282 results on '"Brunklaus, Andreas"'
Search Results
2. Cost-of-illness review of status epilepticus in Europe
- Author
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Strzelczyk, Adam, Brunklaus, Andreas, Rosenow, Felix, Paprocka, Justyna, Schubert-Bast, Susanne, and Kämppi, Leena
- Published
- 2024
- Full Text
- View/download PDF
3. Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial
- Author
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Schoeler, Natasha E, Marston, Louise, Lyons, Laura, Halsall, Sally, Jain, Ruchika, Titre-Johnson, Siobhan, Balogun, Maryam, Heales, Simon J R, Eaton, Simon, Orford, Michael, Neal, Elizabeth, Reilly, Colin, Eltze, Christin, Stephen, Elma, Mallick, Andrew A, O’Callaghan, Finbar, Agrawal, Shakti, Parker, Alasdair, Kirkpatrick, Martin, Brunklaus, Andreas, McLellan, Ailsa, McCullagh, Helen, Samanta, Rajib, Kneen, Rachel, Tan, Hui Jeen, Devlin, Anita, Prasad, Manish, Rattihalli, Rohini, Basu, Helen, Desurkar, Archana, Williams, Ruth, Fallon, Penny, Nazareth, Irwin, Freemantle, Nick, and Cross, J Helen
- Published
- 2023
- Full Text
- View/download PDF
4. Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy (TAMDMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
- Author
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Ridout, Deborah, Muntoni, Francesco, Manzur, Adnan., Quinlivan, Rosaline, Baranello, Giovanni, Main, Marion, Abbott, Lianne, Burnett, Nicola, Rohwer, Anne-Marie, Milev, Evelin, Wolfe, Adrian, O'Reilly, Emer, Straub, Volker, Guglieri, Michela, Bettolo, Chiara, Muni-Lofra, Robert, James, Meredith, Sodhi, Jassi, Willis, Tracey, Wright, Elizabeth, Rylance, Claire, Birchall, Nicola, Childs, Anne-Marie, Pysden, Karen, Martos-Lozano, Cristina, Pallant, Lindsey, Wadsworth, Steph, Spinty, Stefan, Madhu, Rajesh, Karuvattil, Rajesh, Gregson, Sarah, Clark, Stuart, Wraige, Elizabeth, Jungbluth, Heinz, Gowda, Vasantha, Vanegas, Maria, Sheehan, Ennie, Wolfe, Amy, Schofield, Alex, Hughes, Imelda, McCullagh, Gary, Whitehouse, Emily, Varma, Uma., Warner, Sinead, Reading, Emily, Benson, Lucy., Moustoukas, Jenny, Strachan, Kate, Emery, Nicholas, Ong, Min, Atherton, Mark, Durso, Sarah, White, Kay, Hinde, Neil, Skone, Kate, Sanchez Marco, Silvia, Saxena, Anurag, Gibbon, Frances, TeWaterNaude, Johann, Davis, Hayley, Thompson, Laura, Majumdar, Anirban, Murugan, Archana, Lynch, Mollie, Milton, Emily, Guarino, Iolanda, Tomlinson, Richard, Jarvis, Heather, Berry, Jane, Wills, Lucy, Frimpong-Ansah, Claire, Watson, Jackie, Robertson, Gemma, Cobb, Gavin, Burslem, Julie, Horrocks, Iain, Wong, Jarod, Brunklaus, Andreas, DiMarco, Marina, Brown, Sarah, Mckenzie, Susanne, Torne, Krupa, Mohamed, Rana, Velmurugan, Vel, Prasad, Manish, Sedehizadeh, Saam, Williamson, Sarah, Fenty, Paula, Degoede, Christian, Parkes, Amy, Illingworth, Marjorie, Bhangu, Neeraj, Geary, Michelle, Palmer, Jenni, Shill, Catherine, White, Cathy, Greenfield, Kathryn, Tomos, Heledd, Gates, Sarah, Tirupathi, Sandya, Shah, Ayaz, O'Donoghue, Dara, McVeigh, Janine, McFetridge, Jaci, Nic Fhirleinn, Grainne, Hussain, Nahin, Baskaran, Dhinesh, Lambat, Zubeida, Ambegaonkar, Gautam, Krishnakumar, Deepa, Taylor, Jacqui, Moores, Jo, Stephen, Elma, Tewnion, Jane, Ramdas, Sithara, Sa, Mario, Servais, Laurent, Lilien, Charlotte, Ramjattan, Hayley, Taylor, Francesca, English, Hayley, Parasuraman, Deepak, Rabb, Rosanna, McMurchie, Heather, Henzi, Bettina C, Schmidt, Simone, Nagy, Sara, Rubino-Nacht, Daniela, Schaedelin, Sabine, Putananickal, Niveditha, Stimpson, Georgia, Amthor, Helge, Deconinck, Nicolas, de Groot, Imelda, Houwen-van Opstal, Saskia, Laugel, Vincent, Lopez Lobato, Mercedes, Madruga Garrido, Marcos, Nascimento Osorio, Andrés, Schara-Schmidt, Ulrike, von Moers, Arpad, Lawrence, Fiona, Hafner, Patricia, Dorchies, Olivier M, and Fischer, Dirk
- Published
- 2023
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5. Autism and attention‐deficit/hyperactivity disorder in Dravet syndrome
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Brunklaus, Andreas, primary
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- 2024
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6. Defining causal variants in rare epilepsies: an essential team effort between biomedical scientists, geneticists and epileptologists
- Author
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McTague, Amy, Brunklaus, Andreas, Barcia, Giulia, Varadkar, Sophia, Zuberi, Sameer M., Chatron, Nicolas, Parrini, Elena, Mei, Davide, Nabbout, Rima, and Lesca, Gaetan
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- 2022
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7. Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial
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Belousova, Elena, Belyaev, Oleg, Ben-Zeev, Bruria, Brunklaus, Andreas, Ciliberto, Michael A., Darra, Francesca, Davis, Ronald, De Giorgis, Valentina, Doronina, Olga, Fahey, Michael, Guerrini, Renzo, Heydemann, Peter, Khaletskaya, Olga, Lisewski, Pawel, Marsh, Eric D., Moosa, Ahsan N., Perry, Scott, Philip, Sunny, Rajaraman, Rajsekar R., Renfroe, Ben, Saneto, Russell P., Scheffer, Ingrid E., Sogawa, Yoshimi, Suter, Bernhardt, Sweney, Matthew T., Tarquinio, Daniel, Veggiotti, Pierangelo, Wallace, Geoff, Weisenberg, Judy, Wilfong, Angus, Wirrell, Elaine C., Zafar, Muhammad, Zolnowska, Marta, Knight, Elia M Pestana, Amin, Sam, Bahi-Buisson, Nadia, Benke, Tim A, Cross, J Helen, Demarest, Scott T, Olson, Heather E, Specchio, Nicola, Fleming, Thomas R, Aimetti, Alex A, Gasior, Maciej, and Devinsky, Orrin
- Published
- 2022
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8. POLR3B is associated with a developmental and epileptic encephalopathy with myoclonic‐atonic seizures and ataxia.
- Author
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Symonds, Joseph D., Park, Kristen L., Mignot, Cyril, Macleod, Stewart, Armstrong, Martin, Ashrafian, Houman, Bernard, Geneviève, Brown, Kathleen, Brunklaus, Andreas, Callaghan, Mary, Classen, Georg, Cohen, Julie S., Cutcutache, Ioana, de Sainte Agathe, Jean‐Madeleine, Dyment, David, Elliot, Katherine S., Isapof, Arnaud, Joss, Shelagh, Keren, Boris, and Marble, Michael
- Abstract
Objective: POLR3B encodes the second largest subunit of RNA polymerase III, which is essential for transcription of small non‐coding RNAs. Biallelic pathogenic variants in POLR3B are associated with an inherited hypomyelinating leukodystrophy. Recently, de novo heterozygous variants in POLR3B were reported in six individuals with ataxia, spasticity, and demyelinating peripheral neuropathy. Three of these individuals had epileptic seizures. The aim of this article is to precisely define the epilepsy phenotype associated with de novo heterozygous POLR3B variants. Methods: We used online gene‐matching tools to identify 13 patients with de novoPOLR3B variants. We systematically collected genotype and phenotype data from clinicians using two standardized proformas. Results: All 13 patients had novel POLR3B variants. Twelve of 13 variants were classified as pathogenic or likely pathogenic as per American College of Medical Genetics (ACMG) criteria. Patients presented with generalized myoclonic, myoclonic‐atonic, atypical absence, or tonic‐clonic seizures between the ages of six months and 4 years. Epilepsy was classified as epilepsy with myoclonic‐atonic seizures (EMAtS) in seven patients and "probable EMAtS" in two more. Seizures were treatment resistant in all cases. Three patients became seizure‐free. All patients had some degree of developmental delay or intellectual disability. In most cases developmental delay was apparent before the onset of seizures. Three of 13 cases were reported to have developmental stagnation or regression in association with seizure onset. Treatments for epilepsy that were reported by clinicians to be effective were: sodium valproate, which was effective in five of nine patients (5/9) who tried it; rufinamide (2/3); and ketogenic diet (2/3). Additional features were ataxia/incoordination (8/13); microcephaly (7/13); peripheral neuropathy (4/13), and spasticity/hypertonia (6/13). Significance: POLR3B is a novel genetic developmental and epileptic encephalopathy (DEE) in which EMAtS is the predominant epilepsy phenotype. Ataxia, neuropathy, and hypertonia may be variously observed in these patients. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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9. Efficacy and safety of ketogenic diet in infants with epilepsy: KIWE RCT.
- Author
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Schoeler, Natasha E, Marston, Louise, Lyons, Laura, Halsall, Sally, Jain, Ruchika, Titre-Johnson, Siobhan, Balogun, Maryam, Heales, Simon J R, Eaton, Simon, Orford, Michael, Neal, Elizabeth, Eltze, Christin, Stephen, Elma, Mallick, Andrew A, O'Callaghan, Finbar, Agrawal, Shakti, Parker, Alasdair, Kirkpatrick, Martin, Brunklaus, Andreas, and McLellan, Ailsa
- Published
- 2024
- Full Text
- View/download PDF
10. Optimizing clinical interpretability of functional evidence in epilepsy-related ion channel variants
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Parthasarathy, Shridhar, primary, Cohen, Stacey R, additional, Fitch, Eryn, additional, Vaidiswaran, Priya, additional, Ruggiero, Sarah M, additional, Lusk, Laina, additional, Chisari, Victoria, additional, Lewis-Smith, David, additional, Lauxmann, Stephan, additional, Bosselmann, Christian M, additional, Thompson, Christopher H, additional, Wengert, Eric R, additional, Hedrich, Ulrike, additional, Ganesan, Shiva, additional, Balagura, Ganna, additional, Krause, Roland, additional, Xian, Julie, additional, Galer, Peter D, additional, Pendziwiat, Manuela, additional, Perez-Palma, Eduardo, additional, Vihinen, Mauno, additional, Hart, Jennifer, additional, Landrum, Melissa J, additional, Lal, Dennis, additional, Cooper, Edward C, additional, Lerche, Holger, additional, Goldberg, Ethan M, additional, Brunklaus, Andreas, additional, Vanoye, Carlos G, additional, Schorge, Stephanie, additional, George, Alfred L, additional, and Helbig, Ingo, additional
- Published
- 2024
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11. Brainstem depolarization–induced lethal apnea associated with gain-of-function SCN1A L263V is prevented by sodium channel blockade
- Author
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Jansen, Nico A., primary, Cestèle, Sandrine, additional, Marco, Silvia Sanchez, additional, Schenke, Maarten, additional, Stewart, Kirsty, additional, Patel, Jayesh, additional, Tolner, Else A., additional, Brunklaus, Andreas, additional, Mantegazza, Massimo, additional, and van den Maagdenberg, Arn M. J. M., additional
- Published
- 2024
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12. Genotype–phenotype associations in 1018 individuals with SCN1A-related epilepsies
- Author
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Genetica, Genetica Klinische Genetica, Brain, Genetica Oper.Mang. Clinical Genetics, Child Health, Gallagher, Declan, Pérez-Palma, Eduardo, Bruenger, Tobias, Ghanty, Ismael, Brilstra, Eva, Ceulemans, Berten, Chemaly, Nicole, de Lange, Iris, Depienne, Christel, Guerrini, Renzo, Mei, Davide, Møller, Rikke S., Nabbout, Rima, Regan, Brigid M., Schneider, Amy L., Scheffer, Ingrid E., Schoonjans, An Sofie, Symonds, Joseph D., Weckhuysen, Sarah, Zuberi, Sameer M., Lal, Dennis, Brunklaus, Andreas, Genetica, Genetica Klinische Genetica, Brain, Genetica Oper.Mang. Clinical Genetics, Child Health, Gallagher, Declan, Pérez-Palma, Eduardo, Bruenger, Tobias, Ghanty, Ismael, Brilstra, Eva, Ceulemans, Berten, Chemaly, Nicole, de Lange, Iris, Depienne, Christel, Guerrini, Renzo, Mei, Davide, Møller, Rikke S., Nabbout, Rima, Regan, Brigid M., Schneider, Amy L., Scheffer, Ingrid E., Schoonjans, An Sofie, Symonds, Joseph D., Weckhuysen, Sarah, Zuberi, Sameer M., Lal, Dennis, and Brunklaus, Andreas
- Published
- 2024
13. Unraveling unmet needs in ketogenic dietary services: An ERN EpiCARE survey.
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De Giorgis, Valentina, Pasca, Ludovica, Aznar‐Lain, Gemma, Bibic, Irena, Bibic, Vedrana, Darra, Francesca, Dianin, Alice, Dressler, Anastasia, Jonsson, Henna, Komulainen‐Ebrahim, Jonna, Kverneland, Magnhild, Molteberg, Ellen, Ragona, Francesca, de Saint‐Martin, Anne, Varesio, Costanza, Cross, J. Helen, Baumgartner, Tobias, Bjellvi, Johan, Brunklaus, Andreas, and Buttle, Janette
- Subjects
PATIENTS' families ,INTERNET surveys ,EVERYDAY life ,MEDICAL personnel ,EPILEPSY - Abstract
The implementation and potential of ketogenic dietary therapies (KDTs) have changed over time. The organization of KDT services, the availability of multidisciplinary teams, resources and support for patients and families still vary widely around the world. This diversity is reflected by a lack of consistency in reported outcomes, optimization of using KDT and KDT compliance. To highlight the unmet needs for KDT services, the ERN EpiCARE Ketogenic Dietary Therapy Special Interest Group (KDT SIG) conducted an online survey on KDT implementation and utilization, addressing the following topics: Use and completeness of guidelines and protocols; assessment of compliance and outcome parameters, sustainability and inclusivity in daily life. Consistently reported unmet needs included the lack of psychological support and resources to measure and improve adherence to KDT, the lack of inclusion strategies, and shared guidelines and protocols adapting to specific needs. Future interventions should focus primarily on educational and informative measures together with creation of shared protocols for complex care. Plain Language Summary: This study provides the results of a survey compiled by clinicians and patients representatives belonging to ERN Epicare, designed to unravel unmet needs from both patients' and healthcare practitioners' perspectives during ketogenic dietary therapies (KDT) provision. Importantly, results show the need to create new shared protocols and guidelines meant for KDT use in complex care situations and to develop future strategies initiatives to support patients improving their social inclusivity. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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14. Time to move beyond genetics towards biomedical data-driven translational genomic research in severe paediatric epilepsies
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Brunklaus, Andreas, Leu, Costin, Gramm, Marie, Pérez-Palma, Eduardo, Iqbal, Sumaiya, and Lal, Dennis
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- 2020
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15. Differential excitatory vs inhibitory SCN expression at single cell level regulates brain sodium channel function in neurodevelopmental disorders
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Du, Juanjiangmeng, Simmons, Sean, Brunklaus, Andreas, Adiconis, Xian, Hession, Cynthia C., Fu, Zhanyan, Li, Yinqing, Shema, Reut, Møller, Rikke S., Barak, Boaz, Feng, Guoping, Meisler, Miriam, Sanders, Stephan, Lerche, Holger, Campbell, Arthur J., McCarroll, Steven, Levin, Joshua Z., and Lal, Dennis
- Published
- 2020
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16. Genotype–phenotype associations in 1018 individuals with SCN1A‐related epilepsies
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Gallagher, Declan, primary, Pérez‐Palma, Eduardo, additional, Bruenger, Tobias, additional, Ghanty, Ismael, additional, Brilstra, Eva, additional, Ceulemans, Berten, additional, Chemaly, Nicole, additional, de Lange, Iris, additional, Depienne, Christel, additional, Guerrini, Renzo, additional, Mei, Davide, additional, Møller, Rikke S., additional, Nabbout, Rima, additional, Regan, Brigid M., additional, Schneider, Amy L., additional, Scheffer, Ingrid E., additional, Schoonjans, An‐Sofie, additional, Symonds, Joseph D., additional, Weckhuysen, Sarah, additional, Zuberi, Sameer M., additional, Lal, Dennis, additional, and Brunklaus, Andreas, additional
- Published
- 2024
- Full Text
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17. Molecular dynamics simulations reveal molecular mechanisms for the gain and loss of function effects of fourSCN2Avariants
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Bhattarai, Nisha, primary, Montanucci, Ludovica, additional, Brünger, Tobias, additional, Pérez-Palma, Eduardo, additional, Martin, William, additional, Smith, Iris Nira, additional, Eng, Charis, additional, Cheng, Feixiong, additional, Helbig, Ingo, additional, Møller, Rikke S, additional, Brunklaus, Andreas, additional, Schorge, Stephanie, additional, and Lal, Dennis, additional
- Published
- 2024
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18. Long-term predictors of developmental outcome and disease burden in SCN1A-positive Dravet syndrome
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Feng, Tony, primary, Makiello, Phoebe, additional, Dunwoody, Benjamin, additional, Steckler, Felix, additional, Symonds, Joseph D, additional, Zuberi, Sameer M, additional, Dorris, Liam, additional, and Brunklaus, Andreas, additional
- Published
- 2023
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19. Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study
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Perry, M. Scott, primary, Scheffer, Ingrid E., additional, Sullivan, Joseph, additional, Brunklaus, Andreas, additional, Boronat, Susana, additional, Wheless, James W., additional, Laux, Linda, additional, Patel, Anup D., additional, Roberts, Colin M., additional, Dlugos, Dennis, additional, Holder, Deborah, additional, Knupp, Kelly G., additional, Lallas, Matt, additional, Phillips, Steven, additional, Segal, Eric, additional, Smeyers, Patricia, additional, Lal, Dennis, additional, Wirrell, Elaine, additional, Zuberi, Sameer, additional, Brünger, Tobias, additional, Wojnaroski, Mary, additional, Maru, Benit, additional, O'Donnell, Penrose, additional, Morton, Magda, additional, James, Emma, additional, Vila, Maria Candida, additional, Huang, Norman, additional, Gofshteyn, Jacqueline S., additional, and Rico, Salvador, additional
- Published
- 2023
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20. Brainstem depolarization-induced lethal apnea associated with gain-of-function SCN1AL263V is prevented by sodium channel blockade.
- Author
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Jansen, Nico A., Cestèle, Sandrine, Marco, Silvia Sanchez, Schenke, Maarten, Stewart, Kirsty, Patel, Jayesh, Tolner, Else A., Brunklaus, Andreas, Mantegazza, Massimo, and van den Maagdenberg, Arn M. J. M.
- Subjects
SODIUM channels ,SUDDEN infant death syndrome ,PEOPLE with epilepsy ,MIGRAINE aura ,BRAIN stem ,APNEA - Abstract
Apneic events are frightening but largely benign events that often occur in infants. Here, we report apparent life-threatening apneic events in an infant with the homozygous SCN1A
L263V missense mutation, which causes familial hemiplegic migraine type 3 in heterozygous family members, in the absence of epilepsy. Observations consistent with the events in the infant were made in an Scn1aL263V knock-in mouse model, in which apnea was preceded by a large brainstem DC-shift, indicative of profound brainstem depolarization. The L263V mutation caused gain of NaV1.1 function effects in transfected HEK293 cells. Sodium channel blockade mitigated the gain-of-function characteristics, rescued lethal apnea in Scn1aL263V mice, and decreased the frequency of severe apneic events in the patient. Hence, this study shows that SCN1AL263V can cause life-threatening apneic events, which in a mouse model were caused by profound brainstem depolarization. In addition to being potentially relevant to sudden infant death syndrome pathophysiology, these data indicate that sodium channel blockers may be considered therapeutic for apneic events in patients with these and other gain-of-function SCN1A mutations. [ABSTRACT FROM AUTHOR]- Published
- 2024
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21. Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy (TAMDMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
- Author
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Henzi, Bettina C, primary, Schmidt, Simone, additional, Nagy, Sara, additional, Rubino-Nacht, Daniela, additional, Schaedelin, Sabine, additional, Putananickal, Niveditha, additional, Stimpson, Georgia, additional, Amthor, Helge, additional, Childs, Anne-Marie, additional, Deconinck, Nicolas, additional, de Groot, Imelda, additional, Horrocks, Iain, additional, Houwen-van Opstal, Saskia, additional, Laugel, Vincent, additional, Lopez Lobato, Mercedes, additional, Madruga Garrido, Marcos, additional, Nascimento Osorio, Andrés, additional, Schara-Schmidt, Ulrike, additional, Spinty, Stefan, additional, von Moers, Arpad, additional, Lawrence, Fiona, additional, Hafner, Patricia, additional, Dorchies, Olivier M, additional, Fischer, Dirk, additional, Ridout, Deborah, additional, Muntoni, Francesco, additional, Manzur, Adnan., additional, Quinlivan, Rosaline, additional, Baranello, Giovanni, additional, Main, Marion, additional, Abbott, Lianne, additional, Burnett, Nicola, additional, Rohwer, Anne-Marie, additional, Milev, Evelin, additional, Wolfe, Adrian, additional, .O'Reilly, Emer, additional, Straub, Volker, additional, Guglieri, Michela, additional, Bettolo, Chiara, additional, Muni-Lofra, Robert, additional, James, Meredith, additional, Sodhi, Jassi, additional, Willis, Tracey, additional, Wright, Elizabeth, additional, Rylance, Claire, additional, Birchall, Nicola, additional, Pysden, Karen, additional, Martos-Lozano, Cristina, additional, Pallant, Lindsey, additional, Wadsworth, Steph, additional, Madhu, Rajesh, additional, Karuvattil, Rajesh, additional, Gregson, Sarah, additional, Clark, Stuart, additional, Wraige, Elizabeth, additional, Jungbluth, Heinz, additional, Gowda, Vasantha, additional, Vanegas, Maria, additional, Sheehan, Ennie, additional, Wolfe, Amy, additional, Schofield, Alex, additional, Hughes, Imelda, additional, McCullagh, Gary, additional, Whitehouse, Emily, additional, Varma, Uma., additional, Warner, Sinead, additional, Reading, Emily, additional, Benson, Lucy., additional, Moustoukas, Jenny, additional, Strachan, Kate, additional, Emery, Nicholas, additional, Ong, Min, additional, Atherton, Mark, additional, Durso, Sarah, additional, White, Kay, additional, Hinde, Neil, additional, Skone, Kate, additional, Sanchez Marco, Silvia, additional, Saxena, Anurag, additional, Gibbon, Frances, additional, TeWaterNaude, Johann, additional, Davis, Hayley, additional, Thompson, Laura, additional, Majumdar, Anirban, additional, Murugan, Archana, additional, Lynch, Mollie, additional, Milton, Emily, additional, Guarino, Iolanda, additional, Tomlinson, Richard, additional, Jarvis, Heather, additional, Berry, Jane, additional, Wills, Lucy, additional, Frimpong-Ansah, Claire, additional, Watson, Jackie, additional, Robertson, Gemma, additional, Cobb, Gavin, additional, Burslem, Julie, additional, Wong, Jarod, additional, Brunklaus, Andreas, additional, DiMarco, Marina, additional, Brown, Sarah, additional, Mckenzie, Susanne, additional, Torne, Krupa, additional, Mohamed, Rana, additional, Velmurugan, Vel, additional, Prasad, Manish, additional, Sedehizadeh, Saam, additional, Williamson, Sarah, additional, Fenty, Paula, additional, Degoede, Christian, additional, Parkes, Amy, additional, Illingworth, Marjorie, additional, Bhangu, Neeraj, additional, Geary, Michelle, additional, Palmer, Jenni, additional, Shill, Catherine, additional, White, Cathy, additional, Greenfield, Kathryn, additional, Tomos, Heledd, additional, Gates, Sarah, additional, Tirupathi, Sandya, additional, Shah, Ayaz, additional, O'Donoghue, Dara, additional, McVeigh, Janine, additional, .McFetridge, Jaci, additional, Nic Fhirleinn, Grainne, additional, Hussain, Nahin, additional, Baskaran, Dhinesh, additional, Lambat, Zubeida, additional, Ambegaonkar, Gautam, additional, Krishnakumar, Deepa, additional, Taylor, Jacqui, additional, Moores, Jo, additional, Stephen, Elma, additional, Tewnion, Jane, additional, Ramdas, Sithara, additional, Sa, Mario, additional, Servais, Laurent, additional, Lilien, Charlotte, additional, Ramjattan, Hayley, additional, Taylor, Francesca, additional, English, Hayley, additional, Parasuraman, Deepak, additional, Rabb, Rosanna, additional, and McMurchie, Heather, additional
- Published
- 2023
- Full Text
- View/download PDF
22. Dravet syndrome: a systematic literature review of the illness burden
- Author
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Strzelczyk, Adam, primary, Lagae, Lieven, additional, Wilmshurst, Jo, additional, Brunklaus, Andreas, additional, Striano, Pasquale, additional, Rosenow, Felix, additional, and Schubert‐Bast, Susanne, additional
- Published
- 2023
- Full Text
- View/download PDF
23. Genotype phenotype relationships in SCN1A related childhood epilepsies
- Author
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Brunklaus, Andreas
- Subjects
618.92 ,RJ101 Child Health. Child health services - Abstract
Most mutations in SCN1A-related epilepsies are novel and when an infant presents with febrile seizures (FS) it is uncertain if they will have simple FS, FS+ or develop a severe epilepsy such as Dravet Syndrome. The main aim of this work has been to translate specific genetic findings in SCN1A related epilepsies not only to the phenotype, but to examine the implications this has on treatment and quality of life in children and their families. Clinical and genetic data were collected from 273 individuals with SCN1A mutations identified in our laboratory between November 2005 and February 2010. I examined whether the mutation class, distribution or nature of amino acid substitution correlated with the epilepsy phenotype, using the Grantham Score (GS) as a measure of physicochemical difference between amino acids. From structured referral data I analysed a range of clinical characteristics including epilepsy phenotype, seizure precipitants, EEG data, imaging studies, mutation class and response to medication and determined predictors of developmental outcome. I developed novel ideas on how to characterise mutations in SCN1A related epilepsies, showing that phenotypes are not determined by chance, but are in part determined by defined physico-chemical changes affecting a specific location in the protein structure. I was able to demonstrate that these principles not only apply to the SCN1A gene but also to the wider voltage gated sodium channel family and related diseases. This study has been the largest to date to systematically examine the prognostic, clinical and demographic features of Dravet syndrome. The overall incidence of Dravet syndrome was found to be at least one in every 28,600 UK births. Clinical features predicting a worse developmental outcome included status epilepticus, interictal EEG abnormalities in the first year of life and a motor disorder. No significant effect was seen for seizure precipitants, MRI abnormalities or mutation class (truncating vs. missense). Sodium valproate, benzodiazepines and topiramate were reported the most helpful medications and aggravation of seizures was reported for carbamazepine and lamotrigine. Health related quality of life (HRQOL) has emerged as a widely accepted measure to evaluate how chronic disease impacts on an individual’s well-being and I examined in detail the comorbidities and predictors of health related quality of life in Dravet syndrome. HRQOL was evaluated with two epilepsy-specific instruments, the Impact of Pediatric Epilepsy Scale (IPES) and the Epilepsy & Learning Disabilities Quality of Life Questionnaire (ELDQOL), a generic HRQOL instrument the Pediatric Quality of Life Inventory (PedsQL) and a behavioural screening tool, the Strength and Difficulties Questionnaire (SDQ). 163 individuals with Dravet syndrome and their families participated in the questionnaire study. HRQOL was significantly lower for children with Dravet syndrome compared to normative data. One third of children had conduct problems and two thirds had hyperactive or inattentive behaviour. Regression analysis revealed that behavioural problems were the strongest predictors of poorer HRQOL. Identification of specific comorbidities will help us to better recognise and understand the needs of children and families with Dravet syndrome and facilitate a distinct multi-disciplinary approach to management. Genetic testing in the epilepsies has become an increasingly accessible clinical tool and this is the first study to assess the impact of SCN1A testing on patient management from both carer and physician perspectives. The vast majority of parents whose children tested positive for a mutation reported genetic testing helpful, leading to treatment changes resulting in fewer seizures, and improved access to therapies and respite care. Nearly half of the physicians reported that a positive test facilitated diagnosis earlier than with clinical and EEG data alone. In two thirds it prevented additional investigations and altered the treatment approach; it influenced medication choice in three quarters of cases and through medication change improved seizure control in forty percent. In addition to confirming a clinical diagnosis, a positive SCN1A test enabled early diagnosis, influenced treatment choice and facilitated improvements in clinical management, especially in the very young. Finally I hope that this work will contribute to a better understanding of the causes of SCN1A related epilepsies. Furthermore I hope that it will provide evidence to aid earlier diagnosis and treatment of children with severe infantile epilepsies and that it will offer more information for genetic counselling. These improvements in epilepsy care and seizure control could help prevent or reduce the disability associated with SCN1A related epilepsies such as learning and behaviour problems and would improve the quality of life for children and families.
- Published
- 2013
24. Neuronal antibody prevalence in children with seizures < 3 years: a prospective national cohort
- Author
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Symonds, Joseph D., Moloney, Teresa C., Lang, Bethan, McLellan, Ailsa, O’Regan, Mary E., MacLeod, Stewart, Jollands, Alice, Vincent, Angela, Kirkpatrick, Martin, Brunklaus, Andreas, Shetty, Jayakara, Dorris, Liam, Forbes, Kirsten, Abu-Arafeh, Ishaq, Andrew, Jamie, Brink, Philip, Callaghan, Mary, Cruden, Jamie, Findlay, Christine, Grattan, Rosemary, MacDonnell, Jane, McKnight, Jean, Morrison, Calum A., Nairn, Lesley, Pilley, Elizabeth, Stephen, Elma, Thomsen, Selina, Webb, Alan, Wilson, Margaret, and Zuberi, Sameer M.
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- 2020
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25. Prophecy or empiricism? Clinical value of predicting versus determining genetic variant functions
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Brunklaus, Andreas, primary, George, Alfred L., additional, Lal, Dennis, additional, Heinzen, Erin L., additional, and Goldman, Alica M., additional
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- 2023
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26. Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.
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Perry, M. Scott, Scheffer, Ingrid E., Sullivan, Joseph, Brunklaus, Andreas, Boronat, Susana, Wheless, James W., Laux, Linda, Patel, Anup D., Roberts, Colin M., Dlugos, Dennis, Holder, Deborah, Knupp, Kelly G., Lallas, Matt, Phillips, Steven, Segal, Eric, Smeyers, Patricia, Lal, Dennis, Wirrell, Elaine, Zuberi, Sameer, and Brünger, Tobias
- Abstract
Objective: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment‐resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. Methods: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent‐reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6–2:0 years:months (Y:M; youngest), 2:1–3:6 Y:M (middle), and 3:7–5:0 Y:M (oldest). Results: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow‐up was 17.5 months (range =.0–24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum–maximum] = 1.0 in the youngest [1.0–70.0] and middle [1.0–242.0] age groups and 4.5 [.0–2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size =.52, p =.024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. Significance: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age. [ABSTRACT FROM AUTHOR]
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- 2024
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27. Long-term predictors of developmental outcome and disease burden in SCN1A-positive Dravet syndrome.
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Feng, Tony, Makiello, Phoebe, Dunwoody, Benjamin, Steckler, Felix, Symonds, Joseph D, Zuberi, Sameer M, Dorris, Liam, and Brunklaus, Andreas
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- 2024
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28. Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes
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Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Brünger, Tobias, Pérez-Palma, Eduardo, Montanucci, Ludovica, Nothnagel, Michael, Møller, Rikke S., Schorge, Stephanie, Zuberi, Sameer, Symonds, Joseph, Lemke, Johannes R., Brunklaus, Andreas, Traynelis, Stephen F., May, Patrick, Lal, Dennis, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Brünger, Tobias, Pérez-Palma, Eduardo, Montanucci, Ludovica, Nothnagel, Michael, Møller, Rikke S., Schorge, Stephanie, Zuberi, Sameer, Symonds, Joseph, Lemke, Johannes R., Brunklaus, Andreas, Traynelis, Stephen F., May, Patrick, and Lal, Dennis
- Abstract
Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. Consequently, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated.We sought to systematically identify biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion channel families. We collected and curated 3,049 pathogenic variants from hundreds of neurodevelopmental and other disorders and 12,546 population variants for 30 ion channel or channel subunits for which a high-quality protein structure was available. Using a wide range of bioinformatics approaches, we computed 163 structural features and tested them for pathogenic variant enrichment. We developed a novel 3D spatial distance scoring approach that enables comparisons of pathogenic and population variant distribution across protein structures.We discovered and independently replicated that several pore residue properties and proximity to the pore axis were most significantly enriched for pathogenic variants compared to population variants. Using our 3D scoring approach, we showed that the strongest pathogenic variant enrichment was observed for pore-lining residues and alpha-helix residues within 5Å distance from the pore axis center and not involved in gating. Within the subset of residues located at the pore, the hydrophobicity of the pore was the feature most strongly associated with variant pathogenicity. We also found an association between the identified properties and both clinical phenotypes and functional in vitro assays for voltage-gated sodium channels (SCN1A, SCN2A, SCN8A) and N-methyl-D-aspartate (NMDA) receptor (GRIN1, GRIN2A, GRIN2B) encoding genes. In an independent expert-curated dataset of 1,422 neurodeve
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- 2023
29. Delineation of functionally essential protein regions for 242 neurodevelopmental genes
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Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], DFG [sponsor], BMBF [sponsor], Iqbal, Sumaiya, Brünger, Tobias, Pérez-Palma, Eduardo, Macnee, Marie, Brunklaus, Andreas, Daly, Mark J., Campbell, Arthur J., Hoksza, David, May, Patrick, Lal, Dennis, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], DFG [sponsor], BMBF [sponsor], Iqbal, Sumaiya, Brünger, Tobias, Pérez-Palma, Eduardo, Macnee, Marie, Brunklaus, Andreas, Daly, Mark J., Campbell, Arthur J., Hoksza, David, May, Patrick, and Lal, Dennis
- Abstract
Neurodevelopmental disorders (NDDs), including severe pediatric epilepsy, autism, and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are ‘Variants of Uncertain Significance’. To safely enroll patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can ‘tolerate’ missense variants and which ones are ‘essential’ and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the three-dimensional (3D) structure context of proteins can also provide insights into the molecular mechanisms of disease variants. We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14,377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including >360,000 NDD
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- 2023
30. Delineation of functionally essential protein regions for 242 neurodevelopmental genes
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Iqbal, Sumaiya, Bruenger, Tobias, Perez-Palma, Eduardo, Macnee, Marie, Brunklaus, Andreas, Daly, Mark J., Campbell, Arthur J., Hoksza, David, May, Patrick, Lal, Dennis, Iqbal, Sumaiya, Bruenger, Tobias, Perez-Palma, Eduardo, Macnee, Marie, Brunklaus, Andreas, Daly, Mark J., Campbell, Arthur J., Hoksza, David, May, Patrick, and Lal, Dennis
- Abstract
Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are variants of uncertain significance'. To safely enrol patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can tolerate' missense variants and which ones are essential' and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the 3D structure context of proteins can also provide insights into the molecular mechanisms of disease variants. We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14 377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including > 360 000 NDD patients and population
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- 2023
31. Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes
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Brunger, Tobias, Perez-Palma, Eduardo, Montanucci, Ludovica, Nothnagel, Michael, Moller, Rikke S., Schorge, Stephanie, Zuberi, Sameer, Symonds, Joseph, Lemke, Johannes R., Brunklaus, Andreas, Traynelis, Stephen F., May, Patrick, Lal, Dennis, Brunger, Tobias, Perez-Palma, Eduardo, Montanucci, Ludovica, Nothnagel, Michael, Moller, Rikke S., Schorge, Stephanie, Zuberi, Sameer, Symonds, Joseph, Lemke, Johannes R., Brunklaus, Andreas, Traynelis, Stephen F., May, Patrick, and Lal, Dennis
- Abstract
Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. As a consequence, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion-channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated. We sought to systematically identify biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion-channel families. We collected and curated 3049 pathogenic variants from hundreds of neurodevelopmental and other disorders and 12 546 population variants for 30 ion channel or channel subunits for which a high-quality protein structure was available. Using a wide range of bioinformatics approaches, we computed 163 structural features and tested them for pathogenic variant enrichment. We developed a novel 3D spatial distance scoring approach that enables comparisons of pathogenic and population variant distribution across protein structures. We discovered and independently replicated that several pore residue properties and proximity to the pore axis were most significantly enriched for pathogenic variants compared to population variants. Using our 3D scoring approach, we showed that the strongest pathogenic variant enrichment was observed for pore-lining residues and alpha-helix residues within 5 angstrom distance from the pore axis centre and not involved in gating. Within the subset of residues located at the pore, the hydrophobicity of the pore was the feature most strongly associated with variant pathogenicity. We also found an association between the identified properties and both clinical phenotypes and functional in vitro assays for voltage-gated sodium channels (SCN1A, SCN2A, SCN8A) and N-methyl-D-aspartate receptor (GRIN1, GRIN2A, GRIN2B) encoding genes. In an independent expert-curated dataset of 1422 neur
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- 2023
32. Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition.
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Custodio, Helena Martins, Clayton, Lisa M, Bellampalli, Ravishankara, Pagni, Susanna, Silvennoinen, Katri, Caswell, Richard, Consortium, Genomics England Research, Brunklaus, Andreas, Guerrini, Renzo, Koeleman, Bobby P C, Lemke, Johannes R, Møller, Rikke S, Scheffer, Ingrid E, Weckhuysen, Sarah, Zara, Federico, Zuberi, Sameer, Kuchenbaecker, Karoline, Balestrini, Simona, Mills, James D, and Sisodiya, Sanjay M
- Subjects
EPILEPSY ,FOCAL cortical dysplasia ,DISEASE risk factors ,MONOGENIC & polygenic inheritance (Genetics) ,PHENOTYPES ,EARLY death - Abstract
Dravet syndrome is an archetypal rare severe epilepsy, considered 'monogenic', typically caused by loss-of-function SCN1A variants. Despite a recognizable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A -related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. The polygenic risk score for intelligence was lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors. [ABSTRACT FROM AUTHOR]
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- 2023
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33. Comorbidities and predictors of health‐related quality of life in Dravet syndrome: A 10‐year, prospective follow‐up study
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Makiello, Phoebe, primary, Feng, Tony, additional, Dunwoody, Benjamin, additional, Steckler, Felix, additional, Symonds, Joseph, additional, Zuberi, Sameer M., additional, Dorris, Liam, additional, and Brunklaus, Andreas, additional
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- 2023
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34. Delineation of functionally essential protein regions for 242 neurodevelopmental genes
- Author
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Iqbal, Sumaiya, primary, Brünger, Tobias, additional, Pérez-Palma, Eduardo, additional, Macnee, Marie, additional, Brunklaus, Andreas, additional, Daly, Mark J, additional, Campbell, Arthur J, additional, Hoksza, David, additional, May, Patrick, additional, and Lal, Dennis, additional
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- 2022
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35. The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications
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Brunklaus, Andreas, Brünger, Tobias, Feng, Tony, Fons, Carmen, Lehikoinen, Anni, Panagiotakaki, Eleni, Vintan, Mihaela-Adela, Symonds, Joseph, Andrew, James, Arzimanoglou, Alexis, Gallois, Julie, Delima, Sarah, Hanrahan, Donncha, Lesca, Gaetan, MacLeod, Stewart, Marjanovic, Dragan, McTague, Amy, Nuñez-Enamorado, Noemi, Perez-Palma, Eduardo, Perry, M. Scott, Pysden, Karen, Russ-Hall, Sophie J., Scheffer, Ingrid E., Sully, Krystal, Syrbe, Steffen, Vaher, Ulvi, Velayutham, Murugan, Vogt, Julie, Weiss, Shelly, Wirrell, Elaine, Zuberi, Sameer M., Lal, Dennis, Møller, Rikke S., and Mantegazza, Massimo
- Abstract
No abstract available.
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- 2022
36. ILAE Genetics Literacy series: Progressive myoclonus epilepsies
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Cameron, Jillian M., Ellis, Colin A., Berkovic, Samuel F., Perucca, Piero, Cross, J. Helen, Lerche, Holger, Esterhuizen, Alina I., Lopes‐Cendes, Iscia, Tsai, Meng‐Han, Lowenstein, Daniel H., Tan, Nigel C. K., Helbig, Ingo, Mefford, Heather C., Brunklaus, Andreas, Lesca, Gaetan, Palmer, Elizabeth Emma, McTague, Amy, Fakhfakh, Faiza, Delanty, Norman, Lowenstein, Daniel H., Tan, Nigel C. K., and Esterhuizen, Alina I.
- Abstract
Progressive Myoclonus Epilepsy (PME) is a rare epilepsy syndrome characterized by the development of progressively worsening myoclonus, ataxia, and seizures. A molecular diagnosis can now be established in approximately 80% of individuals with PME. Almost fifty genetic causes of PME have now been established, although some remain extremely rare. Herein, we provide a review of clinical phenotypes and genotypes of the more commonly encountered PMEs. Using an illustrative case example, we describe appropriate clinical investigation and therapeutic strategies to guide the management of this often relentlessly progressive and devastating epilepsy syndrome. This manuscript in the Genetic Literacy series maps to Learning Objective 1.2 of the ILAE Curriculum for Epileptology (Epileptic Disord. 2019;21:129).
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- 2023
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37. Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes
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Brünger, Tobias, primary, Pérez-Palma, Eduardo, additional, Montanucci, Ludovica, additional, Nothnagel, Michael, additional, Møller, Rikke S, additional, Schorge, Stephanie, additional, Zuberi, Sameer, additional, Symonds, Joseph, additional, Lemke, Johannes R, additional, Brunklaus, Andreas, additional, Traynelis, Stephen F, additional, May, Patrick, additional, and Lal, Dennis, additional
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- 2022
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38. Longwing: An extension study for patients with Dravet syndrome, a severe form of epilepsy, who previously participated in studies of STK-001 in the United Kingdom
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Avendaño, Javier, primary, Avendaño, Javier, additional, and Brunklaus, Andreas, additional
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- 2022
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39. Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes 2022.03.23.485339
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Brünger, Tobias, Perez-Palma, Eduardo, Montanucci, Ludovica, Nothnagel, Michael, Moller, Rikke S., Schorge, Stephanie, Zuberi, Sameer, Symonds, Joseph, Lemke, Johannes R., Brunklaus, Andreas, Traynelis, Stephen F., May, Patrick, Lal, Dennis, FNR [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]
- Subjects
Neurologie [D14] [Sciences de la santé humaine] ,Neurology [D14] [Human health sciences] ,Genetics & genetic processes [F10] [Life sciences] ,Génétique & processus génétiques [F10] [Sciences du vivant] - Abstract
Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. Consequently, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated.We sought to systematically identify biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion channel families. We collected and curated 3,049 pathogenic variants from hundreds of neurodevelopmental and other disorders and 12,546 population variants for 30 ion channel or channel subunits for which a high-quality protein structure was available. Using a wide range of bioinformatics approaches, we computed 163 structural features and tested them for pathogenic variant enrichment. We developed a novel 3D spatial distance scoring approach that enables comparisons of pathogenic and population variant distribution across protein structures.We discovered and independently replicated that several pore residue properties and proximity to the pore axis were most significantly enriched for pathogenic variants compared to population variants. Using our novel 3D scoring approach, we showed that the strongest pathogenic variant enrichment was observed for pore-lining residues and alpha-helix residues within 5 A distance from the pore axis center and not involved in gating. Within the subset of residues located at the pore, the hydrophobicity of the pore was the feature most strongly associated with variant pathogenicity. We also found an association between the identified properties and both clinical phenotypes and fucntional in vitro assays for voltage-gated sodium channels (SCN1A, SCN2A, SCN8A) and N-methyl-D-aspartate (NMDA) receptor (GRIN1, GRIN2A, GRIN2B) encoding genes. In an independent expert-curated dataset of 1,422 neurodevelopmental disorder pathogenic patient variants, and 679 electrophysiological experiments that pore axis distance is associated with seizure age of onset and cognitive performance as well as differential gain vs. loss-of-channel function.In summary, we identified biological properties associated with ion-channel malfunction and show that these are correlated with in vitro functional read-outs and clinical phenotypes in patients with neurodevelopmental disorders. Our results suggest that clinical decision support algorithms that predict variant pathogenicity and function are feasible in the future.Competing Interest StatementThe authors have declared no competing interest.DSSPDictionary of Protein Secondary StructuregnomADGenome aggregation DatabaseGoFGain of functionGRIN genesGRIN1, GRIN2A. GRIN2BHGMDHuman Gene Mutation DatabaseNMDA receptorN-methyl-D-aspartate receptorGABA receptorGamma-aminobutyric acid receptorLoFLoss of functionSCN genesSCN1A, SCN2A, SCN8AVCFVariant Call Format
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- 2022
40. Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes 2022.03.23.485339
- Author
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Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], FNR [sponsor], Brünger, Tobias, Perez-Palma, Eduardo, Montanucci, Ludovica, Nothnagel, Michael, Moller, Rikke S., Schorge, Stephanie, Zuberi, Sameer, Symonds, Joseph, Lemke, Johannes R., Brunklaus, Andreas, Traynelis, Stephen F., May, Patrick, Lal, Dennis, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], FNR [sponsor], Brünger, Tobias, Perez-Palma, Eduardo, Montanucci, Ludovica, Nothnagel, Michael, Moller, Rikke S., Schorge, Stephanie, Zuberi, Sameer, Symonds, Joseph, Lemke, Johannes R., Brunklaus, Andreas, Traynelis, Stephen F., May, Patrick, and Lal, Dennis
- Abstract
Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. Consequently, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated.We sought to systematically identify biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion channel families. We collected and curated 3,049 pathogenic variants from hundreds of neurodevelopmental and other disorders and 12,546 population variants for 30 ion channel or channel subunits for which a high-quality protein structure was available. Using a wide range of bioinformatics approaches, we computed 163 structural features and tested them for pathogenic variant enrichment. We developed a novel 3D spatial distance scoring approach that enables comparisons of pathogenic and population variant distribution across protein structures.We discovered and independently replicated that several pore residue properties and proximity to the pore axis were most significantly enriched for pathogenic variants compared to population variants. Using our novel 3D scoring approach, we showed that the strongest pathogenic variant enrichment was observed for pore-lining residues and alpha-helix residues within 5 A distance from the pore axis center and not involved in gating. Within the subset of residues located at the pore, the hydrophobicity of the pore was the feature most strongly associated with variant pathogenicity. We also found an association between the identified properties and both clinical phenotypes and fucntional in vitro assays for voltage-gated sodium channels (SCN1A, SCN2A, SCN8A) and N-methyl-D-aspartate (NMDA) receptor (GRIN1, GRIN2A, GRIN2B) encoding genes. In an independent expert-curated dataset of 1,422 ne
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- 2022
41. Development and Validation of a Prediction Model for Early Diagnosis of SCN1A-Related Epilepsies
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Brunklaus, Andreas, Perez-Palma, Eduardo, Ghanty, Ismael, Xinge, Ji, Brilstra, Eva, Ceulemans, Berten, Chemaly, Nicole, de Lange, Iris, Depienne, Christel, Guerrini, Renzo, Mei, Davide, Moller, Rikke S., Nabbout, Rima, Regan, Brigid M., Schneider, Amy L., Scheffer, Ingrid E., Schoonjans, An-Sofie, Symonds, Joseph D., Weckhuysen, Sarah, Kattan, Michael W., Zuberi, Sameer M., Lal, Dennis, Brunklaus, Andreas, Perez-Palma, Eduardo, Ghanty, Ismael, Xinge, Ji, Brilstra, Eva, Ceulemans, Berten, Chemaly, Nicole, de Lange, Iris, Depienne, Christel, Guerrini, Renzo, Mei, Davide, Moller, Rikke S., Nabbout, Rima, Regan, Brigid M., Schneider, Amy L., Scheffer, Ingrid E., Schoonjans, An-Sofie, Symonds, Joseph D., Weckhuysen, Sarah, Kattan, Michael W., Zuberi, Sameer M., and Lal, Dennis
- Abstract
Background and Objectives Pathogenic variants in the neuronal sodium channel alpha 1 subunit gene (SCN1A) are the most frequent monogenic cause of epilepsy. Phenotypes comprise a wide clinical spectrum, including severe childhood epilepsy; Dravet syndrome, characterized by drug-resistant seizures, intellectual disability, and high mortality; and the milder genetic epilepsy with febrile seizures plus (GEFS+), characterized by normal cognition. Early recognition of a child's risk for developing Dravet syndrome vs GEFS+ is key for implementing disease-modifying therapies when available before cognitive impairment emerges. Our objective was to develop and validate a prediction model using clinical and genetic biomarkers for early diagnosis of SCN1A-related epilepsies. Methods We performed a retrospective multicenter cohort study comprising data from patients with SCN1A-positive Dravet syndrome and patients with GEFS+ consecutively referred for genetic testing (March 2001-June 2020) including age at seizure onset and a newly developed SCN1A genetic score. A training cohort was used to develop multiple prediction models that were validated using 2 independent blinded cohorts. Primary outcome was the discriminative accuracy of the model predicting Dravet syndrome vs other GEFS+ phenotypes. Results A total of 1,018 participants were included. The frequency of Dravet syndrome was 616/743 (83%) in the training cohort, 147/203 (72%) in validation cohort 1, and 60/72 (83%) in validation cohort 2. A high SCN1A genetic score (133.4 [SD 78.5] vs 52.0 [SD 57.5]; p < 0.001) and young age at onset (6.0 [SD 3.0] vs 14.8 [SD 11.8] months; p < 0.001) were each associated with Dravet syndrome vs GEFS+. A combined SCN1A genetic score and seizure onset model separated Dravet syndrome from GEFS+ more effectively (area under the curve [AUC] 0.89 [95% CI 0.86-0.92]) and outperformed all other models (AUC 0.79-0.85; p < 0.001). Model performance was replicated in both validation cohorts 1 (AUC
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- 2022
42. Gene variant effects across sodium channelopathies predict function and guide precision therapy
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Brunklaus, Andreas, Feng, Tony, Brunger, Tobias, Perez-Palma, Eduardo, Heyne, Henrike, Matthews, Emma, Semsarian, Christopher, Symonds, Joseph D., Zuberi, Sameer M., Lal, Dennis, Schorge, Stephanie, Brunklaus, Andreas, Feng, Tony, Brunger, Tobias, Perez-Palma, Eduardo, Heyne, Henrike, Matthews, Emma, Semsarian, Christopher, Symonds, Joseph D., Zuberi, Sameer M., Lal, Dennis, and Schorge, Stephanie
- Abstract
Pathogenic variants in the voltage-gated sodium channel gene family lead to early onset epilepsies, neurodevelopmental disorders, skeletal muscle channelopathies, peripheral neuropathies and cardiac arrhythmias. Disease-associated variants have diverse functional effects ranging from complete loss-of-function to marked gain-of-function. Therapeutic strategy is likely to depend on functional effect. Experimental studies offer important insights into channel function but are resource intensive and only performed in a minority of cases. Given the evolutionarily conserved nature of the sodium channel genes, we investigated whether similarities in biophysical properties between different voltage-gated sodium channels can predict function and inform precision treatment across sodium channelopathies. We performed a systematic literature search identifying functionally assessed variants in any of the nine voltage-gated sodium channel genes until 28 April 2021. We included missense variants that had been electrophysiologically characterized in mammalian cells in whole-cell patch-clamp recordings. We performed an alignment of linear protein sequences of all sodium channel genes and correlated variants by their overall functional effect on biophysical properties. Of 951 identified records, 437 sodium channel-variants met our inclusion criteria and were reviewed for functional properties. Of these, 141 variants were epilepsy-associated (SCN1/2/3/8A), 79 had a neuromuscular phenotype (SCN4/9/10/11A), 149 were associated with a cardiac phenotype (SCN5/10A) and 68 (16%) were considered benign. We detected 38 missense variant pairs with an identical disease-associated variant in a different sodium channel gene. Thirty-five out of 38 of those pairs resulted in similar functional consequences, indicating up to 92% biophysical agreement between corresponding sodium channel variants (odds ratio = 11.3; 95% confidence interval = 2.8 to 66.9; P < 0.001). Pathogenic missense variants were
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- 2022
43. Development and Validation of a Prediction Model for Early Diagnosis of SCN1A-Related Epilepsies
- Author
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Genetica Klinische Genetica, Brain, Genetica Oper.Mang. Clinical Genetics, Child Health, Brunklaus, Andreas, Pérez-Palma, Eduardo, Ghanty, Ismael, Xinge, Ji, Brilstra, Eva, Ceulemans, Berten, Chemaly, Nicole, de Lange, Iris, Depienne, Christel, Guerrini, Renzo, Mei, Davide, Møller, Rikke S, Nabbout, Rima, Regan, Brigid M, Schneider, Amy L, Scheffer, Ingrid E, Schoonjans, An-Sofie, Symonds, Joseph D, Weckhuysen, Sarah, Kattan, Michael W, Zuberi, Sameer M, Lal, Dennis, Genetica Klinische Genetica, Brain, Genetica Oper.Mang. Clinical Genetics, Child Health, Brunklaus, Andreas, Pérez-Palma, Eduardo, Ghanty, Ismael, Xinge, Ji, Brilstra, Eva, Ceulemans, Berten, Chemaly, Nicole, de Lange, Iris, Depienne, Christel, Guerrini, Renzo, Mei, Davide, Møller, Rikke S, Nabbout, Rima, Regan, Brigid M, Schneider, Amy L, Scheffer, Ingrid E, Schoonjans, An-Sofie, Symonds, Joseph D, Weckhuysen, Sarah, Kattan, Michael W, Zuberi, Sameer M, and Lal, Dennis
- Published
- 2022
44. Dravet syndrome and its mimics: Beyond SCN1A
- Author
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Steel, Dora, Symonds, Joseph D., Zuberi, Sameer M., and Brunklaus, Andreas
- Published
- 2017
- Full Text
- View/download PDF
45. Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial
- Author
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Knight, Elia M Pestana, primary, Amin, Sam, additional, Bahi-Buisson, Nadia, additional, Benke, Tim A, additional, Cross, J Helen, additional, Demarest, Scott T, additional, Olson, Heather E, additional, Specchio, Nicola, additional, Fleming, Thomas R, additional, Aimetti, Alex A, additional, Gasior, Maciej, additional, Devinsky, Orrin, additional, Belousova, Elena, additional, Belyaev, Oleg, additional, Ben-Zeev, Bruria, additional, Brunklaus, Andreas, additional, Ciliberto, Michael A., additional, Darra, Francesca, additional, Davis, Ronald, additional, De Giorgis, Valentina, additional, Doronina, Olga, additional, Fahey, Michael, additional, Guerrini, Renzo, additional, Heydemann, Peter, additional, Khaletskaya, Olga, additional, Lisewski, Pawel, additional, Marsh, Eric D., additional, Moosa, Ahsan N., additional, Perry, Scott, additional, Philip, Sunny, additional, Rajaraman, Rajsekar R., additional, Renfroe, Ben, additional, Saneto, Russell P., additional, Scheffer, Ingrid E., additional, Sogawa, Yoshimi, additional, Suter, Bernhardt, additional, Sweney, Matthew T., additional, Tarquinio, Daniel, additional, Veggiotti, Pierangelo, additional, Wallace, Geoff, additional, Weisenberg, Judy, additional, Wilfong, Angus, additional, Wirrell, Elaine C., additional, Zafar, Muhammad, additional, and Zolnowska, Marta, additional
- Published
- 2022
- Full Text
- View/download PDF
46. Development and Validation of a Prediction Model for Early Diagnosis of SCN1A-Related Epilepsies
- Author
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Brunklaus, Andreas, primary, Pérez-Palma, Eduardo, additional, Ghanty, Ismael, additional, Xinge, Ji, additional, Brilstra, Eva, additional, Ceulemans, Berten, additional, Chemaly, Nicole, additional, de Lange, Iris, additional, Depienne, Christel, additional, Guerrini, Renzo, additional, Mei, Davide, additional, Møller, Rikke S., additional, Nabbout, Rima, additional, Regan, Brigid M., additional, Schneider, Amy L., additional, Scheffer, Ingrid E., additional, Schoonjans, An-Sofie, additional, Symonds, Joseph D., additional, Weckhuysen, Sarah, additional, Kattan, Michael W., additional, Zuberi, Sameer M., additional, and Lal, Dennis, additional
- Published
- 2022
- Full Text
- View/download PDF
47. ILAE Genetic Literacy Series: Self‐limited familial epilepsy syndromes with onset in neonatal age and infancy
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Millevert, Charissa, Weckhuysen, Sarah, Perucca, Piero, Cross, J. Helen, Lerche, Holger, Esterhuizen, Alina I., Lopes‐Cendes, Iscia, Tsai, Meng‐Han, Berkovic, Samuel F., Lowenstein, Daniel H., Tan, Nigel C. K., Helbig, Ingo, Mefford, Heather C., Brunklaus, Andreas, and Lesca, Gaetan
- Abstract
The self‐limited (familial) epilepsies with onset in neonates or infants, formerly called benign familial neonatal and/or infantile epilepsies, are autosomal dominant disorders characterized by neonatal‐ or infantile‐onset focal motor seizures and the absence of neurodevelopmental complications. Seizures tend to remit during infancy or early childhood and are therefore called “self‐limited”. A positive family history for epilepsy usually suggests the genetic etiology, but incomplete penetrance and de novo inheritance occur. Here, we review the phenotypic spectrum and the genetic architecture of self‐limited (familial) epilepsies with onset in neonates or infants. Using an illustrative case study, we describe important clues in recognition of these syndromes, diagnostic steps including genetic testing, management, and genetic counseling.
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- 2023
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48. ILAE Genetic Literacy Series: Postmortem Genetic Testing in Sudden Unexpected Death in Epilepsy
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Bagnall, Richard D., Perucca, Piero, Cross, J. Helen, Lerche, Holger, Esterhuizen, Alina I., Lopes‐Cendes, Iscia, Tsai, Meng‐Han, Berkovic, Samuel F., Lowenstein, Daniel H., Tan, Nigel C. K., Helbig, Ingo, Mefford, Heather C., Brunklaus, Andreas, and Lesca, Gaetan
- Abstract
A 24‐year‐old man with non‐lesional bitemporal lobe epilepsy since age 16 years was found dead in bed around midday. He was last seen the previous night when he was witnessed to have a tonic–clonic seizure. Before his death, he was experiencing weekly focal impaired awareness seizures and up to two focal‐to‐bilateral tonic–clonic seizures each year. He had trialed several antiseizure medications and was on levetiracetam 1500 mg/day, lamotrigine 400 mg/day, and clobazam 10 mg/day at the time of death. Other than epilepsy, his medical history was unremarkable. Of note, he had an older brother with a history of febrile seizures and a paternal first cousin with epilepsy. No cause of death was identified following a comprehensive postmortem investigation. The coroner classified the death as “sudden unexpected death in epilepsy” (SUDEP), and it would qualify as “definite SUDEP” using the current definitions.1This left the family with many questions unanswered; in particular, they wish to know what caused the death and whether it could happen to other family members. Could postmortem genetic testing identify a cause of death, provide closure to the family, and facilitate cascade genetic testing of first‐degree family members who may be at risk of sudden death? While grieving family members struggle with uncertainty about the cause of death, we as clinicians also face similar uncertainties about genetic contributions to SUDEP, especially when the literature is sparse, and the utility of genetic testing is still being worked out. We aim to shed some light on this topic, highlighting areas where data is emerging but also areas where uncertainty remains, keeping our case in mind as we examine this clinically important area.
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- 2023
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49. Gene variant effects across sodium channelopathies predict function and guide precision therapy
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Brunklaus, Andreas, primary, Feng, Tony, additional, Brünger, Tobias, additional, Perez-Palma, Eduardo, additional, Heyne, Henrike, additional, Matthews, Emma, additional, Semsarian, Christopher, additional, Symonds, Joseph D, additional, Zuberi, Sameer M, additional, Lal, Dennis, additional, and Schorge, Stephanie, additional
- Published
- 2022
- Full Text
- View/download PDF
50. Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants
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Symonds, Joseph D, primary, Elliott, Katherine S, additional, Shetty, Jay, additional, Armstrong, Martin, additional, Brunklaus, Andreas, additional, Cutcutache, Ioana, additional, Diver, Louise A, additional, Dorris, Liam, additional, Gardiner, Sarah, additional, Jollands, Alice, additional, Joss, Shelagh, additional, Kirkpatrick, Martin, additional, McLellan, Ailsa, additional, MacLeod, Stewart, additional, O’Regan, Mary, additional, Page, Matthew, additional, Pilley, Elizabeth, additional, Pilz, Daniela T, additional, Stephen, Elma, additional, Stewart, Kirsty, additional, Ashrafian, Houman, additional, Knight, Julian C, additional, and Zuberi, Sameer M, additional
- Published
- 2021
- Full Text
- View/download PDF
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