, Emanuele, additional, Hamandi, Khalid, additional, Foley, Sonya, additional, Rüber, Theodor, additional, Bauer, Tobias, additional, Weber, Bernd, additional, Caldairou, Benoit, additional, Depondt, Chantal, additional, Absil, Julie, additional, Carr, Sarah J. A., additional, Abela, Eugenio, additional, Richardson, Mark P., additional, Devinsky, Orrin, additional, Pardoe, Heath, additional, Severino, Mariasavina, additional, Striano, Pasquale, additional, Tortora, Domenico, additional, Kaestner, Erik, additional, Hatton, Sean N., additional, Arienzo, Donatello, additional, Vos, Sjoerd B., additional, Ryten, Mina, additional, Taylor, Peter N., additional, Duncan, John S., additional, Whelan, Christopher D., additional, Galovic, Marian, additional, Winston, Gavin P., additional, Thomopoulos, Sophia I., additional, Thompson, Paul M., additional, Sisodiya, Sanjay M., additional, Labate, Angelo, additional, McDonald, Carrie R., additional, Caciagli, Lorenzo, additional, Bernasconi, Neda, additional, Bernasconi, Andrea, additional, Larivière, Sara, additional, Schrader, Dewi, additional, and Bernhardt, Boris C., additional

Published
2024
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35. Climate change and epilepsy: Insights from clinical and basic science studies

Author

Balestrini, Simona, Berkovic, Samuel, Cavalleri, Gianpiero, Correa, Daniel José, Martins Custodio, Helena, Galovic, Marian, Guerrini, Renzo, Henshall, David, Howard, Olga, Hughes, Kelvin, Katsarou, Anna, Koeleman, Bobby P.C., Krause, Roland, Lowenstein, Daniel, Mandelenaki, Despoina, Marini, Carla, O’Brien, Terence J., Pace, Adrian, De Palma, Luca, Perucca, Piero, Pitkänen, Asla, Quinn, Finola, Selmer, Kaja Kristine, Steward, Charles A., Swanborough, Nicola, Thijs, Roland, Tittensor, Phil, Trivisano, Marina, Weckhuysen, Sarah, Zara, Federico, Gulcebi, Medine I., Bartolini, Emanuele, Lee, Omay, Lisgaras, Christos Panagiotis, Onat, Filiz, Mifsud, Janet, Striano, Pasquale, Vezzani, Annamaria, Hildebrand, Michael S., Jimenez-Jimenez, Diego, Junck, Larry, Lewis-Smith, David, Scheffer, Ingrid E., Thijs, Roland D., Zuberi, Sameer M., Blenkinsop, Stephen, Fowler, Hayley J., Foley, Aideen, and Sisodiya, Sanjay M.

Published
2021
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36. DNM1 encephalopathy

Author

von Spiczak, Sarah, Helbig, Katherine L, Shinde, Deepali N, Huether, Robert, Pendziwiat, Manuela, Lourenço, Charles, Nunes, Mark E, Sarco, Dean P, Kaplan, Richard A, Dlugos, Dennis J, Kirsch, Heidi, Slavotinek, Anne, Cilio, Maria R, Cervenka, Mackenzie C, Cohen, Julie S, McClellan, Rebecca, Fatemi, Ali, Yuen, Amy, Sagawa, Yoshimi, Littlejohn, Rebecca, McLean, Scott D, Hernandez-Hernandez, Laura, Maher, Bridget, Møller, Rikke S, Palmer, Elizabeth, Lawson, John A, Campbell, Colleen A, Joshi, Charuta N, Kolbe, Diana L, Hollingsworth, Georgie, Neubauer, Bernd A, Muhle, Hiltrud, Stephani, Ulrich, Scheffer, Ingrid E, Pena, Sérgio DJ, Sisodiya, Sanjay M, and Helbig, Ingo

Subjects
Neurosciences, Intellectual and Developmental Disabilities (IDD), Genetics, Clinical Research, Brain Disorders, Epilepsy, Pediatric, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Brain Diseases, Child, Child, Preschool, Cohort Studies, DNA Mutational Analysis, Dynamins, Female, GTP Phosphohydrolases, Homeodomain Proteins, Humans, Infant, Male, Microtubule-Associated Proteins, Mitochondrial Proteins, Models, Molecular, Mutation, Phenotype, Short Stature Homeobox Protein, Siblings, Synaptic Vesicles, Young Adult, Epi4K Consortium, EuroEPINOMICS-RES NLES Working Group, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.MethodsWe reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.ResultsWe identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.ConclusionsThe phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.

Published
2017

37. DNM1 encephalopathy: A new disease of vesicle fission.

Author

von Spiczak, Sarah, Helbig, Katherine L, Shinde, Deepali N, Huether, Robert, Pendziwiat, Manuela, Lourenço, Charles, Nunes, Mark E, Sarco, Dean P, Kaplan, Richard A, Dlugos, Dennis J, Kirsch, Heidi, Slavotinek, Anne, Cilio, Maria R, Cervenka, Mackenzie C, Cohen, Julie S, McClellan, Rebecca, Fatemi, Ali, Yuen, Amy, Sagawa, Yoshimi, Littlejohn, Rebecca, McLean, Scott D, Hernandez-Hernandez, Laura, Maher, Bridget, Møller, Rikke S, Palmer, Elizabeth, Lawson, John A, Campbell, Colleen A, Joshi, Charuta N, Kolbe, Diana L, Hollingsworth, Georgie, Neubauer, Bernd A, Muhle, Hiltrud, Stephani, Ulrich, Scheffer, Ingrid E, Pena, Sérgio DJ, Sisodiya, Sanjay M, Helbig, Ingo, Epi4K Consortium, and EuroEPINOMICS-RES NLES Working Group

Subjects
Epi4K Consortium, EuroEPINOMICS-RES NLES Working Group, Synaptic Vesicles, Humans, Brain Diseases, GTP Phosphohydrolases, Microtubule-Associated Proteins, Homeodomain Proteins, Mitochondrial Proteins, Cohort Studies, DNA Mutational Analysis, Siblings, Phenotype, Mutation, Models, Molecular, Adolescent, Child, Child, Preschool, Infant, Female, Male, Young Adult, Short Stature Homeobox Protein, Dynamins, Models, Molecular, Preschool, Clinical Sciences, Neurosciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.MethodsWe reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.ResultsWe identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.ConclusionsThe phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.

Published
2017

38. ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide

Author

Thompson, Paul M, Andreassen, Ole A, Arias-Vasquez, Alejandro, Bearden, Carrie E, Boedhoe, Premika S, Brouwer, Rachel M, Buckner, Randy L, Buitelaar, Jan K, Bulayeva, Kazima B, Cannon, Dara M, Cohen, Ronald A, Conrod, Patricia J, Dale, Anders M, Deary, Ian J, Dennis, Emily L, de Reus, Marcel A, Desrivieres, Sylvane, Dima, Danai, Donohoe, Gary, Fisher, Simon E, Fouche, Jean-Paul, Francks, Clyde, Frangou, Sophia, Franke, Barbara, Ganjgahi, Habib, Garavan, Hugh, Glahn, David C, Grabe, Hans J, Guadalupe, Tulio, Gutman, Boris A, Hashimoto, Ryota, Hibar, Derrek P, Holland, Dominic, Hoogman, Martine, Pol, Hilleke E Hulshoff, Hosten, Norbert, Jahanshad, Neda, Kelly, Sinead, Kochunov, Peter, Kremen, William S, Lee, Phil H, Mackey, Scott, Martin, Nicholas G, Mazoyer, Bernard, McDonald, Colm, Medland, Sarah E, Morey, Rajendra A, Nichols, Thomas E, Paus, Tomas, Pausova, Zdenka, Schmaal, Lianne, Schumann, Gunter, Shen, Li, Sisodiya, Sanjay M, Smit, Dirk JA, Smoller, Jordan W, Stein, Dan J, Stein, Jason L, Toro, Roberto, Turner, Jessica A, van den Heuvel, Martijn P, van den Heuvel, Odile L, van Erp, Theo GM, van Rooij, Daan, Veltman, Dick J, Walter, Henrik, Wang, Yalin, Wardlaw, Joanna M, Whelan, Christopher D, Wright, Margaret J, Ye, Jieping, and Consortium, for the ENIGMA

Subjects
Biomedical and Clinical Sciences, Health Sciences, Genetics, Mental Health, Prevention, Brain Disorders, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Mental health, Neurological, Good Health and Well Being, Brain Diseases, Genome-Wide Association Study, Humans, Mental Disorders, Multicenter Studies as Topic, ENIGMA Consortium, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Abstract

In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) - a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date - of schizophrenia and major depression - ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others1, ENIGMA's genomic screens - now numbering over 30,000 MRI scans - have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants - and genetic variants in general - may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures - from tens of thousands of people - that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.

Published
2017

40. Clinical outcomes of COVID-19 in long-term care facilities for people with epilepsy

Author

Aitken, Jim, Allen, Zoe, Ambler, Rachel, Ambrose, Karen, Ashton, Emma, Avola, Alida, Balakrishnan, Samutheswari, Barns-Jenkins, Caitlin, Barr, Genevieve, Barrell, Sam, Basu, Souradeep, Beale, Rupert, Beesley, Clare, Bhardwaj, Nisha, Bibi, Shahnaz, Bineva-Todd, Ganka, Biswas, Dhruva, Blackman, Michael J., Bonnet, Dominique, Bowker, Faye, Broncel, Malgorzata, Brooks, Claire, Buck, Michael D., Buckton, Andrew, Budd, Timothy, Burrell, Alana, Busby, Louise, Bussi, Claudio, Butterworth, Simon, Byott, Matthew, Byrne, Fiona, Byrne, Richard, Caidan, Simon, Campbell, Joanna, Canton, Johnathan, Cardoso, Ana, Carter, Nick, Carvalho, Luiz, Carzaniga, Raffaella, Chandler, Natalie, Chen, Qu, Cherepanov, Peter, Churchward, Laura, Clark, Graham, Clayton, Bobbi, Cobolli Gigli, Clementina, Collins, Zena, Cottrell, Sally, Crawford, Margaret, Cubitt, Laura, Cullup, Tom, Davies, Heledd, Davis, Patrick, Davison, Dara, Dearing, Vicky, Debaisieux, Solene, Diaz-Romero, Monica, Dibbs, Alison, Diring, Jessica, Driscoll, Paul C., D'Avola, Annalisa, Earl, Christopher, Edwards, Amelia, Ekin, Chris, Evangelopoulos, Dimitrios, Faraway, Rupert, Fearns, Antony, Ferron, Aaron, Fidanis, Efthymios, Fitz, Dan, Fleming, James, Frampton, Daniel, Frederico, Bruno, Gaiba, Alessandra, Gait, Anthony, Gamblin, Steve, Gärtner, Kathleen, Gaul, Liam, Golding, Helen M., Goldman, Jacki, Goldstone, Robert, Gomez Dominguez, Belen, Gong, Hui, Grant, Paul R., Greco, Maria, Grobler, Mariana, Guedan, Anabel, Gutierrez, Maximiliano G., Hackett, Fiona, Hall, Ross, Halldorsson, Steinar, Harris, Suzanne, Hashim, Sugera, Hatipoglu, Emine, Healy, Lyn, Heaney, Judith, Herbst, Susanne, Hewitt, Graeme, Higgins, Theresa, Hindmarsh, Steve, Hirani, Rajnika, Hope, Joshua, Horton, Elizabeth, Hoskins, Beth, Howell, Michael, Howitt, Louise, Hoyle, Jacqueline, Htun, Mint R., Hubank, Michael, Huerga Encabo, Hector, Hughes, Deborah, Hughes, Jane, Huseynova, Almaz, Hwang, Ming-Shih, Instrell, Rachael, Jackson, Deborah, Jamal-Hanjani, Mariam, Jenkins, Lucy, Jiang, Ming, Johnson, Mark, Jones, Leigh, Kanu, Nnennaya, Kassiotis, George, Kelly, Gavin, Kiely, Louise, Teixeira, Anastacio King Spert, Kirk, Stuart, Kjaer, Svend, Knuepfer, Ellen, Komarov, Nikita, Kotzampaltiris, Paul, Kousis, Konstantinos, Krylova, Tammy, Kucharska, Ania, Labrum, Robyn, Lambe, Catherine, Lappin, Michelle, Lee, Stacey-Ann, Levett, Andrew, Levett, Lisa, Levi, Marcel, Liu, Hon Wing, Loughlin, Sam, Lu, Wei-Ting, MacRae, James I., Madoo, Akshay, Marczak, Julie A., Martensson, Mimmi, Martinez, Thomas, Marzook, Bishara, Matthews, John, Matz, Joachim M., McCall, Samuel, McCoy, Laura E., McKay, Fiona, McNamara, Edel C., Minutti, Carlos M., Mistry, Gita, Molina-Arcas, Miriam, Montaner, Beatriz, Montgomery, Kylie, Moore, Catherine, Moore, David, Moraiti, Anastasia, Moreira-Teixeira, Lucia, Mukherjee, Joyita, Naceur-Lombardelli, Cristina, Nelson, Aileen, Nicod, Jerome, Nightingale, Luke, Nofal, Stephanie, Nurse, Paul, Nutan, Savita, Oedekoven, Caroline, O'Garra, Anne, O'Leary, Jean D., Olsen, Jessica, O'Neill, Olga, O'Reilly, Nicola, Suarez, Paula Ordonez, Osborne, Neil, Pabari, Amar, Pajak, Aleksandra, Papayannopoulos, Venizelos, Paraskevopoulou, Stavroula M, Patel, Namita, Patel, Yogen, Paun, Oana, Peat, Nigel, Peces-Barba Castano, Laura, Caballero, Ana Perez, Perez-Lloret, Jimena, Perrault, Magali S., Perrin, Abigail, Poh, Roy, Poirier, Enzo Z., Polke, James M., Pollitt, Marc, Prieto-Godino, Lucia, Proust, Alize, Puvirajasinghe, Clinda, Queval, Christophe, Ramachandran, Vijaya, Ramaprasad, Abhinay, Ratcliffe, Peter, Reed, Laura, Reis e Sousa, Caetano, Richardson, Kayleigh, Ridewood, Sophie, Roberts, Fiona, Roberts, Rowenna, Rodgers, Angela, Romero Clavijo, Pablo, Rosa, Annachiara, Rossi, Alice, Roustan, Chloe, Rowan, Andrew, Sahai, Erik, Sait, Aaron, Sala, Katarzyna, Sanchez, Emilie, Sanderson, Theo, Santucci, Pierre, Sardar, Fatima, Sateriale, Adam, Saunders, Jill A., Sawyer, Chelsea, Schlott, Anja, Schweighoffer, Edina, Segura-Bayona, Sandra, Shah Punatar, Rajvee, Shahmanesh, Maryam, Shaw, Joe, Silva Dos Santos, Mariana, Silvestre, Margaux, Singer, Matthew, Snell, Daniel M., Song, Ok-Ryul, Spyer, Moira J., Steel, Louisa, Strange, Amy, Sullivan, Adrienne E., Tan, Michele S.Y., Tautz-Davis, Zoe H., Taylor, Effie, Taylor, Gunes, Taylor, Harriet B., Taylor-Beadling, Alison, Teixeira Subtil, Fernanda, Terré Torras, Berta, Toolan-Kerr, Patrick, Torelli, Francesca, Toteva, Tea, Treeck, Moritz, Trojer, Hadija, Tsai, Ming-Han C., Turner, James M.A., Turner, Melanie, Ule, Jernej, Ulferts, Rachel, Vanloo, Sharon P., Veeriah, Selvaraju, Venkatesan, Subramanian, Vousden, Karen, Wack, Andreas, Walder, Claire, Walker, Philip A., Wang, Yiran, Ward, Sophia, Wenman, Catharina, Williams, Luke, Williams, Matthew J., Keong Wong, Wai, Wright, Joshua, Wu, Mary, Wynne, Lauren, Xiang, Zheng, Yap, Melvyn, Zagalak, Julian A., Zecchin, Davide, Zillwood, Rachel, Carthiyaniamma, Santhakumari, DeTisi, Jane, Dick, Julie, Hill, Andrea, Kipper, Karin, Kullar, Birinder, Norris, Sarah, Rugg-Gunn, Fergus, Salvatierra, Rebecca, Shaya, Gabriel, Sloan, Astrid, Singh, Priyanka, Varley, James, Whatley, Ben, Balestrini, Simona, Koepp, Matthias J., Gandhi, Sonia, Rickman, Hannah M., Shin, Gee Yen, Houlihan, Catherine F., Anders-Cannon, Jonny, Silvennoinen, Katri, Xiao, Fenglai, Zagaglia, Sara, Hudgell, Kirsty, Ziomek, Mariusz, Haimes, Paul, Sampson, Adam, Parker, Annie, Helen Cross, J., Pardington, Rosemarie, Nastouli, Eleni, Swanton, Charles, Sander, Josemir W., and Sisodiya, Sanjay M.

Published
2021
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41. Beyond the Global Brain Differences:Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers

Author

Boen, Rune, Kaufmann, Tobias, van der Meer, Dennis, Frei, Oleksandr, Agartz, Ingrid, Ames, David, Andersson, Micael, Armstrong, Nicola J., Artiges, Eric, Atkins, Joshua R., Bauer, Jochen, Benedetti, Francesco, Boomsma, Dorret I., Brodaty, Henry, Brosch, Katharina, Buckner, Randy L., Cairns, Murray J., Calhoun, Vince, Caspers, Svenja, Cichon, Sven, Corvin, Aiden P., Crespo-Facorro, Benedicto, Dannlowski, Udo, David, Friederike S., de Geus, Eco J.C., de Zubicaray, Greig I., Desrivières, Sylvane, Doherty, Joanne L., Donohoe, Gary, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fisher, Simon E., Forstner, Andreas J., Fortaner-Uyà, Lidia, Frouin, Vincent, Fukunaga, Masaki, Ge, Tian, Glahn, David C., Goltermann, Janik, Grabe, Hans J., Green, Melissa J., Groenewold, Nynke A., Grotegerd, Dominik, Grøntvedt, Gøril Rolfseng, Hahn, Tim, Hashimoto, Ryota, Hehir-Kwa, Jayne Y., Henskens, Frans A., Holmes, Avram J., Håberg, Asta K., Haavik, Jan, Jacquemont, Sebastien, Jansen, Andreas, Jockwitz, Christiane, Jönsson, Erik G., Kikuchi, Masataka, Kircher, Tilo, Kumar, Kuldeep, Le Hellard, Stephanie, Leu, Costin, Linden, David E., Liu, Jingyu, Loughnan, Robert, Mather, Karen A., McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meinert, Susanne, Moreau, Clara A., Morris, Derek W., Mowry, Bryan J., Mühleisen, Thomas W., Nenadić, Igor, Nöthen, Markus M., Nyberg, Lars, Ophoff, Roel A., Owen, Michael J., Pantelis, Christos, Paolini, Marco, Paus, Tomas, Pausova, Zdenka, Persson, Karin, Quidé, Yann, Marques, Tiago Reis, Sachdev, Perminder S., Sando, Sigrid B., Schall, Ulrich, Scott, Rodney J., Selbæk, Geir, Shumskaya, Elena, Silva, Ana I., Sisodiya, Sanjay M., Stein, Frederike, Stein, Dan J., Straube, Benjamin, Streit, Fabian, Strike, Lachlan T., Teumer, Alexander, Teutenberg, Lea, Thalamuthu, Anbupalam, Tooney, Paul A., Tordesillas-Gutierrez, Diana, Trollor, Julian N., van ’t Ent, Dennis, van den Bree, Marianne B.M., van Haren, Neeltje E.M., Vázquez-Bourgon, Javier, Völzke, Henry, Wen, Wei, Wittfeld, Katharina, Ching, Christopher R.K., Westlye, Lars T., Thompson, Paul M., Bearden, Carrie E., Selmer, Kaja K., Alnæs, Dag, Andreassen, Ole A., Sønderby, Ida E., Boen, Rune, Kaufmann, Tobias, van der Meer, Dennis, Frei, Oleksandr, Agartz, Ingrid, Ames, David, Andersson, Micael, Armstrong, Nicola J., Artiges, Eric, Atkins, Joshua R., Bauer, Jochen, Benedetti, Francesco, Boomsma, Dorret I., Brodaty, Henry, Brosch, Katharina, Buckner, Randy L., Cairns, Murray J., Calhoun, Vince, Caspers, Svenja, Cichon, Sven, Corvin, Aiden P., Crespo-Facorro, Benedicto, Dannlowski, Udo, David, Friederike S., de Geus, Eco J.C., de Zubicaray, Greig I., Desrivières, Sylvane, Doherty, Joanne L., Donohoe, Gary, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fisher, Simon E., Forstner, Andreas J., Fortaner-Uyà, Lidia, Frouin, Vincent, Fukunaga, Masaki, Ge, Tian, Glahn, David C., Goltermann, Janik, Grabe, Hans J., Green, Melissa J., Groenewold, Nynke A., Grotegerd, Dominik, Grøntvedt, Gøril Rolfseng, Hahn, Tim, Hashimoto, Ryota, Hehir-Kwa, Jayne Y., Henskens, Frans A., Holmes, Avram J., Håberg, Asta K., Haavik, Jan, Jacquemont, Sebastien, Jansen, Andreas, Jockwitz, Christiane, Jönsson, Erik G., Kikuchi, Masataka, Kircher, Tilo, Kumar, Kuldeep, Le Hellard, Stephanie, Leu, Costin, Linden, David E., Liu, Jingyu, Loughnan, Robert, Mather, Karen A., McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meinert, Susanne, Moreau, Clara A., Morris, Derek W., Mowry, Bryan J., Mühleisen, Thomas W., Nenadić, Igor, Nöthen, Markus M., Nyberg, Lars, Ophoff, Roel A., Owen, Michael J., Pantelis, Christos, Paolini, Marco, Paus, Tomas, Pausova, Zdenka, Persson, Karin, Quidé, Yann, Marques, Tiago Reis, Sachdev, Perminder S., Sando, Sigrid B., Schall, Ulrich, Scott, Rodney J., Selbæk, Geir, Shumskaya, Elena, Silva, Ana I., Sisodiya, Sanjay M., Stein, Frederike, Stein, Dan J., Straube, Benjamin, Streit, Fabian, Strike, Lachlan T., Teumer, Alexander, Teutenberg, Lea, Thalamuthu, Anbupalam, Tooney, Paul A., Tordesillas-Gutierrez, Diana, Trollor, Julian N., van ’t Ent, Dennis, van den Bree, Marianne B.M., van Haren, Neeltje E.M., Vázquez-Bourgon, Javier, Völzke, Henry, Wen, Wei, Wittfeld, Katharina, Ching, Christopher R.K., Westlye, Lars T., Thompson, Paul M., Bearden, Carrie E., Selmer, Kaja K., Alnæs, Dag, Andreassen, Ole A., and Sønderby, Ida E.

Abstract

BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual’s regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

Published
2024

42. Mono-allelic KCNB2 variants lead to a neurodevelopmental syndrome caused by altered channel inactivation

Author

Metabole ziekten patientenzorg, Genetica, Child Health, Infection & Immunity, Bhat, Shreyas, Rousseau, Justine, Michaud, Coralie, Lourenço, Charles Marques, Stoler, Joan M., Louie, Raymond J., Clarkson, Lola K., Lichty, Angie, Koboldt, Daniel C., Reshmi, Shalini C., Sisodiya, Sanjay M., Hoytema van Konijnenburg, Eva M.M., Koop, Klaas, van Hasselt, Peter M., Démurger, Florence, Dubourg, Christèle, Sullivan, Bonnie R., Hughes, Susan S., Thiffault, Isabelle, Tremblay, Elisabeth Simard, Accogli, Andrea, Srour, Myriam, Blunck, Rikard, Campeau, Philippe M., Metabole ziekten patientenzorg, Genetica, Child Health, Infection & Immunity, Bhat, Shreyas, Rousseau, Justine, Michaud, Coralie, Lourenço, Charles Marques, Stoler, Joan M., Louie, Raymond J., Clarkson, Lola K., Lichty, Angie, Koboldt, Daniel C., Reshmi, Shalini C., Sisodiya, Sanjay M., Hoytema van Konijnenburg, Eva M.M., Koop, Klaas, van Hasselt, Peter M., Démurger, Florence, Dubourg, Christèle, Sullivan, Bonnie R., Hughes, Susan S., Thiffault, Isabelle, Tremblay, Elisabeth Simard, Accogli, Andrea, Srour, Myriam, Blunck, Rikard, and Campeau, Philippe M.

Published
2024

43. Abstract 15039: International Multicenter Registry Study of Patients With Variants in ATP1A3-Encoded Sodium-Potassium ATPase 3 Finds an Association With Short QT and Life-Threatening Ventricular Arrhythmias

Author

Moya-Mendez, Mary E, Bidzimou, Minu-Tshyeto, Ezekian, Jordan E, Perelli, Robin M, Parker, Lauren, Prange, Lyndsey, Kim, Jeffrey J, Howard, Taylor S, Reyes Valenzuela, Gabriel, Caraballo, Roberto, Garone, Giacomo, Vigevano, Federico, Weckhuysen, Sarah, Millevert, Charissa, Troncoso, Monica, Matamala, Mario, Balestrini, Simona, Sisodiya, Sanjay, Poole, Josephine, Zucca, Claudio, Panagiotakaki, Eleni, Tchaicha, Sébile, Sauquet, Julie, Zawadzka, Marta, Mazurkiewicz-Beldzinska, Maria, Fons, Carmen, Anticona, Jennifer, De Grandis, Elisa, Groppa, Sergiu, Paryjas, Sandra, Megvinov, Andrey, VAVASSORI, ROSARIA, and Landstrom, Andrew P

Published
2022
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44. Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA‐Epilepsy study

Author

Kerestes, Rebecca, primary, Perry, Andrew, additional, Vivash, Lucy, additional, O'Brien, Terence J., additional, Alvim, Marina K. M., additional, Arienzo, Donatello, additional, Aventurato, Ítalo K., additional, Ballerini, Alice, additional, Baltazar, Gabriel F., additional, Bargalló, Núria, additional, Bender, Benjamin, additional, Brioschi, Ricardo, additional, Bürkle, Eva, additional, Caligiuri, Maria Eugenia, additional, Cendes, Fernando, additional, de Tisi, Jane, additional, Duncan, John S., additional, Engel, Jerome P., additional, Foley, Sonya, additional, Fortunato, Francesco, additional, Gambardella, Antonio, additional, Giacomini, Thea, additional, Guerrini, Renzo, additional, Hall, Gerard, additional, Hamandi, Khalid, additional, Ives‐Deliperi, Victoria, additional, João, Rafael B., additional, Keller, Simon S., additional, Kleiser, Benedict, additional, Labate, Angelo, additional, Lenge, Matteo, additional, Marotta, Cassandra, additional, Martin, Pascal, additional, Mascalchi, Mario, additional, Meletti, Stefano, additional, Owens‐Walton, Conor, additional, Parodi, Costanza B., additional, Pascual‐Diaz, Saül, additional, Powell, David, additional, Rao, Jun, additional, Rebsamen, Michael, additional, Reiter, Johannes, additional, Riva, Antonella, additional, Rüber, Theodor, additional, Rummel, Christian, additional, Scheffler, Freda, additional, Severino, Mariasavina, additional, Silva, Lucas S., additional, Staba, Richard J., additional, Stein, Dan J., additional, Striano, Pasquale, additional, Taylor, Peter N., additional, Thomopoulos, Sophia I., additional, Thompson, Paul M., additional, Tortora, Domenico, additional, Vaudano, Anna Elisabetta, additional, Weber, Bernd, additional, Wiest, Roland, additional, Winston, Gavin P., additional, Yasuda, Clarissa L., additional, Zheng, Hong, additional, McDonald, Carrie R., additional, Sisodiya, Sanjay M., additional, and Harding, Ian H., additional

Published
2024
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45. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Author

Stamberger, Hannah, Hammer, Trine B., Gardella, Elena, Vlaskamp, Danique R. M., Bertelsen, Birgitte, Mandelstam, Simone, de Lange, Iris, Zhang, Jing, Myers, Candace T., Fenger, Christina, Afawi, Zaid, Almanza Fuerte, Edith P., Andrade, Danielle M., Balcik, Yunus, Ben Zeev, Bruria, Bennett, Mark F., Berkovic, Samuel F., Isidor, Bertrand, Bouman, Arjan, Brilstra, Eva, Busk, Øyvind L., Cairns, Anita, Caumes, Roseline, Chatron, Nicolas, Dale, Russell C., de Geus, Christa, Edery, Patrick, Gill, Deepak, Granild-Jensen, Jacob Bie, Gunderson, Lauren, Gunning, Boudewijn, Heimer, Gali, Helle, Johan R., Hildebrand, Michael S., Hollingsworth, Georgie, Kharytonov, Volodymyr, Klee, Eric W., Koeleman, Bobby P. C., Koolen, David A., Korff, Christian, Küry, Sébastien, Lesca, Gaetan, Lev, Dorit, Leventer, Richard J., Mackay, Mark T., Macke, Erica L., McEntagart, Meriel, Mohammad, Shekeeb S., Monin, Pauline, Montomoli, Martino, Morava, Eva, Moutton, Sebastien, Muir, Alison M., Parrini, Elena, Procopis, Peter, Ranza, Emmanuelle, Reed, Laura, Reif, Philipp S., Rosenow, Felix, Rossi, Massimiliano, Sadleir, Lynette G., Sadoway, Tara, Schelhaas, Helenius J., Schneider, Amy L., Shah, Krati, Shalev, Ruth, Sisodiya, Sanjay M., Smol, Thomas, Stumpel, Connie T. R. M., Stuurman, Kyra, Symonds, Joseph D., Mau-Them, Frederic Tran, Verbeek, Nienke, Verhoeven, Judith S., Wallace, Geoffrey, Yosovich, Keren, Zarate, Yuri A., Zerem, Ayelet, Zuberi, Sameer M., Guerrini, Renzo, Mefford, Heather C., Patel, Chirag, Zhang, Yue-Hua, Møller, Rikke S., and Scheffer, Ingrid E.

Published
2021
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46. DOORS syndrome and a recurrent truncating ATP6V1B2 variant

Author

Beauregard-Lacroix, Eliane, Pacheco-Cuellar, Guillermo, Ajeawung, Norbert F., Tardif, Jessica, Dieterich, Klaus, Dabir, Tabib, Vind-Kezunovic, Dina, White, Susan M., Zadori, Denes, Castiglioni, Claudia, Tranebjærg, Lisbeth, Tørring, Pernille Mathiesen, Blair, Ed, Wisniewska, Marzena, Camurri, Maria Vittoria, van Bever, Yolande, Molidperee, Sirinart, Taylor, Juliet, Dionne-Laporte, Alexandre, Sisodiya, Sanjay M., Hennekam, Raoul C. M., and Campeau, Philippe M.

Published
2021
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47. Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing

Author

Coppola, Antonietta, primary, Krithika, S., additional, Iacomino, Michele, additional, Bobbili, Dheeraj, additional, Balestrini, Simona, additional, Bagnasco, Irene, additional, Bilo, Leonilda, additional, Buti, Daniela, additional, Casellato, Susanna, additional, Cuccurullo, Claudia, additional, Ferlazzo, Edoardo, additional, Leu, Costin, additional, Giordano, Lucio, additional, Gobbi, Giuseppe, additional, Hernandez‐Hernandez, Laura, additional, Lench, Nick, additional, Martins, Helena, additional, Meletti, Stefano, additional, Messana, Tullio, additional, Nigro, Vincenzo, additional, Pinelli, Michele, additional, Pippucci, Tommaso, additional, Bellampalli, Ravishankara, additional, Salis, Barbara, additional, Sofia, Vito, additional, Striano, Pasquale, additional, Striano, Salvatore, additional, Tassi, Laura, additional, Vignoli, Aglaia, additional, Vaudano, Anna Elisabetta, additional, Viri, Maurizio, additional, Scheffer, Ingrid E., additional, May, Patrick, additional, Zara, Federico, additional, and Sisodiya, Sanjay M., additional

Published
2023
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