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26 results on '"Koch, Nils A"'

3. Oculomotor analysis to assess brain health: preliminary findings from a longitudinal study of multiple sclerosis using novel tablet-based eye-tracking software

Author

de Villers-Sidani, Étienne, primary, Voss, Patrice, additional, Bastien, Natacha, additional, Cisneros-Franco, J. Miguel, additional, Hussein, Shamiza, additional, Mayo, Nancy E., additional, Koch, Nils A., additional, Drouin-Picaro, Alexandre, additional, Blanchette, François, additional, Guitton, Daniel, additional, and Giacomini, Paul S., additional

Published
2023
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6. A novel tablet-based software for the acquisition and analysis of gaze and eye movement parameters: a preliminary validation study in Parkinson's disease.

Author

de Villers-Sidani, Étienne, Voss, Patrice, Guitton, Daniel, Cisneros-Franco, J. Miguel, Koch, Nils A., and Ducharme, Simon

Subjects
PARKINSON'S disease, MOVEMENT disorders, EYE movements, ALZHEIMER'S disease, GAZE, NEURODEGENERATION
Abstract

The idea that eye movements can reflect certain aspects of brain function and inform on the presence of neurodegeneration is not a new one. Indeed, a growing body of research has shown that several neurodegenerative disorders, such as Alzheimer's and Parkinson's Disease, present characteristic eye movement anomalies and that specific gaze and eye movement parameters correlate with disease severity. The use of detailed eye movement recordings in research and clinical settings, however, has been limited due to the expensive nature and limited scalability of the required equipment. Here we test a novel technology that can track and measure eye movement parameters using the embedded camera of a mobile tablet. We show that using this technology can replicate several wellknown findings regarding oculomotor anomalies in Parkinson's disease (PD), and furthermore show that several parameters significantly correlate with disease severity as assessed with the MDS-UPDRS motor subscale. A logistic regression classifier was able to accurately distinguish PD patients from healthy controls on the basis of six eye movement parameters with a sensitivity of 0.93 and specificity of 0.86. This tablet-based tool has the potential to accelerate eye movement research via affordable and scalable eye-tracking and aid with the identification of disease status and monitoring of disease progression in clinical settings. [ABSTRACT FROM AUTHOR]

Published
2023
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7. 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

8. 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

9. 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

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

Author

Johannesen, Katrine Marie, Liu, Yuanyuan, Gjerulfsen, Catherine E., Koko, Mahmoud, Sonnenberg, Lukas, Schubert, Julian, Fenger, Christina Duhring, Eltokhi, Ahmed, Rannap, Maert, Koch, Nils, Lauxmann, Stephan, Krueger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthova, Petra, Vlckova, Marketa, Lemke, Johannes, Krey, Ilona, Heine, Constanze, Wieczorek, Dagmar, Kroell, Judith, Lund, Caroline, Klein, Karl Martin, Au, Py Billie, Rho, Jong, Ho, Alice, Masnada, Silvia, Veggiotti, Pierangelo, Giordano, Lucio, Accorsi, Patrizia, Hoi-Hansen, Christina, Striano, Pasquale, Zara, Federico, Verhelst, Helene, Verhoeven, Judith S., van der Zwaag, Bert, Harder, Aster, Brilstra, Eva, Pendziwiat, Manuela, Lebon, Sebastien, Vaccarezza, Maria, Le, Ngoc Minh, Christensen, Jakob, Schmidt-Petersen, Mette, Gronborg, Sabine, Scherer, Stephen, Howe, Jennifer, Fazeli, Walid, Howell, Katherine, Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Benedicte, Matricardi, Sara, Bonardi, Claudia M., Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vollo, Arve, Motazacker, M. Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caumes, Roseline, Roubertie, Agathe, Gelisse, Philippe, Marini, Carla, Guerrini, Renzo, Bilan, Frederic, Koch-Hogrebe, Margarete, Perry, 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, Mueller-Schlueter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie-Cecile, Destree, Anne, Schoonjans, An-Sofie, Meuwissen, Marije, Buzatu, Marga, Jansen, Anna, Scalais, Emmanuel, Srivastava, Siddarth, Tan, Wen-Hann, Olson, Heather, Loddenkemper, Tobias, Poduri, Annapurna, Helbig, Katherine L., Helbig, Ingo, Fitzgerald, Mark, Goldberg, Ethan M., Roser, Timo, Borggrafe, Ingo, Brunger, Tobias, May, Patrick, Lal, Dennis, Lederer, Damien, Rubboli, Guido, Lesca, Gaetan, Hedrich, Ulrike, Benda, Jan, Gardella, Elena, Lerche, Holger, and Moeller, Rikke Steensbjerre

Published
2021
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11. Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature

Author

Lauxmann, Stephan, primary, Sonnenberg, Lukas, additional, Koch, Nils A., additional, Bosselmann, Christian, additional, Winter, Natalie, additional, Schwarz, Niklas, additional, Wuttke, Thomas V., additional, Hedrich, Ulrike B. S., additional, Liu, Yuanyuan, additional, Lerche, Holger, additional, Benda, Jan, additional, and Kegele, Josua, additional

Published
2021
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12. 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

13. 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, and Alber, Michael

Subjects
GENETIC mutation, SODIUM channel blockers, EPILEPSY, PROGNOSIS, MEMBRANE transport proteins, RESEARCH funding, SEIZURES (Medicine), GENETIC techniques, INTELLECTUAL disabilities
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 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in 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 loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life. [ABSTRACT FROM AUTHOR]

Published
2022
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14. 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
Full Text
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15. 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

23. 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, Krueger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthova, 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, Christensen, Jakob, Gronborg, Sabine, Scherer, Stephen W., Howe, Jennifer, Fazeli, Walid, Howell, Katherine B., Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Benedicte, Matricardi, Sara, Bonardi, Claudia M., Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vollo, Arve, Motazacker, M. Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gelisse, 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., Muller-Schluter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie-Cecile, Destree, 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, Brunger, Tobias, May, Patrick, Lal, Dennis, Lederer, Damien, Rubboli, Guido, Heyne, Henrike O., Lesca, Gaetan, Hedrich, Ulrike B. S., Benda, Jan, Gardella, Elena, Lerche, Holger, Moller, 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, Krueger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthova, 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, Christensen, Jakob, Gronborg, Sabine, Scherer, Stephen W., Howe, Jennifer, Fazeli, Walid, Howell, Katherine B., Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Benedicte, Matricardi, Sara, Bonardi, Claudia M., Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vollo, Arve, Motazacker, M. Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gelisse, 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., Muller-Schluter, Karen, Bassan, Haim, Borovikov, Artem, Nassogne, Marie-Cecile, Destree, 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, Brunger, 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 Moller, 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 Na(v)1.6, 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 Na(v)1.6 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

24. Bill on transfer pricing documentation requirements released.

Author

von Koch, Nils

Subjects
LEGISLATIVE bills, TRANSFER pricing laws, PUBLIC finance, INTERNATIONAL business enterprises
Abstract

The article reports on a draft bill released by Sweden's Ministry of Finance focusing on compulsory transfer pricing documentation. The bill introduces a formal obligation for multinational enterprises to document in writing their intra-group transfer pricing for all cross-border transactions. Entities that have economic relations with foreign entities are affected by the proposed law.

Published
2006

25. SWEDEN.

Author

Koch, Nils von

Subjects
TRANSFER pricing, DOCUMENTATION, TAX returns, FINANCIAL disclosure, LEGISLATIVE bills
Abstract

This article discusses the transfer pricing documentation requirements in Sweden. At present Swedish tax law does not contain any requirements for specific transfer pricing documentation. However, the Finance Bill for 2006 that was presented to parliament by the government on September 20, 2005, is about to change that. The government states that it intends to present a bill during 2006 on compulsory tax return disclosure and documentation requirements for transfer pricing. The contents of the bill will likely be based on the March 26, 2003 report by the Swedish Tax Agency's predecessor, the National Tax Board.

Published
2005

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

Author

Johannesen KM, Liu Y, Koko M, Gjerulfsen CE, Sonnenberg L, Schubert J, Fenger CD, Eltokhi A, Rannap M, Koch NA, Lauxmann S, Krüger J, Kegele J, Canafoglia L, Franceschetti S, Mayer T, Rebstock J, Zacher P, Ruf S, Alber M, Sterbova K, Lassuthová P, Vlckova M, Lemke JR, Platzer K, Krey I, Heine C, Wieczorek D, Kroell-Seger J, Lund C, Klein KM, Au PYB, Rho JM, Ho AW, Masnada S, Veggiotti P, Giordano L, Accorsi P, Hoei-Hansen CE, Striano P, Zara F, Verhelst H, Verhoeven JS, Braakman HMH, van der Zwaag B, Harder AVE, Brilstra E, Pendziwiat M, Lebon S, Vaccarezza M, Le NM, Christensen J, Grønborg S, Scherer SW, Howe J, Fazeli W, Howell KB, Leventer R, Stutterd C, Walsh S, Gerard M, Gerard B, Matricardi S, Bonardi CM, Sartori S, Berger A, Hoffman-Zacharska D, Mastrangelo M, Darra F, Vøllo A, Motazacker MM, Lakeman P, Nizon M, Betzler C, Altuzarra C, Caume R, Roubertie A, Gélisse P, Marini C, Guerrini R, Bilan F, Tibussek D, Koch-Hogrebe M, Perry MS, Ichikawa S, Dadali E, Sharkov A, Mishina I, Abramov M, Kanivets I, Korostelev S, Kutsev S, Wain KE, Eisenhauer N, Wagner M, Savatt JM, Müller-Schlüter K, Bassan H, Borovikov A, Nassogne MC, Destrée A, Schoonjans AS, Meuwissen M, Buzatu M, Jansen A, Scalais E, Srivastava S, Tan WH, Olson HE, Loddenkemper T, Poduri A, Helbig KL, Helbig I, Fitzgerald MP, Goldberg EM, Roser T, Borggraefe I, Brünger T, May P, Lal D, Lederer D, Rubboli G, Heyne HO, Lesca G, Hedrich UBS, Benda J, Gardella E, Lerche H, and Møller RS

Subjects
Genetic Association Studies, Humans, Infant, Mutation, Prognosis, Seizures drug therapy, Seizures genetics, Sodium Channel Blockers therapeutic use, Epilepsy, Generalized drug therapy, Epilepsy, Generalized genetics, Epileptic Syndromes drug therapy, Epileptic Syndromes genetics, Intellectual Disability genetics, NAV1.6 Voltage-Gated Sodium Channel genetics
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 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in 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 loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2022
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