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2. Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies

Author

Stegmann, Jil D., Kalanithy, Jeshurun C., Dworschak, Gabriel C., Ishorst, Nina, Mingardo, Enrico, Lopes, Filipa M., Ho, Yee Mang, Grote, Phillip, Lindenberg, Tobias T., Yilmaz, Öznur, Channab, Khadija, Seltzsam, Steve, Shril, Shirlee, Hildebrandt, Friedhelm, Boschann, Felix, Heinen, André, Jolly, Angad, Myers, Katherine, McBride, Kim, Bekheirnia, Mir Reza, Bekheirnia, Nasim, Scala, Marcello, Morleo, Manuela, Nigro, Vincenzo, Torella, Annalaura, Pinelli, Michele, Capra, Valeria, Accogli, Andrea, Maitz, Silvia, Spano, Alice, Olson, Rory J., Klee, Eric W., Lanpher, Brendan C., Jang, Se Song, Chae, Jong-Hee, Steinbauer, Philipp, Rieder, Dietmar, Janecke, Andreas R., Vodopiutz, Julia, Vogel, Ida, Blechingberg, Jenny, Cohen, Jennifer L., Riley, Kacie, Klee, Victoria, Walsh, Laurence E., Begemann, Matthias, Elbracht, Miriam, Eggermann, Thomas, Stoppe, Arzu, Stuurman, Kyra, van Slegtenhorst, Marjon, Barakat, Tahsin Stefan, Mulhern, Maureen S., Sands, Tristan T., Cytrynbaum, Cheryl, Weksberg, Rosanna, Isidori, Federica, Pippucci, Tommaso, Severi, Giulia, Montanari, Francesca, Kruer, Michael C., Bakhtiari, Somayeh, Darvish, Hossein, Reutter, Heiko, Hagelueken, Gregor, Geyer, Matthias, Woolf, Adrian S., Posey, Jennifer E., Lupski, James R., Odermatt, Benjamin, and Hilger, Alina C.

Published
2024
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3. Lack of association of first and second-line medication dosing and progression to refractory status epilepticus in children

Author

Barcia Aguilar, Cristina, Amengual-Gual, Marta, Brenton, J. Nicholas, Chapman, Kevin E., Clark, Justice, Gaillard, William D., Goldstein, Joshua L., Goodkin, Howard P., Kahoud, Robert, Lai, Yi-Chen, Mikati, Mohamad A., Morgan, Lindsey A., Payne, Eric T., Press, Craig A., Reece, Latania, Sands, Tristan T., Sannagowdara, Kumar, Sheehan, Theodore, Shellhaas, Renée A., Tasker, Robert C., Wainwright, Mark S., Zhang, Bo, and Loddenkemper, Tobias

Published
2024
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5. Do germline genetic variants influence surgical outcomes in drug-resistant epilepsy?

Author

Marques, Paula, Moloney, Patrick B., Ji, Caihong, Zulfiqar Ali, Quratulain, Ramesh, Archana, Goldstein, David B., Barboza, Karen, Chandran, Ilakkiah, Rong, Marlene, Selvarajah, Arunan, Qaiser, Farah, Lira, Victor S.T., Valiante, Taufik A., Bazil, Carl W., Choi, Hyunmi, Devinsky, Orrin, Depondt, Chantal, O’Brien, Terence, Perucca, Piero, Sen, Arjune, Dugan, Patricia, Sands, Tristan T., Delanty, Norman, and Andrade, Danielle M.

Published
2024
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6. Heterogeneity of comprehensive clinical phenotype and longitudinal adaptive function and correlation with computational predictions of severity of missense genotypes in KIF1A-associated neurological disorder

Author

Sudnawa, Khemika K., Li, Wenxing, Calamia, Sean, Kanner, Cara H., Bain, Jennifer M., Abdelhakim, Aliaa H., Geltzeiler, Alexa, Mebane, Caroline M., Provenzano, Frank A., Sands, Tristan T., Fee, Robert J., Montes, Jacqueline, Shen, Yufeng, and Chung, Wendy K.

Published
2024
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8. Neonatal presentation of genetic epilepsies: Early differentiation from acute provoked seizures

Author

Cornet, Marie‐Coralie, Morabito, Valeria, Lederer, Damien, Glass, Hannah C, Santos, Susana Ferrao, Numis, Adam L, Ferriero, Donna M, Sands, Tristan T, and Cilio, Maria Roberta

Subjects
Genetics, Brain Disorders, Neurosciences, Epilepsy, Neurodegenerative, Pediatric, Neurological, Good Health and Well Being, Adult, Child, Electroencephalography, Humans, Hypoxia-Ischemia, Brain, Infant, Newborn, Nerve Tissue Proteins, Potassium Channels, Sodium-Activated, Retrospective Studies, Seizures, epilepsy, neonates, semiology, tonic, video-EEG, Clinical Sciences, Neurology & Neurosurgery
Abstract

ObjectiveAlthough most seizures in neonates are due to acute brain injury, some represent the first sign of neonatal onset genetic epilepsies. Delay in recognition and lack of expert assessment of neonates with epilepsy may result in worse developmental outcomes. As in older children and adults, seizure semiology in neonates is an essential determinant in diagnosis. We aimed to establish whether seizure type at presentation in neonates can suggest a genetic etiology.MethodsWe retrospectively analyzed the clinical and electroencephalographic (EEG) characteristics of seizures in neonates admitted in two Level IV neonatal intensive care units, diagnosed with genetic epilepsy, for whom a video-EEG recording at presentation was available for review, and compared them on a 1:2 ratio with neonates with seizures due to stroke or hypoxic-ischemic encephalopathy.ResultsTwenty neonates with genetic epilepsy were identified and compared to 40 neonates with acute provoked seizures. Genetic epilepsies were associated with pathogenic variants in KCNQ2 (n = 12), KCNQ3 (n = 2), SCN2A (n = 2), KCNT1 (n = 1), PRRT2 (n = 1), and BRAT1 (n = 2). All neonates with genetic epilepsy had seizures with clinical correlates that were either tonic (18/20) or myoclonic (2/20). In contrast, 17 of 40 (42%) neonates with acute provoked seizures had electrographic only seizures, and the majority of the remainder had clonic seizures. Time to first seizure was longer in neonates with genetic epilepsies (median = 60 h of life) compared to neonates with acute provoked seizures (median = 15 h of life, p

Published
2021

9. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author

Palmer, Elizabeth E., Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew H., Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogné, Benjamin, Beneteau, Claire, Alkuraya, Fowzan S., Chedrawi, Aziza, Hashem, Mais O., Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stéphanie, Raynaud, Martine, Motter, Constance S., Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias B., Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda J., Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Bénédicte, Abi Warde, Marie-Thérèse, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer M., Sands, Tristan T., Wilson, Golder N., Silvertooth, Erin J., Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein H., Ockeloen, Charlotte W., Pfundt, Rolph, Kroft, Sanne D., Field, Michael, Laranjeira, Francisco E. R., Fortuna, Ana M., Soares, Ana R., Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David D., Bird, Lynne M., Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Pölsler, Laura, Campeau, Philippe M., Blazo, Maria, Bijlsma, Emilia K., Rosenfeld, Jill A., Beetz, Christian, Powis, Zöe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikaël, Mohammad, Shekeeb S., Armstrong, Ruth, and Kalscheuer, Vera M.

Published
2023
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10. RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.

Author

Dharmadhikari, Avinash V., Abad, Maria Alba, Khan, Sheraz, Maroofian, Reza, Sands, Tristan T., Ullah, Farid, Samejima, Itaru, Shen, Yanwen, Wear, Martin A., Moore, Kiara E., Kondakova, Elena, Mitina, Natalia, Schaub, Theres, Lee, Grace K., Umandap, Christine H., Berger, Sara M., Iglesias, Alejandro D., Popp, Bernt, Abou Jamra, Rami, and Gabriel, Heinz

Subjects
LIFE sciences, SPINDLE apparatus, MISSENSE mutation, SHORT stature, CELL cycle
Abstract

SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, here we identify 28 individuals with neurodevelopmental delays from 21 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants show reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicate that SPOUT1/CENP-32 missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 reveals that most disease-associated missense variants are located within the catalytic domain. Additionally, SPOUT1/CENP-32 recurrent missense variants show reduced methyltransferase activity in vitro and compromised centrosome tethering to the spindle poles in human cells. Thus, SPOUT1/CENP-32 pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS (SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors. The RNA methyltransferase activity of SPOUT1/CENP-32 is crucial for accurate mitotic spindle organization. Here, the authors describe a neurodevelopmental disorder caused by bi-allelic pathogenic SPOUT1 variants with reduced activity and compromised function in spindle organization. [ABSTRACT FROM AUTHOR]

Published
2025
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13. Time to Treatment in Pediatric Convulsive Refractory Status Epilepticus: The Weekend Effect

Author

Barcia Aguilar, Cristina, Amengual-Gual, Marta, Sánchez Fernández, Iván, Abend, Nicholas S., Anderson, Anne, Appavu, Brian, Arya, Ravindra, Brenton, J. Nicholas, Carpenter, Jessica L., Chapman, Kevin E., Clark, Justice, Farias-Moeller, Raquel, Gaillard, William D., Gaínza-Lein, Marina, Glauser, Tracy, Goldstein, Joshua L., Goodkin, Howard P., Guerriero, Rejean M., Huh, Linda, Lai, Yi-Chen, McDonough, Tiffani L., Mikati, Mohamad A., Morgan, Lyndsey A., Novotny, Edward J., Ostendorf, Adam, Payne, Eric T., Peariso, Katrina, Piantino, Juan, Riviello, James, Sannagowdara, Kumar, Sheehan, Theodore, Sands, Tristan T., Tasker, Robert C., Tchapyjnikov, Dmitry, Topjian, Alexis A., Vasquez, Alejandra, Wainwright, Mark S., Wilfong, Angus A., Williams, Korwyn, and Loddenkemper, Tobias

Published
2021
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14. Tracking Multisite Seizure Propagation Using Ictal High-Gamma Activity

Author

Tobochnik, Steven, Bateman, Lisa M., Akman, Cigdem I., Anbarasan, Deepti, Bazil, Carl W., Bell, Michelle, Choi, Hyunmi, Feldstein, Neil A., Kent, Paul F., McBrian, Danielle, McKhann, Guy M., II, Mendiratta, Anil, Pack, Alison M., Sands, Tristan T., Sheth, Sameer A., Srinivasan, Shraddha, and Schevon, Catherine A.

Published
2022
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15. Effective knockdown-replace gene therapy in a novel mouse model of DNM1developmental and epileptic encephalopathy

Author

Jones, Devin J., Soundararajan, Divya, Taylor, Noah K., Aimiuwu, Osasumwen V., Mathkar, Pranav, Shore, Amy, Teoh, Jia Jie, Wang, Wanqi, Sands, Tristan T., Weston, Matthew C., Harper, Scott Q., and Frankel, Wayne N.

Abstract

Effective gene therapy for gain-of-function or dominant-negative disease mutations may require eliminating expression of the mutant copy together with wild-type replacement. We evaluated such a knockdown-replace strategy in a mouse model of DNM1disease, a debilitating and intractable neurodevelopmental epilepsy. To challenge the approach robustly, we expressed a patient-based variant in GABAergic neurons—which resulted in growth delay and lethal seizures evident by postnatal week three—and delivered to newborn pups an AAV9-based vector encoding a ubiquitously expressed, Dnm1-specific interfering RNA (RNAi) bivalently in tail-to-tail configuration with a neuron-specific, RNAi-resistant, codon-optimized Dnm1cDNA. Pups receiving RNAi or cDNA alone fared no better than untreated pups, whereas the vast majority of mutants receiving modest doses survived with almost full growth recovery. Synaptic recordings of cortical neurons derived from treated pups revealed that significant alterations in transmission from inhibitory to excitatory neurons were rectified by bivalent vector application. To examine the mutant transcriptome and impact of treatment, we used RNA sequencing and functional annotation clustering. Mutants displayed abnormal expression of more than 1,000 genes in highly significant and relevant functional clusters, clusters that were abrogated by treatment. Together these results suggest knockdown-replace as a potentially effective strategy for treating DNM1and related genetic neurodevelopmental disease.

Published
2024
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16. Heterogeneity of comprehensive clinical phenotype and longitudinal adaptive function and correlation with computational predictions of severity of missense genotypes in KIF1A-associated neurological disorder

Author

Sudnawa, Khemika K., primary, Li, Wenxing, additional, Calamia, Sean, additional, Kanner, Cara H., additional, Bain, Jennifer M., additional, Abdelhakim, Aliaa H., additional, Geltzeiler, Alexa, additional, Mebane, Caroline M., additional, Provenzano, Frank A., additional, Sands, Tristan T., additional, Fee, Robert J., additional, Montes, Jacqueline, additional, Shen, Yufeng, additional, and Chung, Wendy K., additional

Published
2024
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17. RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS

Author

Dharmadhikari, Avinash V, primary, Abad, Maria Alba, additional, Khan, Sheraz, additional, Maroofian, Reza, additional, Sands, Tristan T, additional, Ullah, Farid, additional, Samejima, Itaru, additional, Wear, Martin A, additional, Moore, Kiara E, additional, Kondakova, Elena, additional, Mitina, Natalia, additional, Schaub, Theres, additional, Lee, Grace K, additional, Umandap, Christine H, additional, Berger, Sara M, additional, Iglesias, Alejandro D, additional, Popp, Bernt, additional, Jamra, Rami Abou, additional, Gabriel, Heinz, additional, Rentas, Stefan, additional, Rippert, Alyssa L, additional, Izumi, Kosuke, additional, Conlin, Laura K, additional, Koboldt, Daniel C, additional, Mihalic Mosher, Theresa, additional, Hickey, Scott E, additional, Albert, Dara VF, additional, Norwood, Haley, additional, Lewanda, Amy Feldman, additional, Dai, Hongzheng, additional, Liu, Pengfei, additional, Mitani, Tadahiro, additional, Marafi, Dana, additional, Pehlivan, Davut, additional, Posey, Jennifer E, additional, Lippa, Natalie, additional, Vena, Natalie, additional, Heinzen, Erin L, additional, Goldstein, David B, additional, Mignot, Cyril, additional, Agathe, Jean-Madeleine de Sainte, additional, Al-Sannaa, Nouriya Abbas, additional, Zamani, Mina, additional, Sadeghian, Saeid, additional, Seifia, Tahere, additional, Zaki, Maha S, additional, Abdel-Salam, Ghada MH, additional, Abdel-Hamid, Mohamed, additional, Alabdi, Lama, additional, Alkuraya, Fowzan Sami, additional, Dawoud, Heba, additional, Lofty, Aya, additional, Bauer, Peter, additional, Zifarelli, Giovanni, additional, Afzal, Erum, additional, Zafar, Faisal, additional, Efthymiou, Stephanie, additional, Gossett, Daniel, additional, Towne, Meghan C, additional, Yeneabat, Raey, additional, Wontakal, Sandeep N, additional, Aggarwal, Vimla S, additional, Rosenfeld, Jill A, additional, Tarabykin, Victor, additional, Ohta, Shinya, additional, Lupski, James R, additional, Houlden, Henry, additional, Earnshaw, William C, additional, Davis, Erica E, additional, Jeyaprakash, A Arockia, additional, and Liao, Jun, additional

Published
2024
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18. Population‐based study of rare epilepsy incidence in a US urban population.

Author

Barbour, Kristen, Tian, Niu, Yozawitz, Elissa G., Wolf, Steven, McGoldrick, Patricia E., Sands, Tristan T., Nelson, Aaron, Basma, Natasha, and Grinspan, Zachary M.

Subjects
AICARDI syndrome, TUBEROUS sclerosis, PARTIAL epilepsy, SEIZURES (Medicine), ELECTRONIC health records, HAMARTOMA
Abstract

Objective: This study was undertaken to estimate incidence of rare epilepsies and compare with literature. Methods: We used electronic health record text search to identify children with 28 rare epilepsies in New York City (2010–2014). We estimated cumulative incidence and compared with literature. Results: Eight of 28 rare epilepsies had five or more prior estimates, and our measurements were within the published range for all. The most common were infantile epileptic spasms syndrome (1 in 2920 live births), Lennox–Gastaut syndrome (1 in 9690), and seizures associated with tuberous sclerosis complex (1 in 14 300). Fifteen of 28 had fewer than five prior estimates, and of these, we provided additional estimates for early infantile developmental and epileptic encephalopathy (1 in 32 700), epilepsy with myoclonic–atonic seizures (1 in 34 100), Sturge–Weber syndrome plus seizures/epilepsy (1 in 40 900), epilepsy in infancy with migrating focal seizures (1 in 54 500), Aicardi syndrome plus seizures/epilepsy (1 in 71 600), hypothalamic hamartoma with seizures (1 in 225 000), and Rasmussen syndrome (1 in 450 000). Five of 28 rare epilepsies had no prior estimates, and of these, we provided a new estimate for developmental/epileptic encephalopathy with spike‐and‐wave activation in sleep and/or continuous spikes and waves during sleep (1 in 34 100). Data were limited for the remaining 12 rare epilepsies, which were all genetic epilepsies, including PCDH19, CDKL5, Alpers disease, SCN8A, KCNQ2, SCN2A, GLUT1 deficiency, Phelan‐McDermid syndrome, myoclonic epilepsy with ragged‐red fibers, dup15q syndrome, ring chromosome 14, and ring chromosome 20. Significance: We estimated the incidence of rare epilepsies using population‐based electronic health record data and literature review. More research is needed to better estimate the incidence of genetic epilepsies with nonspecific clinical features. Electronic health records may be a valuable data source for studying rare epilepsies and other rare diseases, particularly as genetic testing becomes more widely adopted. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Super-Refractory Status Epilepticus in Children: A Retrospective Cohort Study

Author

Vasquez, Alejandra, Farias-Moeller, Raquel, Sánchez-Fernández, Iván, Abend, Nicholas S., Amengual-Gual, Marta, Anderson, Anne, Arya, Ravindra, Brenton, James N., Carpenter, Jessica L., Chapman, Kevin, Clark, Justice, Gaillard, William D., Glauser, Tracy, Goldstein, Joshua L., Goodkin, Howard P., Guerriero, Rejean M., Lai, Yi-Chen, McDonough, Tiffani L., Mikati, Mohamad A., Morgan, Lindsey A., Novotny, Edward J., Ostendorf, Adam P., Payne, Eric T., Peariso, Katrina, Piantino, Juan, Riviello, James J., Sands, Tristan T., Sannagowdara, Kumar, Tasker, Robert C., Tchapyjnikov, Dmitry, Topjian, Alexis, Wainwright, Mark S., Wilfong, Angus, Williams, Korwyn, and Loddenkemper, Tobias

Published
2021
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26. Contributors

Author

Bertini, Enrico, primary, Bingham, Adrienne, additional, Chau, Vann, additional, Cilio, Maria Roberta, additional, D’Amico, Adele, additional, de Vries, Linda S., additional, Ferriero, Donna M., additional, Gano, Dawn, additional, Glass, Torin J.A., additional, Kabani, Nazia, additional, Kasdorf, Ericalyn, additional, Kaufman, David, additional, Kimberlin, David W., additional, Laptook, Abbot R., additional, Le Pichon, Jean-Baptiste, additional, Marlow, Neil, additional, McLean, Claire, additional, Noori, Shahab, additional, Perlman, Jeffrey M., additional, Pisani, Francesco, additional, Riordan, Sean M., additional, Sánchez, Pablo J., additional, Sands, Tristan T., additional, Seed, Michael, additional, Seri, Istvan, additional, Shapiro, Steven M., additional, Spagnoli, Carlotta, additional, Toet, Mona C., additional, Weeke, Lauren C., additional, Wei-Wu, Tai, additional, Whitelaw, Andrew, additional, Yager, Jerome Y., additional, Yap, Vivien, additional, and Zanelli, Santina, additional

Published
2019
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30. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author

Palmer, Elizabeth E., primary, Pusch, Michael, additional, Picollo, Alessandra, additional, Forwood, Caitlin, additional, Nguyen, Matthew H., additional, Suckow, Vanessa, additional, Gibbons, Jessica, additional, Hoff, Alva, additional, Sigfrid, Lisa, additional, Megarbane, Andre, additional, Nizon, Mathilde, additional, Cogné, Benjamin, additional, Beneteau, Claire, additional, Alkuraya, Fowzan S., additional, Chedrawi, Aziza, additional, Hashem, Mais O., additional, Stamberger, Hannah, additional, Weckhuysen, Sarah, additional, Vanlander, Arnaud, additional, Ceulemans, Berten, additional, Rajagopalan, Sulekha, additional, Nunn, Kenneth, additional, Arpin, Stéphanie, additional, Raynaud, Martine, additional, Motter, Constance S., additional, Ward-Melver, Catherine, additional, Janssens, Katrien, additional, Meuwissen, Marije, additional, Beysen, Diane, additional, Dikow, Nicola, additional, Grimmel, Mona, additional, Haack, Tobias B., additional, Clement, Emma, additional, McTague, Amy, additional, Hunt, David, additional, Townshend, Sharron, additional, Ward, Michelle, additional, Richards, Linda J., additional, Simons, Cas, additional, Costain, Gregory, additional, Dupuis, Lucie, additional, Mendoza-Londono, Roberto, additional, Dudding-Byth, Tracy, additional, Boyle, Jackie, additional, Saunders, Carol, additional, Fleming, Emily, additional, El Chehadeh, Salima, additional, Spitz, Marie-Aude, additional, Piton, Amelie, additional, Gerard, Bénédicte, additional, Abi Warde, Marie-Thérèse, additional, Rea, Gillian, additional, McKenna, Caoimhe, additional, Douzgou, Sofia, additional, Banka, Siddharth, additional, Akman, Cigdem, additional, Bain, Jennifer M., additional, Sands, Tristan T., additional, Wilson, Golder N., additional, Silvertooth, Erin J., additional, Miller, Lauren, additional, Lederer, Damien, additional, Sachdev, Rani, additional, Macintosh, Rebecca, additional, Monestier, Olivier, additional, Karadurmus, Deniz, additional, Collins, Felicity, additional, Carter, Melissa, additional, Rohena, Luis, additional, Willemsen, Marjolein H., additional, Ockeloen, Charlotte W., additional, Pfundt, Rolph, additional, Kroft, Sanne D., additional, Field, Michael, additional, Laranjeira, Francisco E. R., additional, Fortuna, Ana M., additional, Soares, Ana R., additional, Michaud, Vincent, additional, Naudion, Sophie, additional, Golla, Sailaja, additional, Weaver, David D., additional, Bird, Lynne M., additional, Friedman, Jennifer, additional, Clowes, Virginia, additional, Joss, Shelagh, additional, Pölsler, Laura, additional, Campeau, Philippe M., additional, Blazo, Maria, additional, Bijlsma, Emilia K., additional, Rosenfeld, Jill A., additional, Beetz, Christian, additional, Powis, Zöe, additional, McWalter, Kirsty, additional, Brandt, Tracy, additional, Torti, Erin, additional, Mathot, Mikaël, additional, Mohammad, Shekeeb S., additional, Armstrong, Ruth, additional, and Kalscheuer, Vera M., additional

Published
2022
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32. Contributors

Author

Aaen, Gregory S., primary, Abend, Nicholas Scott, additional, Abou-Hamden, Amal, additional, Allen, Jeffrey C., additional, Amato, Anthony A., additional, Amlie-Lefond, Catherine, additional, Ashwal, Stephen, additional, Bailey, Russell C., additional, Bale, James F., additional, Banwell, Brenda, additional, Barañano, Kristin W., additional, Barkovich, A. James, additional, Barohn, Richard J., additional, Bartels, Ute K., additional, Bartnik-Olson, Brenda, additional, Barzilai, Ori, additional, Bassuk, Alexander, additional, Bearden, David R., additional, Ben-Sira, Liat, additional, Bernard, Timothy J., additional, Berry-Kravis, Elizabeth, additional, Beslow, Lauren A., additional, Biegel, Jaclyn A., additional, Billinghurst, Lori, additional, Birnbaum, Angela K., additional, Blackburn, Joanna S., additional, Bobowski, Nuala, additional, Boire, Adrienne, additional, Bönnemann, Carsten G., additional, Bonifacio, Sonia L., additional, Bonthius, Daniel J., additional, Borcherding, Breck, additional, Branchford, Brian R., additional, Brandsema, John, additional, Brennan, Kathryn M., additional, Brenton, J. Nicholas, additional, Brooks-Kayal, Amy R., additional, Brown, Lawrence W., additional, Buchalter, Jeffrey, additional, Camfield, Carol S., additional, Camfield, Peter R., additional, Campoy, Cristina, additional, Carpenter, Jessica L., additional, Chang, Taeun, additional, Chau, Vann, additional, Chi, Susan N., additional, Chiriboga, Claudia A., additional, Cho, Yoon-Jae, additional, Christian, Cindy W., additional, Chrestian, Nicholas, additional, Cilio, Maria Roberta, additional, Clark, Robin D., additional, Cohen, Bruce H., additional, Cohn, Ronald D., additional, Connolly, Anne M., additional, Constable, Todd, additional, Constantini, Shlomi, additional, Conway, Jeannine M., additional, Coulter, David L., additional, Cowan, Tina M., additional, Dale, Russell C., additional, Darbro, Benjamin, additional, Darras, Basil T., additional, Dastgir, Jahannaz, additional, De Meirleir, Linda, additional, De Vivo, Darryl C., additional, de Vries, Linda S., additional, Deisch, Jeremy K., additional, Deltenre, Paul, additional, Desai, Jay, additional, Descartes, Maria, additional, deVeber, Gabrielle, additional, Dhamne, Sameer C., additional, Diaz, Jullianne, additional, DiMauro, Salvatore, additional, Dobyns, William B., additional, Doherty, Dan, additional, Donner, Elizabeth J., additional, Dosenbach, Nico U.F., additional, Dowling, James J., additional, Drake, James M., additional, Ejerskov, Cecile, additional, Engel, Andrew G., additional, Enns, Gregory M., additional, Escolano-Margarit, María Victoria, additional, Etzion, Iris, additional, Fatemi, S. Ali, additional, Fehlings, Darcy L., additional, Feinberg, Michelle Lauren, additional, Ferriero, Donna M., additional, Filipek, Pauline A., additional, Finkel, Richard S., additional, Fisher, Paul G., additional, Flanigan, Kevin, additional, Foreman, Nicholas K., additional, Franco, Israel, additional, Frank, Yitzchak, additional, Fredrick, Douglas R., additional, Freeze, Hudson H., additional, Fuente-Mora, Cristina, additional, Furman, Joseph M., additional, Gallagher, Renata C., additional, Garel, Catherine, additional, Gertsch, Emily, additional, Gilbert, Donald L., additional, Gilles, Elizabeth E., additional, Giza, Christopher C., additional, Glaser, Carol A., additional, Glass, Hannah C., additional, Glauser, Tracy, additional, Glykys, Joseph, additional, Goldstein, Amy, additional, Gonorazky, Hernan Dario, additional, Gonzalez, Rodolfo, additional, Goodkin, Howard P., additional, Graham, John M., additional, Greninger, Alexander L., additional, Gronseth, Gary, additional, Gropman, Andrea L., additional, Grundy, Richard, additional, Guerrini, Renzo, additional, Gupta, Nalin, additional, Hahn, Jin S., additional, Hamblin, Milton H., additional, Hani, Abeer J., additional, Hanmantgad, Sharyu, additional, Harbert, Mary J., additional, Harini, Chellamani, additional, Harriott, Andrea M., additional, Heatwole, Chad, additional, Hershey, Andrew D., additional, Hirtz, Deborah G., additional, Holmes, Gregory L., additional, Holshouser, Barbara A., additional, Hurwitz, Kathleen A., additional, Hwang, Eugene, additional, Ichord, Rebecca N., additional, Jafar-Nejad, Paymaan, additional, Jain, Sejal V., additional, Jordan, Lori, additional, Kabbouche, Marielle A., additional, Kacperski, Joanne, additional, Kang, Peter B., additional, Kariannis, Matthias A., additional, Kaufmann, Horacio, additional, Kaye, Harper L., additional, Keating, Robert, additional, Kennedy, Colin R., additional, Khakoo, Yasmin, additional, Kirton, Adam, additional, Kissel, John T., additional, Knupp, Kelly G., additional, Korf, Bruce R., additional, Kossoff, Eric H., additional, Kothare, Sanjeev V., additional, Kupfer, Oren, additional, LaFrance, W. Curt, additional, Latal, Beatrice, additional, Leber, Steven M., additional, Lee, Jean-Pyo, additional, Leppik, Ilo E., additional, Lerman-Sagie, Tally, additional, Lerner, Jason T., additional, Leventer, Richard J., additional, Licht, Daniel J., additional, Lichter-Konecki, Uta, additional, Lidar, Zvi, additional, Liem, Djin Gie, additional, Loddenkemper, Tobias, additional, Long, Roger K., additional, Luc, Quyen N., additional, Mackay, Mark, additional, Majnemer, Annette, additional, Makhani, Naila, additional, Malinger, Gustavo, additional, Mandelbaum, David E., additional, Maricich, Stephen M., additional, Maski, Kiran P., additional, Mathur, Mudit, additional, Matthews, Dennis J., additional, McMahon, Kelly, additional, DeMara-Hoth, Megan B., additional, Mendelsohn, Bryce, additional, Mennella, Julie A., additional, Ment, Laura R., additional, Mercuri, Eugenio, additional, Michelson, David J., additional, Mikati, Mohamad A., additional, Mikhail, Fady M., additional, Miller, Steven Paul, additional, Milunsky, Jeff M., additional, Mink, Jonathan W., additional, Mirzaa, Ghayda M., additional, Mitchell, Wendy G., additional, Mohan, Michael A., additional, Mohassel, Payam, additional, Moharir, Mahendranath, additional, Monani, Umrao R., additional, Monje Deisseroth, Michelle, additional, Moodley, Manikum, additional, Mower, Andrew, additional, Moxley, Richard T., additional, Mueller, Sabine, additional, Muotri, Alysson R., additional, Nagamani, Sandesh C.S., additional, Narayanan, Mohan J., additional, Narayanan, Vinodh, additional, Nass, Ruth D., additional, Neul, Jeffrey L., additional, Nevo, Yoram, additional, Ng, Bobby G., additional, Nickels, Katherine C., additional, Nimmo, Graeme A.M., additional, Noetzel, Michael J., additional, Norcliffe-Kaufmann, Lucy, additional, Nordli, Douglas R., additional, Nowak-Göttl, Ulrike, additional, O'Brien, Hope L., additional, Oleszek, Joyce, additional, Oskoui, Maryam, additional, Paciorkowski, Alex R., additional, Packer, Roger J., additional, Packman, Seymour, additional, Palma, Jose-Alberto, additional, Pardo, Andrea C., additional, Parsons, Julie A., additional, Partridge, John Colin, additional, Pastores, Gregory M., additional, Patterson, Marc C., additional, Pearce, William J., additional, Pearl, Phillip L., additional, Penner, Melanie, additional, Percival, Leila, additional, Pereira, Marcia, additional, Pfister, Stefan M., additional, Phillips, John, additional, Plecko, Barbara, additional, Plioplys, Sigita, additional, Poduri, Annapurna, additional, Poisson, Sharon, additional, Pomeroy, Scott L., additional, Poretti, Andrea, additional, Powers, Scott W., additional, Pranzatelli, Michael R., additional, Przekop, Allison, additional, Rabie, Malcolm, additional, Rangasamy, Sampathkumar, additional, Raymond, Gerald V., additional, Reddy, Alyssa T., additional, Rendleman, Rebecca L., additional, Rho, Jong M., additional, Rodan, Lance H., additional, Roddy, Sarah M., additional, Rogers, Elizabeth E., additional, Rosenthal, Stephen M., additional, Rosman, N. Paul, additional, Ross, M. Elizabeth, additional, Rotenberg, Alexander, additional, Rust, Robert S., additional, Sanchez, Cheryl P., additional, Sanchez, Pedro, additional, Sánchez Fernández, Iván, additional, Sands, Tristan T., additional, Sanger, Terence D., additional, Sannagowdara, Kumar, additional, Scheinost, Dustin, additional, Scher, Mark S., additional, Schor, Nina F., additional, Schrauwen, Isabelle, additional, Segal, Michael M., additional, Seinfeld, Syndi, additional, Selcen, Duygu, additional, Seltzer, Laurie E., additional, Semrud-Clikeman, Margaret, additional, Shaw, Dennis W., additional, Shaywitz, Bennett A., additional, Shaywitz, Sally E., additional, Shellhaas, Renée A., additional, Sherr, Elliott H., additional, Sheth, Rita D., additional, Shevell, Michael I., additional, Shinnar, Shlomo, additional, Shofty, Ben, additional, Shu, Stanford K., additional, Shy, Michael E., additional, Silveira Moriyama, Laura, additional, Silvestri, Nicholas J., additional, Sims, Katherine B., additional, Singer, Harvey S., additional, Singhal, Nilika Shah, additional, Smith, Craig M., additional, Smith, Edward, additional, Smith, Stephen A., additional, Snyder, Evan Y., additional, Soul, Janet, additional, Spalink, Christy L., additional, Spencer, Karen A., additional, Stafstrom, Carl E., additional, Steinfeld, Robert, additional, Strober, Jonathan B., additional, Sullivan, Joseph, additional, Swaiman, Kenneth F., additional, Swoboda, Kathryn J., additional, Tate, Elizabeth D., additional, Tatum, William O., additional, Tein, Ingrid, additional, Tekulve, Kristyn, additional, Tenney, Jeffrey R., additional, Thiele, Elizabeth A., additional, Thompson-Stone, Robert, additional, Tochen, Laura, additional, Tormoehlen, Laura M., additional, Tran, Lily, additional, Trauner, Doris A., additional, Turnacioglu, Sinan O., additional, Ullrich, Nicole J., additional, Urion, David K., additional, Van Camp, Guy, additional, Van Hirtum-Das, Michèle, additional, van Karnebeek, Clara D.M., additional, Van Maldergem, Lionel, additional, Vanderver, Adeline, additional, Vitanza, Nicholas A., additional, von Rhein, Michael, additional, von Scheven, Emily, additional, Wagner, Ann, additional, Wainwright, Mark S., additional, Walker, Melissa A., additional, Walkup, John T., additional, Walsh, Laurence, additional, Walters-Sen, Lauren C., additional, Wang, Raymond Y., additional, Warner, Thomas T., additional, Whelan, Harry T., additional, Weinberg, Geoffrey A., additional, Wells, Elizabeth M., additional, Wheless, James W., additional, Wirrell, Elaine C., additional, Wisoff, Jeffrey H., additional, Wolf, Nicole I., additional, Wolfe, Gil I., additional, Wright, F. Virginia, additional, Wycliffe, Nathaniel D., additional, Yang, Michele L., additional, Yuskaitis, Christopher J., additional, Zoghbi, Huda Y., additional, and Zupanc, Mary L., additional

Published
2017
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33. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author

UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Palmer, Elizabeth E, Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew H, Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogné, Benjamin, Beneteau, Claire, Alkuraya, Fowzan S, Chedrawi, Aziza, Hashem, Mais O, Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stéphanie, Raynaud, Martine, Motter, Constance S, Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias B, Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda J, Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Bénédicte, Abi Warde, Marie-Thérèse, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer M, Sands, Tristan T, Wilson, Golder N, Silvertooth, Erin J, Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein H, Ockeloen, Charlotte W, Pfundt, Rolph, Kroft, Sanne D, Field, Michael, Laranjeira, Francisco E R, Fortuna, Ana M, Soares, Ana R, Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David D, Bird, Lynne M, Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Pölsler, Laura, Campeau, Philippe M, Blazo, Maria, Bijlsma, Emilia K, Rosenfeld, Jill A, Beetz, Christian, Powis, Zöe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikaël, Mohammad, Shekeeb S, Armstrong, Ruth, Kalscheuer, Vera M, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Palmer, Elizabeth E, Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew H, Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogné, Benjamin, Beneteau, Claire, Alkuraya, Fowzan S, Chedrawi, Aziza, Hashem, Mais O, Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stéphanie, Raynaud, Martine, Motter, Constance S, Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias B, Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda J, Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Bénédicte, Abi Warde, Marie-Thérèse, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer M, Sands, Tristan T, Wilson, Golder N, Silvertooth, Erin J, Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein H, Ockeloen, Charlotte W, Pfundt, Rolph, Kroft, Sanne D, Field, Michael, Laranjeira, Francisco E R, Fortuna, Ana M, Soares, Ana R, Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David D, Bird, Lynne M, Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Pölsler, Laura, Campeau, Philippe M, Blazo, Maria, Bijlsma, Emilia K, Rosenfeld, Jill A, Beetz, Christian, Powis, Zöe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikaël, Mohammad, Shekeeb S, Armstrong, Ruth, and Kalscheuer, Vera M

Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2022

34. Somatic variants in diverse genes leads to a spectrum of focal cortical malformations

Author

Lai, Dulcie, primary, Gade, Meethila, additional, Yang, Edward, additional, Koh, Hyun Yong, additional, Lu, Jinfeng, additional, Walley, Nicole M, additional, Buckley, Anne F, additional, Sands, Tristan T, additional, Akman, Cigdem I, additional, Mikati, Mohamad A, additional, McKhann, Guy M, additional, Goldman, James E, additional, Canoll, Peter, additional, Alexander, Allyson L, additional, Park, Kristen L, additional, Von Allmen, Gretchen K, additional, Rodziyevska, Olga, additional, Bhattacharjee, Meenakshi B, additional, Lidov, Hart G W, additional, Vogel, Hannes, additional, Grant, Gerald A, additional, Porter, Brenda E, additional, Poduri, Annapurna H, additional, Crino, Peter B, additional, and Heinzen, Erin L, additional

Published
2022
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35. Somatic mutation involving diverse genes leads to a spectrum of focal cortical malformations

Author

Lai, Dulcie, primary, Gade, Meethila, additional, Yang, Edward, additional, Koh, Hyun Yong, additional, Walley, Nicole M., additional, Buckley, Anne F., additional, Sands, Tristan T., additional, Akman, Cigdem I., additional, Mikati, Mohamad A., additional, McKhann, Guy M., additional, Goldman, James E., additional, Canoll, Peter D., additional, Alexander, Allyson L., additional, Park, Kristen L., additional, Allmen, Gretchen K. Von, additional, Bhattacharjee, Meenakshi B., additional, Lidov, Hart G.W., additional, Vogel, Hannes, additional, Grant, Gerald A., additional, Porter, Brenda E., additional, Poduri, Annapurna H., additional, Crino, Peter B., additional, and Heinzen, Erin L., additional

Published
2021
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36. Neonatal presentation of genetic epilepsies: Early differentiation from acute provoked seizures.

Author

Cornet, Marie-Coralie, Cornet, Marie-Coralie, Morabito, Valeria, Lederer, Damien, Glass, Hannah C, Ferrao Santos, Susana, Numis, Adam L, Ferriero, Donna M, Sands, Tristan T, Cilio, Maria Roberta, Cornet, Marie-Coralie, Cornet, Marie-Coralie, Morabito, Valeria, Lederer, Damien, Glass, Hannah C, Ferrao Santos, Susana, Numis, Adam L, Ferriero, Donna M, Sands, Tristan T, and Cilio, Maria Roberta

Abstract

ObjectiveAlthough most seizures in neonates are due to acute brain injury, some represent the first sign of neonatal onset genetic epilepsies. Delay in recognition and lack of expert assessment of neonates with epilepsy may result in worse developmental outcomes. As in older children and adults, seizure semiology in neonates is an essential determinant in diagnosis. We aimed to establish whether seizure type at presentation in neonates can suggest a genetic etiology.MethodsWe retrospectively analyzed the clinical and electroencephalographic (EEG) characteristics of seizures in neonates admitted in two Level IV neonatal intensive care units, diagnosed with genetic epilepsy, for whom a video-EEG recording at presentation was available for review, and compared them on a 1:2 ratio with neonates with seizures due to stroke or hypoxic-ischemic encephalopathy.ResultsTwenty neonates with genetic epilepsy were identified and compared to 40 neonates with acute provoked seizures. Genetic epilepsies were associated with pathogenic variants in KCNQ2 (n = 12), KCNQ3 (n = 2), SCN2A (n = 2), KCNT1 (n = 1), PRRT2 (n = 1), and BRAT1 (n = 2). All neonates with genetic epilepsy had seizures with clinical correlates that were either tonic (18/20) or myoclonic (2/20). In contrast, 17 of 40 (42%) neonates with acute provoked seizures had electrographic only seizures, and the majority of the remainder had clonic seizures. Time to first seizure was longer in neonates with genetic epilepsies (median = 60 h of life) compared to neonates with acute provoked seizures (median = 15 h of life, p < .001). Sodium channel-blocking antiseizure medications were effective in 13 of 14 (92%) neonates with tonic seizures who were trialed at onset or during the course of the epilepsy.SignificanceSeizure semiology is an easily accessible sign of genetic epilepsies in neonates. Early identification of the seizure type can promp

Published
2021

37. Neonatal presentation of genetic epilepsies: Early differentiation from acute provoked seizures.

Author

UCL - (SLuc) Service de neurologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Cornet, Marie-Coralie, Morabito, Valeria, Lederer, Damien, Glass, Hannah C, Ferrao Santos, Susana, Numis, Adam L, Ferriero, Donna M, Sands, Tristan T, Cilio, Maria Roberta, UCL - (SLuc) Service de neurologie, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Cornet, Marie-Coralie, Morabito, Valeria, Lederer, Damien, Glass, Hannah C, Ferrao Santos, Susana, Numis, Adam L, Ferriero, Donna M, Sands, Tristan T, and Cilio, Maria Roberta

Abstract

Although most seizures in neonates are due to acute brain injury, some represent the first sign of neonatal onset genetic epilepsies. Delay in recognition and lack of expert assessment of neonates with epilepsy may result in worse developmental outcomes. As in older children and adults, seizure semiology in neonates is an essential determinant in diagnosis. We aimed to establish whether seizure type at presentation in neonates can suggest a genetic etiology. We retrospectively analyzed the clinical and electroencephalographic (EEG) characteristics of seizures in neonates admitted in two Level IV neonatal intensive care units, diagnosed with genetic epilepsy, for whom a video-EEG recording at presentation was available for review, and compared them on a 1:2 ratio with neonates with seizures due to stroke or hypoxic-ischemic encephalopathy. Twenty neonates with genetic epilepsy were identified and compared to 40 neonates with acute provoked seizures. Genetic epilepsies were associated with pathogenic variants in KCNQ2 (n = 12), KCNQ3 (n = 2), SCN2A (n = 2), KCNT1 (n = 1), PRRT2 (n = 1), and BRAT1 (n = 2). All neonates with genetic epilepsy had seizures with clinical correlates that were either tonic (18/20) or myoclonic (2/20). In contrast, 17 of 40 (42%) neonates with acute provoked seizures had electrographic only seizures, and the majority of the remainder had clonic seizures. Time to first seizure was longer in neonates with genetic epilepsies (median = 60 h of life) compared to neonates with acute provoked seizures (median = 15 h of life, p < .001). Sodium channel-blocking antiseizure medications were effective in 13 of 14 (92%) neonates with tonic seizures who were trialed at onset or during the course of the epilepsy. Seizure semiology is an easily accessible sign of genetic epilepsies in neonates. Early identification of the seizure type can prompt appropriate workup and treatment. Tonic seizures are associated with channelopathies and are often controlled by

Published
2021

38. CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity

Author

Genetica Klinische Genetica, Brain, Genetica Sectie Genoomdiagnostiek, Child Health, Ernst, Michelle E, Baugh, Evan H, Thomas, Amanda, Bier, Louise, Lippa, Natalie, Stong, Nicholas, Mulhern, Maureen S, Kushary, Sulagna, Akman, Cigdem I, Heinzen, Erin L, Yeh, Raymond, Bi, Weimin, Hanchard, Neil A, Burrage, Lindsay C, Leduc, Magalie S, Chong, Josephine S C, Bend, Renee, Lyons, Michael J, Lee, Jennifer A, Suwannarat, Pim, Brilstra, Eva, Simon, Marleen, Koopmans, Marije, van Binsbergen, Ellen, Groepper, Daniel, Fleischer, Julie, Nava, Caroline, Keren, Boris, Mignot, Cyril, Mathieu, Sophie, Mancini, Grazia M S, Madan-Khetarpal, Suneeta, Infante, Elena M, Bluvstein, Judith, Seeley, Andrea, Bachman, Kristine, Klee, Eric W, Schultz-Rogers, Laura E, Hasadsri, Linda, Barnett, Sarah, Ellingson, Marissa S, Ferber, Matthew J, Narayanan, Vinodh, Ramsey, Keri, Rauch, Anita, Joset, Pascal, Steindl, Katharina, Sheehan, Theodore, Poduri, Annapurna, Vasquez, Alejandra, Ruivenkamp, Claudia, White, Susan M, Pais, Lynn, Monaghan, Kristin G, Goldstein, David B, Sands, Tristan T, Aggarwal, Vimla, Genetica Klinische Genetica, Brain, Genetica Sectie Genoomdiagnostiek, Child Health, Ernst, Michelle E, Baugh, Evan H, Thomas, Amanda, Bier, Louise, Lippa, Natalie, Stong, Nicholas, Mulhern, Maureen S, Kushary, Sulagna, Akman, Cigdem I, Heinzen, Erin L, Yeh, Raymond, Bi, Weimin, Hanchard, Neil A, Burrage, Lindsay C, Leduc, Magalie S, Chong, Josephine S C, Bend, Renee, Lyons, Michael J, Lee, Jennifer A, Suwannarat, Pim, Brilstra, Eva, Simon, Marleen, Koopmans, Marije, van Binsbergen, Ellen, Groepper, Daniel, Fleischer, Julie, Nava, Caroline, Keren, Boris, Mignot, Cyril, Mathieu, Sophie, Mancini, Grazia M S, Madan-Khetarpal, Suneeta, Infante, Elena M, Bluvstein, Judith, Seeley, Andrea, Bachman, Kristine, Klee, Eric W, Schultz-Rogers, Laura E, Hasadsri, Linda, Barnett, Sarah, Ellingson, Marissa S, Ferber, Matthew J, Narayanan, Vinodh, Ramsey, Keri, Rauch, Anita, Joset, Pascal, Steindl, Katharina, Sheehan, Theodore, Poduri, Annapurna, Vasquez, Alejandra, Ruivenkamp, Claudia, White, Susan M, Pais, Lynn, Monaghan, Kristin G, Goldstein, David B, Sands, Tristan T, and Aggarwal, Vimla

Published
2021

39. CSNK2B : A broad spectrum of neurodevelopmental disability and epilepsy severity

Author

Ernst, Michelle E., primary, Baugh, Evan H., additional, Thomas, Amanda, additional, Bier, Louise, additional, Lippa, Natalie, additional, Stong, Nicholas, additional, Mulhern, Maureen S., additional, Kushary, Sulagna, additional, Akman, Cigdem I., additional, Heinzen, Erin L., additional, Yeh, Raymond, additional, Bi, Weimin, additional, Hanchard, Neil A., additional, Burrage, Lindsay C., additional, Leduc, Magalie S., additional, Chong, Josephine S. C., additional, Bend, Renee, additional, Lyons, Michael J., additional, Lee, Jennifer A., additional, Suwannarat, Pim, additional, Brilstra, Eva, additional, Simon, Marleen, additional, Koopmans, Marije, additional, Binsbergen, Ellen, additional, Groepper, Daniel, additional, Fleischer, Julie, additional, Nava, Caroline, additional, Keren, Boris, additional, Mignot, Cyril, additional, Mathieu, Sophie, additional, Mancini, Grazia M. S., additional, Madan‐Khetarpal, Suneeta, additional, Infante, Elena M., additional, Bluvstein, Judith, additional, Seeley, Andrea, additional, Bachman, Kristine, additional, Klee, Eric W., additional, Schultz‐Rogers, Laura E., additional, Hasadsri, Linda, additional, Barnett, Sarah, additional, Ellingson, Marissa S., additional, Ferber, Matthew J., additional, Narayanan, Vinodh, additional, Ramsey, Keri, additional, Rauch, Anita, additional, Joset, Pascal, additional, Steindl, Katharina, additional, Sheehan, Theodore, additional, Poduri, Annapurna, additional, Vasquez, Alejandra, additional, Ruivenkamp, Claudia, additional, White, Susan M., additional, Pais, Lynn, additional, Monaghan, Kristin G., additional, Goldstein, David B., additional, Sands, Tristan T., additional, and Aggarwal, Vimla, additional

Published
2021
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41. Tracking Multisite Seizure Propagation Using Ictal High-Gamma Activity

Author

Tobochnik, Steven, primary, Bateman, Lisa M., additional, Akman, Cigdem I., additional, Anbarasan, Deepti, additional, Bazil, Carl W., additional, Bell, Michelle, additional, Choi, Hyunmi, additional, Feldstein, Neil A., additional, Kent, Paul F., additional, McBrian, Danielle, additional, McKhann, Guy M., additional, Mendiratta, Anil, additional, Pack, Alison M., additional, Sands, Tristan T., additional, Sheth, Sameer A., additional, Srinivasan, Shraddha, additional, and Schevon, Catherine A., additional

Published
2021
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42. A Novel Kv7.3 Variant in the Voltage-Sensing S4 Segment in a Family With Benign Neonatal Epilepsy: Functional Characterization and in vitro Rescue by β-Hydroxybutyrate

Author

Miceli, Francesco, primary, Carotenuto, Lidia, additional, Barrese, Vincenzo, additional, Soldovieri, Maria Virginia, additional, Heinzen, Erin L., additional, Mandel, Arthur M., additional, Lippa, Natalie, additional, Bier, Louise, additional, Goldstein, David B., additional, Cooper, Edward C., additional, Cilio, Maria Roberta, additional, Taglialatela, Maurizio, additional, and Sands, Tristan T., additional

Published
2020
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43. Tracking multi-site seizure propagation using ictal high frequency activity

Author

Tobochnik, Steven, primary, Bateman, Lisa M., additional, Akman, Cigdem I., additional, Anbarasan, Deepti, additional, Bazil, Carl W., additional, Bell, Michelle, additional, Choi, Hyunmi, additional, Feldstein, Neil A., additional, Kent, Paul F., additional, McBrian, Danielle, additional, McKhann, Guy M., additional, Mendiratta, Anil, additional, Pack, Alison M., additional, Sands, Tristan T., additional, Sheth, Sameer A., additional, Srinivasan, Shraddha, additional, and Schevon, Catherine A., additional

Published
2020
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45. Rasmussen Encephalitis: An Update

Author

Cay-Martinez, Karla C., additional, Hickman, Richard A., additional, McKhann II, Guy M., additional, Provenzano, Frank A., additional, and Sands, Tristan T., additional

Published
2020
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46. Autism and developmental disability caused by KCNQ3 gain‐of‐function variants

Author

Sands, Tristan T., primary, Miceli, Francesco, additional, Lesca, Gaetan, additional, Beck, Anita E., additional, Sadleir, Lynette G., additional, Arrington, Daniel K., additional, Schönewolf‐Greulich, Bitten, additional, Moutton, Sébastien, additional, Lauritano, Anna, additional, Nappi, Piera, additional, Soldovieri, Maria Virginia, additional, Scheffer, Ingrid E., additional, Mefford, Heather C., additional, Stong, Nicholas, additional, Heinzen, Erin L., additional, Goldstein, David B., additional, Perez, Ana Grijalvo, additional, Kossoff, Eric H., additional, Stocco, Amber, additional, Sullivan, Jennifer A., additional, Shashi, Vandana, additional, Gerard, Benedicte, additional, Francannet, Christine, additional, Bisgaard, Anne‐Marie, additional, Tümer, Zeynep, additional, Willems, Marjolaine, additional, Rivier, François, additional, Vitobello, Antonio, additional, Thakkar, Kavita, additional, Rajan, Deepa S., additional, Barkovich, A. James, additional, Weckhuysen, Sarah, additional, Cooper, Edward C., additional, Taglialatela, Maurizio, additional, and Cilio, M. Roberta, additional

Published
2019
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47. Autism and developmental disability caused by KCNQ3 gain-of-function variants

Author

Sands, Tristan T, Miceli, Francesco, Lesca, Gaetan, Beck, Anita E, Sadleir, Lynette G, Arrington, Daniel K, Schönewolf-Greulich, Bitten, Moutton, Sébastien, Lauritano, Anna, Nappi, Piera, Soldovieri, Maria Virginia, Scheffer, Ingrid E, Mefford, Heather C, Stong, Nicholas, Heinzen, Erin L, Goldstein, David B, Perez, Ana Grijalvo, Kossoff, Eric H, Stocco, Amber, Sullivan, Jennifer A, Shashi, Vandana, Gerard, Benedicte, Francannet, Christine, Bisgaard, Anne-Marie, Tümer, Zeynep, Willems, Marjolaine, Rivier, François, Vitobello, Antonio, Thakkar, Kavita, Rajan, Deepa S, Barkovich, A James, Weckhuysen, Sarah, Cooper, Edward C, Taglialatela, Maurizio, Cilio, M Roberta, Sands, Tristan T, Miceli, Francesco, Lesca, Gaetan, Beck, Anita E, Sadleir, Lynette G, Arrington, Daniel K, Schönewolf-Greulich, Bitten, Moutton, Sébastien, Lauritano, Anna, Nappi, Piera, Soldovieri, Maria Virginia, Scheffer, Ingrid E, Mefford, Heather C, Stong, Nicholas, Heinzen, Erin L, Goldstein, David B, Perez, Ana Grijalvo, Kossoff, Eric H, Stocco, Amber, Sullivan, Jennifer A, Shashi, Vandana, Gerard, Benedicte, Francannet, Christine, Bisgaard, Anne-Marie, Tümer, Zeynep, Willems, Marjolaine, Rivier, François, Vitobello, Antonio, Thakkar, Kavita, Rajan, Deepa S, Barkovich, A James, Weckhuysen, Sarah, Cooper, Edward C, Taglialatela, Maurizio, and Cilio, M Roberta

Abstract

OBJECTIVE: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms.METHODS: Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording.RESULTS: Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects.INTERPRETATION: Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192.

Published
2019

49. A Novel Kv7.3 Variant in the Voltage-Sensing S4 Segment in a Family With Benign Neonatal Epilepsy: Functional Characterization and in vitro Rescue by β-Hydroxybutyrate.

Author

Miceli, Francesco, Carotenuto, Lidia, Barrese, Vincenzo, Soldovieri, Maria Virginia, Heinzen, Erin L., Mandel, Arthur M., Lippa, Natalie, Bier, Louise, Goldstein, David B., Cooper, Edward C., Cilio, Maria Roberta, Taglialatela, Maurizio, and Sands, Tristan T.

Subjects
KETOGENIC diet, EPILEPSY, FAMILIES, MOLECULAR models, SIBLINGS
Abstract

Pathogenic variants in KCNQ2 and KCNQ3 , paralogous genes encoding Kv7.2 and Kv7.3 voltage-gated K+ channel subunits, are responsible for early−onset developmental/epileptic disorders characterized by heterogeneous clinical phenotypes ranging from benign familial neonatal epilepsy (BFNE) to early−onset developmental and epileptic encephalopathy (DEE). KCNQ2 variants account for the majority of pedigrees with BFNE and KCNQ3 variants are responsible for a much smaller subgroup, but the reasons for this imbalance remain unclear. Analysis of additional pedigrees is needed to further clarify the nature of this genetic heterogeneity and to improve prediction of pathogenicity for novel variants. We identified a BFNE family with two siblings and a parent affected. Exome sequencing on samples from both parents and siblings revealed a novel KCNQ3 variant (c.719T>G; p.M240R), segregating in the three affected individuals. The M240 residue is conserved among human Kv7.2-5 and lies between the two arginines (R5 and R6) closest to the intracellular side of the voltage-sensing S4 transmembrane segment. Whole cell patch-clamp recordings in Chinese hamster ovary (CHO) cells revealed that homomeric Kv7.3 M240R channels were not functional, whereas heteromeric channels incorporating Kv7.3 M240R mutant subunits with Kv7.2 and Kv7.3 displayed a depolarizing shift of about 10 mV in activation gating. Molecular modeling results suggested that the M240R substitution preferentially stabilized the resting state and possibly destabilized the activated state of the Kv7.3 subunits, a result consistent with functional data. Exposure to β-hydroxybutyrate (BHB), a ketone body generated during the ketogenic diet (KD), reversed channel dysfunction induced by the M240R variant. In conclusion, we describe the first missense loss-of-function (LoF) pathogenic variant within the S4 segment of Kv7.3 identified in patients with BFNE. Studied under conditions mimicking heterozygosity, the M240R variant mainly affects the voltage sensitivity, in contrast to previously analyzed BFNE Kv7.3 variants that reduce current density. Our pharmacological results provide a rationale for the use of KD in patients carrying LoF variants in Kv7.2 or Kv7.3 subunits. [ABSTRACT FROM AUTHOR]

Published
2020
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