48 results on '"Hedrich, Ulrike B. S."'
Search Results
2. Epileptogenese und Konsequenzen für die Therapie
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Hedrich, Ulrike B. S., Koch, Henner, Becker, Albert, and Lerche, Holger
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- 2019
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3. KCNC2 variants of uncertain significance are also associated to various forms of epilepsy
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Seiffert, Simone, primary, Pendziwiat, Manuela, additional, Hedrich, Ulrike B. S., additional, Helbig, Ingo, additional, Weber, Yvonne, additional, and Schwarz, Niklas, additional
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- 2023
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4. Loss or gain of function? Effects of ion channel mutations on neuronal firing depend on the neuron type
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Koch, Nils A., primary, Sonnenberg, Lukas, additional, Hedrich, Ulrike B. S., additional, Lauxmann, Stephan, additional, and Benda, Jan, additional
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- 2023
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5. Predicting functional effects of ion channel variants using new phenotypic machine learning methods
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Boßelmann, Christian Malte, primary, Hedrich, Ulrike B. S., additional, Lerche, Holger, additional, and Pfeifer, Nico, additional
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- 2023
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6. KCNA1 gain‐of‐function epileptic encephalopathy treated with 4‐aminopyridine
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Müller, Peter, primary, Takacs, Danielle S., additional, Hedrich, Ulrike B. S., additional, Coorg, Rohini, additional, Masters, Laura, additional, Glinton, Kevin E., additional, Dai, Hongzheng, additional, Cokley, Jon A., additional, Riviello, James J., additional, Lerche, Holger, additional, and Cooper, Edward C., additional
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- 2023
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7. In vitro effects of eslicarbazepine (S‐licarbazepine) as a potential precision therapy on SCN8A variants causing neuropsychiatric disorders
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Bayraktar, Erva, primary, Liu, Yuanyuan, additional, Sonnenberg, Lukas, additional, Hedrich, Ulrike B. S., additional, Sara, Yildirim, additional, Eltokhi, Ahmed, additional, Lyu, Hang, additional, Lerche, Holger, additional, Wuttke, Thomas V., additional, and Lauxmann, Stephan, additional
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- 2022
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8. In vitro effects of eslicarbazepine (S‐licarbazepine) as a potential precision therapy on SCN8A variants causing neuropsychiatric disorders.
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Bayraktar, Erva, Liu, Yuanyuan, Sonnenberg, Lukas, Hedrich, Ulrike B. S., Sara, Yildirim, Eltokhi, Ahmed, Lyu, Hang, Lerche, Holger, Wuttke, Thomas V., and Lauxmann, Stephan
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SODIUM channels ,NEUROBEHAVIORAL disorders ,EPILEPSY ,CHANNEL coding ,BRAIN diseases ,GENETIC code - Abstract
Background and Purpose: Variants in SCN8A, the NaV1.6 channel's coding gene, are characterized by a variety of symptoms, including intractable epileptic seizures, psychomotor delay, progressive cognitive decline, autistic features, ataxia or dystonia. Standard anticonvulsant treatment has a limited impact on the course of disease. Experimental Approach: We investigated the therapeutic potential of eslicarbazepine (S‐licarbazepine; S‐lic), an enhancer of slow inactivation of voltage gated sodium channels, on two variants with biophysical and neuronal gain‐of‐function (G1475R and M1760I) and one variant with biophysical gain‐of‐function but neuronal loss‐of‐function (A1622D) in neuroblastoma cells and in murine primary hippocampal neuron cultures. These three variants cover the broad spectrum of NaV1.6‐associated disease and are linked to representative phenotypes of mild to moderate epilepsy (G1475R), developmental and epileptic encephalopathy (M1760I) and intellectual disability without epilepsy (A1622D). Key Results: Similar to known effects on NaV1.6 wildtype channels, S‐lic predominantly enhances slow inactivation on all tested variants, irrespective of their particular biophysical mechanisms. Beyond that, S‐lic exhibits variant‐specific effects including a partial reversal of pathologically slowed fast inactivation dynamics (A1622D and M1760I) and a trend to reduce enhanced persistent Na+ current by A1622D variant channels. Furthermore, our data in primary transfected neurons reveal that not only variant‐associated hyperexcitability (M1760I and G1475R) but also hypoexcitability (A1622D) can be modulated by S‐lic. Conclusions and Implications: S‐lic has not only substance‐specific effects but also variant‐specific effects. Personalized treatment regimens optimized to achieve such variant‐specific pharmacological modulation may help to reduce adverse side effects and improve the overall therapeutic outcome of SCN8A‐related disease. [ABSTRACT FROM AUTHOR]
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- 2023
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9. Pathophysiologische Mechanismen genetischer Epilepsien
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Hedrich, Ulrike B. S. and Maljevic, Snezana
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- 2016
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10. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants
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Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brünger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Lejla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Phillip S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M., Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, Weber, Yvonne, Schwarz N., Seiffert S., Pendziwiat M., Rademacher A.V., Brunger T., Hedrich U.B.S., Augustijn P.B., Baier H., Bayat A., Bisulli F., Buono R.J., Bruria B.Z., Doyle M.G., Guerrini R., Heimer G., Iacomino M., Kearney H., Klein K.M., Kousiappa I., Kunz W.S., Lerche H., Licchetta L., Lohmann E., Minardi R., McDonald M., Montgomery S., Mulahasanovic L., Oegema R., Ortal B., Papacostas S.S., Ragona F., Granata T., Reif P.S., Rosenow F., Rothschild A., Scudieri P., Striano P., Tinuper P., Tanteles G.A., Vetro A., Zahnert F., Goldberg E.M., Zara F., Lal D., May P., Muhle H., Helbig I., and Weber Y.
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Phenotype ,Epilepsy ,Shaw Potassium Channel ,Epilepsy, Generalized ,Seizure ,Whole Exome Sequencing ,Human - Abstract
Neurology : official journal of the American Academy of Neurology 98(20), e2046-e2059 (2022). doi:10.1212/WNL.0000000000200660, Published by Ovid, [S.l.]
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- 2022
11. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Epilepsy Patients With KCNC2 Pathogenic Variants
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Niklas, Schwarz, Simone, Seiffert, Msc, Manuela, Pendziwiat, Annika Verena Rademacher, Tobias, Br¨unger, Phd, Hedrich, Ulrike B. S., Augustijn, Paul B., Hartmut, Baier, Allan, Bayat, Francesca, Bisulli, Phd, Md, Buono, Russell J., Ben Zeev Bruria, Doyle, Michael G., Guerrini, Renzo, Gali, Heimer, Iacomino, Michele, Hugh, Kearney, Karl Martin Klein, Ioanna, Kousiappa, Kunz, Wolfram S., Holger, Lerche, Laura, Licchetta, Ebba, Lohmann, Raffaella, Minardi, Marie, Mcdonald, Sarah, Montgomery, Lejla, Mulahasanovic, Renske, Oegema, Barel, Ortal, Papacostas, Savvas S., Francesca, Ragona, Tiziana, Granata, Reif, Phillip S., Felix, Rosenow, Annick, Rothschild, Scudieri, Paolo, Striano, Pasquale, Paolo, Tinuper, Tanteles, George A., Annalisa, Vetro, Felix, Zahnert, Goldberg, Ethan M., Zara, Federico, Dennis, Lal, Patrick, May, Hiltrud, Muhle, Ingo, Helbig, and and Yvonne Weber
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Neurology (clinical) - Abstract
Background:KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyse the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.Methods:Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes.Results:We identified novel KCNC2 variants in 18 patients with various forms of epilepsy including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy (EOAE), focal epilepsy (FE), and myoclonic-atonic epilepsy (MAE). 10/18 variants were de novo and 8/18 variants were classified as modifying variants. 8 drug responsive cases became seizure-free using valproic acid as monotherapy or in combination including severe DEE cases. Functional analysis of four variants demonstrated gain-of-function in three severely affected DEE cases and loss-of-function in one case with a milder phenotype (GGE) as the underlying pathomechanisms.Conclusion:These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.
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- 2022
12. Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies
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Masnada, Silvia, Hedrich, Ulrike B. S., Gardella, Elena, Schubert, Julian, Kaiwar, Charu, Klee, Eric W., Lanpher, Brendan C., Gavrilova, Ralitza H., Synofzik, Matthis, Bast, Thomas, Gorman, Kathleen, King, Mary D., Allen, Nicholas M., Conroy, Judith, Zeev, Bruria Ben, Tzadok, Michal, Korff, Christian, Dubois, Fanny, Ramsey, Keri, Narayanan, Vinodh, Serratosa, Jose M., Giraldez, Beatriz G., Helbig, Ingo, Marsh, Eric, OʼBrien, Margaret, Bergqvist, Christina A., Binelli, Adrian, Porter, Brenda, Zaeyen, Eduardo, Horovitz, Dafne D., Wolff, Markus, Marjanovic, Dragan, Caglayan, Hande S., Arslan, Mutluay, Pena, Sergio D. J., Sisodiya, Sanjay M., Balestrini, Simona, Syrbe, Steffen, Veggiotti, Pierangelo, Lemke, Johannes R., Møller, Rikke S., Lerche, Holger, and Rubboli, Guido
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- 2017
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13. Reply
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Helbig, Katherine L., Hedrich, Ulrike B. S., Scheffer, Ingrid E., Helbig, Ingo, Lerche, Holger, and Lemke, Johannes R.
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- 2017
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14. Dravet Variant SCN1AA1783V Impairs Interneuron Firing Predominantly by Altered Channel Activation
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Layer, Nikolas, primary, Sonnenberg, Lukas, additional, Pardo González, Emilio, additional, Benda, Jan, additional, Hedrich, Ulrike B. S., additional, Lerche, Holger, additional, Koch, Henner, additional, and Wuttke, Thomas V., additional
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- 2021
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15. Heterozygous variants in KCNC2 cause a broad spectrum of epilepsy phenotypes associated with characteristic functional alterations 2021.05.21.21257099
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Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika, Brünger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Lejla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Philipp S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, Weber, Yvonne, BMBF Treat-ION grant (01GM1907). [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]
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KCNC2 ,Neurologie [D14] [Sciences de la santé humaine] ,Neurology [D14] [Human health sciences] ,epilepsy ,Genetics & genetic processes [F10] [Life sciences] ,Génétique & processus génétiques [F10] [Sciences du vivant] ,potassium channel - Abstract
Background KCNC2 encodes a member of the shaw-related voltage-gated potassium channel family (KV3.2), which are important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain.Methods Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic and functional analysis. The cases were referred through clinical and research collaborations in our study. Four de novo variants were examined electrophysiologically in Xenopus laevis oocytes.Results We identified novel KCNC2 variants in 27 patients with various forms of epilepsy. Functional analysis demonstrated gain-of-function in severe and loss-of-function in milder phenotypes as the underlying pathomechanisms with specific response to valproic acid.Conclusion These findings implicate KCNC2 as a novel causative gene for epilepsy emphasizing the critical role of KV3.2 in the regulation of brain excitability with an interesting genotype-phenotype correlation and a potential concept for precision medicine.
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- 2021
16. Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature
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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
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- 2021
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17. 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2 -encephalopathy
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Hedrich, Ulrike B. S., primary, Lauxmann, Stephan, additional, Wolff, Markus, additional, Synofzik, Matthis, additional, Bast, Thomas, additional, Binelli, Adrian, additional, Serratosa, José M., additional, Martínez-Ulloa, Pedro, additional, Allen, Nicholas M., additional, King, Mary D., additional, Gorman, Kathleen M., additional, Zeev, Bruria Ben, additional, Tzadok, Michal, additional, Wong-Kisiel, Lily, additional, Marjanovic, Dragan, additional, Rubboli, Guido, additional, Sisodiya, Sanjay M., additional, Lutz, Florian, additional, Ashraf, Harshad Pannikkaveettil, additional, Torge, Kirsten, additional, Yan, Pu, additional, Bosselmann, Christian, additional, Schwarz, Niklas, additional, Fudali, Monika, additional, and Lerche, Holger, additional
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- 2021
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18. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications
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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
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- 2021
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19. KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating
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Zhang, Yongqiang, primary, Tachtsidis, Georgios, additional, Schob, Claudia, additional, Koko, Mahmoud, additional, Hedrich, Ulrike B S, additional, Lerche, Holger, additional, Lemke, Johannes R, additional, van Haeringen, Arie, additional, Ruivenkamp, Claudia, additional, Prescott, Trine, additional, Tveten, Kristian, additional, Gerstner, Thorsten, additional, Pruniski, Brianna, additional, DiTroia, Stephanie, additional, VanNoy, Grace E, additional, Rehm, Heidi L, additional, McLaughlin, Heather, additional, Bolz, Hanno J, additional, Zechner, Ulrich, additional, Bryant, Emily, additional, McDonough, Tiffani, additional, Kindler, Stefan, additional, and Bähring, Robert, additional
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- 2021
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20. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications
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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]
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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.
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- 2021
21. Dravet Variant SCN1A$^{A1783V}$ Impairs Interneuron Firing Predominantly by Altered Channel Activation
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Layer, Nikolas, Sonnenberg, Lukas, Pardo González, Emilio, Benda, Jan, Hedrich, Ulrike B. S., Lerche, Holger, Koch, Henner, and Wuttke, Thomas V.
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Frontiers in cellular neuroscience 15, 754530 (2021). doi:10.3389/fncel.2021.754530 special issue: "Cellular Neurophysiology / Editors: Enrico Cherubini, Arianna Maffei, Giorgio Aicardi, Joseph P. Albanesi", Published by Frontiers Research Foundation, Lausanne
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- 2021
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22. Endogenous but not sensory-driven activity controls migration, morphogenesis and survival of adult-born neurons in the mouse olfactory bulb
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Li, Kaizhen, primary, Figarella, Katherine, additional, Su, Xin, additional, Kovalchuk, Yury, additional, Gorzolka, Jessika, additional, Neher, Jonas J., additional, Mojtahedi, Nima, additional, Casadei, Nicolas, additional, Hedrich, Ulrike B. S., additional, and Garaschuk, Olga, additional
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- 2021
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23. SCN 2Achannelopathies: Mechanisms and models
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Hedrich, Ulrike B. S., primary, Lauxmann, Stephan, additional, and Lerche, Holger, additional
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- 2019
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24. Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model.
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Auffenberg, Eva, Hedrich, Ulrike B. S., Barbieri, Raffaella, Miely, Daniela, Groschup, Bernhard, Wuttke, Thomas V., Vogel, Niklas, Lührs, Philipp, Zanardi, Ilaria, Bertelli, Sara, Spielmann, Nadine, Gailus-Durner, Valerie, Fuchs, Helmut, de Angelis, Martin Hrabě, Pusch, Michael, Dichgans, Martin, Lerche, Holger, Gavazzo, Paola, Plesnila, Nikolaus, and Freilinger, Tobias
- Abstract
Cortical spreading depression (CSD), a wave of depolarization followed by depression of cortical activity, is a pathophysiological process implicated in migraine with aura and various other brain pathologies, such as ischemic stroke and traumatic brain injury. To gain insight into the pathophysiology of CSD, we generated a mouse model for a severe monogenic subtype of migraine with aura, familial hemiplegic migraine type 3 (FHM3). FHM3 is caused by mutations in SCN1A, encoding the voltage-gated Na+ channel NaV1.1 predominantly expressed in inhibitory interneurons. Homozygous Scn1aL1649Q knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous Scn1aL1649Q knock-in mice compared with WT mice displayed a significantly enhanced susceptibility to CSD. We found L1649Q to cause a gain-of-function effect with an impaired Na+ -channel inactivation and increased ramp Na+ currents leading to hyperactivity of fast-spiking inhibitory interneurons. Brain slice recordings using K+ -sensitive electrodes revealed an increase in extracellular K+ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation. The neuronal phenotype and premature death of homozygous Scn1aL1649Q knock-in mice was partially rescued by GS967, a blocker of persistent Na+ currents. Collectively, our findings identify interneuron hyperactivity as a mechanism to trigger CSD. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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25. Dravet Variant SCN1A A 1783 V Impairs Interneuron Firing Predominantly by Altered Channel Activation.
- Author
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Layer, Nikolas, Sonnenberg, Lukas, Pardo González, Emilio, Benda, Jan, Hedrich, Ulrike B. S., Lerche, Holger, Koch, Henner, and Wuttke, Thomas V.
- Subjects
MISSENSE mutation ,SODIUM channels ,LABORATORY mice ,GENETIC variation ,INTERNEURONS ,PYRAMIDAL neurons ,BRAIN diseases ,ANIMAL disease models - Abstract
Dravet syndrome (DS) is a developmental epileptic encephalopathy mainly caused by functional Na
V 1.1 haploinsufficiency in inhibitory interneurons. Recently, a new conditional mouse model expressing the recurrent human p.(Ala1783Val) missense variant has become available. In this study, we provided an electrophysiological characterization of this variant in tsA201 cells, revealing both altered voltage-dependence of activation and slow inactivation without reduced sodium peak current density. Based on these data, simulated interneuron (IN) firing properties in a conductance-based single-compartment model suggested surprisingly similar firing deficits for NaV 1.1A1783V and full haploinsufficiency as caused by heterozygous truncation variants. Impaired NaV 1.1A1783V channel activation was predicted to have a significantly larger impact on channel function than altered slow inactivation and is therefore proposed as the main mechanism underlying IN dysfunction. The computational model was validated in cortical organotypic slice cultures derived from conditional Scn1aA 1783 V mice. Pan-neuronal activation of the p.Ala1783V in vitro confirmed a predicted IN firing deficit and revealed an accompanying reduction of interneuronal input resistance while demonstrating normal excitability of pyramidal neurons. Altered input resistance was fed back into the model for further refinement. Taken together these data demonstrate that primary loss of function (LOF) gating properties accompanied by altered membrane characteristics may match effects of full haploinsufficiency on the neuronal level despite maintaining physiological peak current density, thereby causing DS. [ABSTRACT FROM AUTHOR]- Published
- 2021
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26. Kultivierung von humanem kortikalem Resektionsgewebe nach epilepsiechirurgischen Eingriffen - Implementierung eines Modellsystems zur Untersuchung pathophysiologischer Mechanismen von ZNS Erkrankungen
- Author
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Wuttke, Thomas, Schwarz, Niklas, Hedrich, Ulrike B. S., Honegger, Jürgen B., Lerche, Holger, and Koch, Henner
- Subjects
ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Objective: Investigation of pathophysiological mechanisms of human disease affecting the CNS, such as epilepsy or neurodegenerative disorders, mostly relies on studies based on human tissue obtained post mortem or by biopsy/surgery and on studies using animal models, cell culture or heterologous[for full text, please go to the a.m. URL], 70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie
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- 2019
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27. KCNC1-related disorders: New de novo variants expand the phenotypic spectrum
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Park, Joohyun, Koko, Mahmoud, Hedrich, Ulrike B. S., Hermann, Andreas, Cremer, Kirsten, Haberlandt, Edda, Grimmel, Mona, Alhaddad, Bader, Beck‐Woedl, Stefanie, Harrer, Merle, Karall, Daniela, Kingelhoefer, Lisa, Tzschach, Andreas, Matthies, Lars C., Strom, Tim M., Ringelstein, Erich Bernd, Sturm, Marc, Engels, Hartmut, Wolff, Markus, Lerche, Holger, and Haack, Tobias B.
- Subjects
Male ,Mutation, Missense ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Brief Communication ,Xenopus laevis ,Seizures ,physiology [Shaw Potassium Channels] ,Intellectual Disability ,Animals ,Humans ,ddc:610 ,RC346-429 ,Child ,Genetic Association Studies ,genetics [Shaw Potassium Channels] ,genetics [Ataxia] ,Myoclonic Epilepsies, Progressive ,genetics [Seizures] ,Shaw Potassium Channels ,Codon, Nonsense ,Ataxia ,Neurology. Diseases of the nervous system ,genetics [Intellectual Disability] ,Brief Communications ,RC321-571 - Abstract
A recurrent de novo missense variant in KCNC1, encoding a voltage‐gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic‐clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant‐negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism.
- Published
- 2019
28. KCNC1 ‐related disorders: new de novo variants expand the phenotypic spectrum
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Park, Joohyun, Koko, Mahmoud, Hedrich, Ulrike B. S., Hermann, Andreas, Cremer, Kirsten, Haberlandt, Edda, Grimmel, Mona, Alhaddad, Bader, Beck‐Woedl, Stefanie, Harrer, Merle, Karall, Daniela, Kingelhoefer, Lisa, Tzschach, Andreas, Matthies, Lars C., Strom, Tim M., Ringelstein, Erich Bernd, Sturm, Marc, Engels, Hartmut, Wolff, Markus, Lerche, Holger, and Haack, Tobias B.
- Subjects
ddc - Published
- 2018
29. KCNC1 ‐related disorders: new de novo variants expand the phenotypic spectrum
- Author
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Park, Joohyun, primary, Koko, Mahmoud, additional, Hedrich, Ulrike B. S., additional, Hermann, Andreas, additional, Cremer, Kirsten, additional, Haberlandt, Edda, additional, Grimmel, Mona, additional, Alhaddad, Bader, additional, Beck‐Woedl, Stefanie, additional, Harrer, Merle, additional, Karall, Daniela, additional, Kingelhoefer, Lisa, additional, Tzschach, Andreas, additional, Matthies, Lars C., additional, Strom, Tim M., additional, Ringelstein, Erich Bernd, additional, Sturm, Marc, additional, Engels, Hartmut, additional, Wolff, Markus, additional, Lerche, Holger, additional, and Haack, Tobias B., additional
- Published
- 2019
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30. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy
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Syrbe, Steffen, Hedrich, Ulrike B S, Arslan, Mutluay, Serratosa, José M, Nothnagel, Michael, May, Patrick, Krause, Roland, Löffler, Heidrun, Detert, Katja, Dorn, Thomas, Vogt, Heinrich, Krämer, Günter, Riesch, Erik, Schöls, Ludger, Mullis, Primus E, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Sterbova, Katalin, Craiu, Dana C, Hoffman-Zacharska, Dorota, Korff, Christian M, Weber, Yvonne G, Steinlin, Maja, Djémié, Tania, Gallati, Sabina, Bertsche, Astrid, Bernhard, Matthias K, Merkenschlager, Andreas, Kiess, Wieland, consortium, EuroEPINOMICS RES, Gonzalez, Michael, Züchner, Stephan, Palotie, Aarno, Suls, Arvid, Müller, Stephan, De Jonghe, Peter, Helbig, Ingo, Biskup, Saskia, Wolff, Markus, Maljevic, Snezana, Schüle, Rebecca, Sisodiya, Sanjay M, Weckhuysen, Sarah, Lerche, Holger, Lemke, Johannes R, Møller, Rikke S, Balling, Rudi, Barisic, Nina, Baulac, Stéphanie, Caglayan, Hande S, Depienne, Christel, Gormley, Padhraig, Guerrini, Renzo, Maher, Bridget, Hjalgrim, Helle, Jähn, Johanna, Klein, Karl Martin, Koeleman, Bobby P C, Komarek, Vladimir, LeGuern, Eric, Hernandez-Hernandez, Laura, Marini, Carla, Muhle, Hiltrud, Pal, Deb, Rosenow, Felix, Selmer, Kaja, Synofzik, Matthis, Stephani, Ulrich, Striano, Pasquale, Talvik, Tiina, von Spiczak, Sarah, Zara, Federico, and EuroEPINOMICS RES Consortium
- Subjects
Adult ,Male ,Ataxia ,genetics [Epilepsy] ,genetics [Kv1.2 Potassium Channel] ,Biology ,medicine.disease_cause ,Bioinformatics ,Infantile ,Epilepsy/genetics ,Article ,Spasms ,Cohort Studies ,Epilepsy ,Young Adult ,Spasms, Infantile/genetics ,ddc:570 ,Amino Acid Sequence ,Child ,Child, Preschool ,Female ,Genetic Predisposition to Disease ,Humans ,Infant ,Kv1.2 Potassium Channel ,Pedigree ,Spasms, Infantile ,Mutation ,Genetics ,Intellectual disability ,medicine ,KCNA2 protein, human ,Preschool ,Loss function ,Kv1.2 Potassium Channel/genetics ,ddc:618 ,Genetic heterogeneity ,Seizure types ,genetics [Spasms, Infantile] ,medicine.disease ,Myoclonic epilepsy ,Human medicine ,medicine.symptom - Abstract
Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features(1-6). Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel K(V)1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of K(V)1.2-expressing neurons.
- Published
- 2015
31. SCN2A channelopathies: Mechanisms and models.
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Hedrich, Ulrike B. S., Lauxmann, Stephan, and Lerche, Holger
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- *
SODIUM channels , *BRUGADA syndrome , *INTELLECTUAL disabilities , *FUNCTIONAL analysis , *SEIZURES (Medicine) , *PARTIAL epilepsy , *AUTISM - Abstract
Summary: Variants in the SCN2A gene, encoding the voltage‐gated sodium channel NaV1.2, cause a variety of neuropsychiatric syndromes with different severity ranging from self‐limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability (ID), as well as ID or autism without seizures. Functional analysis of channel defects demonstrated a genotype‐phenotype correlation and suggested effective treatment options for one group of affected patients carrying gain‐of‐function variants. Here, we sum up the functional mechanisms underlying different phenotypes of patients with SCN2A channelopathies and present currently available models that can help in understanding SCN2A‐related disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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32. SCN2A channelopathies: Mechanisms and models.
- Author
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Hedrich, Ulrike B. S., Lauxmann, Stephan, and Lerche, Holger
- Subjects
- *
SODIUM channels , *INTELLECTUAL disabilities , *FUNCTIONAL analysis , *SEIZURES (Medicine) , *BRUGADA syndrome , *AUTISM - Abstract
Summary: Variants in the SCN2A gene, encoding the voltage‐gated sodium channel NaV1.2, cause a variety of neuropsychiatric syndromes with different severity ranging from self‐limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability (ID), as well as ID or autism without seizures. Functional analysis of channel defects demonstrated a genotype‐phenotype correlation and suggested effective treatment options for one group of affected patients carrying gain‐of‐function variants. Here, we sum up the functional mechanisms underlying different phenotypes of patients with SCN2A channelopathies and present currently available models that can help in understanding SCN2A‐related disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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33. Human Cerebrospinal fluid promotes long-term neuronal viability and network function in human neocortical organotypic brain slice cultures
- Author
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Schwarz, Niklas, primary, Hedrich, Ulrike B. S., additional, Schwarz, Hannah, additional, P.A., Harshad, additional, Dammeier, Nele, additional, Auffenberg, Eva, additional, Bedogni, Francesco, additional, Honegger, Jürgen B., additional, Lerche, Holger, additional, Wuttke, Thomas V., additional, and Koch, Henner, additional
- Published
- 2017
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34. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders
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Wolff, Markus, primary, Johannesen, Katrine M., additional, Hedrich, Ulrike B. S., additional, Masnada, Silvia, additional, Rubboli, Guido, additional, Gardella, Elena, additional, Lesca, Gaetan, additional, Ville, Dorothée, additional, Milh, Mathieu, additional, Villard, Laurent, additional, Afenjar, Alexandra, additional, Chantot-Bastaraud, Sandra, additional, Mignot, Cyril, additional, Lardennois, Caroline, additional, Nava, Caroline, additional, Schwarz, Niklas, additional, Gérard, Marion, additional, Perrin, Laurence, additional, Doummar, Diane, additional, Auvin, Stéphane, additional, Miranda, Maria J., additional, Hempel, Maja, additional, Brilstra, Eva, additional, Knoers, Nine, additional, Verbeek, Nienke, additional, van Kempen, Marjan, additional, Braun, Kees P., additional, Mancini, Grazia, additional, Biskup, Saskia, additional, Hörtnagel, Konstanze, additional, Döcker, Miriam, additional, Bast, Thomas, additional, Loddenkemper, Tobias, additional, Wong-Kisiel, Lily, additional, Baumeister, Friedrich M., additional, Fazeli, Walid, additional, Striano, Pasquale, additional, Dilena, Robertino, additional, Fontana, Elena, additional, Zara, Federico, additional, Kurlemann, Gerhard, additional, Klepper, Joerg, additional, Thoene, Jess G., additional, Arndt, Daniel H., additional, Deconinck, Nicolas, additional, Schmitt-Mechelke, Thomas, additional, Maier, Oliver, additional, Muhle, Hiltrud, additional, Wical, Beverly, additional, Finetti, Claudio, additional, Brückner, Reinhard, additional, Pietz, Joachim, additional, Golla, Günther, additional, Jillella, Dinesh, additional, Linnet, Karen M., additional, Charles, Perrine, additional, Moog, Ute, additional, Õiglane-Shlik, Eve, additional, Mantovani, John F., additional, Park, Kristen, additional, Deprez, Marie, additional, Lederer, Damien, additional, Mary, Sandrine, additional, Scalais, Emmanuel, additional, Selim, Laila, additional, Van Coster, Rudy, additional, Lagae, Lieven, additional, Nikanorova, Marina, additional, Hjalgrim, Helle, additional, Korenke, G. Christoph, additional, Trivisano, Marina, additional, Specchio, Nicola, additional, Ceulemans, Berten, additional, Dorn, Thomas, additional, Helbig, Katherine L., additional, Hardies, Katia, additional, Stamberger, Hannah, additional, de Jonghe, Peter, additional, Weckhuysen, Sarah, additional, Lemke, Johannes R., additional, Krägeloh-Mann, Ingeborg, additional, Helbig, Ingo, additional, Kluger, Gerhard, additional, Lerche, Holger, additional, and Møller, Rikke S, additional
- Published
- 2017
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35. Pathophysiologische Mechanismen genetischer Epilepsien
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Hedrich, Ulrike B. S., primary and Maljevic, Snezana, additional
- Published
- 2015
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36. Impaired Action Potential Initiation in GAB Aergic Interneurons Causes Hyperexcitable Networks in an Epileptic Mouse Model Carrying a Human NaV1.1 Mutation.
- Author
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Hedrich, Ulrike B. S., Liautard, Camille, Kirschenbaum, Daniel, Pofahl, Martin, Lavigne, Jennifer, Yuanyuan Liu, Theiss, Stephan, Slotta, Johannes, Escayg, Andrew, Dihné, Marcel, Beck, Heinz, Mantegazza, Massimo, and Lerche, Holger
- Subjects
- *
ACTION potentials , *GABA agents , *INTERNEURONS , *PEOPLE with epilepsy , *GENETIC mutation , *SODIUM ions , *LABORATORY mice - Abstract
Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the Nav1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na+ channels in interneurons and persistent Na+ currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca2+ imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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37. Early-onset familial hemiplegic migraine due to a novel SCN1A mutation.
- Author
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Fan, Chunxiang, Wolking, Stefan, Lehmann-Horn, Frank, Hedrich, Ulrike B. S., Freilinger, Tobias, Lerche, Holger, Borck, Guntram, Kubisch, Christian, Jurkat-Rott, Karin, and Hedrich, Ulrike Bs
- Subjects
- *
MIGRAINE , *GENETIC mutation , *GENETIC testing , *INTERNEURONS , *ELECTROPHYSIOLOGY , *GENETICS , *MIGRAINE diagnosis , *DISEASE susceptibility , *GENEALOGY , *GENETIC polymorphisms , *GENETIC techniques , *GENETIC markers , *MEMBRANE transport proteins - Abstract
Introduction Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. The FHM3 subtype is caused by mutations in SCN1A, which is also the most frequent epilepsy gene encoding the voltage-gated Na+ channel NaV1.1. The aim of this study was to explore the clinical, genetic and pathogenetic features of a pure FHM3 family. Methods A three-generation family was enrolled in this study for genetic testing and assessment of clinical features. Whole cell patch-clamp was performed to determine the functions of identified mutant NaV1.1 channels, which were transiently expressed in human tsA201 cells together with β1 and β2 subunits. Results and conclusions We identified a novel SCN1A (p.Leu1624Pro) mutation in a pure FHM family with notably early-onset attacks at mean age of 7. L1624P locates in S3 of domain IV, the same domain as two of four known pure FHM3 mutations. Compared to WT channels, L1624P displayed an increased threshold-near persistent current in addition to other gain-of-function features such as: a slowing of fast inactivation, a positive shift in steady-state inactivation, a faster recovery and higher channel availability during repetitive stimulation. Similar to the known FHM3 mutations, this novel mutation predicts hyperexcitability of GABAergic inhibitory neurons. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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38. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications.
- Author
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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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39. Predicting the functional effects of voltage-gated potassium channel missense variants with multi-task learning.
- Author
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Boßelmann CM, Hedrich UBS, Müller P, Sonnenberg L, Parthasarathy S, Helbig I, Lerche H, and Pfeifer N
- Subjects
- Humans, Mutation, Missense, Shaw Potassium Channels genetics, Epilepsy genetics, Intellectual Disability genetics, Potassium Channels, Voltage-Gated chemistry, Potassium Channels, Voltage-Gated genetics
- Abstract
Background: Variants in genes encoding voltage-gated potassium channels are associated with a broad spectrum of neurological diseases including epilepsy, ataxia, and intellectual disability. Knowledge of the resulting functional changes, characterized as overall ion channel gain- or loss-of-function, is essential to guide clinical management including precision medicine therapies. However, for an increasing number of variants, little to no experimental data is available. New tools are needed to evaluate variant functional effects., Methods: We catalogued a comprehensive dataset of 959 functional experiments across 19 voltage-gated potassium channels, leveraging data from 782 unique disease-associated and synthetic variants. We used these data to train a taxonomy-based multi-task learning support vector machine (MTL-SVM), and compared performance to several baseline methods., Findings: MTL-SVM maintains channel family structure during model training, improving overall predictive performance (mean balanced accuracy 0·718 ± 0·041, AU-ROC 0·761 ± 0·063) over baseline (mean balanced accuracy 0·620 ± 0·045, AU-ROC 0·711 ± 0·022). We can obtain meaningful predictions even for channels with few known variants (KCNC1, KCNQ5)., Interpretation: Our model enables functional variant prediction for voltage-gated potassium channels. It may assist in tailoring current and future precision therapies for the increasing number of patients with ion channel disorders., Funding: This work was supported by intramural funding of the Medical Faculty, University of Tuebingen (PATE F.1315137.1), the Federal Ministry for Education and Research (Treat-ION, 01GM1907A/B/G/H) and the German Research Foundation (FOR-2715, Le1030/16-2, He8155/1-2)., Competing Interests: Declaration of interests The authors declare no conflict of interest related to this work., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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40. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.
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Schwarz N, Seiffert S, Pendziwiat M, Rademacher AV, Brünger T, Hedrich UBS, Augustijn PB, Baier H, Bayat A, Bisulli F, Buono RJ, Bruria BZ, Doyle MG, Guerrini R, Heimer G, Iacomino M, Kearney H, Klein KM, Kousiappa I, Kunz WS, Lerche H, Licchetta L, Lohmann E, Minardi R, McDonald M, Montgomery S, Mulahasanovic L, Oegema R, Ortal B, Papacostas SS, Ragona F, Granata T, Reif PS, Rosenow F, Rothschild A, Scudieri P, Striano P, Tinuper P, Tanteles GA, Vetro A, Zahnert F, Goldberg EM, Zara F, Lal D, May P, Muhle H, Helbig I, and Weber Y
- Subjects
- Humans, Phenotype, Seizures genetics, Shaw Potassium Channels genetics, Exome Sequencing, Epilepsy genetics, Epilepsy, Generalized genetics
- Abstract
Background and Objectives: KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants., Methods: Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes., Results: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms., Discussion: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of K
V 3.2 in the regulation of brain excitability., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)- Published
- 2022
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41. Dravet Variant SCN1A A 1783 V Impairs Interneuron Firing Predominantly by Altered Channel Activation.
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Layer N, Sonnenberg L, Pardo González E, Benda J, Hedrich UBS, Lerche H, Koch H, and Wuttke TV
- Abstract
Dravet syndrome (DS) is a developmental epileptic encephalopathy mainly caused by functional Na
V 1.1 haploinsufficiency in inhibitory interneurons. Recently, a new conditional mouse model expressing the recurrent human p.(Ala1783Val) missense variant has become available. In this study, we provided an electrophysiological characterization of this variant in tsA201 cells, revealing both altered voltage-dependence of activation and slow inactivation without reduced sodium peak current density. Based on these data, simulated interneuron (IN) firing properties in a conductance-based single-compartment model suggested surprisingly similar firing deficits for NaV 1.1A1783V and full haploinsufficiency as caused by heterozygous truncation variants. Impaired NaV 1.1A1783V channel activation was predicted to have a significantly larger impact on channel function than altered slow inactivation and is therefore proposed as the main mechanism underlying IN dysfunction. The computational model was validated in cortical organotypic slice cultures derived from conditional Scn1aA 1783 V mice. Pan-neuronal activation of the p.Ala1783V in vitro confirmed a predicted IN firing deficit and revealed an accompanying reduction of interneuronal input resistance while demonstrating normal excitability of pyramidal neurons. Altered input resistance was fed back into the model for further refinement. Taken together these data demonstrate that primary loss of function (LOF) gating properties accompanied by altered membrane characteristics may match effects of full haploinsufficiency on the neuronal level despite maintaining physiological peak current density, thereby causing DS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Layer, Sonnenberg, Pardo González, Benda, Hedrich, Lerche, Koch and Wuttke.)- Published
- 2021
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42. Novel treatment approaches and pediatric research networks in status epilepticus.
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Bialer M, Cross H, Hedrich UBS, Lagae L, Lerche H, and Loddenkemper T
- Subjects
- Animals, Child, Humans, Sodium Channels genetics, Sodium Channels metabolism, Status Epilepticus drug therapy, Status Epilepticus genetics, Anticonvulsants therapeutic use, Pediatrics methods, Research, Status Epilepticus therapy
- Abstract
This paper contains five contributions which were presented as part of the novel therapies section of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures. These illustrate recent advances being made in the management and therapy of status epilepticus. The five contributions concern: genetic variations in Na + channel genes and their importance in status epilepticus; the European Reference Network for rare and complex epilepsies EpiCARE; the North American Pediatric Status Epilepticus Research Group (pSERG); Fenfluramine as a potential therapy for status epilepticus' and the valproate derivatives, valnoctamide and sec-butylpropylacetamide (SPD), as potential therapies for status epilepticus. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures"., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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43. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
- Author
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Helbig KL, Lauerer RJ, Bahr JC, Souza IA, Myers CT, Uysal B, Schwarz N, Gandini MA, Huang S, Keren B, Mignot C, Afenjar A, Billette de Villemeur T, Héron D, Nava C, Valence S, Buratti J, Fagerberg CR, Soerensen KP, Kibaek M, Kamsteeg EJ, Koolen DA, Gunning B, Schelhaas HJ, Kruer MC, Fox J, Bakhtiari S, Jarrar R, Padilla-Lopez S, Lindstrom K, Jin SC, Zeng X, Bilguvar K, Papavasileiou A, Xing Q, Zhu C, Boysen K, Vairo F, Lanpher BC, Klee EW, Tillema JM, Payne ET, Cousin MA, Kruisselbrink TM, Wick MJ, Baker J, Haan E, Smith N, Sadeghpour A, Davis EE, Katsanis N, Corbett MA, MacLennan AH, Gecz J, Biskup S, Goldmann E, Rodan LH, Kichula E, Segal E, Jackson KE, Asamoah A, Dimmock D, McCarrier J, Botto LD, Filloux F, Tvrdik T, Cascino GD, Klingerman S, Neumann C, Wang R, Jacobsen JC, Nolan MA, Snell RG, Lehnert K, Sadleir LG, Anderlid BM, Kvarnung M, Guerrini R, Friez MJ, Lyons MJ, Leonhard J, Kringlen G, Casas K, El Achkar CM, Smith LA, Rotenberg A, Poduri A, Sanchis-Juan A, Carss KJ, Rankin J, Zeman A, Raymond FL, Blyth M, Kerr B, Ruiz K, Urquhart J, Hughes I, Banka S, Hedrich UBS, Scheffer IE, Helbig I, Zamponi GW, Lerche H, and Mefford HC
- Published
- 2019
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44. Relationship of electrophysiological dysfunction and clinical severity in SCN2A-related epilepsies.
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Lauxmann S, Verbeek NE, Liu Y, Zaichuk M, Müller S, Lemke JR, van Kempen MJA, Lerche H, and Hedrich UBS
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- Cell Line, Electrophysiological Phenomena, Epileptic Syndromes genetics, Epileptic Syndromes metabolism, Female, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Pedigree, Phenotype, Severity of Illness Index, Amino Acid Substitution, Epileptic Syndromes physiopathology, NAV1.2 Voltage-Gated Sodium Channel genetics, NAV1.2 Voltage-Gated Sodium Channel metabolism
- Abstract
Variants in the SCN2A gene cause a broad spectrum of epilepsy syndromes of variable severity including benign neonatal-infantile epilepsy (BFNIE), developmental and epileptic encephalopathies (DEE), and other neuropsychiatric disorders. Here, we studied three newly identified variants, which caused distinct phenotypes observed in nine affected individuals of three families, including BFNIE, and DEE with intractable neonatal seizures. Whole cell patch-clamp recordings of transfected tsA201 cells disclosed an increased current density and an increased subthreshold sodium inward current upon an action potential stimulus (p.(Lys908Glu)), a hyperpolarizing shift of the activation curve (p.(Val208Glu) and p.(Thr773Ile)), and an increased persistent current (p.(Thr773Ile)). To evaluate genotype-phenotype correlations, we next developed scoring systems for both the extent of the electrophysiological dysfunction and the severity of the clinical phenotype and applied those to 21 previously and newly functionally characterized SCN2A variants. All inherited variants were associated with a mild clinical phenotype and a lower electrophysiological score compared to those occurring de novo and causing severe phenotypes. Our results thus reveal a nice correlation between the extent of channel dysfunction and the clinical severity., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
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45. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
- Author
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Helbig KL, Lauerer RJ, Bahr JC, Souza IA, Myers CT, Uysal B, Schwarz N, Gandini MA, Huang S, Keren B, Mignot C, Afenjar A, Billette de Villemeur T, Héron D, Nava C, Valence S, Buratti J, Fagerberg CR, Soerensen KP, Kibaek M, Kamsteeg EJ, Koolen DA, Gunning B, Schelhaas HJ, Kruer MC, Fox J, Bakhtiari S, Jarrar R, Padilla-Lopez S, Lindstrom K, Jin SC, Zeng X, Bilguvar K, Papavasileiou A, Xing Q, Zhu C, Boysen K, Vairo F, Lanpher BC, Klee EW, Tillema JM, Payne ET, Cousin MA, Kruisselbrink TM, Wick MJ, Baker J, Haan E, Smith N, Sadeghpour A, Davis EE, Katsanis N, Corbett MA, MacLennan AH, Gecz J, Biskup S, Goldmann E, Rodan LH, Kichula E, Segal E, Jackson KE, Asamoah A, Dimmock D, McCarrier J, Botto LD, Filloux F, Tvrdik T, Cascino GD, Klingerman S, Neumann C, Wang R, Jacobsen JC, Nolan MA, Snell RG, Lehnert K, Sadleir LG, Anderlid BM, Kvarnung M, Guerrini R, Friez MJ, Lyons MJ, Leonhard J, Kringlen G, Casas K, El Achkar CM, Smith LA, Rotenberg A, Poduri A, Sanchis-Juan A, Carss KJ, Rankin J, Zeman A, Raymond FL, Blyth M, Kerr B, Ruiz K, Urquhart J, Hughes I, Banka S, Hedrich UBS, Scheffer IE, Helbig I, Zamponi GW, Lerche H, and Mefford HC
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Male, Neurodevelopmental Disorders genetics, Calcium Channels, R-Type genetics, Cation Transport Proteins genetics, Contracture genetics, Dyskinesias genetics, Epilepsy genetics, Genetic Variation genetics, Megalencephaly genetics, Spasms, Infantile genetics
- Abstract
Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α
1 -subunit of the voltage-gated CaV 2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV 2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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46. GRIN2D Recurrent De Novo Dominant Mutation Causes a Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers.
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Li D, Yuan H, Ortiz-Gonzalez XR, Marsh ED, Tian L, McCormick EM, Kosobucki GJ, Chen W, Schulien AJ, Chiavacci R, Tankovic A, Naase C, Brueckner F, von Stülpnagel-Steinbeis C, Hu C, Kusumoto H, Hedrich UB, Elsen G, Hörtnagel K, Aizenman E, Lemke JR, Hakonarson H, Traynelis SF, and Falk MJ
- Subjects
- Amino Acid Sequence, Base Sequence, Cell Death, Child, DNA Mutational Analysis, Dendrites pathology, Electroencephalography, Exome genetics, Female, Glutamic Acid metabolism, Humans, Infant, Infant, Newborn, Ketamine therapeutic use, Magnesium therapeutic use, Memantine administration & dosage, Memantine therapeutic use, Models, Molecular, Precision Medicine, Receptors, N-Methyl-D-Aspartate chemistry, Receptors, N-Methyl-D-Aspartate genetics, Receptors, N-Methyl-D-Aspartate metabolism, Seizures drug therapy, Seizures genetics, Seizures metabolism, Spasms, Infantile metabolism, Genes, Dominant genetics, Mutation, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Spasms, Infantile drug therapy, Spasms, Infantile genetics
- Abstract
N-methyl-D-aspartate receptors (NMDARs) are ligand-gated cation channels that mediate excitatory synaptic transmission. Genetic mutations in multiple NMDAR subunits cause various childhood epilepsy syndromes. Here, we report a de novo recurrent heterozygous missense mutation-c.1999G>A (p.Val667Ile)-in a NMDAR gene previously unrecognized to harbor disease-causing mutations, GRIN2D, identified by exome and candidate panel sequencing in two unrelated children with epileptic encephalopathy. The resulting GluN2D p.Val667Ile exchange occurs in the M3 transmembrane domain involved in channel gating. This gain-of-function mutation increases glutamate and glycine potency by 2-fold, increases channel open probability by 6-fold, and reduces receptor sensitivity to endogenous negative modulators such as extracellular protons. Moreover, this mutation prolongs the deactivation time course after glutamate removal, which controls the synaptic time course. Transfection of cultured neurons with human GRIN2D cDNA harboring c.1999G>A leads to dendritic swelling and neuronal cell death, suggestive of excitotoxicity mediated by NMDAR over-activation. Because both individuals' seizures had proven refractory to conventional antiepileptic medications, the sensitivity of mutant NMDARs to FDA-approved NMDAR antagonists was evaluated. Based on these results, oral memantine was administered to both children, with resulting mild to moderate improvement in seizure burden and development. The older proband subsequently developed refractory status epilepticus, with dramatic electroclinical improvement upon treatment with ketamine and magnesium. Overall, these results suggest that NMDAR antagonists can be useful as adjuvant epilepsy therapy in individuals with GRIN2D gain-of-function mutations. This work further demonstrates the value of functionally evaluating a mutation, enabling mechanistic understanding and therapeutic modeling to realize precision medicine for epilepsy., (Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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47. A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia.
- Author
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Helbig KL, Hedrich UB, Shinde DN, Krey I, Teichmann AC, Hentschel J, Schubert J, Chamberlin AC, Huether R, Lu HM, Alcaraz WA, Tang S, Jungbluth C, Dugan SL, Vainionpää L, Karle KN, Synofzik M, Schöls L, Schüle R, Lehesjoki AE, Helbig I, Lerche H, and Lemke JR
- Subjects
- Adult, Animals, Ataxia physiopathology, Child, Exome, Female, Humans, Intellectual Disability physiopathology, Male, Middle Aged, Mutation, Oocytes metabolism, Pedigree, Spastic Paraplegia, Hereditary physiopathology, Xenopus laevis, Young Adult, Ataxia genetics, Intellectual Disability genetics, Kv1.2 Potassium Channel genetics, Spastic Paraplegia, Hereditary genetics
- Abstract
The hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders with over 50 known causative genes. We identified a recurrent mutation in KCNA2 (c.881G>A, p.R294H), encoding the voltage-gated K(+) -channel, KV 1.2, in two unrelated families with HSP, intellectual disability (ID), and ataxia. Follow-up analysis of > 2,000 patients with various neurological phenotypes identified a de novo p.R294H mutation in a proband with ataxia and ID. Two-electrode voltage-clamp recordings of Xenopus laevis oocytes expressing mutant KV 1.2 channels showed loss of function with a dominant-negative effect. Our findings highlight the phenotypic spectrum of a recurrent KCNA2 mutation, implicating ion channel dysfunction as a novel HSP disease mechanism. Ann Neurol 2016., (© 2016 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)
- Published
- 2016
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48. Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation.
- Author
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Hedrich UB, Liautard C, Kirschenbaum D, Pofahl M, Lavigne J, Liu Y, Theiss S, Slotta J, Escayg A, Dihné M, Beck H, Mantegazza M, and Lerche H
- Subjects
- Animals, Axons metabolism, Axons physiology, Brain cytology, Brain metabolism, Brain physiopathology, Calcium metabolism, Cells, Cultured, Epilepsy genetics, Epilepsy metabolism, GABAergic Neurons metabolism, Humans, Inhibitory Postsynaptic Potentials, Interneurons metabolism, Interneurons physiology, Mice, Mice, Inbred C57BL, NAV1.1 Voltage-Gated Sodium Channel metabolism, Nerve Net cytology, Nerve Net metabolism, Action Potentials, Epilepsy physiopathology, GABAergic Neurons physiology, Mutation, NAV1.1 Voltage-Gated Sodium Channel genetics, Nerve Net physiopathology
- Abstract
Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na(+) channels in interneurons and persistent Na(+) currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca(2+) imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation., (Copyright © 2014 the authors 0270-6474/14/3414874-16$15.00/0.)
- Published
- 2014
- Full Text
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