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2. Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study

Author

D'Gama, Alissa M, Mulhern, Sarah, Sheidley, Beth R, Boodhoo, Fadil, Buts, Sarah, Chandler, Natalie J, Cobb, Joanna, Curtis, Meredith, Higginbotham, Edward J, Holland, Jonathon, Khan, Tayyaba, Koh, Julia, Liang, Nicole S Y, McRae, Lyndsey, Nesbitt, Sarah E, Oby, Brandon T, Paternoster, Ben, Patton, Alistair, Rose, Graham, Scotchman, Elizabeth, Valentine, Rozalia, Wiltrout, Kimberly N, Hayeems, Robin Z, Jain, Puneet, Lunke, Sebastian, Marshall, Christian R, Rockowitz, Shira, Sebire, Neil J, Stark, Zornitza, White, Susan M, Chitty, Lyn S, Cross, J Helen, Scheffer, Ingrid E, Chau, Vann, Costain, Gregory, Poduri, Annapurna, Howell, Katherine B, and McTague, Amy

Published
2023
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4. Infantile Spasms of Unknown Cause: Predictors of Outcome and Genotype-Phenotype Correlation

Author

Yuskaitis, Christopher J, Ruzhnikov, Maura RZ, Howell, Katherine B, Allen, I Elaine, Kapur, Kush, Dlugos, Dennis J, Scheffer, Ingrid E, Poduri, Annapurna, and Sherr, Elliott H

Subjects
Epilepsy, Pediatric, Genetics, Neurodegenerative, Clinical Research, Neurosciences, Prevention, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Age of Onset, Child, Child Development, Child, Preschool, Developmental Disabilities, Female, Humans, Infant, Male, Phenotype, Prognosis, Retrospective Studies, Spasms, Infantile, Whole Exome Sequencing, Infantile spasms, Cryptogenic infantile spasms, Developmental outcomes, Epileptic encephalopathy, Seizures, Epilepsy genetics, Genotype-phenotype, Exome Sequencing, Paediatrics and Reproductive Medicine, Neurology & Neurosurgery
Abstract

BackgroundNo large-scale studies have specifically evaluated the outcomes of infantile spasms (IS) of unknown cause, previously known as cryptogenic or idiopathic. The Epilepsy Phenome/Genome Project aimed to characterize IS of unknown cause by phenotype and genotype analysis.MethodsWe undertook a retrospective multicenter observational cohort of 133 individuals within the Epilepsy Phenome/Genome Project database met criteria for IS of unknown cause with at least six months of follow-up data. Clinical medical records, imaging, and electroencephalography were examined.ResultsNormal development occurred in only 15% of IS of unknown cause. The majority (85%) had clinically documented developmental delay (15% mild, 20% moderate, and 50% severe) at last assessment (median 2.7 years; interquartile interval 1.71-6.25 years). Predictors of positive developmental outcomes included no delay prior to IS (P < 0.001), older age of IS onset (median six months old), and resolution of IS after initial treatment (P < 0.001). Additional seizures after IS occurred in 67%, with predictors being seizures prior to IS (P = 0.018), earlier age of IS onset (median five months old), and refractory IS (P = 0.008). On a research basis, whole exome sequencing identified 15% with de novo variants in known epilepsy genes. Individuals with a genetic finding were more likely to have poor developmental outcomes (P = 0.035).ConclusionsThe current study highlights the predominately unfavorable developmental outcomes and that subsequent seizures are common in children with IS of unknown cause. Ongoing genetic evaluation of IS of seemingly unknown cause is likely to yield a diagnosis and provide valuable prognostic information.

Published
2018

9. Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia.

Author

Wan, Jijun, Steffen, Janos, Yourshaw, Michael, Mamsa, Hafsa, Andersen, Erik, Rudnik-Schöneborn, Sabine, Pope, Kate, Howell, Katherine B, McLean, Catriona A, Kornberg, Andrew J, Joseph, Jörg, Lockhart, Paul J, Zerres, Klaus, Ryan, Monique M, Nelson, Stanley F, Koehler, Carla M, and Jen, Joanna C

Subjects
Biomedical and Clinical Sciences, Neurosciences, Genetics, Pediatric, Orphan Drug, Neurodegenerative, Rare Diseases, Brain Disorders, Congenital Structural Anomalies, Aetiology, 2.1 Biological and endogenous factors, Neurological, Amino Acids, Animals, Animals, Genetically Modified, Brain, Cell Line, Transformed, Cells, Cultured, Cerebellar Diseases, Cohort Studies, Embryo, Nonmammalian, Female, Genetic Predisposition to Disease, Humans, Infant, Magnetic Resonance Imaging, Male, Mitochondria, Mitochondrial Dynamics, Mitochondrial Proteins, Models, Molecular, Mutation, Phosphate Transport Proteins, Polymorphism, Single Nucleotide, Zebrafish, pontocerebellar hypoplasia, SLC25A46, mitochondria, optic atrophy spectrum disorder, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Disturbed mitochondrial fusion and fission have been linked to various neurodegenerative disorders. In siblings from two unrelated families who died soon after birth with a profound neurodevelopmental disorder characterized by pontocerebellar hypoplasia and apnoea, we discovered a missense mutation and an exonic deletion in the SLC25A46 gene encoding a mitochondrial protein recently implicated in optic atrophy spectrum disorder. We performed functional studies that confirmed the mitochondrial localization and pro-fission properties of SLC25A46. Knockdown of slc24a46 expression in zebrafish embryos caused brain malformation, spinal motor neuron loss, and poor motility. At the cellular level, we observed abnormally elongated mitochondria, which was rescued by co-injection of the wild-type but not the mutant slc25a46 mRNA. Conversely, overexpression of the wild-type protein led to mitochondrial fragmentation and disruption of the mitochondrial network. In contrast to mutations causing non-lethal optic atrophy, missense mutations causing lethal congenital pontocerebellar hypoplasia markedly destabilize the protein. Indeed, the clinical severity appears inversely correlated with the relative stability of the mutant protein. This genotype-phenotype correlation underscores the importance of SLC25A46 and fine tuning of mitochondrial fission and fusion in pontocerebellar hypoplasia and central neurodevelopment in addition to optic and peripheral neuropathy across the life span.

Published
2016

10. Mono and biallelic variants in HCN2 cause severe neurodevelopmental disorders

Author

Houdayer, Clara, Phillips, A Marie, Chabbert, Marie, Bourreau, Jennifer, Maroofian, Reza, Houlden, Henry, Richards, Kay, Saadi, Nebal Waill, Dad'ová, Eliška, Van Bogaert, Patrick, Rupin, Mailys, Keren, Boris, Charles, Perrine, Smol, Thomas, Riquet, Audrey, Pais, Lynn, O'Donnell-Luria, Anne, VanNoy, Grace E, Bayat, Allan, Møller, Rikke S, Olofsson, Kern, Abou Jamra, Rami, Syrbe, Steffen, Dasouki, Majed, Seaver, Laurie H, Sullivan, Jennifer A, Shashi, Vandana, Alkuraya, Fowzan S, Poss, Alexis F, Spence, J Edward, Schnur, Rhonda E, Forster, Ian C, Mckenzie, Chaseley E, Simons, Cas, Wang, Min, Snell, Penny, Kothur, Kavitha, Buckley, Michael, Roscioli, Tony, Elserafy, Noha, Dauriat, Benjamin, Procaccio, Vincent, Henrion, Daniel, Lenaers, Guy, Colin, Estelle, Verbeek, Nienke E, Van Gassen, Koen L, Legendre, Claire, Bonneau, Dominique, Reid, Christopher A, Howell, Katherine B, Ziegler, Alban, Legros, Christian, Houdayer, Clara, Phillips, A Marie, Chabbert, Marie, Bourreau, Jennifer, Maroofian, Reza, Houlden, Henry, Richards, Kay, Saadi, Nebal Waill, Dad'ová, Eliška, Van Bogaert, Patrick, Rupin, Mailys, Keren, Boris, Charles, Perrine, Smol, Thomas, Riquet, Audrey, Pais, Lynn, O'Donnell-Luria, Anne, VanNoy, Grace E, Bayat, Allan, Møller, Rikke S, Olofsson, Kern, Abou Jamra, Rami, Syrbe, Steffen, Dasouki, Majed, Seaver, Laurie H, Sullivan, Jennifer A, Shashi, Vandana, Alkuraya, Fowzan S, Poss, Alexis F, Spence, J Edward, Schnur, Rhonda E, Forster, Ian C, Mckenzie, Chaseley E, Simons, Cas, Wang, Min, Snell, Penny, Kothur, Kavitha, Buckley, Michael, Roscioli, Tony, Elserafy, Noha, Dauriat, Benjamin, Procaccio, Vincent, Henrion, Daniel, Lenaers, Guy, Colin, Estelle, Verbeek, Nienke E, Van Gassen, Koen L, Legendre, Claire, Bonneau, Dominique, Reid, Christopher A, Howell, Katherine B, Ziegler, Alban, and Legros, Christian

Abstract

Hyperpolarization activated Cyclic Nucleotide (HCN) gated channels are crucial for various neurophysiological functions, including learning and sensory functions, and their dysfunction are responsible for brain disorders, such as epilepsy. To date, HCN2 variants have only been associated with mild epilepsy and recently, one monoallelic missense variant has been linked to developmental and epileptic encephalopathy. Here, we expand the phenotypic spectrum of HCN2- related disorders by describing twenty-one additional individuals from fifteen unrelated families carrying HCN2 variants. Seventeen individuals had developmental delay/intellectual disability (DD/ID), two had borderline DD/ID, and one had borderline DD. Ten individuals had epilepsy with DD/ID, with median age of onset of 10 months, and one had epilepsy with normal development. Molecular diagnosis identified thirteen different pathogenic HCN2 variants, including eleven missense variants affecting highly conserved amino acids, one frameshift variant, and one in-frame deletion. Seven variants were monoallelic of which five occurred de novo, one was not maternally inherited, one was inherited from a father with mild learning disabilities, and one was of unknown inheritance. The remaining six variants were biallelic, with four homozygous and two compound heterozygous variants. Functional studies using two-electrode voltage-clamp recordings in Xenopus laevis oocytes were performed on three monoallelic variants, p.(Arg324His), p.(Ala363Val), and p.(Met374Leu), and three biallelic variants, p.(Leu377His), p.(Pro493Leu) and p.(Gly587Asp). The p.(Arg324His) variant induced a strong increase of HCN2 conductance, while p.(Ala363Val) and p.(Met374Leu) displayed dominant negative effects, leading to a partial loss of HCN2 channel function. By confocal imaging, we found that the p.(Leu377His), p.(Pro493Leu) and p.(Gly587Asp) pathogenic variants impaired membrane trafficking, resulting in a complete loss of HCN2 elicited

Published
2024

11. Identification and treatment of surgically-remediable causes of infantile epileptic spasms syndrome.

Author

Macdonald-Laurs, Emma, Dzau, Winston, Warren, Aaron E.L., Coleman, Matthew, Mignone, Cristina, Stephenson, Sarah E. M., and Howell, Katherine B.

Abstract

Infantile epileptic spasms syndrome (IESS) is a common developmental and epileptic encephalopathy with poor long-term outcomes. A substantial proportion of patients with IESS have a potentially surgically remediable etiology. Despite this, epilepsy surgery is underutilized in this patient group. Some surgically remediable etiologies, such as focal cortical dysplasia and malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE), are under-diagnosed in infants and young children. Even when a surgically remediable etiology is recognised, for example, tuberous sclerosis or focal encephalomalacia, epilepsy surgery may be delayed or not considered due to diffuse EEG changes, unclear surgical boundaries, or concerns about operating in this age group. In this review, the authors discuss the common surgically remediable etiologies of IESS, their clinical and EEG features, and the imaging techniques that can aid in their diagnosis. They then describe the surgical approaches used in this patient group, and the beneficial impact that early epilepsy surgery can have on developing brain networks. Epilepsy surgery remains underutilized even when a potentially surgically remediable cause is recognized. Overcoming the barriers that result in under-recognition of surgical candidates and underutilization of epilepsy surgery in IESS will improve long-term seizure and developmental outcomes. [ABSTRACT FROM AUTHOR]

Published
2024
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13. SLC6A1 variant pathogenicity, molecular function, and phenotype: a genetic and clinical analysis

Author

Stefanski, Arthur, primary, Pérez-Palma, Eduardo, additional, Brünger, Tobias, additional, Montanucci, Ludovica, additional, Gati, Cornelius, additional, Klöckner, Chiara, additional, Johannesen, Katrine M, additional, Goodspeed, Kimberly, additional, Macnee, Marie, additional, Deng, Alexander T, additional, Aledo-Serrano, Ángel, additional, Borovikov, Artem, additional, Kava, Maina, additional, Bouman, Arjan M, additional, Hajianpour, M J, additional, Pal, Deb K, additional, Engelen, Marc, additional, Hagebeuk, Eveline E O, additional, Shinawi, Marwan, additional, Heidlebaugh, Alexis R, additional, Oetjens, Kathryn, additional, Hoffman, Trevor L, additional, Striano, Pasquale, additional, Freed, Amanda S, additional, Futtrup, Line, additional, Balslev, Thomas, additional, Abulí, Anna, additional, Danvoye, Leslie, additional, Lederer, Damien, additional, Balci, Tugce, additional, Nabavi Nouri, Maryam, additional, Butler, Elizabeth, additional, Drewes, Sarah, additional, van Engelen, Kalene, additional, Howell, Katherine B, additional, Khoury, Jean, additional, May, Patrick, additional, Trinidad, Marena, additional, Froelich, Steven, additional, Lemke, Johannes R, additional, Tiller, Jacob, additional, Freed, Amber N, additional, Kang, Jing-Qiong, additional, Wuster, Arthur, additional, Møller, Rikke S, additional, and Lal, Dennis, additional

Published
2023
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16. Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System

Author

Lunke, Sebastian, Eggers, Stefanie, Wilson, Meredith, Patel, Chirag, Barnett, Christopher P., Pinner, Jason, Sandaradura, Sarah A., Buckley, Michael F., Krzesinski, Emma I., de Silva, Michelle G., Brett, Gemma R., Boggs, Kirsten, Mowat, David, Kirk, Edwin P., Adès, Lesley C., Akesson, Lauren S., Amor, David J., Ayres, Samantha, Baxendale, Anne, Borrie, Sarah, Bray, Alessandra, Brown, Natasha J., Chan, Cheng Yee, Chong, Belinda, Cliffe, Corrina, Delatycki, Martin B., Edwards, Matthew, Elakis, George, Fahey, Michael C., Fennell, Andrew, Fowles, Lindsay, Gallacher, Lyndon, Higgins, Megan, Howell, Katherine B., Hunt, Lauren, Hunter, Matthew F., Jones, Kristi J., King, Sarah, Kumble, Smitha, Lang, Sarah, Le Moing, Maelle, Ma, Alan, Phelan, Dean, Quinn, Michael C. J., Richards, Anna, Richmond, Christopher M., Riseley, Jessica, Rodgers, Jonathan, Sachdev, Rani, Sadedin, Simon, Schlapbach, Luregn J., Smith, Janine, Springer, Amanda, Tan, Natalie B., Tan, Tiong Y., Temple, Suzanna L., Theda, Christiane, Vasudevan, Anand, White, Susan M., Yeung, Alison, Zhu, Ying, Martyn, Melissa, Best, Stephanie, Roscioli, Tony, Christodoulou, John, and Stark, Zornitza

Published
2020
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17. SLC6A1 variant pathogenicity, molecular function, and phenotype: a genetic and clinical analysis

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Stefanski, Arthur, Pérez-Palma, Eduardo, Brünger, Tobias, Montanucci, Ludovica, Gati, Cornelius, Klöckner, Chiara, Johannesen, Katrine M., Goodspeed, Kimberly, Macnee, Marie, Deng, Alexander T., Aledo-Serrano, Ángel, Borovikov, Artem, Kava, Maina, Bouman, Arjan M., Hajianpour, M. J., Pal, Deb K., Engelen, Marc, Hagebeuk, Eveline E. O., Shinawi, Marwan, Heidlebaugh, Alexis R., Oetjens, Kathryn, Hoffman, Trevor L., Striano, Pasquale, Freed, Amanda S., Futtrup, Line, Balslev, Thomas, Abulí, Anna, Danvoye, Leslie, Lederer, Damien, Balci, Tugce, Nabavi Nouri, Maryam, Butler, Elizabeth, Drewes, Sarah, van Engelen, Kalene, Howell, Katherine B., Khoury, Jean, May, Patrick, Trinidad, Marena, Froelich, Steven, Lemke, Johannes R., Tiller, Jacob, Freed, Amber N., Kang, Jing-Qiong, Wuster, Arthur, Møller, Rikke S., Lal, Dennis, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Stefanski, Arthur, Pérez-Palma, Eduardo, Brünger, Tobias, Montanucci, Ludovica, Gati, Cornelius, Klöckner, Chiara, Johannesen, Katrine M., Goodspeed, Kimberly, Macnee, Marie, Deng, Alexander T., Aledo-Serrano, Ángel, Borovikov, Artem, Kava, Maina, Bouman, Arjan M., Hajianpour, M. J., Pal, Deb K., Engelen, Marc, Hagebeuk, Eveline E. O., Shinawi, Marwan, Heidlebaugh, Alexis R., Oetjens, Kathryn, Hoffman, Trevor L., Striano, Pasquale, Freed, Amanda S., Futtrup, Line, Balslev, Thomas, Abulí, Anna, Danvoye, Leslie, Lederer, Damien, Balci, Tugce, Nabavi Nouri, Maryam, Butler, Elizabeth, Drewes, Sarah, van Engelen, Kalene, Howell, Katherine B., Khoury, Jean, May, Patrick, Trinidad, Marena, Froelich, Steven, Lemke, Johannes R., Tiller, Jacob, Freed, Amber N., Kang, Jing-Qiong, Wuster, Arthur, Møller, Rikke S., and Lal, Dennis

Abstract

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function, and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6, and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease vs. non-severe disease (P = 2.9e-3, 95% CI: 1.5 - 15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function, and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 Portal (https://slc6a1-portal.broadinstitute.org/).

Published
2023

18. SLC6A1 variant pathogenicity, molecular function and phenotype:a genetic and clinical analysis

Author

Stefanski, Arthur, Pérez-Palma, Eduardo, Brünger, Tobias, Montanucci, Ludovica, Gati, Cornelius, Klöckner, Chiara, Johannesen, Katrine M., Goodspeed, Kimberly, Macnee, Marie, Deng, Alexander T., Aledo-Serrano, Ángel, Borovikov, Artem, Kava, Maina, Bouman, Arjan M., Hajianpour, M. J., Pal, Deb K., Engelen, Marc, Hagebeuk, Eveline E.O., Shinawi, Marwan, Heidlebaugh, Alexis R., Oetjens, Kathryn, Hoffman, Trevor L., Striano, Pasquale, Freed, Amanda S., Futtrup, Line, Balslev, Thomas, Abulí, Anna, Danvoye, Leslie, Lederer, Damien, Balci, Tugce, Nouri, Maryam Nabavi, Butler, Elizabeth, Drewes, Sarah, van Engelen, Kalene, Howell, Katherine B., Khoury, Jean, May, Patrick, Trinidad, Marena, Froelich, Steven, Lemke, Johannes R., Tiller, Jacob, Freed, Amber N., Kang, Jing Qiong, Wuster, Arthur, Møller, Rikke S., Lal, Dennis, Stefanski, Arthur, Pérez-Palma, Eduardo, Brünger, Tobias, Montanucci, Ludovica, Gati, Cornelius, Klöckner, Chiara, Johannesen, Katrine M., Goodspeed, Kimberly, Macnee, Marie, Deng, Alexander T., Aledo-Serrano, Ángel, Borovikov, Artem, Kava, Maina, Bouman, Arjan M., Hajianpour, M. J., Pal, Deb K., Engelen, Marc, Hagebeuk, Eveline E.O., Shinawi, Marwan, Heidlebaugh, Alexis R., Oetjens, Kathryn, Hoffman, Trevor L., Striano, Pasquale, Freed, Amanda S., Futtrup, Line, Balslev, Thomas, Abulí, Anna, Danvoye, Leslie, Lederer, Damien, Balci, Tugce, Nouri, Maryam Nabavi, Butler, Elizabeth, Drewes, Sarah, van Engelen, Kalene, Howell, Katherine B., Khoury, Jean, May, Patrick, Trinidad, Marena, Froelich, Steven, Lemke, Johannes R., Tiller, Jacob, Freed, Amber N., Kang, Jing Qiong, Wuster, Arthur, Møller, Rikke S., and Lal, Dennis

Abstract

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 1.5-15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).

Published
2023

19. Complications of Influenza A or B Virus Infection in Individuals WithSCN1A-Positive Dravet Syndrome

Author

Howell, Katherine B., primary, Butcher, Sophie, additional, Schneider, Amy L., additional, Russ-Hall, Sophie, additional, Muzariri, Pearl R., additional, Kerr, Rachel, additional, Overmars, Isabella, additional, Hayman, Michael, additional, Kornberg, Andrew J., additional, Danchin, Margie, additional, Crawford, Nigel W., additional, and Scheffer, Ingrid E., additional

Published
2022
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20. A single point in protein trafficking by Plasmodium falciparum determines the expression of major antigens on the surface of infected erythrocytes targeted by human antibodies

Author

Chan, Jo-Anne, Howell, Katherine B., Langer, Christine, Maier, Alexander G., Hasang, Wina, Rogerson, Stephen J., Petter, Michaela, Chesson, Joanne, Stanisic, Danielle I., Duffy, Michael F., Cooke, Brian M., Siba, Peter M., Mueller, Ivo, Bull, Peter C., Marsh, Kevin, Fowkes, Freya J.I., and Beeson, James G.

Published
2016
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22. The phenotype of SCN8A developmental and epileptic encephalopathy

Author

Gardella, Elena, Marini, Carla, Trivisano, Marina, Fitzgerald, Mark P., Alber, Michael, Howell, Katherine B., Darra, Francesca, Siliquini, Sabrina, Bölsterli, Bigna K., Masnada, Silva, Pichiecchio, Anna, Johannesen, Katrine M., Jepsen, Birgit, Fontana, Elena, Anibaldi, Gaia, Russo, Silvia, Cogliati, Francesca, Montomoli, Martino, Specchio, Nicola, Rubboli, Guido, Veggiotti, Pierangelo, Beniczky, Sandor, Wolff, Markus, Helbig, Ingo, Vigevano, Federico, Scheffer, Ingrid E., Guerrini, Renzo, and Møller, Rikke S.

Published
2018
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23. Peri‐ictal EEGin infants with PRRT2‐related self‐limited infantile epilepsy

Author

Fearn, Nicola, Macdonald‐Laurs, Emma, Moylan, Laura, and Howell, Katherine B.

Abstract

Pathogenic PRRT2variants cause self‐limited (familial) infantile epilepsy (SeLIE), which is responsive to sodium channel blocking antiseizure medications. The interictal EEG is typically normal. We describe a cohort of infants with PRRT2‐related SeLIE with striking peri‐ictal EEG abnormalities. We included all infants diagnosed with PRRT2‐related SeLIE during July 2020 to November 2021 at the Royal Children's Hospital, Melbourne. Clinical features and results of aetiologic investigations were collected from electronic medical records. All EEGs were reviewed independently by two epileptologists. Ten infants presented with focal seizures at a median age of 5 months (range: 3–6 months). Eight had a family history of epilepsy, paroxysmal kinesigenic dyskinesia (PKD) or hemiplegic migraine. Seven of the eight infants with an EEG performed within 24 h of the most recent seizure had epileptiform discharges. Their EEGs showed focal sharp waves, spikes, polyspikes or fast activity independently over the left and right temporo‐occipital regions. Conversely, the two infants with last known seizure greater than 24 h prior to their EEG had no epileptiform discharges. Oxcarbazepine was commenced in two infants and was effective. Eight infants were initially treated with levetiracetam, and all were subsequently switched to oxcarbazepine due to ongoing seizures or side effects. Posterior polymorphic focal epileptiform discharges on a peri‐ictal EEG recording are a feature of PRRT2‐related SeLIE. This finding, particularly in the presence of a family history of infantile epilepsy, PKD or hemiplegic migraine, suggests a diagnosis of PRRT2‐related SeLIE and has important treatment implications.

Published
2023
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26. Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25

Author

Barbier, Mathieu, primary, Bahlo, Melanie, additional, Pennisi, Alessandra, additional, Jacoupy, Maxime, additional, Tankard, Rick M., additional, Ewenczyk, Claire, additional, Davies, Kayli C., additional, Lino‐Coulon, Patricia, additional, Colace, Claire, additional, Rafehi, Haloom, additional, Auger, Nicolas, additional, Ansell, Brendan R. E., additional, van der Stelt, Ivo, additional, Howell, Katherine B., additional, Coutelier, Marie, additional, Amor, David J., additional, Mundwiller, Emeline, additional, Guillot‐Noël, Lena, additional, Storey, Elsdon, additional, Gardner, R. J. McKinlay, additional, Wallis, Mathew J., additional, Brusco, Alfredo, additional, Corti, Olga, additional, Rötig, Agnès, additional, Leventer, Richard J., additional, Brice, Alexis, additional, Delatycki, Martin B., additional, Stevanin, Giovanni, additional, Lockhart, Paul J., additional, and Durr, Alexandra, additional

Published
2022
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27. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], BMBF, Treat-ION, 01GM1907 [sponsor], Johannesen, Katrine M., Liu, Yuanyuan, Koko, Mahmoud, Gjerulfsen, Cathrine E., Sonnenberg, Lukas, Schubert, Julian, Fenger, Christina D., Eltokhi, Ahmed, Rannap, Maert, Koch, Nils A., Lauxmann, Stephan, Krüger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthová, Petra, Vlckova, Marketa, Lemke, Johannes R., Platzer, Konrad, Krey, Ilona, Heine, Constanze, Wieczorek, Dagmar, Kroell-Seger, Judith, Lund, Caroline, Klein, Karl Martin, Billie Au, P. Y., Rho, Jong M., Ho, Alice W., Masnada, Silvia, Veggiotti, Pierangelo, Giordano, Lucio, Accorsi, Patrizia, Hoei-Hansen, Christina E., Striano, Pasquale, Zara, Federico, Verhelst, Helene, Verhoeven, Judith S., van der Zwaag, Bert, Harder, Aster V. E., Brilstra, Eva, Pendziwiat, Manuela, Lebon, Sebastian, Vaccarezza, Maria, Minh Le, Ngoc, Christensen, Jakob, Grønborg, Sabine, Scherer, Stephen W., Howe, Jennifer, Fazeli, Walid, Howell, Katherine B., Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Bénédicte, Matricardi, Sara, Bonardi, Claudia M., Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vøllo, Arve, Motazacker, M. Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gélisse, Philippe, Marini, Carla, Guerrini, Renzo, Bilan, Frederic, Tibussek, Daniel, Koch-Hogrebe, Margarete, Perry, M. Scott, Ichikawa, Shoji, Dadali, Elena, Sharkov, Artem, Mishina, Irina, Abramov, Mikhail, Kanivets, Ilya, Korostelev, Sergey, Kutsev, Sergey, Wain, Karen E., Eisenhauer, Nancy, Wagner, Monisa, Savatt, Juliann M., Müller-Schlüter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie-Cecile, Destrée, Anne, Schoonjans, An-Sofie, Meuwissen, Marije, Buzatu, Marga, Jansen, Anna, Scalais, Emmanuel, Srivastava, Siddharth, Tan, Wen-Hann, Olson, Heather E., Loddenkemper, Tobias, Poduri, Annapurna, Helbig, Katherine L., Helbig, Ingo, Fitzgerald, Mark P., Goldberg, Ethan M., Roser, Timo, Borggraefe, Ingo, Brünger, Tobias, May, Patrick, Lal, Dennis, Lederer, Damien, Rubboli, Guido, Heyne, Henrike O., Lesca, Gaetan, Hedrich, Ulrike B. S., Benda, Jan, Gardella, Elena, Lerche, Holger, Møller, Rikke S., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], BMBF, Treat-ION, 01GM1907 [sponsor], Johannesen, Katrine M., Liu, Yuanyuan, Koko, Mahmoud, Gjerulfsen, Cathrine E., Sonnenberg, Lukas, Schubert, Julian, Fenger, Christina D., Eltokhi, Ahmed, Rannap, Maert, Koch, Nils A., Lauxmann, Stephan, Krüger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthová, Petra, Vlckova, Marketa, Lemke, Johannes R., Platzer, Konrad, Krey, Ilona, Heine, Constanze, Wieczorek, Dagmar, Kroell-Seger, Judith, Lund, Caroline, Klein, Karl Martin, Billie Au, P. Y., Rho, Jong M., Ho, Alice W., Masnada, Silvia, Veggiotti, Pierangelo, Giordano, Lucio, Accorsi, Patrizia, Hoei-Hansen, Christina E., Striano, Pasquale, Zara, Federico, Verhelst, Helene, Verhoeven, Judith S., van der Zwaag, Bert, Harder, Aster V. E., Brilstra, Eva, Pendziwiat, Manuela, Lebon, Sebastian, Vaccarezza, Maria, Minh Le, Ngoc, Christensen, Jakob, Grønborg, Sabine, Scherer, Stephen W., Howe, Jennifer, Fazeli, Walid, Howell, Katherine B., Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Bénédicte, Matricardi, Sara, Bonardi, Claudia M., Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vøllo, Arve, Motazacker, M. Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gélisse, Philippe, Marini, Carla, Guerrini, Renzo, Bilan, Frederic, Tibussek, Daniel, Koch-Hogrebe, Margarete, Perry, M. Scott, Ichikawa, Shoji, Dadali, Elena, Sharkov, Artem, Mishina, Irina, Abramov, Mikhail, Kanivets, Ilya, Korostelev, Sergey, Kutsev, Sergey, Wain, Karen E., Eisenhauer, Nancy, Wagner, Monisa, Savatt, Juliann M., Müller-Schlüter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie-Cecile, Destrée, Anne, Schoonjans, An-Sofie, Meuwissen, Marije, Buzatu, Marga, Jansen, Anna, Scalais, Emmanuel, Srivastava, Siddharth, Tan, Wen-Hann, Olson, Heather E., Loddenkemper, Tobias, Poduri, Annapurna, Helbig, Katherine L., Helbig, Ingo, Fitzgerald, Mark P., Goldberg, Ethan M., Roser, Timo, Borggraefe, Ingo, Brünger, Tobias, May, Patrick, Lal, Dennis, Lederer, Damien, Rubboli, Guido, Heyne, Henrike O., Lesca, Gaetan, Hedrich, Ulrike B. S., Benda, Jan, Gardella, Elena, Lerche, Holger, and Møller, Rikke S.

Abstract

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n = 15, normal cognition, treatable seizures), 2) intermediate epilepsy (n = 33, mild ID, partially pharmaco-responsive), 3) developmental and epileptic encephalopathy (DEE, n = 177, severe ID, majority pharmaco-resistant), 4) generalized epilepsy (n = 20, mild to moderate ID, frequently with absence seizures), 5) unclassifiable epilepsy (n = 127), and 6) neurodevelopmental disorder without epilepsy (n = 20, mild to moderate ID). Groups 1–3 presented with focal or multifocal seizures (median age of onset: four months) and focal epileptiform discharges, whereas the onset of seizures in group 4 was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human NaV1.6 channels and whole-cell patch-clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested GOF variant had either focal (97, groups 1–3), or unclassifiable epilepsy (39), whereas 34 with a LOF variant had either generalized (14), no

Published
2022

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

Author

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

Abstract

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 i

Published
2022

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

Author

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

Published
2022

30. Epilepsy syndromes in cerebral palsy: varied, evolving and mostly self-limited.

Author

Cooper, Monica S, Mackay, Mark T, Dagia, Charuta, Fahey, Michael C, Howell, Katherine B, Reddihough, Dinah, Reid, Susan, and Harvey, A Simon

Subjects
EPILEPSY, CEREBRAL palsy, CHILDREN with cerebral palsy, PARTIAL epilepsy, CHILDREN with epilepsy, LENNOX-Gastaut syndrome
Abstract

Seizures occur in approximately one-third of children with cerebral palsy. This study aimed to determine epilepsy syndromes in children with seizures and cerebral palsy due to vascular injury, anticipating that this would inform treatment and prognosis. We studied a population-based cohort of children with cerebral palsy due to prenatal or perinatal vascular injuries, born 1999–2006. Each child's MRI was reviewed to characterize patterns of grey and white matter injury. Children with syndromic or likely genetic causes of cerebral palsy were excluded, given their inherent association with epilepsy and our aim to study a homogeneous cohort of classical cerebral palsy. Chart review, parent interview and EEGs were used to determine epilepsy syndromes and seizure outcomes. Of 256 children, 93 (36%) had one or more febrile or afebrile seizures beyond the neonatal period and 87 (34%) had epilepsy. Children with seizures were more likely to have had neonatal seizures, have spastic quadriplegic cerebral palsy and function within Gross Motor Function Classification System level IV or V. Fifty-six (60%) children with seizures had electroclinical features of a self-limited focal epilepsy of childhood; we diagnosed these children with a self-limited focal epilepsy-variant given the current International League Against Epilepsy classification precludes a diagnosis of self-limited focal epilepsy in children with a brain lesion. Other epilepsy syndromes were focal epilepsy—not otherwise specified in 28, infantile spasms syndrome in 11, Lennox–Gastaut syndrome in three, genetic generalized epilepsies in two and febrile seizures in nine. No epilepsy syndrome could be assigned in seven children with no EEG. Twenty-one changed syndrome classification during childhood. Self-limited focal epilepsy-variant usually manifested with a mix of autonomic and brachio-facial motor features, and occipital and/or centro-temporal spikes on EEG. Of those with self-limited focal epilepsy-variant, 42/56 (75%) had not had a seizure for >2 years. Favourable seizure outcomes were also seen in some children with infantile spasms syndrome and focal epilepsy-not otherwise specified. Of the 93 children with seizures, at last follow-up (mean age 15 years), 61/91 (67%) had not had a seizure in >2 years. Children with cerebral palsy and seizures can be assigned specific epilepsy syndrome diagnoses typically reserved for normally developing children, those syndromes commonly being age-dependent and self-limited. Compared to typically developing children with epilepsy, self-limited focal epilepsy-variant occurs much more commonly in children with cerebral palsy and epilepsy. These findings have important implications for treatment and prognosis of epilepsy in cerebral palsy, and research into pathogenesis of self-limited focal epilepsy. [ABSTRACT FROM AUTHOR]

Published
2023
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33. Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice.

Author

Scheffer, Ingrid E., Bennett, Caitlin A., Gill, Deepak, de Silva, Michelle G., Boggs, Kirsten, Marum, Justine, Baker, Naomi, Palmer, Elizabeth E., Howell, Katherine B., Andrews, Ian, Antony, Jayne, Ardern‐Holmes, Simone, Bye, Ann M, Cardamone, Michael, Chelakkadan, Shabeed, Clark, Damian, Curnow, Sarah R, Dabscheck, Gabriel, Fahey, Michael C, and Freeman, Jeremy L

Subjects
PEOPLE with epilepsy, GENOMICS, MOLECULAR diagnosis, CHILD care, CLINICAL medicine, EPILEPSY, PSYCHOGENIC nonepileptic seizures
Abstract

Aim: To assess the clinical utility of exome sequencing for patients with developmental and epileptic encephalopathies (DEEs). Method: Over 2 years, patients with DEEs were recruited for singleton exome sequencing. Parental segregation was performed where indicated. Results: Of the 103 patients recruited (54 males, 49 females; aged 2 weeks–17 years), the genetic aetiology was identified in 36 out of 103 (35%) with management implications in 13 out of 36. Exome sequencing revealed pathogenic or likely pathogenic variants in 30 out of 103 (29%) patients, variants of unknown significance in 39 out of 103 (38%), and 34 out of 103 (33%) were negative on exome analysis. After the description of new genetic diseases, a molecular diagnosis was subsequently made for six patients or through newly available high‐density chromosomal microarray testing. Interpretation: We demonstrate the utility of exome sequencing in routine clinical care of children with DEEs. We highlight that molecular diagnosis often leads to changes in management and informs accurate prognostic and reproductive counselling. Our findings reinforce the need for ongoing analysis of genomic data to identify the aetiology in patients in whom the cause is unknown. The implementation of genomic testing in the care of children with DEEs should become routine in clinical practice. What this paper adds: The cause was identified in 35% of patients with developmental and epileptic encephalopathies.KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes.Reanalysis of genomic data found the cause in an additional six patients.Genetic aetiology was identified in 41% of children with seizure onset under 2 years, compared to 18% with older onset.Finding the molecular cause led to management changes in 36% of patients with DEEs. What this paper adds: The cause was identified in 35% of patients with developmental and epileptic encephalopathies.KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes.Reanalysis of genomic data found the cause in an additional six patients.Genetic aetiology was identified in 41% of children with seizure onset under 2 years, compared to 18% with older onset.Finding the molecular cause led to management changes in 36% of patients with DEEs. [ABSTRACT FROM AUTHOR]

Published
2023
Full Text
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34. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

Author

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

Published
2021
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35. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

Author

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

Subjects
Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant]
Abstract

We report detailed functional analyses and genotype-phenotype correlations in 433 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6. Five different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n=17, normal cognition, treatable seizures), 2) intermediate epilepsy (n=36, mild ID, partially pharmacoresponsive), 3) developmental and epileptic encephalopathy (DEE, n=191, severe ID, majority pharmacoresistant), 4) generalized epilepsy (n=21, mild to moderate ID, frequently with absence seizures), and 5) affected individuals without epilepsy (n=25, mild to moderate ID). Groups 1-3 presented with early-onset (median: four months) focal or multifocal seizures and epileptic discharges, whereas the onset of seizures in group 4 was later (median: 39 months) with generalized epileptic discharges. The epilepsy was not classifiable in 143 individuals. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin insensitive human NaV1.6 channels and whole-cell patch clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 165 individuals. All 133 individuals carrying GOF variants had either focal (76, groups 1-3), or unclassifiable epilepsy (37), whereas 32 with LOF variants had either generalized (14), no (11) or unclassifiable (5) epilepsy; only two had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of groups 1-3.In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a therapeutic treatment option in early onset SCN8A-related focal epilepsy.

Published
2021

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

Author

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

Abstract

We report detailed functional analyses and genotype-phenotype correlations in 433 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6. Five different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n=17, normal cognition, treatable seizures), 2) intermediate epilepsy (n=36, mild ID, partially pharmacoresponsive), 3) developmental and epileptic encephalopathy (DEE, n=191, severe ID, majority pharmacoresistant), 4) generalized epilepsy (n=21, mild to moderate ID, frequently with absence seizures), and 5) affected individuals without epilepsy (n=25, mild to moderate ID). Groups 1-3 presented with early-onset (median: four months) focal or multifocal seizures and epileptic discharges, whereas the onset of seizures in group 4 was later (median: 39 months) with generalized epileptic discharges. The epilepsy was not classifiable in 143 individuals. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin insensitive human NaV1.6 channels and whole-cell patch clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 165 individuals. All 133 individuals carrying GOF variants had either focal (76, groups 1-3), or unclassifiable epilepsy (37), whereas 32 with LOF variants had either generalized (14), no (11) or unclassifiable (5) epilepsy; only two had DEE. Computational modeling in the GOF group revealed a signific

Published
2021

37. Targets of antibodies against plasmodium falciparum-infected erythrocytes in malaria immunity

Author

Chan, Jo-Anne, Howell, Katherine B., Reiling, Linda, Ataide, Ricardo, Mackintosh, Claire L., Fowkes, Freya J.I., Petter, Michaela, Chesson, Joanne M., Langer, Christine, Warimwe, George M., Duffy, Michael F., Rogerson, Stephen J., Bull, Peter C., Cowman, Alan F., Marsh, Kevin, and Beeson, James G.

Subjects
Antigen-antibody reactions -- Genetic aspects, Gene targeting -- Research, Erythrocytes -- Genetic aspects, Malaria -- Genetic aspects -- Care and treatment, Health care industry
Abstract

Plasmodium falciparum is the major cause of malaria globally and is transmitted by mosquitoes. During parasitic development, P. falciparum-infected erythrocytes (P. falciparum-IEs) express multiple polymorphic proteins known as variant surface antigens (VSAs), including the P. falciparum erythrocyte membrane protein 1 (PfEMP1). VSA-specific antibodies are associated with protection from symptomatic and severe malaria. However, the importance of the different VSA targets of immunity to malaria remains unclear, which has impeded an understanding of malaria immunity and vaccine development. In this study, we developed assays using transgenic P. falciparum with modified PfEMP1 expression to quantify serum antibodies to VSAs among individuals exposed to malaria. We found that the majority of the human antibody response to the IE targets PfEMP1. Furthermore, our longitudinal studies showed that individuals with PfEMP1-specific antibodies had a significantly reduced risk of developing symptomatic malaria, whereas antibodies to other surface antigens were not associated with protective immunity. Using assays that measure antibody-mediated phagocytosis of IEs, an important mechanism in parasite clearance, we identified PfEMP1 as the major target of these functional antibodies. Taken together, these data demonstrate that PfEMP1 is a key target of humoral immunity. These findings advance our understanding of the targets and mediators of human immunity to malaria and have major implications for malaria vaccine development., Introduction Malaria caused by the protozoan parasite Plasmodium falciparum is a major burden of disease globally, causing an estimated 225 million illness episodes and around 800,000 deaths per year (1). [...]

Published
2012
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41. Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome.

Author

UCL - (SLuc) Service de neurologie, UCL - (SLuc) Centre de référence pour l'épilepsie réfractaire, Bar, Claire, Kuchenbuch, Mathieu, Barcia, Giulia, Schneider, Amy, Jennesson, Mélanie, Le Guyader, Gwenaël, Lesca, Gaetan, Mignot, Cyril, Montomoli, Martino, Parrini, Elena, Isnard, Hervé, Rolland, Anne, Keren, Boris, Afenjar, Alexandra, Dorison, Nathalie, Sadleir, Lynette G, Breuillard, Delphine, Levy, Raphael, Rio, Marlène, Dupont, Sophie, Negrin, Susanna, Danieli, Alberto, Scalais, Emmanuel, De Saint Martin, Anne, El Chehadeh, Salima, Chelly, Jamel, Poisson, Alice, Lebre, Anne-Sophie, Nica, Anca, Odent, Sylvie, Sekhara, Tayeb, Brankovic, Vesna, Goldenberg, Alice, Vrielynck, Pascal, Lederer, Damien, Maurey, Hélène, Terrone, Gaetano, Besmond, Claude, Hubert, Laurence, Berquin, Patrick, Billette de Villemeur, Thierry, Isidor, Bertrand, Freeman, Jeremy L, Mefford, Heather C, Myers, Candace T, Howell, Katherine B, Rodríguez-Sacristán Cascajo, Andrés, Meyer, Pierre, Genevieve, David, Guët, Agnès, Doummar, Diane, Durigneux, Julien, van Dooren, Marieke F, de Wit, Marie Claire Y, Gerard, Marion, Marey, Isabelle, Munnich, Arnold, Guerrini, Renzo, Scheffer, Ingrid E, Kabashi, Edor, Nabbout, Rima, UCL - (SLuc) Service de neurologie, UCL - (SLuc) Centre de référence pour l'épilepsie réfractaire, Bar, Claire, Kuchenbuch, Mathieu, Barcia, Giulia, Schneider, Amy, Jennesson, Mélanie, Le Guyader, Gwenaël, Lesca, Gaetan, Mignot, Cyril, Montomoli, Martino, Parrini, Elena, Isnard, Hervé, Rolland, Anne, Keren, Boris, Afenjar, Alexandra, Dorison, Nathalie, Sadleir, Lynette G, Breuillard, Delphine, Levy, Raphael, Rio, Marlène, Dupont, Sophie, Negrin, Susanna, Danieli, Alberto, Scalais, Emmanuel, De Saint Martin, Anne, El Chehadeh, Salima, Chelly, Jamel, Poisson, Alice, Lebre, Anne-Sophie, Nica, Anca, Odent, Sylvie, Sekhara, Tayeb, Brankovic, Vesna, Goldenberg, Alice, Vrielynck, Pascal, Lederer, Damien, Maurey, Hélène, Terrone, Gaetano, Besmond, Claude, Hubert, Laurence, Berquin, Patrick, Billette de Villemeur, Thierry, Isidor, Bertrand, Freeman, Jeremy L, Mefford, Heather C, Myers, Candace T, Howell, Katherine B, Rodríguez-Sacristán Cascajo, Andrés, Meyer, Pierre, Genevieve, David, Guët, Agnès, Doummar, Diane, Durigneux, Julien, van Dooren, Marieke F, de Wit, Marie Claire Y, Gerard, Marion, Marey, Isabelle, Munnich, Arnold, Guerrini, Renzo, Scheffer, Ingrid E, Kabashi, Edor, and Nabbout, Rima

Abstract

OBJECTIVE: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. METHODS: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature. RESULTS: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. SIGNIFICANCE: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechani

Published
2020

42. The severe epilepsy syndromes of infancy: A population‐based study

Author

Howell, Katherine B., primary, Freeman, Jeremy L., additional, Mackay, Mark T., additional, Fahey, Michael C., additional, Archer, John, additional, Berkovic, Samuel F., additional, Chan, Eunice, additional, Dabscheck, Gabriel, additional, Eggers, Stefanie, additional, Hayman, Michael, additional, Holberton, James, additional, Hunt, Rodney W., additional, Jacobs, Susan E., additional, Kornberg, Andrew J., additional, Leventer, Richard J., additional, Mandelstam, Simone, additional, McMahon, Jacinta M., additional, Mefford, Heather C., additional, Panetta, Julie, additional, Riseley, Jessica, additional, Rodriguez‐Casero, Victoria, additional, Ryan, Monique M., additional, Schneider, Amy L., additional, Smith, Lindsay J., additional, Stark, Zornitza, additional, Wong, Flora, additional, Yiu, Eppie M., additional, Scheffer, Ingrid E., additional, and Harvey, A. Simon, additional

Published
2021
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43. De novo mutations in epileptic encephalopathies

Author

Allen, Andrew S., Cossette, Patrick, Delanty, Norman, Eichler, Evan E., Epstein, Michael P., Glauser, Tracy, Goldstein, David B., Han, Yujun, Heinzen, Erin L., Hitomi, Yuki, Howell, Katherine B., Johnson, Michael R., Kuzniecky, Ruben, Lowenstein, Daniel H., Lu, Yi-Fan, Madou, Maura R. Z., Marson, Anthony G., Mefford, Heather C., Nieh, Sahar Esmaeeli, OʼBrien, Terence J., Ottman, Ruth, Petrovski, Slavé, Poduri, Annapurna, Ruzzo, Elizabeth K., Sherr, Elliott H., Yuskaitis, Christopher J., Abou-Khalil, Bassel, Alldredge, Brian K., Bautista, Jocelyn F., Berkovic, Samuel F., Boro, Alex, Cascino, Gregory D., Consalvo, Damian, Crumrine, Patricia, Devinsky, Orrin, Dlugos, Dennis, Fiol, Miguel, Fountain, Nathan B., French, Jacqueline, Friedman, Daniel, Geller, Eric B., Glynn, Simon, Haut, Sheryl R., Hayward, Jean, Helmers, Sandra L., Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E., Knowlton, Robert C., Kossoff, Eric H., Kuperman, Rachel, McGuire, Shannon M., Motika, Paul V., Novotny, Edward J., Paolicchi, Juliann M., Parent, Jack M., Park, Kristen, Scheffer, Ingrid E., Shellhaas, Renée A., Shih, Jerry J., Singh, Rani, Sirven, Joseph, Smith, Michael C., Sullivan, Joseph, Thio, Liu Lin, Venkat, Anu, Vining, Eileen P. G., Von Allmen, Gretchen K., Weisenberg, Judith L., Widdess-Walsh, Peter, and Winawer, Melodie R.

Published
2013
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47. Developmental and epilepsy spectrum of KCNB1 encephalopathy with long‐term outcome

Author

Bar, Claire, primary, Kuchenbuch, Mathieu, additional, Barcia, Giulia, additional, Schneider, Amy, additional, Jennesson, Mélanie, additional, Le Guyader, Gwenaël, additional, Lesca, Gaetan, additional, Mignot, Cyril, additional, Montomoli, Martino, additional, Parrini, Elena, additional, Isnard, Hervé, additional, Rolland, Anne, additional, Keren, Boris, additional, Afenjar, Alexandra, additional, Dorison, Nathalie, additional, Sadleir, Lynette G., additional, Breuillard, Delphine, additional, Levy, Raphael, additional, Rio, Marlène, additional, Dupont, Sophie, additional, Negrin, Susanna, additional, Danieli, Alberto, additional, Scalais, Emmanuel, additional, De Saint Martin, Anne, additional, El Chehadeh, Salima, additional, Chelly, Jamel, additional, Poisson, Alice, additional, Lebre, Anne‐Sophie, additional, Nica, Anca, additional, Odent, Sylvie, additional, Sekhara, Tayeb, additional, Brankovic, Vesna, additional, Goldenberg, Alice, additional, Vrielynck, Pascal, additional, Lederer, Damien, additional, Maurey, Hélène, additional, Terrone, Gaetano, additional, Besmond, Claude, additional, Hubert, Laurence, additional, Berquin, Patrick, additional, Billette de Villemeur, Thierry, additional, Isidor, Bertrand, additional, Freeman, Jeremy L., additional, Mefford, Heather C., additional, Myers, Candace T., additional, Howell, Katherine B., additional, Rodríguez‐Sacristán Cascajo, Andrés, additional, Meyer, Pierre, additional, Genevieve, David, additional, Guët, Agnès, additional, Doummar, Diane, additional, Durigneux, Julien, additional, van Dooren, Marieke F., additional, de Wit, Marie Claire Y., additional, Gerard, Marion, additional, Marey, Isabelle, additional, Munnich, Arnold, additional, Guerrini, Renzo, additional, Scheffer, Ingrid E., additional, Kabashi, Edor, additional, and Nabbout, Rima, additional

Published
2020
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48. Bi-allelic LoF NRROS Variants Impairing Active TGF-β1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification

Author

Dong, Xiaomin, primary, Tan, Natalie B., additional, Howell, Katherine B., additional, Barresi, Sabina, additional, Freeman, Jeremy L., additional, Vecchio, Davide, additional, Piccione, Maria, additional, Radio, Francesca Clementina, additional, Calame, Daniel, additional, Zong, Shan, additional, Eggers, Stefanie, additional, Scheffer, Ingrid E., additional, Tan, Tiong Y., additional, Van Bergen, Nicole J., additional, Tartaglia, Marco, additional, Christodoulou, John, additional, and White, Susan M., additional

Published
2020
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49. Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures

Author

Tan, Tiong Yang, primary, Sedmík, Jiří, additional, Fitzgerald, Mark P., additional, Halevy, Rivka Sukenik, additional, Keegan, Liam P., additional, Helbig, Ingo, additional, Basel-Salmon, Lina, additional, Cohen, Lior, additional, Straussberg, Rachel, additional, Chung, Wendy K., additional, Helal, Mayada, additional, Maroofian, Reza, additional, Houlden, Henry, additional, Juusola, Jane, additional, Sadedin, Simon, additional, Pais, Lynn, additional, Howell, Katherine B., additional, White, Susan M., additional, Christodoulou, John, additional, and O’Connell, Mary A., additional

Published
2020
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50. Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature

Author

Bar, Claire, primary, Barcia, Giulia, additional, Jennesson, Mélanie, additional, Le Guyader, Gwenaël, additional, Schneider, Amy, additional, Mignot, Cyril, additional, Lesca, Gaetan, additional, Breuillard, Delphine, additional, Montomoli, Martino, additional, Keren, Boris, additional, Doummar, Diane, additional, Billette de Villemeur, Thierry, additional, Afenjar, Alexandra, additional, Marey, Isabelle, additional, Gerard, Marion, additional, Isnard, Hervé, additional, Poisson, Alice, additional, Dupont, Sophie, additional, Berquin, Patrick, additional, Meyer, Pierre, additional, Genevieve, David, additional, De Saint Martin, Anne, additional, El Chehadeh, Salima, additional, Chelly, Jamel, additional, Guët, Agnès, additional, Scalais, Emmanuel, additional, Dorison, Nathalie, additional, Myers, Candace T., additional, Mefford, Heather C., additional, Howell, Katherine B., additional, Marini, Carla, additional, Freeman, Jeremy L., additional, Nica, Anca, additional, Terrone, Gaetano, additional, Sekhara, Tayeb, additional, Lebre, Anne‐Sophie, additional, Odent, Sylvie, additional, Sadleir, Lynette G., additional, Munnich, Arnold, additional, Guerrini, Renzo, additional, Scheffer, Ingrid E., additional, Kabashi, Edor, additional, and Nabbout, Rima, additional

Published
2019
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