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1. Distinct gene-set burden patterns underlie common generalized and focal epilepsies

Author

Mahmoud Koko, Roland Krause, Thomas Sander, Dheeraj Reddy Bobbili, Michael Nothnagel, Patrick May, Holger Lerche, Yen-Chen Anne Feng, Daniel P Howrigan, Liam E Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L Heinzen, Ryan S Dhindsa, Kate E Stanley, Gianpiero L Cavalleri, Hakon Hakonarson, Ingo Helbig, Sarah Weckhuysen, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M Sisodiya, Patrick Cossette, Chris Cotsapas, Peter DeJonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G Marson, Randy Stewart, Chantal Depondt, Dennis J Dlugos, Ingrid E Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M Regan, Susannah T Bellows, Costin Leu, Caitlin A Bennett, Esther M C Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J O'Brien, Marian Todaro, Hannah Stamberger, Danielle M Andrade, Tara R Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S Papacostas, Ioanna Kousiappa, George A Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S Reif, Susanne Knake, Wolfram S Kunz, Gábor Zsurka, Christian E Elger, Jürgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas vanBaalen, Sarah vonSpiczak, Ulrich Stephani, Zaid Afawi, Amos D Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R Lemke, Ilona Krey, Yvonne G Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F Maisch, Bernhard J Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I Rees, Seo-Kyung Chung, William O Pickrell, Robert Powell, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R Johnson, Pauls Auce, Graeme J Sills, Larry W Baum, Pak C Sham, Stacey S Cherny, Colin H T Lui, Nina Barišić, Norman Delanty, Colin P Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G Sadleir, Chontelle King, Emily Mountier, Hande S Caglayan, Mutluay Arslan, Zuhal Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, Annapurna Poduri, Beth R Shiedley, Catherine Shain, Russell J Buono, Thomas N Ferraro, Michael R Sperling, Warren Lo, Michael Privitera, Jacqueline A French, Steven Schachter, Ruben I Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L Helbig, Colin A Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T Pato, Carlos N Pato, Evelyn J Bromet, Celia Barreto Carvalho, Eric D Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S Lehrer, Dolores Malaspina, Stephen R Marder, Helena Medeiros, Christopher P Morley, Diana O Perkins, Janet L Sobell, Peter F Buckley, Fabio Macciardi, Mark H Rapaport, James A Knowles, Genomic Psychiatry Cohort, Ayman H Fanous, Steven A McCarroll, Namrata Gupta, Stacey B Gabriel, Mark J Daly, Eric S Lander, Daniel H Lowenstein, David B Goldstein, Samuel F Berkovic, Benjamin M Neale, Epi25 Collaborative, Koko M., Krause R., Sander T., Bobbili D.R., Nothnagel M., May P., Lerche H., Bisulli F., Tinuper P., Pippucci T., Abbott, Liam E., Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Tashman, Katherine, Korinthenberg, Rudolf, Brockmann, Knut, Kurlemann, Gerhard, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Cerrato, Felecia, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Singh, Tarjinder, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišic, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, Heyne, Henrike, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Byrnes, Andrea, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Churchhouse, Claire, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Watts, Nick, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, Hande S., Arslan, Mutluay, Yapici, Zuhal, Yis, Uluc, Solomonson, Matthew, Topaloglu, Pinar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Asli, Bebek, Nerses, Ugur-Iseri, Sibel, Baykan, Betül, Salman, Baris, Haryanyan, Garen, Yücesan, Emrah, Lal, Dennis, Kesim, Yesim, Özkara, Çigdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, Heinzen, Erin L., French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Dhindsa, Ryan S., Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Stanley, Kate E., Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Cavalleri, Gianpiero L., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Cohort, Genomic Psychiatry, Fanous, Ayman H., Hakonarson, Hakon, McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., Neale, Benjamin M., Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, DeJonghe, Peter, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O'Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Šterbová, Katalin, Vlcková, Markéta, Sedlácková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Feng, Yen-Chen Anne, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, van Baalen, Andreas, von Spiczak, Sarah, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Howrigan, Daniel P., Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany). [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]

Subjects
Exome sequencing, Male, Medicine (General), Neurology [D14] [Human health sciences], Gene-set, Genome-wide association study, Disease, Biology, Epileptogenesis, General Biochemistry, Genetics and Molecular Biology, Whole Exome Sequencing, Epilepsy, R5-920, medicine, Missense mutation, Humans, Exome, Genetic Predisposition to Disease, Gene, Genetic association, Ultra-rare variant, Genetics, Neurologie [D14] [Sciences de la santé humaine], Burden analysis, Genetic Variation, General Medicine, medicine.disease, Ultra-rare variants, Gene-sets, Case-Control Studies, Medicine, epilepsy, Epilepsy, Generalized, Female, Genetics & genetic processes [F10] [Life sciences], Epilepsies, Partial, Human medicine, Burden analysi, Génétique & processus génétiques [F10] [Sciences du vivant], Case-Control Studie, Research Paper, Genome-Wide Association Study, Human
Abstract

EBioMedicine 72, 103588 (2021). doi:10.1016/j.ebiom.2021.103588, Published by Elsevier, Amsterdam [u.a.]

Published
2021
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2. Genotypes and phenotypes of patients with Lafora disease living in Germany

Author

Saskia Biskup, Jan Wagner, Dennis Döcker, Claudia D. Wurster, Roger Weis, Albert C. Ludolph, Anja Grimmer, Berge A. Minassian, Petra Gaspirova, Christian E. Elger, Jan Lewerenz, David A. Brenner, Tobias Baumgartner, Wolfram S. Kunz, and Sarah von Spiczak

Subjects
0301 basic medicine, medicine.medical_specialty, Pediatrics, congenital, hereditary, and neonatal diseases and abnormalities, Neurology, business.industry, Disease, Progressive myoclonus epilepsy, medicine.disease, Lafora disease, Article, lcsh:RC346-429, lcsh:RC321-571, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Genotype-phenotype distinction, Epidemiology, Medicine, business, Laforin, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, 030217 neurology & neurosurgery, Exome sequencing, lcsh:Neurology. Diseases of the nervous system
Abstract

Background Lafora progressive myoclonus epilepsy (Lafora disease) is a rare, usually childhood-onset, fatal neurodegenerative disease caused by biallelic mutations in EPM2A (Laforin) or EPM2B (NHLRC1; Malin). The epidemiology of Lafora disease in Germany is largely unknown. The objective of this retrospective case series is to characterize the genotypes and phenotypes of patients with Lafora disease living in Germany. Methods The patients described in this case series initially had the suspected clinical diagnosis of Lafora disease, or unclassified progressive myoclonus epilepsy. Molecular genetic diagnostics including next generation sequencing-based diagnostic panel analysis or whole exome sequencing was performed. Results The parents of four out of the 11 patients are nonconsanguineous and of German origin while the other patients had consanguineous parents. Various variants were found in EPM2A (six patients) and in EPM2B (five patients). Eight variants have not been reported in the literature so far. The patients bearing novel variants had typical disease onset during adolescence and show classical disease courses. Conclusions This is the first larger case series of Lafora patients in Germany. Our data enable an approximation of the prevalence of manifest Lafora disease in Germany to 1,69 per 10 million people. Broader application of gene panel or whole-exome diagnostics helps clarifying unclassified progressive myoclonus epilepsy and establish an early diagnosis, which will be even more important as causal therapy approaches have been developed and are soon to be tested in a phase I study.

Published
2019
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3. Distinct segregation of the pathogenic m.5667G>A mitochondrial tRNAAsn mutation in extraocular and skeletal muscle in chronic progressive external ophthalmoplegia

Author

E. Schlapakow, Wolfram S. Kunz, Monika Jeub, Cornelia Kornblum, Bettina Wabbels, Gábor Zsurka, and Viktoriya Peeva

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Mitochondrial DNA, Biology, Extraocular muscles, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, medicine, Cytochrome c oxidase, Genetics (clinical), Mutation, Significant difference, Skeletal muscle, medicine.disease, eye diseases, Heteroplasmy, 030104 developmental biology, medicine.anatomical_structure, Neurology, Pediatrics, Perinatology and Child Health, biology.protein, sense organs, Neurology (clinical), Chronic progressive external ophthalmoplegia, 030217 neurology & neurosurgery
Abstract

Chronic progressive external ophthalmoplegia (CPEO) is a frequent clinical manifestation of disorders caused by pathogenic mitochondrial DNA mutations. However, for diagnostic purposes skeletal muscle tissue is used, since extraocular muscle tissue is usually not available for work-up. In the present study we aimed to identify causative factors that are responsible for extraocular muscle to be primarily affected in CPEO. We performed comparative histochemical and molecular genetic analyses of extraocular muscle and skeletal muscle single fibers in a case of isolated CPEO caused by the heteroplasmic m.5667G>A mutation in the mitochondrial tRNAAsn gene (MT-TN). Histochemical analyses revealed higher proportion of cytochrome c oxidase deficient fibers in extraocular muscle (41%) compared to skeletal muscle (10%). However, genetic analyses of single fibers revealed no significant difference either in the mutation loads between extraocular muscle and skeletal muscle cytochrome c oxidase deficient single fibers (extraocular muscle 86% ± 4.6%; skeletal muscle 87.8 %± 5.7%, p = 0.246) nor in the mutation threshold (extraocular muscle 74% ± 3%; skeletal muscle 74% ± 4%). We hypothesize that higher proportion of cytochrome c oxidase deficient fibers in extraocular muscle compared to skeletal muscle might be due to facilitated segregation of the m.5667G>A mutation into extraocular muscle, which may explain the preferential ocular manifestation and clinically isolated CPEO.

Published
2019
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4. Heterozygous variants in KCNC2 cause a broad spectrum of epilepsy phenotypes associated with characteristic functional alterations

Author

Manuela Pendziwiat, Renske Oegema, Ioanna Kousiappa, Yvonne G. Weber, Francesca Ragona, Dennis Lal, Ulrike B. S. Hedrich, Mulahasanovic L, Gali Heimer, Kearney H, Hiltrud Muhle, Pasquale Striano, Paolo Scudieri, Annika Rademacher, Rothschild A, Michele Iacomino, Lohmann E, Augustijn Pb, Russell J. Buono, Holger Lerche, Philipp S. Reif, George A. Tanteles, Karl Martin Klein, Bayat A, Francesca Bisulli, Wolfram S. Kunz, Montgomery S, Bruria Bz, Papacostas Ss, Renzo Guerrini, Laura Licchetta, Ingo Helbig, Bruenger T, Federico Zara, Zahnert F, Marie T. McDonald, Hartmut Baier, Patrick May, Niklas Schwarz, Doyle Mg, Simone Seiffert, Vetro A, Paolo Tinuper, Ortal B, Tiziana Granata, Felix Rosenow, and Raffaella Minardi

Subjects
Genetics, Valproic Acid, Broad spectrum, Epilepsy, biology, Xenopus, medicine, Causative gene, biology.organism_classification, medicine.disease, Phenotype, Exome sequencing, medicine.drug
Abstract

BackgroundKCNC2 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.MethodsIndividuals 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.ResultsWe 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.ConclusionThese 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.

Published
2021
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5. Impaired complex I repair causes recessive Leber’s hereditary optic neuropathy

Author

Yulya S. Itkis, Maja Hempel, Ben Pode-Shakked, Piero Barboni, N.L. Sheremet, Polina G. Tsygankova, Riccardo Berutti, Valerio Carelli, Chiara La Morgia, Daniele Ghezzi, Leonardo Caporali, Jean-Michel Rozet, Natalia A. Andreeva, Amelie T van der Ven, Peter Charbel Issa, Wolfram S. Kunz, Sarah L. Stenton, Claudia B. Catarino, Johannes A. Mayr, Matias Wagner, Maria Lucia Cascavilla, Flavia Palombo, Reka Kovacs-Nagy, Ilka Wittig, Alessandra Maresca, Pedro Felipe Malacarne, Thomas Klopstock, Costanza Lamperti, Sylvie Gerber, Cornelia Kornblum, Holger Prokisch, Nino V. Zhorzholadze, Jana Meisterknecht, Robert Kopajtich, Tatiana A. Nevinitsyna, Ekaterina Zakharova, Michele Carbonelli, Tatiana D. Krylova, Michal Tzadok, Elisabeth Graf, Zahra Assouline, Francesca Tagliavini, Josseline Kaplan, Maria S. Shmelkova, Mariantonietta Capristo, Elise Héon, Ortal Barel, Peter Freisinger, Elisheva Javasky, Igor Bychkov, Christina Ludwig, Tim M. Strom, Catherine Vignal-Clermont, Juliana Heidler, Stenton S.L., Sheremet N.L., Catarino C.B., Andreeva N.A., Assouline Z., Barboni P., Barel O., Berutti R., Bychkov I., Caporali L., Capristo M., Carbonelli M., Cascavilla M.L., Charbel Issa P., Freisinger P., Gerber S., Ghezzi D., Graf E., Heidler J., Hempel M., Heon E., Itkis Y.S., Javasky E., Kaplan J., Kopajtich R., Kornblum C., Kovacs-Nagy R., Krylova T.D., Kunz W.S., La Morgia C., Lamperti C., Ludwig C., Malacarne P.F., Maresca A., Mayr J.A., Meisterknecht J., Nevinitsyna T.A., Palombo F., Pode-Shakked B., Shmelkova M.S., Strom T.M., Tagliavini F., Tzadok M., Van der Ven A.T., Vignal-Clermont C., Wagner M., Zakharova E.Y., Zhorzholadze N.V., Rozet J.-M., Carelli V., Tsygankova P.G., Klopstock T., Wittig I., and Prokisch H.

Subjects
Male, 0301 basic medicine, chemistry [Electron Transport Complex I], genetic structures, deficiency [HSP40 Heat-Shock Proteins], Genetic disease, Respiratory chain, Penetrance, metabolism [Optic Atrophy, Hereditary, Leber], Gene Knockout Techniques, metabolism [HSP40 Heat-Shock Proteins], 0302 clinical medicine, Idebenone, metabolism [Reactive Oxygen Species], Protein Subunit, Genetics, Homozygote, Gene Knockout Technique, Leber's hereditary optic neuropathy, General Medicine, Middle Aged, Pedigree, Phenotype, Child, Preschool, 030220 oncology & carcinogenesis, Female, Reactive Oxygen Specie, genetics [HSP40 Heat-Shock Proteins], Genetic diseases, Human, medicine.drug, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Mitochondrial DNA, Adolescent, Mitochondrial disease, Genes, Recessive, Optic Atrophy, Hereditary, Leber, Biology, Cell Line, Young Adult, 03 medical and health sciences, Genetic, medicine, Humans, ddc:610, metabolism [Electron Transport Complex I], Gene, Electron Transport Complex I, Point mutation, nutritional and metabolic diseases, HSP40 Heat-Shock Proteins, medicine.disease, eye diseases, Protein Subunits, 030104 developmental biology, genetics [Optic Atrophy, Hereditary, Leber], Mutation, Commentary, HSP40 Heat-Shock Protein, Reactive Oxygen Species, Neuroscience
Abstract

Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial DNA (mtDNA). A molecular diagnosis is achieved in up to 95% of cases, the vast majority of which are accounted for by 3 mutations within mitochondrial complex I subunit-encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON were recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30-knockout cellular model, we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function. These results demonstrate that DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism, thereby providing the first example to our knowledge of a disease resulting from impaired exchange of assembled respiratory chain subunits.

Published
2021
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6. Impairment of mitochondrial oxidative phosphorylation in skin fibroblasts of SALS and FALS patients is rescued by in vitro treatment with ROS scavengers

Author

Stefanie Schreiber, Jarosław Walczak, Irina Miller, Werner Zuschratter, Joanna Szczepanowska, Wolfram S. Kunz, Susanne Petri, Grazyna Debska-Vielhaber, Viktoriya Peeva, Frank N. Gellerich, Judith Machts, Andreas Hermann, Stefan Vielhaber, and Susanne Vogt

Subjects
0301 basic medicine, Male, Mitochondrion, medicine.disease_cause, Oxidative Phosphorylation, 0302 clinical medicine, C9orf72, metabolism [Reactive Oxygen Species], Amyotrophic lateral sclerosis, Cells, Cultured, Skin, Free Radical Scavengers, Middle Aged, Mitochondria, Neurology, Female, metabolism [Fibroblasts], Adult, Mitochondrial DNA, SOD1, Skin fibroblasts, Oxidative phosphorylation, Biology, TARDBP, 03 medical and health sciences, Young Adult, metabolism [Skin], Developmental Neuroscience, medicine, Humans, ddc:610, drug effects [Skin], pathology [Amyotrophic Lateral Sclerosis], Aged, drug therapy [Amyotrophic Lateral Sclerosis], metabolism [Amyotrophic Lateral Sclerosis], Amyotrophic Lateral Sclerosis, Fibroblasts, medicine.disease, metabolism [Mitochondria], 030104 developmental biology, pharmacology [Free Radical Scavengers], Oxidative stress, therapeutic use [Free Radical Scavengers], Cancer research, Mitochondrial dysfunction, Reactive Oxygen Species, 030217 neurology & neurosurgery
Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive, neurodegenerative disorder affecting upper and lower motor neurons. Approximately 10% of patients suffer from familial ALS (FALS) with mutations in different ubiquitously expressed genes including SOD1, C9ORF72, TARDBP, and FUS. There is compelling evidence for mitochondrial involvement in the pathogenic mechanisms of FALS and sporadic ALS (SALS), which is believed to be relevant for disease. Owing to the ubiquitous expression of relevant disease-associated genes, mitochondrial dysfunction is also detectable in peripheral patient tissue. We here report results of a detailed investigation of the functional impairment of mitochondrial oxidative phosphorylation (OXPHOS) in cultured skin fibroblasts from 23 SALS and 17 FALS patients, harboring pathogenic mutations in SOD1, C9ORF72, TARDBP and FUS. A considerable functional and structural mitochondrial impairment was detectable in fibroblasts from patients with SALS. Similarly, fibroblasts from patients with FALS, harboring pathogenic mutations in TARDBP, FUS and SOD1, showed mitochondrial defects, while fibroblasts from C9ORF72 associated FALS showed a very mild impairment detectable in mitochondrial ATP production rates only. While we could not detect alterations in the mtDNA copy number in the SALS or FALS fibroblast cultures, the impairment of OXPHOS in SALS fibroblasts and SOD1 or TARDBP FALS could be rescued by in vitro treatments with CoQ10 (5 μM for 3 weeks) or Trolox (300 μM for 5 days). This underlines the role of elevated oxidative stress as a potential cause for the observed functional effects on mitochondria, which might be relevant disease modifying factors.

Published
2021
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7. Novel KCNH1 Mutations Associated with Epilepsy: Broadening the Phenotypic Spectrum of KCNH1-Associated Diseases

Author

Susanne Schoch, Hanns-Georg Klein, Monika Jeub, Wolfram S. Kunz, Idil Ariöz, Randi von Wrede, Albert J. Becker, Hubertus von Voss, Christian E. Elger, and Rainer Surges

Subjects
0301 basic medicine, Adult, Male, Models, Molecular, lcsh:QH426-470, Protein Conformation, Kv10.1 potassium channel, Nonsense mutation, Mutation, Missense, Biology, Article, 03 medical and health sciences, Epilepsy, Structure-Activity Relationship, 0302 clinical medicine, Germline mutation, KCNH1 mutations, Exome Sequencing, Genetics, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Child, Genetics (clinical), Genetic Association Studies, Germ-Line Mutation, Base Sequence, Computational Biology, High-Throughput Nucleotide Sequencing, Electroencephalography, Cortical dysplasia, medicine.disease, Phenotype, Penetrance, Magnetic Resonance Imaging, Ether-A-Go-Go Potassium Channels, lcsh:Genetics, 030104 developmental biology, Mutation, Female, Haploinsufficiency, 030217 neurology & neurosurgery
Abstract

Here, we describe four patients suffering from a rather broad spectrum of epilepsy-related disorders, ranging from developmental and epileptic encephalopathy with intellectual disability (DEE) to genetic generalized epilepsy (GGE), which all harbor novel KCNH1 mutations. In one family, we found a weak association of a novel nonsense mutation with epilepsy, suggesting reduced penetrance, and which shows, in agreement with previous findings, that gain-of-function effects rather than haploinsufficiency are important for the pathogenicity of mutations. De novo missense variants in the pore region of the channel result in severe phenotypes presenting usually with DEE with various malformations. The potential pathogenicity of a novel KCNH1 germline mutation located outside of the critical pore domain observed in a GGE patient with a milder phenotype is supported by the fact that the very same amino acid exchange was detected as a somatic mutation in the resected brain tissue of a patient suffering from a focal cortical dysplasia type IIb. Thus, our case series broadens the phenotypic spectrum of KCNH1-associated diseases.

Published
2021

8. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Joshua E. Motelow, Gundula Povysil, Ryan S. Dhindsa, Kate E. Stanley, Andrew S. Al- len, Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Ka- therine Tashman, Felecia Cerrato, Caroline Cusick, Tarjinder Singh, Henrike Heyne, Andrea E. Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Namrata Gupta, Benjamin M. Neale, Gianpiero L. Cavalleri, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Hakon Hakonarson, Erin L. Heinzen, Ingo Helbig, Patrick Kwan, Anthony G. Marson, Slave ? Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Randy Stewart, Sarah Weckhuysen, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Roland Krause, Patrick May, Kevin McKenna, Brigid M. Regan, Caitlin A. Bennett, Costin Leu, Stephanie L. Leech, Terence J. O'Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Quratulain Zulfiqar Ali, Tara R. Sadoway, Heinz Krestel, Andre ? Schaller, Savvas S. Papacostas, Ioanna Kou- siappa, George A. Tanteles, Yiolanda Christou, Katalin Sterbova ?, Marke ? ta Vlckova ?, Lucie Sedlackova, Petra Lassuthova ?, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Bernd A. Neubauer, Friedrich Zimprich, Martha Feucht, Eva M. Reinthaler, Wolfram S. Kunz, Ga ?bor Zsurka, Rainer Surges, Tobias Baumgart- ner, Randi von Wrede, Manuela Pendziwiat, Hiltrud Muhle, An- nika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Mu ?ller-Schlu ?ter, Gerhard Kluger, Martin Ha ?usler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Stephan Lauxmann, Christian Boßelmann, Josua Kegele, Christian Hengs- bach, Sarah Rau, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, IngoBorggra ?fe, ChristophJ.Schankin, SusanneSchubert-Bast, Herbert Schreiber, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Markus Wolff, Dieter Dennig, Rene Madeleyn, Reetta Ka ?lvia ?inen, Anni Saarela, Oskari Timonen, Tarja Linnankivi, Anna-Elina Lehesjoki, Sylvain Rheims, Gaetan Lesca, Philippe Ryvlin, Louis Maillard, Luc Valton, Philippe Derambure, Fabrice Bartolomei, Edouard Hirsch, Ve ?ronique Michel, Francine Chas- soux, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Mark D. Baker, Beata Fonferko-Shadrach, Charlotte Law- thom, Joseph Anderson, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Norman Delanty, Colin P. Doherty, Arif Shukralla, Hany El-Naggar, Peter Widdess-Walsh, Nina Barisic, Laura 12 The American Journal of Human Genetics 108, 1-18, June 3, 2021 Please cite this article in press as: Epi25 Collaborative, Sub-genic intolerance, ClinVar, the epilepsies: A whole-exome sequencing study of 29, 165 individuals, The American Journal of Human Genetics (2021), https://doi.org/10.1016/j.ajhg.2021.04.009 Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Francesca Ragona, Federico Zara, Michele Iacomino, An- tonella Riva, Francesca Madia, Maria Stella Vari, Vincenzo Salpie- tro, Marcello Scala, Maria Margherita Mancardi, Lino Nobili, Elisa- betta Amadori, Thea Giacomini, Francesca Bisulli, Tommaso Pippucci, Laura Licchetta, Raffaella Minardi, Paolo Tinuper, Lor- enzo Muccioli, Barbara Mostacci, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carmen Barba, Shinichi Hirose, At- sushi Ishii, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Ahmad Beydoun, Wassim Nasreddine, Nathalie Khoueiry Zgheib, Birute Tumiene, Algirdas Utkus, Lynette G. Sadleir, Chontelle King, S. Hande Caglayan, Mutluay Arslan, Zuhal Yap?c?, P?nar To- paloglu, Bulent Kara, Uluc Yis, Dilsad Turkdogan, Asl? Gun- dogdu-Eken, Nerses Bebek, Meng-Han Tsai, Chen-Jui Ho, Chih- Hsiang Lin, Kuang-Lin Lin, I-Jun Chou, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Jeffrey L. Noebels, Alicia Goldman, Robyn M. Busch, Lara Jehi, Imad M. Najm, Lisa Ferguson, Jean Khoury, Tracy A. Glauser, Peggy O. Clark, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jac- queline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, David A. Greenberg, Colin A. Ellis, Ethan Goldberg, Katherine L. Helbig, Mahgenn Cosico, Priya Vaidis- waran, Eryn Fitch, Samuel F. Berkovic, Holger Lerche, Daniel H. Lowenstein, David B. Goldstein., Motelow J.E., Povysil G., Dhindsa R.S., Stanley K.E., Allen A.S., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Cusick C., Singh T., Heyne H., Byrnes A.E., Churchhouse C., Watts N., Solomonson M., Lal D., Gupta N., Neale B.M., Cavalleri G.L., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Sisodiya S.M., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bennett C.A., Leu C., Leech S.L., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Ali Q.Z., Sadoway T.R., Krestel H., Schaller A., Papacostas S.S., Kousiappa I., Tanteles G.A., Christou Y., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Neubauer B.A., Zimprich F., Feucht M., Reinthaler E.M., Kunz W.S., Zsurka G., Surges R., Baumgartner T., von Wrede R., Pendziwiat M., Muhle H., Rademacher A., van Baalen A., von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Lauxmann S., Bosselmann C., Kegele J., Hengsbach C., Rau S., Steinhoff B.J., Schulze-Bonhage A., Borggrafe I., Schankin C.J., Schubert-Bast S., Schreiber H., Mayer T., Korinthenberg R., Brockmann K., Wolff M., Dennig D., Madeleyn R., Kalviainen R., Saarela A., Timonen O., Linnankivi T., Lehesjoki A.-E., Rheims S., Lesca G., Ryvlin P., Maillard L., Valton L., Derambure P., Bartolomei F., Hirsch E., Michel V., Chassoux F., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Baker M.D., Fonferko-Shadrach B., Lawthom C., Anderson J., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Delanty N., Doherty C.P., Shukralla A., El-Naggar H., Widdess-Walsh P., Barisic N., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Ragona F., Zara F., Iacomino M., Riva A., Madia F., Vari M.S., Salpietro V., Scala M., Mancardi M.M., Nobili L., Amadori E., Giacomini T., Bisulli F., Pippucci T., Licchetta L., Minardi R., Tinuper P., Muccioli L., Mostacci B., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Barba C., Hirose S., Ishii A., Suzuki T., Inoue Y., Yamakawa K., Beydoun A., Nasreddine W., Khoueiry Zgheib N., Tumiene B., Utkus A., Sadleir L.G., King C., Caglayan S.H., Arslan M., Yapici Z., Topaloglu P., Kara B., Yis U., Turkdogan D., Gundogdu-Eken A., Bebek N., Tsai M.-H., Ho C.-J., Lin C.-H., Lin K.-L., Chou I.-J., Poduri A., Shiedley B.R., Shain C., Noebels J.L., Goldman A., Busch R.M., Jehi L., Najm I.M., Ferguson L., Khoury J., Glauser T.A., Clark P.O., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Greenberg D.A., Ellis C.A., Goldberg E., Helbig K.L., Cosico M., Vaidiswaran P., Fitch E., Berkovic S.F., Lerche H., Lowenstein D.H., Goldstein D.B., Epi25 Collaborative, Institut de Neurosciences des Systèmes (INS), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, focal epilepsy, Whole Exome Sequencing, Cohort Studies, Epilepsy, 0302 clinical medicine, Genetic Marker, Missense mutation, Exome, whole-exome sequencing, generalized epilepsy, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Exome sequencing, seizures, Genetics, ClinVar, Phenotype, epileptic encephalopathy, Epi25, intolerance, Case-Control Studie, Human, Genetic Markers, seizure, Disease Association, Biology, Article, 03 medical and health sciences, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Generalized epilepsy, Gene, Louvain, [SCCO.NEUR]Cognitive science/Neuroscience, Correction, Genetic Variation, medicine.disease, epilepsy, Human genetics, 030104 developmental biology, Case-Control Studies, Human medicine, Cohort Studie, Genetic generalized epilepsy, 030217 neurology & neurosurgery
Abstract

Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Published
2021
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9. Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Author

Schijven, D., Stevelink, R., Mccormack, M., van Rheenen, W., Luykx, J. J., Koeleman, B. P. C., Veldink, J. H., Aleksey, Shatunov, Mclaughlin, Russell L., van der Spek, Rick A. A., Alfredo, Iacoangeli, Kenna, Kevin P., van Eijk, Kristel R., Nicola, Ticozzi, Boris, Rogelj, Katarina, Vrabec, Metka, Ravnik-Glavač, Blaž, Koritnik, Janez, Zidar, Lea, Leonardis, Leja Dolenc Grošelj, Stéphanie, Millecamps, François, Salachas, Vincent, Meininger, Mamede de Carvalho, Susana, Pinto, Marta, Gromicho, Ana, Pronto-Laborinho, Mora, Jesus S., Ricardo, Rojas-García, Meraida, Polak, Siddharthan, Chandran, Shuna, Colville, Robert, Swingler, Morrison, Karen E., Shaw, Pamela J., John, Hardy, Orrell, Richard W., Alan, Pittman, Katie, Sidle, Pietro, Fratta, Andrea, Malaspina, Simon, Topp, Susanne, Petri, Susanna, Abdulla, Carsten, Drepper, Michael, Sendtner, Thomas, Meyer, Ophoff, Roel A., Staats, Kim A., Martina, Wiedau-Pazos, Catherine, Lomen-Hoerth, Van Deerlin, Vivianna M., Trojanowski, John Q., Lauren, Elman, Leo, Mccluskey, Nazli Basak, A., Thomas, Meitinger, Peter, Lichtner, Milena, Blagojevic-Radivojkov, Andres, Christian R., Gilbert, Bensimon, Bernhard, Landwehrmeyer, Alexis, Brice, Payan, Christine A. M., Safaa, Saker-Delye, Alexandra, Dürr, Wood, Nicholas W., Lukas, Tittmann, Wolfgang, Lieb, Andre, Franke, Marcella, Rietschel, Sven, Cichon, Nöthen, Markus M., Philippe, Amouyel, Christophe, Tzourio, Jean-François, Dartigues, Uitterlinden, Andre G., Fernando, Rivadeneira, Karol, Estrada, Albert, Hofman, Charles, Curtis, van der Kooi, Anneke J., Markus, Weber, Shaw, Christopher E., Smith, Bradley N., Daisy, Sproviero, Cristina, Cereda, Mauro, Ceroni, Luca, Diamanti, Roberto Del Bo, Stefania, Corti, Comi, Giacomo P., Sandra, D'Alfonso, Lucia, Corrado, Bertolin, Cinzia, Soraru', Gianni, Letizia, Mazzini, Viviana, Pensato, Cinzia, Gellera, Cinzia, Tiloca, Antonia, Ratti, Andrea, Calvo, Cristina, Moglia, Maura, Brunetti, Simona, Arcuti, Rosa, Capozzo, Chiara, Zecca, Christian, Lunetta, Silvana, Penco, Nilo, Riva, Alessandro, Padovani, Massimiliano, Filosto, Ian, Blair, Nicholson, Garth A., Rowe, Dominic B., Roger, Pamphlett, Kiernan, Matthew C., Julian, Grosskreutz, Witte, Otto W., Robert, Steinbach, Tino, Prell, Beatrice, Stubendorff, Ingo, Kurth, Hübner, Christian A., Nigel Leigh, P., Federico, Casale, Adriano, Chio, Ettore, Beghi, Elisabetta, Pupillo, Rosanna, Tortelli, Giancarlo, Logroscino, John, Powell, Ludolph, Albert C., Weishaupt, Jochen H., Wim, Robberecht, Philip Van Damme, Brown, Robert H., Glass, Jonathan D., Landers, John E., Orla, Hardiman, Andersen, Peter M., Philippe, Corcia, Patrick, Vourc'H, Vincenzo, Silani, van Es, Michael A., Jeroen Pasterkamp, R., Lewis, Cathryn M., Gerome, Breen, Ammar, Al-Chalabi, van den Berg, Leonard H., Veldink, Jan H., Daniela, Calini, Isabella, Fogh, Barbara, Castellotti, Franco, Taroni, Stella, Gagliardi, Giacomo, Comi, Sandra, D’Alfonso, Pegoraro, Elena, Giorgia, Querin, Francesca, Gerardi, Fabrizio, Rinaldi, Maria Sofia Cotelli, Luca, Chiveri, Maria Cristina Guaita, Patrizia, Perrone, Giancarlo, Comi, Carlo, Ferrarese, Lucio, Tremolizzo, Marialuisa, Delodovici, Giorgio, Bono, Stefania, Cammarosano, Antonio, Canosa, Dario, Cocito, Leonardo, Lopiano, Luca, Durelli, Bruno, Ferrero, Antonio, Bertolotto, Alessandro, Mauro, Luca, Pradotto, Roberto, Cantello, Enrica, Bersano, Dario, Giobbe, Maurizio, Gionco, Daniela, Leotta, Lucia, Appendino, Cavallo, Cavallo, Enrico, Odddenino, Claudio, Geda, Fabio, Poglio, Paola, Santimaria, Umberto, Massazza, Antonio, Villani, Roberto, Conti, Fabrizio, Pisano, Mario, Palermo, Franco, Vergnano, Paolo, Provera, Maria Teresa Penza, Marco, Aguggia, Nicoletta Di Vito, Piero, Meineri, Ilaria, Pastore, Paolo, Ghiglione, Danilo, Seliak, Nicola, Launaro, Giovanni, Astegiano, Bottacchi, Edo, Isabella Laura Simone, Stefano, Zoccolella, Michele, Zarrelli, Franco, Apollo, William, Camu, Jean Sebastien Hulot, Francois, Viallet, Philippe, Couratier, David, Maltete, Christine, Tranchant, Marie, Vidailhet, Bassel, Abou-Khalil, Pauls, Auce, Andreja, Avbersek, Melanie, Bahlo, David, J Balding, Thomas, Bast, Larry, Baum, Albert, J Becker, Felicitas, Becker, Bianca, Berghuis, Samuel, F Berkovic, Katja, E Boysen, Jonathan, P Bradfield, Lawrence, C Brody, Russell, J Buono, Ellen, Campbell, Gregory, D Cascino, Claudia, B Catarino, Gianpiero, L Cavalleri, Stacey, S Cherny, Krishna, Chinthapalli, Alison, J Coffey, Alastair, Compston, Antonietta, Coppola, Patrick, Cossette, John, J Craig, Gerrit-Jan de Haan, Peter De Jonghe, Carolien G, F de Kovel, Norman, Delanty, Chantal, Depondt, Orrin, Devinsky, Dennis, J Dlugos, Colin, P Doherty, Christian, E Elger, Johan, G Eriksson, Thomas, N Ferraro, Martha, Feucht, Ben, Francis, Jacqueline, A French, Saskia, Freytag, Verena, Gaus, Eric, B Geller, Christian, Gieger, Tracy, Glauser, Simon, Glynn, David, B Goldstein, Hongsheng, Gui, Youling, Guo, Kevin, F Haas, Hakon, Hakonarson, Kerstin, Hallmann, Sheryl, Haut, Erin, L Heinzen, Ingo, Helbig, Christian, Hengsbach, Helle, Hjalgrim, Michele, Iacomino, Andrés, Ingason, Michael, R Johnson, Reetta, Kälviäinen, Anne-Mari, Kantanen, Dalia, Kasperavičiūte, Dorothee Kasteleijn-Nolst Trenite, Heidi, E Kirsch, Robert, C Knowlton, Bobby P, C Koeleman, Roland, Krause, Martin, Krenn, Wolfram, S Kunz, Ruben, Kuzniecky, Patrick, Kwan, Dennis, Lal, Yu-Lung, Lau, Anna-Elina, Lehesjoki, Holger, Lerche, Costin, Leu, Dick, Lindhout, Warren, D Lo, Iscia, Lopes-Cendes, Daniel, H Lowenstein, Alberto, Malovini, Anthony, G Marson, Thomas, Mayer, Mark, Mccormack, James, L Mills, Nasir, Mirza, Martina, Moerzinger, Rikke, S Møller, Anne, M Molloy, Hiltrud, Muhle, Mark, Newton, Ping-Wing, Ng, Markus, M Nöthen, Peter, Nürnberg, Terence, J O’Brien, Karen, L Oliver, Aarno, Palotie, Faith, Pangilinan, Sarah, Peter, Slavé, Petrovski, Annapurna, Poduri, Michael, Privitera, Rodney, Radtke, Sarah, Rau, Philipp, S Reif, Eva, M Reinthaler, Felix, Rosenow, Josemir, W Sander, Thomas, Sander, Theresa, Scattergood, Steven, C Schachter, Christoph, J Schankin, Ingrid, E Scheffer, Bettina, Schmitz, Susanne, Schoch, Pak, C Sham, Jerry, J Shih, Graeme, J Sills, Sanjay, M Sisodiya, Lisa, Slattery, Alexander, Smith, David, F Smith, Michael, C Smith, Philip, E Smith, Anja C, M Sonsma, Doug, Speed, Michael, R Sperling, Bernhard, J Steinhoff, Ulrich, Stephani, Remi, Stevelink, Konstantin, Strauch, Pasquale, Striano, Hans, Stroink, Rainer, Surges, K Meng Tan, Liu Lin Thio, G Neil Thomas, Marian, Todaro, Rossana, Tozzi, Maria, S Vari, Eileen P, G Vining, Frank, Visscher, Sarah von Spiczak, Nicole, M Walley, Yvonne, G Weber, Zhi, Wei, Judith, Weisenberg, Christopher, D Whelan, Peter, Widdess-Walsh, Markus, Wolff, Stefan, Wolking, Wanling, Yang, Federico, Zara, Fritz, Zimprich, Project MinE ALS GWAS Consortium, International League Against Epilepsy Consortium on Complex Epilepsies, Department of Medical and Clinical Genetics, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, and HUS Helsinki and Uusimaa Hospital District

Subjects
Risk, 0301 basic medicine, Aging, Genetic correlation, Geriatrics & Gerontology, education, Genome-wide association study, Biology, ALS, Epilepsy, Amyotrophic Lateral Sclerosis, Gene Frequency, Humans, Genetic Variation, Genome-Wide Association Study, Negative Results, Article, 3124 Neurology and psychiatry, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, medicine, Amyotrophic lateral sclerosis, Allele frequency, Genetics, Science & Technology, Mechanism (biology), General Neuroscience, 3112 Neurosciences, Neurosciences, medicine.disease, 3. Good health, Minor allele frequency, 030104 developmental biology, Neurology (clinical), Neurosciences & Neurology, Geriatrics and Gerontology, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins. ispartof: NEUROBIOLOGY OF AGING vol:92 ispartof: location:United States status: published

Published
2020
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10. Epilepsy Subtype-Specific Copy Number Burden Observed in a Genome-Wide Study of 17 458 Subjects

Author

Niestroj, Lisa-Marie, Perez-Palma, Eduardo, Howrigan, Daniel P., Zhou, Yadi, Cheng, Feixiong, Saarentaus, Elmo, Nürnberg, Peter, Stevelink, Remi, Daly, Mark J., Palotie, Aarno, Lal, Dennis, Feng, Yen-Chen Anne, Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Churchhouse, Claire, Gupta, Namrata, Neale, Benjamin M., Berkovic, Samuel F., Lerche, Holger, Goldstein, David B., Lowenstein, Daniel H., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J., Todaro, Marian, Weckhuysen, Sarah, Stamberger, Hannah, De Jonghe, Peter, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Šterbová, Katalin, Vlcková, Markéta, Sedlácková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, van Baalen, Andreas, von Spiczak, Sarah, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišic, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Muccioli, Lorenzo, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Mameniskiene, Ruta, Utkus, Algirdas, Praninskiene, Ruta, Grikiniene, Jurgita, Samaitiene, Ruta, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapici, Zuhal, Yis, Uluc, Topaloglu, Pinar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Asli, Bebek, Nerses, Ugur-Iseri, Sibel, Baykan, Betül, Salman, Baris, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yesim, Özkara, Çigdem, Sheidley, Beth R., Shain, Catherine, Poduri, Annapurna, Buono, Russell J, Ferraro, Thomas N, Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Piras, Federica, Gili, Tommaso, Ciullo, Valentina, YÜCESAN, EMRAH, Niestroj L.-M., Perez-Palma E., Howrigan D.P., Zhou Y., Cheng F., Saarentaus E., Nurnberg P., Stevelink R., Daly M.J., Palotie A., Lal D, Epi 25 Collaborative, Bisulli F., Tinuper P., Licchetta L., and Epi25 Collaborative

Subjects
Developmental and epileptic encephalopathy, Male, 0301 basic medicine, DNA Copy Number Variations, Disease, Bioinformatics, Genome, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, copy number variation, developmental and epileptic encephalopathy, epilepsy, focal epilepsy, genetic generalized epilepsy, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Generalized epilepsy, DNA Copy Number Variation, Copy number variation, business.industry, Breakpoint, Focal epilepsy, Original Articles, medicine.disease, 3. Good health, Genetic generalized epilepsy, 030104 developmental biology, Female, Human medicine, Neurology (clinical), Personalized medicine, business, 030217 neurology & neurosurgery, Genome-Wide Association Study, Human
Abstract

Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.

Published
2020
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11. Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice

Author

Tobias Radecke, Ursula Schlötzer-Schrehardt, Vincent Knappe, Jan W. Schrickel, Viktoriya Peeva, Carolin Berwanger, Lars Eichhorn, Thomas Beiert, Christoph S. Clemen, Florian Stöckigt, Lisa Kamm, Georg Nickenig, Rolf Schröder, Wolfram S. Kunz, Alexei P. Kudin, Dorothea Schultheis, and Martin Steinmetz

Subjects
0301 basic medicine, Male, Cardiac output, Respiratory chain, Cardiomyopathy, Medizin, Muskel- und Knochenstoffwechsel, Biochemistry, Desmin, autosomal-dominant desminopathies, Mice, Electrocardiography, 0302 clinical medicine, Medizinische Fakultät, Medicine and Health Sciences, Missense mutation, Gene Knock-In Techniques, Atrioventricular Block, Energy-Producing Organelles, Multidisciplinary, Ejection fraction, Heart, Animal Models, Mitochondrial DNA, Mitochondria, Nucleic acids, Bioassays and Physiological Analysis, DES-p.R349P, Experimental Organism Systems, Medicine, Female, Cellular Structures and Organelles, Anatomy, Cardiomyopathies, Arrhythmia, Research Article, medicine.medical_specialty, Heterozygote, animal structures, DNA Copy Number Variations, Forms of DNA, Science, Cardiology, Mouse Models, Bioenergetics, Research and Analysis Methods, DNA, Mitochondrial, 03 medical and health sciences, Model Organisms, Internal medicine, medicine, Genetics, Animals, Humans, ddc:610, Pressure overload, business.industry, Electrophysiological Techniques, Biology and Life Sciences, Proteins, Stroke Volume, Cell Biology, DNA, medicine.disease, Disease Models, Animal, Cytoskeletal Proteins, stomatognathic diseases, 030104 developmental biology, Endocrinology, Amino Acid Substitution, Heart failure, Cardiovascular Anatomy, Animal Studies, Cardiac Electrophysiology, business, 030217 neurology & neurosurgery
Abstract

Background Mutations in the human desmin gene (DES) cause autosomal-dominant and -recessive cardiomyopathies, leading to heart failure, arrhythmias, and AV blocks. We analyzed the effects of vascular pressure overload in a patient-mimicking p.R349P desmin knock-in mouse model that harbors the orthologue of the frequent human DES missense mutation p. R350P. Methods and results Transverse aortic constriction (TAC) was performed on heterozygous (HET) DES-p.R349P mice and wild-type (WT) littermates. Echocardiography demonstrated reduced left ventricular ejection fraction in HET-TAC (WT-sham: 69.5 +/- 2.9%, HET-sham: 64.5 +/- 4.7%, WT-TAC: 63.5 +/- 4.9%, HET-TAC: 55.7 +/- 5.4%; p < 0.01). Cardiac output was significantly reduced in HET-TAC (WT sham: 13088 +/- 2385 mu l/min, HET sham: 10391 +/- 1349 mu l/min, WT-TAC: 8097 +/- 1903 mu l/min, HET-TAC: 5793 +/- 2517 mu l/min; p< 0.01). Incidence and duration of AV blocks as well as the probability to induce ventricular tachycardias was highest in HET-TAC. We observed reduced mtDNA copy numbers in HET-TAC (WT-sham: 12546 +/- 406, HET-sham: 13526 +/- 781, WT-TAC: 11155 +/- 3315, HET-TAC: 8649 +/- 1582; p = 0.025), but no mtDNA deletions. The activity of respiratory chain complexes I and IV showed the greatest reductions in HET-TAC. Conclusion Pressure overload in HET mice aggravated the clinical phenotype of cardiomyopathy and resulted in mitochondrial dysfunction. Preventive avoidance of pressure overload/arterial hypertension in desminopathy patients might represent a crucial therapeutic measure.

Published
2020

12. Retinoencephalopathy with occipital lobe epilepsy in an OPA-1 mutation carrier

Author

Eike Steidl, Robert D. Nass, Albert J. Becker, Florian Gärtner, Rainer Surges, Niels Hansen, Christian E. Elger, Wolfgang Block, Carlos M. Quesada, Philipp Hermann, Elke Hattingen, Gábor Zsurka, Wolfram S. Kunz, Theodor Rüber, and Cornelia Kornblum

Subjects
Pathology, medicine.medical_specialty, Epilepsy, Neurology, Mutation Carrier, business.industry, Occipital lobe epilepsy, medicine, Neurology (clinical), General Medicine, business, medicine.disease
Published
2019
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13. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study

Author

Patrick May, Simon Girard, Merle Harrer, Dheeraj R Bobbili, Julian Schubert, Stefan Wolking, Felicitas Becker, Pamela Lachance-Touchette, Caroline Meloche, Micheline Gravel, Cristina E Niturad, Julia Knaus, Carolien De Kovel, Mohamad Toliat, Anne Polvi, Michele Iacomino, Rosa Guerrero-López, Stéphanie Baulac, Carla Marini, Holger Thiele, Janine Altmüller, Kamel Jabbari, Ann-Kathrin Ruppert, Wiktor Jurkowski, Dennis Lal, Raffaella Rusconi, Sandrine Cestèle, Benedetta Terragni, Ian D Coombs, Christopher A Reid, Pasquale Striano, Hande Caglayan, Auli Siren, Kate Everett, Rikke S Møller, Helle Hjalgrim, Hiltrud Muhle, Ingo Helbig, Wolfram S Kunz, Yvonne G Weber, Sarah Weckhuysen, Peter De Jonghe, Sanjay M Sisodiya, Rima Nabbout, Silvana Franceschetti, Antonietta Coppola, Maria S Vari, Dorothée Kasteleijn-Nolst Trenité, Betul Baykan, Ugur Ozbek, Nerses Bebek, Karl M Klein, Felix Rosenow, Dang K Nguyen, François Dubeau, Lionel Carmant, Anne Lortie, Richard Desbiens, Jean-François Clément, Cécile Cieuta-Walti, Graeme J Sills, Pauls Auce, Ben Francis, Michael R Johnson, Anthony G Marson, Bianca Berghuis, Josemir W Sander, Andreja Avbersek, Mark McCormack, Gianpiero L Cavalleri, Norman Delanty, Chantal Depondt, Martin Krenn, Fritz Zimprich, Sarah Peter, Marina Nikanorova, Robert Kraaij, Jeroen van Rooij, Rudi Balling, M Arfan Ikram, André G Uitterlinden, Giuliano Avanzini, Stephanie Schorge, Steven Petrou, Massimo Mantegazza, Thomas Sander, Eric LeGuern, Jose M Serratosa, Bobby P C Koeleman, Aarno Palotie, Anna-Elina Lehesjoki, Michael Nothnagel, Peter Nürnberg, Snezana Maljevic, Federico Zara, Patrick Cossette, Roland Krause, Holger Lerche, Edoardo Ferlazzo, Carlo di Bonaventura, Angela La Neve, Paolo Tinuper, Francesca Bisulli, Aglaia Vignoli, Giuseppe Capovilla, Giovanni Crichiutti, Antonio Gambardella, Vincenzo Belcastro, Amedeo Bianchi, Destina Yalçın, Gulsen Dizdarer, Kezban Arslan, Zuhal Yapıcı, Demet Kuşcu, Costin Leu, Kristin Heggeli, Joseph Willis, Sarah R Langley, Andrea Jorgensen, Prashant Srivastava, Sarah Rau, Christian Hengsbach, Anja C.M. Sonsma, Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Laboratory of Molecular Genetics of Stem Cells [University of Montreal], University of Montreal-Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM)-Université de Montréal (UdeM), University of Tübingen, University Medical Center [Utrecht], Universita degli studi di Genova, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), A.Meyer Children's Hospital, Max Planck Institute for Plant Breeding Research (MPIPZ), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), University of Cologne, The Genome Analysis Centre (TGAC), Cologne Center for Genomics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des protéines (IP), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Department of Neurophysiopathology, Besta Neurological Institute, University of Southern Denmark (SDU), Medical Genetics Laboratory, Children’s Hospital of Philadelphia (CHOP ), Universitätsklinikum Bonn (UKB), Antwerp University Hospital [Edegem] (UZA), University of Antwerp (UA), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituco Neurologico C. Besta, Instituto Neurologico C. Besta, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), University of Liverpool, Institute of Neurology [London], Royal College of Surgeons in Ireland (RCSI), Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Medizinische Universität Wien = Medical University of Vienna, Department of Epilepsy Clinic and Experimental Neurophysiology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Medical Informatics and Statistics, Pediatric Neurology and Neuromuscular Diseases Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Hertie Institute for Clinical Brain Research [Tubingen], Regional Epilepsy Center, Reggio Calabria, Agronomes et Vétérinaires Sans Frontières (AVSF), AVSF, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Wellcome Trust, Commission of the European Communities, Imperial College Healthcare NHS Trust- BRC Funding, Internal Medicine, Epidemiology, Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Università degli studi di Genova = University of Genoa (UniGe), Heart Center Leipzig, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Acibadem University Dspace, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Nice Sophia Antipolis (... - 2019) (UNS), University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Medicum, Research Programme for Molecular Neurology, Research Programs Unit, Neuroscience Center, University of Helsinki, Genomics of Neurological and Neuropsychiatric Disorders, Epicure Consortium, EuroEPINOMICS COGIE Consortium, EpiPGX Consortium, May, Gabriella, Girard, S., Harrer, M., Bobbili, D. R., Schubert, J., Wolking, S., Becker, F., Lachance-Touchette, P., Meloche, C., Gravel, M., Niturad, C. E., Knaus, J., De Kovel, C., Toliat, M., Polvi, A., Iacomino, M., Guerrero-López, R., Baulac, S., Marini, C., Thiele, H., Altmüller, J., Jabbari, K., Ruppert, A. -K., Jurkowski, W., Lal, D., Rusconi, R., Cestèle, S., Terragni, B., Coombs, I. D., Reid, C. A., Striano, P., Caglayan, H., Siren, A., Everett, K., Møller, R. S., Hjalgrim, H., Muhle, H., Helbig, I., Kunz, W. S., Weber, Y. G., Weckhuysen, S., Jonghe, P. D., Sisodiya, S. M., Nabbout, R., Franceschetti, S., Coppola, A., Vari, M. S., Kasteleijn-Nolst Trenité, D., Baykan, B., Ozbek, U., Bebek, N., Klein, K. M., Rosenow, F., Nguyen, D. K., Dubeau, F., Carmant, L., Lortie, A., Desbiens, R., Clément, J. -F., Cieuta-Walti, C., Sills, G. J., Auce, P., Francis, B., Johnson, M. R., Marson, A. G., Berghuis, B., Sander, J. W., Avbersek, A., Mccormack, M., Cavalleri, G. L., Delanty, N., Depondt, C., Krenn, M., Zimprich, F., Peter, S., Nikanorova, M., Kraaij, R., van Rooij, J., Balling, R., Ikram, M. A., Uitterlinden, A. G., Avanzini, Giulio, Schorge, S., Petrou, S., Mantegazza, M., Sander, T., Leguern, E., Serratosa, J. M., Koeleman, B. P. C., Palotie, A., Lehesjoki, A. -E., Nothnagel, M., Nürnberg, P., Maljevic, S., Zara, F., Cossette, P., Krause, R., Lerche, H., De Jonghe, P., Arfan Ikram, M., Ferlazzo, E., di Bonaventura, C., La Neve, A., Tinuper, P., Bisulli, F., Vignoli, Massimo, Capovilla, G., Crichiutti, G., Gambardella, A., Belcastro, V., Bianchi, A., Yalçın, D., Dizdarer, G., Arslan, K., Yapıcı, Z., Kuşcu, D., Leu, C., Heggeli, K., Willis, J., Langley, S. R., Jorgensen, A., Srivastava, P., Rau, S., Hengsbach, C., Sonsma, A. C. M., University of Montreal-Institute for Research in Immunology and Cancer (IRIC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], Hôpital Erasme (Bruxelles), May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R, Schubert, Julian, Wolking, Stefan, Becker, Felicita, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E, Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-López, Rosa, Baulac, Stéphanie, Marini, Carla, Thiele, Holger, Altmüller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Denni, Rusconi, Raffaella, Cestèle, Sandrine, Terragni, Benedetta, Coombs, Ian D, Reid, Christopher A, Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Møller, Rikke S, Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S, Weber, Yvonne G, Weckhuysen, Sarah, Jonghe, Peter De, Sisodiya, Sanjay M, Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S, Kasteleijn-Nolst Trenité, Dorothée, Baykan, Betul, Ozbek, Ugur, Bebek, Nerse, Klein, Karl M, Rosenow, Felix, Nguyen, Dang K, Dubeau, Françoi, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-Françoi, Cieuta-Walti, Cécile, Sills, Graeme J, Auce, Paul, Francis, Ben, Johnson, Michael R, Marson, Anthony G, Berghuis, Bianca, Sander, Josemir W, Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M Arfan, Uitterlinden, André G, Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thoma, LeGuern, Eric, Serratosa, Jose M, Koeleman, Bobby P C, Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nürnberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, De Jonghe, Peter, Ferlazzo, Edoardo, di Bonaventura, Carlo, La Neve, Angela, Tinuper, Paolo, Bisulli, Francesca, Vignoli, Aglaia, Capovilla, Giuseppe, Crichiutti, Giovanni, Gambardella, Antonio, Belcastro, Vincenzo, Bianchi, Amedeo, Yalçın, Destina, Dizdarer, Gulsen, Arslan, Kezban, Yapıcı, Zuhal, Kuşcu, Demet, Leu, Costin, Heggeli, Kristin, Willis, Joseph, Langley, Sarah R, Jorgensen, Andrea, Srivastava, Prashant, Rau, Sarah, Hengsbach, Christian, and Sonsma, Anja C.M.

Subjects
0301 basic medicine, GAMMA-2-SUBUNIT, [SDV]Life Sciences [q-bio], GABRA5, Clinical Neurology, 15Q13.3 MICRODELETIONS, ABSENCE EPILEPSY, SEQUENCE DATA, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 3124 Neurology and psychiatry, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Genetic variation, medicine, EPILEPTIC ENCEPHALOPATHIES, Exome, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetic association, Genetics, RISK, Science & Technology, FEBRILE SEIZURES, Neurology & Neurosurgery, biology, 3112 Neurosciences, 1103 Clinical Sciences, MOUSE MODEL, medicine.disease, ASSOCIATION ANALYSIS, 030104 developmental biology, DE-NOVO MUTATIONS, Cohort, biology.protein, Neurology (clinical), Human medicine, Neurosciences & Neurology, 1109 Neurosciences, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Cohort study
Abstract

BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.INTERPRETATION: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).

Published
2018
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14. Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy

Author

Georgeta Teodorescu, Han-Shen Tae, A. Marie Phillips, Steven Petrou, Holger Lerche, Christopher A. Reid, Kerstin Hallmann, Ailing A. Kleefuss-Lie, Snezana Maljevic, Wolfram S. Kunz, Christian E. Elger, Felicitas Becker, Yvonne G. Weber, and Edward Perez-Reyes

Subjects
0301 basic medicine, Xenopus, Biology, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, CACNA1H, medicine, HCN4, T‐type Ca2+ channels, Generalized epilepsy, Gene, Ion channel, Genetics, Functional analysis, Full‐Length Original Research, Depolarization, medicine.disease, biology.organism_classification, Thalamo‐cortical circuits, 030104 developmental biology, Neurology, biology.protein, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

Summary Objective Genetic generalized epilepsy (GGE) encompasses seizure disorders characterized by spike‐and‐wave discharges (SWD) originating within thalamo‐cortical circuits. Hyperpolarization‐activated (HCN) and T‐type Ca2+ channels are key modulators of rhythmic activity in these brain regions. Here, we screened HCN4 and CACNA1H genes for potentially contributory variants and provide their functional analysis. Methods Targeted gene sequencing was performed in 20 unrelated familial cases with different subtypes of GGE, and the results confirmed in 230 ethnically matching controls. Selected variants in CACNA1H and HCN4 were functionally assessed in tsA201 cells and Xenopus laevis oocytes, respectively. Results We discovered a novel CACNA1H (p.G1158S) variant in two affected members of a single family. One of them also carried an HCN4 (p.P1117L) variant inherited from the unaffected mother. In a separate family, an HCN4 variant (p.E153G) was identified in one of several affected members. Voltage‐clamp analysis of CACNA1H (p.G1158S) revealed a small but significant gain‐of‐function, including increased current density and a depolarizing shift of steady‐state inactivation. HCN4 p.P1117L and p.G153E both caused a hyperpolarizing shift in activation and reduced current amplitudes, resulting in a loss‐of‐function. Significance Our results are consistent with a model suggesting cumulative contributions of subtle functional variations in ion channels to seizure susceptibility and GGE.

Published
2017

15. Peripheral nerve atrophy together with higher cerebrospinal fluid progranulin indicate axonal damage in amyotrophic lateral sclerosis

Author

Reinhard Dengler, Susanne Abdulla, Sonja Körner, Peter J. Nestor, Grazyna Debska-Vielhaber, Katja Kollewe, Wolfram S. Kunz, Stefan Vielhaber, Peter Körtvelyessy, Judith Machts, Siegfried Kropf, Susanne Petri, Frank Schreiber, and Stefanie Schreiber

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Physiology, Serum albumin, Blood–brain barrier, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Atrophy, Cerebrospinal fluid, Forearm, Physiology (medical), medicine, Amyotrophic lateral sclerosis, Ulnar nerve, biology, business.industry, medicine.disease, Peripheral, 030104 developmental biology, medicine.anatomical_structure, biology.protein, Neurology (clinical), business, Neuroscience, 030217 neurology & neurosurgery
Abstract

Introduction: We aimed to investigate whether sonographic peripheral cross-sectional nerve area (CSA) and progranulin (PGRN), a neuritic growth factor, are related to each other and whether they interact to predict clinical and paraclinical measures in amyotrophic lateral sclerosis (ALS). Methods: We included 55 ALS patients who had forearm median and ulnar nerve CSA, cerebrospinal fluid (CSF) PGRN and serum PGRN measures available. CSF PGRN was normalized against the CSF/serum albumin ratio (Qalb). Using age, sex, height and weight adjusted general linear models we examined CSA x CSF PGRN interaction effects on various measures. Results: There was a medium-effect size inverse relationship between CSA and CSF PGRN, but not between CSA and serum PGRN. Lower CSA values together with higher CSF PGRN levels were linked to smaller motor amplitudes. Discussion: In ALS, the constellation of peripheral nerve atrophy together with higher CSF PGRN levels indicates pronounced axonal damage. This article is protected by copyright. All rights reserved.

Published
2017
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16. No evidence for a <scp>BRD</scp> 2 promoter hypermethylation in blood leukocytes of Europeans with juvenile myoclonic epilepsy

Author

Amedeo Bianchi, Ann-Kathrin Ruppert, Saul A. Mullen, Hande Caglayan, Wolfram S. Kunz, Herbert Schulz, Despina Tsortouktzidis, Ingrid E. Scheffer, Holger Lerche, Per Hoffmann, Yvonne G. Weber, Pasquale Striano, Francesca Madia, Rikke S. Møller, Felicitas Becker, Michele Iacomino, Carlo Minetti, Ganna Balagura, Carla Marini, Maria Stella Vari, Susannah T. Bellows, Samuel F. Berkovic, Claudia Kapser, Renzo Guerrini, Thomas Sander, Federico Zara, Karen Oliver, Ugur Ozbek, Albert J. Becker, Christoph J. Schankin, Sara Schramm, and Acibadem University Dspace

Subjects
0301 basic medicine, Medizin, Single-nucleotide polymorphism, Biology, association analysis, BRD2, DNA methylation, genetic generalized epilepsy, juvenile myoclonic epilepsy, neurology, neurology (clinical), 03 medical and health sciences, 0302 clinical medicine, medicine, Epigenetics, Allele, 610 Medicine & health, Genetic association, Genetics, Methylation, medicine.disease, 030104 developmental biology, Neurology, Myoclonic epilepsy, Neurology (clinical), Juvenile myoclonic epilepsy, 030217 neurology & neurosurgery
Abstract

Juvenile myoclonic epilepsy (JME) is a common syndrome of genetic generalized epilepsies (GGEs). Linkage and association studies suggest that the gene encoding the bromodomain-containing protein 2 (BRD2) may increase risk of JME. The present methylation and association study followed up a recent report highlighting that the BRD2 promoter CpG island (CpG76) is differentially hypermethylated in lymphoblastoid cells from Caucasian patients with JME compared to patients with other GGE subtypes and unaffected relatives. In contrast, we found a uniform low average percentage of methylation (

Published
2019
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17. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author

Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L. Heinzen, Ryan S. Dhindsa, Kate E. Stanley, Gianpiero L. Cavalleri, Hakon Hakonarson, Ingo Helbig, Roland Krause, Patrick May, Sarah Weckhuysen, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G. Marson, Randy Stewart, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M. Regan, Susannah T. Bellows, Costin Leu, Caitlin A. Bennett, Esther M.C. Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J. O’Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Tara R. Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S. Papacostas, Ioanna Kousiappa, George A. Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Wolfram S. Kunz, Gábor Zsurka, Christian E. Elger, Jürgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F. Maisch, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J. Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Nina Barišić, Norman Delanty, Colin P. Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G. Sadleir, Chontelle King, Emily Mountier, S. Hande Caglayan, Mutluay Arslan, Zuhal Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jacqueline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L. Helbig, Colin A. Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T. Pato, Carlos N. Pato, Evelyn J. Bromet, Celia Barreto Carvalho, Eric D. Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S. Lehrer, Dolores Malaspina, Stephen R. Marder, Helena Medeiros, Christopher P. Morley, Diana O. Perkins, Janet L. Sobell, Peter F. Buckley, Fabio Macciardi, Mark H. Rapaport, James A. Knowles, Ayman H. Fanous, Steven A. McCarroll, Namrata Gupta, Stacey B. Gabriel, Mark J. Daly, Eric S. Lander, Daniel H. Lowenstein, David B. Goldstein, Holger Lerche, Samuel F. Berkovic, Benjamin M. Neale, Wellcome Trust, Department of Health, Institute of Neurology, UCL, Imperial College Healthcare NHS Trust- BRC Funding, Commission of the European Communities, Medical Research Council (MRC), Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Singh T., Heyne H., Byrnes A., Churchhouse C., Watts N., Solomonson M., Lal D., Heinzen E.L., Dhindsa R.S., Stanley K.E., Cavalleri G.L., Hakonarson H., Helbig I., Krause R., May P., Weckhuysen S., Petrovski S., Kamalakaran S., Sisodiya S.M., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Kwan P., Marson A.G., Stewart R., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., McKenna K., Regan B.M., Bellows S.T., Leu C., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., van Baalen A., von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Tumiene B., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Poduri A., Shiedley B.R., Shain C., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Reif A., McQuillin A., Bass N., McIntosh A., Blackwood D., Johnstone M., Palotie A., Pato M.T., Pato C.N., Bromet E.J., Carvalho C.B., Achtyes E.D., Azevedo M.H., Kotov R., Lehrer D.S., Malaspina D., Marder S.R., Medeiros H., Morley C.P., Perkins D.O., Sobell J.L., Buckley P.F., Macciardi F., Rapaport M.H., Knowles J.A., Fanous A.H., McCarroll S.A., Gupta N., Gabriel S.B., Daly M.J., Lander E.S., Lowenstein D.H., Goldstein D.B., Lerche H., Berkovic S.F., Neale B.M., Epi25 Collaborative, YÜCESAN, EMRAH, Institute for Molecular Medicine Finland, Children's Hospital, HUS Children and Adolescents, Department of Medical and Clinical Genetics, University Management, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
s.berkovic@unimelb.edu.au [Epi25 Collaborative. Electronic address], 0301 basic medicine, GAMMA-2-SUBUNIT, burden analysi, DNA Mutational Analysis, PROTEIN, Neurodegenerative, VARIANTS, SUSCEPTIBILITY, Medical and Health Sciences, Epilepsy, 0302 clinical medicine, 2.1 Biological and endogenous factors, EPIDEMIOLOGY, Missense mutation, Exome, Aetiology, Genetics (clinical), Exome sequencing, 11 Medical and Health Sciences, seizures, GABRG2, Genetics, Genetics & Heredity, 0303 health sciences, biology, COMMON EPILEPSIES, 1184 Genetics, developmental biology, physiology, sequencing, Biological Sciences, Epi25 Collaborative, Phenotype, GENOME, epileptic encephalopathy, burden analysis, Neurological, Biotechnology, Genetic Markers, seizure, EEF1A2, Burden analysis, epilepsy, exome, Article, 03 medical and health sciences, Clinical Research, Exome Sequencing, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Gene, EPILEPTIC SEIZURES, METAANALYSIS, 030304 developmental biology, Human Genome, Neurosciences, Genetic Variation, 06 Biological Sciences, medicine.disease, Brain Disorders, 030104 developmental biology, Genetic marker, DE-NOVO MUTATIONS, Case-Control Studies, biology.protein, 3111 Biomedicine, Human medicine, 030217 neurology & neurosurgery
Abstract

Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.

Published
2019
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18. Mesial temporal lobe epilepsy associated with KCNT1 mutation

Author

Wolfram S. Kunz, Niels Hansen, Guido Widman, Elke Hattingen, and Christian E. Elger

Subjects
Adult, Male, 0301 basic medicine, Potassium Channels, Cerebellar Ataxia, Nerve Tissue Proteins, Potassium Channels, Sodium-Activated, Bioinformatics, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Text mining, Intellectual Disability, Humans, Medicine, business.industry, Siblings, Brain, General Medicine, medicine.disease, Phenotype, 030104 developmental biology, Epilepsy, Temporal Lobe, Neurology, Mutation, Mutation (genetic algorithm), Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Mesial temporal lobe epilepsy
Published
2017
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19. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

Author

Christian E. Elger, Wolfgang Lieb, Claudia B. Catarino, Pasquale Striano, Andreja Avbersek, Daniel H. Lowenstein, Philip E. M. Smith, G. Neil Thomas, Dick Lindhout, Erin L. Heinzen, Sanjay M. Sisodiya, Orrin Devinsky, Alexander R. H. Smith, Rainer Surges, Stefan Wolking, Patrick Cossette, Annapurna Poduri, Eric B. Geller, Stacey S. Cherny, Maria Stella Vari, Peter De Jonghe, Kevin Haas, Andres Ingason, Reetta Kälviäinen, Krishna Chinthapalli, Dennis Lal, Graeme J. Sills, Martina Moerzinger, Jonathan P. Bradfield, Mark R Newton, Federico Zara, Sheryl R. Haut, Warren D. Lo, Holger Lerche, Felix Rosenow, Robert C. Knowlton, Mark McCormack, Sarah Rau, Felicitas Becker, Andre Franke, Heidi E. Kirsch, Patrick Kwan, Remi Stevelink, Rodney A. Radtke, Michele Iacomino, Faith Pangilinan, Ulrich Stephani, David F. Smith, Eva M. Reinthaler, Chantal Depondt, Hiltrud Muhle, Russell J. Buono, Alison J. Coffey, Ellen Campbell, Marvin Johnson, Bernhard J. Steinhoff, Sarah von Spiczak, Yvonne G. Weber, Ping-Wing Ng, Kerstin Hallmann, Philipp S. Reif, David Goldstein, Bettina Schmitz, Antonietta Coppola, Jerry J. Shih, Karen Oliver, Anne-Mari Kantanen, Rossana Tozzi, Markus Wolff, Albert J. Becker, Anne M. Molloy, Lisa Slattery, James L. Mills, Judith L.Z. Weisenberg, Jacqueline A. French, Lawrence C. Brody, Int League Against Epilepsy Conso, Peter Widdess-Walsh, Helle Hjalgrim, Christian Hengsbach, Christoph J. Schankin, Johan G. Eriksson, Tracy A. Glauser, Yu-Lung Lau, Larry Baum, Anna-Elina Lehesjoki, Nicole M. Walley, Josemir W. Sander, Markus M. Noethen, Simon Glynn, Jennifer Jamnadas-Khoda, Thomas Bast, Susanne Schoch, Iscia Lopes-Cendes, Doug Speed, Anja C M Sonsma, John Craig, Ingo Helbig, Marian Todaro, Gregory D. Cascino, Steven C. Schachter, Fritz Zimprich, Samuel F. Berkovic, Michael Privitera, Ben Francis, Martin Krenn, Rikke S. Møller, Eileen P.G. Vining, Martha Feucht, Bobby P. C. Koeleman, Ruben Kuzniecky, Christian Gieger, K. Meng Tan, Dalia Kasperaviciute, Pauls Auce, Gianpiero L. Cavalleri, Melanie Bahlo, Zhi Wei, Nasir Mirza, David J. Balding, Mike Smith, Liu Lin Thio, Alastair Compston, Katja E. Boysen, Gerrit-Jan de Haan, Hongsheng Gui, Hakon Hakonarson, Christopher D. Whelan, Colin P. Doherty, Youling Guo, Aarno Palotie, Wolfram S. Kunz, Slavé Petrovski, Thomas Sander, Frank Visscher, Bianca Berghuis, Costin Leu, Verena Gaus, Dennis J. Dlugos, Ingrid E. Scheffer, Alberto Malovini, Konstantin Strauch, Wanling Yang, Saskia Freytag, H. Stroink, Pak C. Sham, Norman Delanty, Terence J. O'Brien, Carolien G.F. de Kovel, Thomas U. Mayer, Anthony G Marson, Bassel Abou-Khalil, Thomas N. Ferraro, Dorothée G.A. Kasteleijn-Nolst Trenité, Roland Krause, Sarah Peter, Peter Nuernberg, Theresa Scattergood, Michael R. Sperling, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, Department of Medical and Clinical Genetics, Medicum, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Int League Against Epilepsy Conso, Abou-Khalil, Bassel, Auce, Paul, Avbersek, Andreja, Bahlo, Melanie, J Balding, David, Bast, Thoma, Baum, Larry, J Becker, Albert, Becker, Felicita, Berghuis, Bianca, F Berkovic, Samuel, E Boysen, Katja, P Bradfield, Jonathan, C Brody, Lawrence, J Buono, Russell, Campbell, Ellen, D Cascino, Gregory, B Catarino, Claudia, L Cavalleri, Gianpiero, S Cherny, Stacey, Chinthapalli, Krishna, J Coffey, Alison, Compston, Alastair, Coppola, Antonietta, Cossette, Patrick, J Craig, John, de Haan, Gerrit-Jan, De Jonghe, Peter, F de Kovel, Carolien G, Delanty, Norman, Depondt, Chantal, Devinsky, Orrin, J Dlugos, Denni, P Doherty, Colin, E Elger, Christian, G Eriksson, Johan, N Ferraro, Thoma, Feucht, Martha, Francis, Ben, Franke, Andre, A French, Jacqueline, Freytag, Saskia, Gaus, Verena, B Geller, Eric, Gieger, Christian, Glauser, Tracy, Glynn, Simon, B Goldstein, David, Gui, Hongsheng, Guo, Youling, F Haas, Kevin, Hakonarson, Hakon, Hallmann, Kerstin, Haut, Sheryl, L Heinzen, Erin, Helbig, Ingo, Hengsbach, Christian, Hjalgrim, Helle, Iacomino, Michele, Ingason, André, Jamnadas-Khoda, Jennifer, R Johnson, Michael, Kälviäinen, Reetta, Kantanen, Anne-Mari, Kasperavičiūte, Dalia, Kasteleijn-Nolst Trenite, Dorothee, E Kirsch, Heidi, C Knowlton, Robert, C Koeleman, Bobby P, Krause, Roland, Krenn, Martin, S Kunz, Wolfram, Kuzniecky, Ruben, Kwan, Patrick, Lal, Denni, Lau, Yu-Lung, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lieb, Wolfgang, Lindhout, Dick, D Lo, Warren, Lopes-Cendes, Iscia, H Lowenstein, Daniel, Malovini, Alberto, G Marson, Anthony, Mayer, Thoma, Mccormack, Mark, L Mills, Jame, Mirza, Nasir, Moerzinger, Martina, S Møller, Rikke, M Molloy, Anne, Muhle, Hiltrud, Newton, Mark, Ng, Ping-Wing, M Nöthen, Marku, Nürnberg, Peter, J O'Brien, Terence, L Oliver, Karen, Palotie, Aarno, Pangilinan, Faith, Peter, Sarah, Petrovski, Slavé, Poduri, Annapurna, Privitera, Michael, Radtke, Rodney, Rau, Sarah, S Reif, Philipp, M Reinthaler, Eva, Rosenow, Felix, W Sander, Josemir, Sander, Thoma, Scattergood, Theresa, C Schachter, Steven, J Schankin, Christoph, E Scheffer, Ingrid, Schmitz, Bettina, Schoch, Susanne, C Sham, Pak, J Shih, Jerry, J Sills, Graeme, M Sisodiya, Sanjay, Slattery, Lisa, Smith, Alexander, F Smith, David, C Smith, Michael, E Smith, Philip, M Sonsma, Anja C, Speed, Doug, R Sperling, Michael, J Steinhoff, Bernhard, Stephani, Ulrich, Stevelink, Remi, Strauch, Konstantin, Striano, Pasquale, Stroink, Han, Surges, Rainer, Meng Tan, K, Lin Thio, Liu, Neil Thomas, G, Todaro, Marian, Tozzi, Rossana, S Vari, Maria, G Vining, Eileen P, Visscher, Frank, von Spiczak, Sarah, M Walley, Nicole, G Weber, Yvonne, Wei, Zhi, Weisenberg, Judith, D Whelan, Christopher, Widdess-Walsh, Peter, Wolff, Marku, Wolking, Stefan, Yang, Wanling, Zara, Federico, Zimprich, Fritz, Wellcome Trust, GlaxoSmithKline Services Unlimited, Commission of the European Communities, Medical Research Council (MRC), and Imperial College Healthcare NHS Trust- BRC Funding

Subjects
0301 basic medicine, Linkage disequilibrium, LD SCORE REGRESSION, Neurology [D14] [Human health sciences], General Physics and Astronomy, Genome-wide association study, ILAE COMMISSION, Neurodegenerative, Genome, Linkage Disequilibrium, Epilepsy, Gene Frequency, Missing heritability problem, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, International League Against Epilepsy Consortium on Complex Epilepsies, Multidisciplinary, Genetic Predisposition to Disease/genetics, Chromosome Mapping, ASSOCIATION, Epilepsy/classification, Single Nucleotide, ABSENCE, 3. Good health, Technologie de l'environnement, contrôle de la pollution, SNP HERITABILITY, Neurological, Genome-Wide Association Study/methods, Case-Control Studie, Engineering sciences. Technology, Human, Biotechnology, EXPRESSION, SUSCEPTIBILITY LOCI, Genotype, Science, Quantitative Trait Loci, 610 Medicine & health, Computational biology, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, GENETIC ARCHITECTURE, 03 medical and health sciences, MD Multidisciplinary, medicine, Genetics, SNP, Chimie, FRONTAL-LOBE, Humans, Genetic Predisposition to Disease, Polymorphism, METAANALYSIS, Neurologie [D14] [Sciences de la santé humaine], Physique, Human Genome, Neurosciences, General Chemistry, Astronomie, medicine.disease, Genetic architecture, Brain Disorders, 030104 developmental biology, Gene Expression Regulation, Case-Control Studies, epilepsy, lcsh:Q, 3111 Biomedicine, Quantitative Trait Loci/genetics, Genome-Wide Association Study
Abstract

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2018
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20. Mitochondrial dysfunction and seizures: the neuronal energy crisis

Author

Wolfram S. Kunz and Gábor Zsurka

Subjects
Neurons, Neurotransmitter transporter, Membrane potential, medicine.medical_treatment, Brain, Biology, Neurotransmission, Mitochondrion, medicine.disease, medicine.disease_cause, Mitochondria, Oxidative Stress, Epilepsy, Anticonvulsant, Seizures, medicine, Animals, Humans, Neurology (clinical), Energy Metabolism, Neuroscience, Oxidative stress, Homeostasis
Abstract

Seizures are often the key manifestation of neurological diseases caused by pathogenic mutations in 169 of the genes that have so far been identified to affect mitochondrial function. Mitochondria are the main producers of ATP needed for normal electrical activities of neurons and synaptic transmission. Additionally, they have a central role in neurotransmitter synthesis, calcium homoeostasis, redox signalling, production and modulation of reactive oxygen species, and neuronal death. Hypotheses link mitochondrial failure to seizure generation through changes in calcium homoeostasis, oxidation of ion channels and neurotransmitter transporters by reactive oxygen species, a decrease in neuronal plasma membrane potential, and reduced network inhibition due to interneuronal dysfunction. Seizures, irrespective of their origin, represent an excessive acute energy demand in the brain. Accordingly, secondary mitochondrial dysfunction has been described in various epileptic disorders, including disorders that are mainly of non-mitochondrial origin. An understanding of the reciprocal relation between mitochondrial dysfunction and epilepsy is crucial to select appropriate anticonvulsant treatment and has the potential to open up new therapeutic approaches in the subset of epileptic disorders caused by mitochondrial dysfunction.

Published
2015
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21. Do Glut1 (glucose transporter type 1) defects exist in epilepsy patients responding to a ketogenic diet?

Author

Yvonne G. Weber, Jürgen Sperner, Steffen Grüninger, Sarah Weckhuysen, Julian Schubert, Kerstin Hallmann, Wolfram S. Kunz, Anne Hofmann-Peters, Elisabeth Korn-Merker, René Madeleyen, Christian E. Elger, Felicitas Becker, Arvid Suls, Helen Cross, and Holger Lerche

Subjects
Adult, Male, Drug Resistant Epilepsy, medicine.medical_specialty, Deficiency syndrome, Adolescent, medicine.medical_treatment, Cohort Studies, Young Adult, Epilepsy, Internal medicine, medicine, Humans, Child, Glucose Transporter Type 1, biology, business.industry, Glucose transporter, Transporter, medicine.disease, 3. Good health, carbohydrates (lipids), Endocrinology, Neurology, Dyskinesia, Child, Preschool, Mutation, biology.protein, Female, GLUT1, Human medicine, Neurology (clinical), medicine.symptom, Diet, Ketogenic, business, Ketogenic diet
Abstract

In the recent years, several neurological syndromes related to defects of the glucose transporter type 1 (Glut1) have been descried. They include the glucose transporter deficiency syndrome (Glut1-DS) as the most severe form, the paroxysmal exertion-induced dyskinesia (FED), a form of spastic paraparesis (CSE) as well as the childhood (CAE) and the early-onset absence epilepsy (EOAE). Glut1, encoded by the gene SLC2A1, is the most relevant glucose transporter in the brain. All Glut1 syndromes respond well to a ketogenic diet (KD) and most of the patients show a rapid seizure control. Ketogenic Diet developed to an established treatment for other forms of pharmaco-resistant epilepsies. Since we were interested in the question if those patients might have an underlying Glut1 defect, we sequenced SLC2A1 in a cohort of 28 patients with different forms of pharmaco-resistant epilepsies responding well to a KD. Unfortunately, we could not detect any mutations in SLC2A1. The exact action mechanisms of MD in pharmaco-resistant epilepsy are not well understood, but bypassing the Glut1 transporter seems not to play an important role. (C) 2015 Elsevier B.V. All rights reserved.

Published
2015
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22. Metabolic Epilepsies-Commemorative Issue in Honor of Professor Uwe Heinemann

Author

Wolfram S. Kunz and Richard Kovács

Subjects
0301 basic medicine, Gerontology, medicine.medical_specialty, macromolecular substances, Neurological disorder, Catalysis, lcsh:Chemistry, Inorganic Chemistry, Very frequent, 03 medical and health sciences, Epilepsy, medicine, Humans, Physical and Theoretical Chemistry, Psychiatry, lcsh:QH301-705.5, Molecular Biology, Spectroscopy, Disease burden, business.industry, musculoskeletal, neural, and ocular physiology, Organic Chemistry, Brain, General Medicine, medicine.disease, Computer Science Applications, n/a, 030104 developmental biology, Editorial, lcsh:Biology (General), lcsh:QD1-999, nervous system, Honor, business
Abstract

Epilepsy is a very frequent, severe, and disabling neurological disorder with has a considerable disease burden worldwide [...].

Published
2017

23. Mitochondrial Liver Toxicity of Valproic Acid and Its Acid Derivatives Is Related to Inhibition of α-Lipoamide Dehydrogenase

Author

Arik Eisenkraft, Christian E. Elger, Alexei P. Kudin, Wolfram S. Kunz, Hafiz Mawasi, and Meir Bialer

Subjects
0301 basic medicine, Pyruvate decarboxylation, Valpromide, Pyruvate transport, mitochondrial epilepsy, Mitochondria, Liver, Pharmacology, Mitochondrion, Catalysis, Article, Inorganic Chemistry, lcsh:Chemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pyruvic Acid, medicine, Valnoctamide, Animals, Physical and Theoretical Chemistry, Molecular Biology, lcsh:QH301-705.5, Spectroscopy, analogues of valproic acid, Dihydrolipoamide Dehydrogenase, Dihydrolipoamide dehydrogenase, Chemistry, Valproic Acid, Organic Chemistry, General Medicine, medicine.disease, liver toxicity, Amides, valproic acid, metabolic epilepsy, Computer Science Applications, Mitochondria, Rats, Mitochondrial toxicity, 030104 developmental biology, Biochemistry, lcsh:Biology (General), lcsh:QD1-999, Liver, lipids (amino acids, peptides, and proteins), Pyruvic acid, 030217 neurology & neurosurgery, medicine.drug
Abstract

The liver toxicity of valproic acid (VPA) is an established side effect of this widely used antiepileptic drug, which is extremely problematic for patients with metabolic epilepsy and particularly epilepsy due to mitochondrial dysfunction. In the present report, we investigated the reason for liver mitochondrial toxicity of VPA and several acid and amide VPA analogues. While the pyruvate and 2-oxoglutarate oxidation rates of rat brain mitochondria were nearly unaffected by VPA, rat liver mitochondrial pyruvate and 2-oxoglutarate oxidation was severely impaired by VPA concentrations above 100 µM. Among the reactions involved in pyruvate oxidation, pyruvate transport and dehydrogenation steps were not affected by VPA, while α-lipoamide dehydrogenase was strongly inhibited. Strong inhibition of α-lipoamide dehydrogenase was also noted for the VPA one-carbon homolog sec -butylpropylacetic acid (SPA) and to a lesser extent for the VPA constitutional isomer valnoctic acid (VCA), while the corresponding amides of the above three acids valpromide (VPD), sec -butylpropylacetamide (SPD) and valnoctamide (VCD) showed only small effects. We conclude that the active inhibitors of pyruvate and 2-oxoglutarate oxidation are the CoA conjugates of VPA and its acid analogues affecting selectively α-lipoamide dehydrogenase in liver. Amide analogues of VPA, like VCD, show low inhibitory effects on mitochondrial oxidative phosphorylation in the liver, which might be relevant for treatment of patients with mitochondrial epilepsy.

Published
2017
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24. Hemin inhibits the large conductance potassium channel in brain mitochondria: A putative novel mechanism of neurodegeneration

Author

Adam Szewczyk, Bartłomiej Augustynek, Piotr Bednarczyk, Alexei P. Kudin, and Wolfram S. Kunz

Subjects
Patch-Clamp Techniques, Astrocytoma, Mitochondrion, Pathogenesis, chemistry.chemical_compound, Developmental Neuroscience, Cell Line, Tumor, Potassium Channel Blockers, medicine, Animals, Humans, Large-Conductance Calcium-Activated Potassium Channels, Membrane Potential, Mitochondrial, Dose-Response Relationship, Drug, Neurodegeneration, Brain, Conductance, Hydrogen Peroxide, medicine.disease, Cytoprotection, Potassium channel, Mitochondria, Rats, Cell biology, Neurology, Biochemistry, chemistry, Cell culture, Hemin, Benzimidazoles, Calcium, Peptides, Reactive Oxygen Species
Abstract

Intracerebral hemorrhage (ICH) is a pathological condition that accompanies certain neurological diseases like hemorrhagic stroke or brain trauma. Its effects are severely destructive to the brain and can be fatal. There is an entire spectrum of harmful factors which are associated with the pathogenesis of ICH. One of them is a massive release of hemin from the decomposed erythrocytes. It has been previously shown, that hemin can inhibit the large-conductance Ca(2+)-regulated potassium channel in the plasma membrane. However, it remained unclear whether this phenomenon applies also to the mitochondrial large-conductance Ca(2+)-regulated potassium channel. The aim of the present study was to determine the impact of hemin on the activity of the large conductance Ca(2+)-regulated potassium channel in the brain mitochondria (mitoBKCa). In order to do so, we have used a patch-clamp technique and shown that hemin inhibits mitoBKCa in human astrocytoma U-87 MG cell line mitochondria. Since opening of the mitochondrial potassium channels is known to be cytoprotective, we have elucidated whether hemin can attenuate some of the beneficiary effects of potassium channel opening. We have studied the effect of hemin on reactive oxygen species synthesis, and mild mitochondrial uncoupling in isolated rat brain mitochondria. Taken together, our data show that hemin inhibits mitoBKCa and partially abolishes some of the cytoprotective properties of potassium channel opening. Considering the role of the mitoBKCa in cytoprotection, it can be presumed that its inhibition by hemin may be a novel mechanism contributing to the severity of the ICH symptoms. However, the validity of the presented results shall be further verified in an experimental model of ICH.

Published
2014
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25. Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy

Author

Borislav Dejanovic, Dennis Lal, Claudia B. Catarino, Sita Arjune, Abdel A. Belaidi, Holger Trucks, Christian Vollmar, Rainer Surges, Wolfram S. Kunz, Susanne Motameny, Janine Altmüller, Anna Köhler, Bernd A. Neubauer, null EPICURE Consortium, Peter Nürnberg, Soheyl Noachtar, Günter Schwarz, and Thomas Sander

Subjects
Adult, Male, Idiopathic generalized epilepsy, GPHN, Neurotransmission, Inhibitory postsynaptic potential, Epileptogenesis, lcsh:RC321-571, Frameshift mutation, Young Adult, Epilepsy, Risk Factors, medicine, Humans, RNA, Messenger, GABAergic Neurons, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Sequence Deletion, Genetics, Gephyrin, biology, Membrane Proteins, Exons, medicine.disease, Pedigree, Neurology, Synapses, biology.protein, Microdeletion, GABAergic, Epilepsy, Generalized, Female, Carrier Proteins, Neuroscience
Abstract

Gephyrin is a postsynaptic scaffolding protein, essential for the clustering of glycine and γ-aminobutyric acid type-A receptors (GABAARs) at inhibitory synapses. An impairment of GABAergic synaptic inhibition represents a key pathway of epileptogenesis. Recently, exonic microdeletions in the gephyrin (GPHN) gene have been associated with neurodevelopmental disorders including autism spectrum disorder, schizophrenia and epileptic seizures. Here we report the identification of novel exonic GPHN microdeletions in two patients with idiopathic generalized epilepsy (IGE), representing the most common group of genetically determined epilepsies. The identified GPHN microdeletions involve exons 5–9 (Δ5–9) and 2–3 (Δ2–3), both affecting the gephyrin G-domain. Molecular characterization of the GPHN Δ5–9 variant demonstrated that it perturbs the clustering of regular gephyrin at inhibitory synapses in cultured mouse hippocampal neurons in a dominant-negative manner, resulting in a significant loss of γ2-subunit containing GABAARs. GPHN Δ2–3 causes a frameshift resulting in a premature stop codon (p.V22Gfs*7) leading to haplo-insufficiency of the gene. Our results demonstrate that structural exonic microdeletions affecting the GPHN gene constitute a rare genetic risk factor for IGE and other neuropsychiatric disorders by an impairment of the GABAergic inhibitory synaptic transmission.

Published
2014
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26. Sustained seizure remission on perampanel in progressive myoclonic epilepsy (Lafora disease)☆

Author

Wolfram S. Kunz, Felix Rosenow, Adam Strzelczyk, Kathrin Schorlemmer, Sebastian Bauer, Philipp S. Reif, Anke Hermsen, Marcus Belke, Susanne Knake, Karl Martin Klein, and Wolfgang H. Oertel

Subjects
Myoclonus, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Pediatrics, EPM2A, Case Report, Progressive myoclonus epilepsy, Progressive myoclonic epilepsy, Perampanel, Lafora disease, Behavioral Neuroscience, chemistry.chemical_compound, Epilepsy, medicine, Lafora, Psychiatry, business.industry, medicine.disease, Neurology, chemistry, Neurology (clinical), medicine.symptom, business
Abstract

Aim The aim of this report is to provide initial evidence that add-on treatment with perampanel might be highly effective in progressive myoclonic epilepsy such as Lafora disease. Case report We report on a 21-year-old woman suffering from persistent myoclonus and generalized tonic–clonic seizures for more than seven years. Additionally, ataxia, a disturbance in speech and gait, as well as a cognitive decline were rapidly progressing. Subsequently, the diagnosis of Lafora disease was confirmed by the identification of a novel homozygous missense mutation in exon 3 of the EPM2A gene (c.538C>G; p.L180V). Adjunctive therapy with perampanel was started in this patient with advanced Lafora disease and was titrated up to 8 mg/day. A sustained and reproducible remission of myoclonus and GTCS could be achieved for a follow-up of three months. After dosage reduction to 6 mg/day, seizures recurred; however, on increasing the daily dose to 10 mg, seizures stopped for another three months. The patient also regained her ability to walk with help and the aid of a walker. Conclusions Perampanel is a selective, noncompetitive antagonist of AMPA-type glutamate receptors and recently licensed as adjunctive therapy for the treatment of refractory focal onset seizures. There is evidence for its effectiveness in generalized epilepsies, and phase III studies for this indication are on the way. Our case illustrates the possibility that perampanel might be a valuable option for treatment in PME. Considering its impressive efficacy in this case, we suggest a prospective, multicenter study evaluating perampanel in PME.

Published
2013

27. Mutation in the mitochondrial tRNAIle gene causes progressive myoclonus epilepsy

Author

Yvonne G. Weber, Gábor Zsurka, Holger Lerche, Wolfram S. Kunz, Felicitas Becker, Hans-Jürgen Gdynia, and Markus Heinen

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Mitochondrial DNA, Clinical Neurology, Progressive myoclonus epilepsy, Biology, MERRF, Epilepsy, Progressive, RNA, Transfer, Photosensitivity, medicine, Humans, Muscle, Skeletal, Myoclonic epilepsy with ragged red fibres, Muscle biopsy, medicine.diagnostic_test, Skeletal muscle, Electroencephalography, General Medicine, medicine.disease, Myoclonic Epilepsies, Progressive, Magnetic Resonance Imaging, Heteroplasmy, Mitochondria, Muscle, medicine.anatomical_structure, Metabolism, Neurology, Mutation, Myoclonic epilepsy, Neurology (clinical), Chronic progressive external ophthalmoplegia, Myoclonic
Abstract

A B S T R A C T Purpose: The group of the rare progressive myoclonic epilepsies (PME) include a wide spectrum of mitochondrial and metabolic diseases. In juvenile and adult ages, MERRF (myoclonic epilepsy with ragged red fibres) is the most common form. The underlying genetic defect in most patients with the syndrome of MERRF is a mutation in the tRNALys gene, but mutations were also detected in the tRNAPhe gene. Method: Here, we describe a 40 year old patient with prominent myoclonic seizures since 39 years of age without a mutation in the known genes who underwent intensive clinical, genetic and functional workup. Results: The patient had a slight mental retardation and a severe progressive hearing loss based on a defect of the inner ear on both sides. Ictal electroencephalography (EEG) showed bilateral occipital and generalized spikes and polyspikes induced and aggravated by photostimulation. A cranial magnetic resonance imaging (cMRI) detected a global cortical atrophy of the brain and mild periventricular white matter lesions. The electromyography (EMG) was normal but the muscle biopsy showed abundant ragged red fibres. Sequencing of the mitochondrial DNA from the skeletal muscle biopsy revealed a novel heteroplasmic mutation (m.4279A>G) in the tRNAIle gene which was functionally relevant as tested in single skeletal muscle fibre investigations. Conclusion: Mutations in tRNAIle were described in patients with chronic progressive external ophthalmoplegia (CPEO), prominent deafness or cardiomyopathy but, up to now, not in patients with myoclonic epilepsy. The degree of heteroplasmy of this novel mitochondrial DNA mutation was 70% in skeletal muscle but only 15% in blood, pointing to the diagnostic importance of a skeletal muscle biopsy also in patients with myoclonic epilepsy.

Published
2013
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28. Mitochondrial involvement in neurodegenerative diseases

Author

Wolfram S. Kunz and Gábor Zsurka

Subjects
Programmed cell death, Mitochondrial DNA, Clinical Biochemistry, Presynaptic Terminals, Oxidative phosphorylation, Mitochondrion, medicine.disease_cause, DNA, Mitochondrial, Biochemistry, Oxidative Phosphorylation, Mitochondrial Proteins, Adenosine Triphosphate, Genetics, medicine, Humans, Molecular Biology, Mutation, Cell Death, ATP synthase, biology, Neurodegeneration, Neurodegenerative Diseases, Cell Biology, medicine.disease, Mitochondria, Cell biology, Oxidative Stress, Disease Progression, biology.protein, Reactive Oxygen Species, Oxidative stress
Abstract

The classical bioenergetical view of the involvement of mitochondria in neurogeneration is based on the fact that mitochondria are the central players of ATP synthesis in neurons and their failure leads to neuronal dysfunction and eventually to cell death. Mutations in at least 39 genes in inherited neurodegenerative disorders seem to alter directly or indirectly mitochondrial function. Most of these mutations do not directly affect oxidative phosphorylation, but act through disturbed mitochondrial dynamics and quality control. This, however, does not invalidate the bioenergetic hypothesis. Neurodegeneration is not necessarily associated with a gross failure of ATP production, but might rather be a consequence of local insufficiencies of ATP supply in critical compartments of neurons, like the presynaptic terminal. We hypothesize that slow disease progression, at least in a subgroup of neurodegenerative diseases, can be explained by the parallel action of subcellular ATP insufficiency and clonal expansion of somatic mitochondrial DNA mutations, and particularly deletions.

Published
2013
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29. Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease

Author

Miriam H. Meisler, David A. Hsu, Anna Walczak, Grazyna Debska-Vielhaber, Rafał Płoski, Piotr Stawiński, Stefan Vielhaber, Wolfram S. Kunz, Guy M. Lenk, Kerstin Hallmann, Sonja Buehring, Małgorzata Rydzanicz, Monika Bekiesińska-Figatowska, and Krystyna Szymańska

Subjects
0301 basic medicine, Proband, Male, Heterozygote, Mutation, Missense, Genes, Recessive, Neurological disorder, Biology, Compound heterozygosity, 03 medical and health sciences, 0302 clinical medicine, Report, medicine, Polymicrogyria, Genetics, Missense mutation, Humans, Genetics(clinical), Exome, Amino Acid Sequence, Age of Onset, Child, Genetics (clinical), Exome sequencing, Alleles, Dystonia, Intracellular Signaling Peptides and Proteins, Infant, Membrane Proteins, Exons, medicine.disease, Pedigree, 030104 developmental biology, Child, Preschool, Mutation, Female, Age of onset, Nervous System Diseases, 030217 neurology & neurosurgery
Abstract

In the PI(3,5)P2 biosynthetic complex, the lipid kinase PIKFYVE and the phosphatase FIG4 are bound to the dimeric scaffold protein VAC14, which is composed of multiple heat-repeat domains. Mutations of FIG4 result in the inherited disorders Charcot-Marie-Tooth disease type 4J, Yunis-Varon syndrome, and polymicrogyria with seizures. We here describe inherited variants of VAC14 in two unrelated children with sudden onset of a progressive neurological disorder and regression of developmental milestones. Both children developed impaired movement with dystonia, became nonambulatory and nonverbal, and exhibited striatal abnormalities on MRI. A diagnosis of Leigh syndrome was rejected due to normal lactate profiles. Exome sequencing identified biallelic variants of VAC14 that were inherited from unaffected heterozygous parents in both families. Proband 1 inherited a splice-site variant that results in skipping of exon 13, p.Ile459Profs(∗)4 (not reported in public databases), and the missense variant p.Trp424Leu (reported in the ExAC database in a single heterozygote). Proband 2 inherited two missense variants in the dimerization domain of VAC14, p.Ala582Ser and p.Ser583Leu, that have not been previously reported. Cultured skin fibroblasts exhibited the accumulation of vacuoles that is characteristic of PI(3,5)P2 deficiency. Vacuolization of fibroblasts was rescued by transfection of wild-type VAC14 cDNA. The similar age of onset and neurological decline in the two unrelated children define a recessive disorder resulting from compound heterozygosity for deleterious variants of VAC14.

Published
2016

30. Genetic variation in dopaminergic activity is associated with the risk for psychiatric side effects of levetiracetam

Author

Mohammad R. Toliat, Holger Thiele, Wolfram S. Kunz, Christian E. Elger, Yoan Mihov, Susanne Schoch, René Hurlemann, Rainer Surges, Christoph Helmstaedter, and Peter Nuernberg

Subjects
medicine.medical_specialty, Candidate gene, ANKK1, Dopaminergic, Impulsivity, Irritability, medicine.disease, Epilepsy, Neurology, medicine, Neurology (clinical), Levetiracetam, medicine.symptom, Psychiatry, Psychology, medicine.drug, rs4680
Abstract

SUMMARY Purpose: Levetiracetam (LEV) is a highly effective antiepileptic agent. A clinically relevant psychiatric complication of LEV treatment, however, is the provocation of irritability and aggression. Recent behavioral research indicates that personality traits may predispose to these side effects. To assess the genetic basis of the adverse psychotropic profile of LEV, a candidate gene-based two-stage association study was conducted. Methods: Polymorphisms were a priori selected according to their relevance for impulsivity and reactive-impulsive aggression. Based on data from both stages, a Bonferroni-corrected joint meta-analysis was computed. Key Findings: Stage 1 analysis included 290 patients with epilepsy and revealed a higher load of adverse psychotropic side effects of LEV in patients carrying genetic variants associated with decreased dopaminergic activity: rs1611115 (dopamine-b-hydroxylase, DBH), rs4680 (catechol-O-methyltransferase, COMT), and rs1800497 (dopamine receptor D2-associated ANKK1 TAQ-1A). Stage II analysis including 100 patients with epilepsy, and joint meta-analysis confirmed the effect of the rs1800497 polymorphism (Bonferroni corrected significance of the joint meta-analysis, p = 0.0096). Significance: Confirming the suggestion from behavioral observations that patients might be predisposed to develop irritation and aggression under treatment with LEV, the findings provide first evidence of an association of genetic variation in dopaminergic activity and the risk for psychiatric complications of LEV treatment. Replication and further work is required to prove a true causal relationship. Overall, the pharmacogenomic approach to behavioral side effects may provide a future tool to predict adverse psychotropic effects related to antiepileptic drugs.

Published
2012
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31. Mitochondrial dysfunction in epilepsy

Author

Jaroslava Folbergrová and Wolfram S. Kunz

Subjects
Neurons, Programmed cell death, Epilepsy, Immature animal, Neurodegeneration, Cell Biology, Oxidative phosphorylation, Mitochondrion, Biology, Neurotransmission, medicine.disease, Neuroprotection, Mitochondria, Disease Models, Animal, medicine, Animals, Homeostasis, Humans, Molecular Medicine, Calcium, Energy Metabolism, Reactive Oxygen Species, Molecular Biology, Neuroscience
Abstract

Mitochondrial dysfunction has been identified as one potential cause of epileptic seizures. Impaired mitochondrial function has been reported for the seizure focus of patients with temporal lobe epilepsy and Ammon's horn sclerosis and of adult and immature animal models of epilepsy. Since mitochondrial oxidative phosphorylation provides the major source of ATP in neurons and mitochondria participate in cellular Ca(2+) homeostasis and generation of reactive oxygen species, their dysfunction strongly affects neuronal excitability and synaptic transmission. Therefore, mitochondrial dysfunction is proposed to be highly relevant for seizure generation. Additionally, mitochondrial dysfunction is known to trigger neuronal cell death, which is a prominent feature of therapy-resistant epilepsy. For this reason mitochondria have to be considered as promising targets for neuroprotective strategies in epilepsy.

Published
2012
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32. Mitochondriale Dysfunktion bei Epilepsien

Author

Wolfram S. Kunz

Subjects
Gynecology, medicine.medical_specialty, business.industry, Pediatrics, Perinatology and Child Health, MERRF syndrome, medicine, Neurology (clinical), medicine.disease, business, MELAS syndrome
Abstract

Eine Vielzahl von Mutationen der mitochondrialen Desoxyribonukleinsaure (mtDNA) oder nuklearer Gene, die zur Beeintrachtigung der mitochondrialen Atmungskette oder der mitochondrialen Adenosintriphosphat- (ATP-)Synthese fuhren, ist bisher mit epileptischen Phanotypen assoziiert worden. Zusatzlich dazu gibt es Hinweise fur eine Beeintrachtigung der mitochondrialen Funktion in der Anfallsursprungszone von Patienten mit Temporallappenepilepsie (TLE) und Ammonshornsklerose (AHS). Das deutet auf eine direkte pathogene Rolle der mitochondrialen Dysfunktion im Prozess der Epileptogenese und Anfallsgenerierung bei speziellen Formen von Epilepsie hin. Deshalb mussen Mitochondriopathien als mogliche Ursachen schwerer Epilepsien in Betracht gezogen werden.

Published
2011
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33. Dose-dependent memory effects and cerebral volume changes after in utero exposure to valproate in the rat

Author

Christian E. Elger, Frank Angenstein, Christoph Helmstaedter, Christian Frisch, Kerstin Hüsch, Alexei P. Kudin, and Wolfram S. Kunz

Subjects
Male, medicine.medical_specialty, Dose, Offspring, medicine.medical_treatment, Statistics as Topic, Central nervous system, Drinking, Motor Activity, Epilepsy, Pregnancy, Internal medicine, medicine, Animals, Maze Learning, Cerebral Cortex, Analysis of Variance, Memory Disorders, Valproic Acid, Behavior, Animal, Dose-Response Relationship, Drug, medicine.diagnostic_test, Uterus, Age Factors, Abnormalities, Drug-Induced, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, Rats, Endocrinology, Anticonvulsant, medicine.anatomical_structure, Animals, Newborn, Neurology, In utero, Prenatal Exposure Delayed Effects, Exploratory Behavior, Anticonvulsants, Female, Neurology (clinical), Psychology, medicine.drug
Abstract

Summary Purpose: Recent clinical studies raised concern of a cognitive teratogenicity of the major antiepileptic drug valproate. To investigate possible cerebral correlates, we established a forced self-application schedule by diluting valproate in the drinking water of pregnant Wistar rats. Methods: After application of medium (MD) and high doses (HDs) with mean daily intakes of about 470 and 720 mg/kg during the entire pregnancy, we analyzed effects on offspring performance in a series of behavioral paradigms as well as brain volumetric changes by magnetic resonance imaging (MRI). Results: While high dosages with peak serum concentrations slightly above 100 μg/ml induced early decrements in general activity and deficits in learning and memory, medium dosages led to improved watermaze performance in 30-day-old rats. MRI analyses indicated increased hippocampal volumes in the MD condition, whereas in the HD condition significantly decreased cortical and brainstem volumes were registered. Cortical volume reduction was correlated with spatial acuity in the watermaze. Conclusions: The results indicate that effects of valproate in utero on offspring cognitive capabilities might depend on total drug load differentially affecting cerebral development during adolescence in the rat.

Published
2009
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34. Myofiber integrity depends on desmin network targeting to Z-disks and costameres via distinct plectin isoforms

Author

Irmgard Fischer, Peter Fuchs, Anikó Zeöld, Siegfried Reipert, Wolfram S. Kunz, Gerhard Wiche, Denise Paulin, Patryk Konieczny, and Rolf Schröder

Subjects
Sarcomeres, Muscle Fibers, Skeletal, Intermediate Filaments, macromolecular substances, Biology, Models, Biological, Article, Desmin, Mice, 03 medical and health sciences, Sarcolemma, 0302 clinical medicine, medicine, Animals, Protein Isoforms, Myocyte, Muscular dystrophy, Intermediate filament, Research Articles, Costamere, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Costameres, Cell Biology, Plectin, Anatomy, medicine.disease, Survival Analysis, Muscle, Striated, Mitochondria, Cell biology, Disease Progression, Physical Endurance, 030217 neurology & neurosurgery, Muscle Contraction
Abstract

Dysfunction of plectin, a 500-kD cytolinker protein, leads to skin blistering and muscular dystrophy. Using conditional gene targeting in mice, we show that plectin deficiency results in progressive degenerative alterations in striated muscle, including aggregation and partial loss of intermediate filament (IF) networks, detachment of the contractile apparatus from the sarcolemma, profound changes in myofiber costameric cytoarchitecture, and decreased mitochondrial number and function. Analysis of newly generated plectin isoform–specific knockout mouse models revealed that IF aggregates accumulate in distinct cytoplasmic compartments, depending on which isoform is missing. Our data show that two major plectin isoforms expressed in muscle, plectin 1d and 1f, integrate fibers by specifically targeting and linking desmin IFs to Z-disks and costameres, whereas plectin 1b establishes a linkage to mitochondria. Furthermore, disruption of Z-disk and costamere linkages leads to the pathological condition of epidermolysis bullosa with muscular dystrophy. Our findings establish plectin as the major organizer of desmin IFs in myofibers and provide new insights into plectin- and desmin-related muscular dystrophies.

Published
2008
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35. Concerted action of two novel tRNA mtDNA point mutations in chronic progressive external ophthalmoplegia

Author

Cornelia Kornblum, Rudolf J. Wiesner, Wolfram S. Kunz, Gábor Zsurka, and Rolf Schröder

Subjects
Adult, Male, Ophthalmoplegia, Chronic Progressive External, Mitochondrial DNA, Adolescent, Mitochondrial disease, Molecular Sequence Data, Biophysics, Biology, medicine.disease_cause, DNA, Mitochondrial, Biochemistry, RNA, Transfer, medicine, Humans, Point Mutation, Child, Muscle, Skeletal, Molecular Biology, Gene, Aged, Genetics, Mutation, Base Sequence, Point mutation, Cell Biology, Middle Aged, medicine.disease, Phenotype, Molecular biology, Heteroplasmy, Child, Preschool, Nucleic Acid Conformation, Female, Chronic progressive external ophthalmoplegia
Abstract

CPEO (chronic progressive external ophthalmoplegia) is a common mitochondrial disease phenotype in adults which is due to mtDNA (mitochondrial DNA) point mutations in a subset of patients. Attributing pathogenicity to novel tRNA mtDNA mutations still poses a challenge, particularly when several mtDNA sequence variants are present. In the present study we report a CPEO patient for whom sequencing of the mitochondrial genome revealed three novel tRNA mtDNA mutations: G5835A, del4315A, T1658C in tRNATyr, tRNAIle and tRNAVal genes. In skeletal muscle, the tRNAVal and tRNAIle mutations were homoplasmic, whereas the tRNATyr mutation was heteroplasmic. To address the pathogenic relevance, we performed two types of functional tests: (i) single skeletal muscle fibre analysis comparing G5835A mutation loads and biochemical phenotypes of corresponding fibres, and (ii) Northern-blot analyses of mitochondrial tRNATyr, tRNAIle and tRNAVal. We demonstrated that both the G5835A tRNATyr and del4315A tRNAIle mutation have serious functional consequences. Single-fibre analyses displayed a high threshold of the tRNATyr mutation load for biochemical phenotypic expression at the single-cell level, indicating a rather mild pathogenic effect. In contrast, skeletal muscle tissue showed a severe decrease in respiratory-chain activities, a reduced overall COX (cytochrome c oxidase) staining intensity and abundant COX-negative fibres. Northern-blot analyses showed a dramatic reduction of tRNATyr and tRNAIle levels in muscle, with impaired charging of tRNAIle, whereas tRNAVal levels were only slightly decreased, with amino-acylation unaffected. Our findings suggest that the heteroplasmic tRNATyr and homoplasmic tRNAIle mutation act together, resulting in a concerted effect on the biochemical and histological phenotype. Thus homoplasmic mutations may influence the functional consequences of pathogenic heteroplasmic mtDNA mutations.

Published
2008
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36. Metabolic progression markers of neurodegeneration in the transgenic G93A-SOD1 mouse model of amyotrophic lateral sclerosis

Author

Dieter Leibfritz, Wolfram S. Kunz, Hans-Jochen Heinze, Heiko G. Niessen, Frank Angenstein, Wieland Willker, Liane Hilfert, Stefan Vielhaber, Kerstin Sander, Albert C. Ludolph, and Grazyna Debska-Vielhaber

Subjects
Genetically modified mouse, Pathology, medicine.medical_specialty, General Neuroscience, Neurodegeneration, SOD1, Motor neuron, Biology, medicine.disease, Spinal cord, Glutamine, medicine.anatomical_structure, medicine, Brainstem, Amyotrophic lateral sclerosis, Neuroscience
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. Visualizing corresponding metabolic changes in the brain of patients with ALS with proton magnetic resonance spectroscopy ( 1 H-MRS) may provide surrogate markers for an early disease detection, for monitoring the progression and for evaluating a treatment response. The primary objective of our study was to evaluate whether modifications in MR metabolite levels occur before clinical disease onset, and whether these changes are directly linked to a distinct spatial progression pattern in the CNS. Therefore, age-dependent alterations in the cerebral and spinal metabolic profile in the mouse model of ALS overexpressing the mutated human G93A-superoxide dismutase 1 (G93A-SOD1) were determined by high-resolution MRS of tissue extracts at 14.1 Tesla. Both non-transgenic mice (control mice) and transgenic mice overexpressing the non-mutated human SOD1 (tg-SOD1) served as controls. In the spinal cord of G93A-SOD1 mice significantly decreased levels of N-acetyl aspartate were already detected 34 days postpartum, i.e. about 60 days before the average disease onset caused by motor neuron decline. In addition, glutamine and c-aminobutyric acid concentrations were significantly diminished at Day 75, which is still in the presymptomatic phase of the disease. These metabolic changes were further progressive in the course of the disease and started to involve the brainstem at Day 75. Overall, high-resolution 1 H-MRS allows a sensitive spatial and temporal metabolite profiling in the presymptomatic phase of ALS even before significant neuronal cell loss occurs.

Published
2007
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37. Amelioration of water maze performance deficits by topiramate applied during pilocarpine-induced status epilepticus is negatively dose-dependent

Author

Christoph Helmstaedter, Christian Frisch, Wolfram S. Kunz, Christian E. Elger, and Alexei P. Kudin

Subjects
Male, Topiramate, medicine.medical_specialty, medicine.medical_treatment, Video Recording, Hippocampus, Fructose, Status epilepticus, Water maze, Hippocampal formation, Epilepsy, Status Epilepticus, Memory, Internal medicine, medicine, Animals, Rats, Wistar, Maze Learning, Swimming, Neurons, Diazepam, Dose-Response Relationship, Drug, business.industry, Pilocarpine, Water, medicine.disease, Rats, Disease Models, Animal, Neuroprotective Agents, Anticonvulsant, Endocrinology, Neurology, Anesthesia, Anticonvulsants, Neurology (clinical), medicine.symptom, business, medicine.drug
Abstract

Summary Temporal lobe epilepsy is characterized by a progressive loss of memory capacities, due to sclerosis and functional impairment of mesiotemporal brain areas. We have shown recently that topiramate (TPM) dose-dependently protects hippocampal CA1 and CA3 neurons during initial status epilepticus in the rat pilocarpine model of temporal lobe epilepsy by inhibition of mitochondrial transition pore opening. In the present study, in order to evaluate possible positive effects of the treatment on learning and memory, we investigated water maze performance of rats receiving different dosages of TPM (20 and 100 mg/kg) after 40 min and 4 mg/kg diazepam after 160 min of pilocarpine-induced status epilepticus in relation to performance of animals receiving 4 mg/kg diazepam after 40 min of SE, and to performance of sham-treated control animals. Unexpectedly, 20 but not 100 mg/kg TPM significantly extenuated short-term memory deficits. While neuroprotective effects of TPM were observed in hippocampal CA subfields of animals treated with 100 mg/kg TPM, cell loss in rats treated with 20 mg/kg TPM was indistinguishable from animals receiving diazepam only. The present results indicate a negative dose-dependency of memory-saving effects of TPM applied during status epilepticus apparently dissociated from hippocampal neuroprotection.

Published
2007
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38. Neuropathological signs of inflammation correlate with mitochondrial DNA deletions in mesial temporal lobe epilepsy

Author

Wolfram S. Kunz, Elisa Volmering, Albert J. Becker, Christian E. Elger, Viktoriya Peeva, Gábor Zsurka, Pitt Niehusmann, Peter Nürnberg, Janine Altmüller, Susanne Schoch, and Alexander Grote

Subjects
0301 basic medicine, Adult, Male, Mitochondrial DNA, Pathology, medicine.medical_specialty, Somatic cell, Hippocampus, Inflammation, Mitochondrion, Biology, Hippocampal formation, Epileptogenesis, DNA, Mitochondrial, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Humans, Neurons, Hippocampal sclerosis, Sclerosis, High-Throughput Nucleotide Sequencing, Middle Aged, medicine.disease, Magnetic Resonance Imaging, 3. Good health, 030104 developmental biology, Epilepsy, Temporal Lobe, Female, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery
Abstract

Accumulation of mitochondrial DNA (mtDNA) deletions has been proposed to be responsible for the presence of respiratory-deficient neurons in several CNS diseases. Deletions are thought to originate from double-strand breaks due to attack of reactive oxygen species (ROS) of putative inflammatory origin. In epileptogenesis, emerging evidence points to chronic inflammation as an important feature. Here we aimed to analyze the potential association of inflammation and mtDNA deletions in the hippocampal tissue of patients with mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS). Hippocampal and parahippocampal tissue samples from 74 patients with drug-refractory mTLE served for mtDNA analysis by multiplex PCR as well as long-range PCR, single-molecule PCR and ultra-deep sequencing of mtDNA in selected samples. Patients were sub-classified according to neuropathological findings. Semi-quantitative assessment of neuronal cell loss was performed in the hippocampal regions CA1-CA4. Inflammatory infiltrates were quantified by cell counts in the CA1, CA3 and CA4 regions from well preserved hippocampal samples (n = 33). Samples with HS showed a significantly increased frequency of a 7436-bp mtDNA deletion (p 0.0001) and a higher proportion of somatic GT transversions compared to mTLE patients with different histopathology. Interestingly, the number of T-lymphocytes in the hippocampal CA1, CA3 and CA4 regions was, similar to the 7436-bp mtDNA deletion, significantly increased in samples with HS compared to other subgroups. Our findings show a coincidence of HS, increased somatic GT transversions, the presence of a specific mtDNA deletion, and increased inflammatory infiltrates. These results support the hypothesis that chronic inflammation leads to mitochondrial dysfunction by ROS-mediated mtDNA mutagenesis which promotes epileptogenesis and neuronal cell loss in patients with mTLE and HS.

Published
2015

39. Investigation of GRIN2A in common epilepsy phenotypes

Author

Lal, Dennis, Steinbrücker, Sandra, Schubert, Julian, Sander, Thomas, Becker, Felicitas, Weber, Yvonne, Lerche, Holger, Thiele, Holger, Krause, Roland, Lehesjoki, Anna Elina, Nürnberg, Peter, Palotie, Aarno, Neubauer, Bernd A., Muhle, Hiltrud, Stephani, Ulrich, Helbig, Ingo, Becker, Albert J., Schoch, Susanne, Hansen, Jörg, Dorn, Thomas, Hohl, Christin, Lüscher, Nicole, von Spiczak, Sarah, Lemke, Johannes R., Zimprich, Fritz, Feucht, Martha, Suls, Arvid, Weckhuysen, Sarah, Claes, Lieve, Deprez, Liesbet, Smets, Katrien, Dyck, Tine Van, Deconinck, Tine, De Jonghe, Peter, Møller, Rikke S., Klitten, Laura L., Hjalgrim, Helle, Campus, Kiel, Ostertag, Philipp, Trucks, Hol ger, Elger, Christian E., Kleefuß-Lie, Ailing A., Kunz, Wolfram S., Surges, Rainer, Gaus, Verena, Janz, Dieter, Schmitz, Bettina, Klein, Karl Martin, Reif, Philipp S., Oertel, Wolfgang H., Hamer, Hajo M., Rosenow, Felix, Kapser, Claudia, Schankin, Christoph J., Koeleman, Bobby P C, de Kovel, Carolien, Lindhout, Dick, Reinthaler, Eva M., Steinboeck, Hannelore, Neo-phytou, Birgit, Geldner, Julia, Gruber-Sedlmayr, Ursula, Haberlandt, Edda, Ronen, Gabriel M., Altmueller, Janine, Nuernberg, Peter, Neubauer, Bernd, Sirén, Auli, Neuroscience Center, Research Programs Unit, Department of Medical and Clinical Genetics, Anna-Elina Lehesjoki / Principal Investigator, Research Programme for Molecular Neurology, Medicum, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Suls, Arvid, Weckhuysen, Sarah, Claes, Godelieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Epicure Consortium, and EuroEPINOMICS-CoGIE Consortium

Subjects
Pathology, Idiopathic generalized epilepsy, DEPDC5, Genotyping Techniques, CHILDHOOD, Bioinformatics, GRIN2A, 3124 Neurology and psychiatry, Cohort Studies, Epilepsy, 0302 clinical medicine, Databases, Genetic, Medicine, Copy-number variation, TERMINOLOGY, Non-U.S. Gov't, Temporal lobe epilepsy, FOCAL EPILEPSIES, Exome sequencing, Sanger sequencing, 0303 health sciences, Research Support, Non-U.S. Gov't, Phenotype, Neurology, symbols, Epilepsy, Generalized, medicine.medical_specialty, DNA Copy Number Variations, DISORDERS, Clinical Neurology, Research Support, Receptors, N-Methyl-D-Aspartate, CLASSIFICATION, Juvenile Absence Epilepsy, 03 medical and health sciences, symbols.namesake, Journal Article, Humans, Biology, 030304 developmental biology, business.industry, MUTATIONS, Copy number variation, 3112 Neurosciences, INCLUDING GRIN2A, medicine.disease, DELETIONS, Epilepsy, Absence, Epilepsy, Temporal Lobe, Epilepsy syndromes, Mutation, SEIZURES, Neurology (clinical), Human medicine, business, 030217 neurology & neurosurgery
Abstract

Recently, mutations and deletions in the GRIN2A gene have been identified to predispose to benign and severe idiopathic focal epilepsies (IFE), revealing a higher incidence of GRIN2A alterations among the more severe phenotypes. This study aimed to explore the phenotypic boundaries of GRIN2A mutations by investigating patients with the two most common epilepsy syndromes: (i) idiopathic generalized epilepsy (IGE) and (ii) temporal lobe epilepsy (TLE). Whole exome sequencing data of 238 patients with IGE as well as Sanger sequencing of 84 patients with TLE were evaluated for GRIN2A sequence alterations. Two additional independent cohorts comprising 1469 IGE and 330 TLE patients were screened for structural deletions (>40 kb) involving GRIN2A. Apart from a presumably benign, non-segregating variant in a patient with juvenile absence epilepsy, neither mutations nor deletions were detected in either cohort. These findings suggest that mutations in GRIN2A preferentially are involved in genetic variance of pediatric IFE and do not contribute significantly to either adult focal epilepsies as TLE or generalized epilepsies. (C) 2015 Elsevier B.V. All rights reserved.

Published
2015
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40. Extending the phenotypic spectrum of RBFOX1 deletions: Sporadic focal epilepsy

Author

Philipp S. Reif, Rossana Tozzi, Wolfram S. Kunz, Dennis Lal, Karl Martin Klein, Albert J. Becker, Felicitas Becker, Peter Nürnberg, Mitja I. Kurki, Thomas Sander, Per Hoffmann, Katharina Pernhorst, Bernd A. Neubauer, Yvonne G. Weber, Emilio Perucca, Mohammad R. Toliat, Felix Rosenow, Holger Lerche, Georg Winterer, and Federico Zara

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Copy number variation, Cryptogenic, Genetic, Idiopathic, Lesional, Magnet resonance imaging negative, Adolescent, Child, Child, Preschool, DNA Mutational Analysis, Epilepsies, Partial, Female, Genetic Predisposition to Disease, Humans, Meta-Analysis as Topic, Middle Aged, Phenotype, RNA Splicing Factors, RNA-Binding Proteins, Sequence Deletion, RBFOX1, Epilepsies, Biology, Temporal lobe, Epilepsy, medicine, Copy-number variation, Preschool, Hippocampal sclerosis, medicine.disease, Rolandic epilepsy, Neurology, Epilepsy syndromes, Autism, Neurology (clinical), Partial
Abstract

Summary Partial deletions of the RBFOX1 gene encoding the neuronal splicing regulator have been reported in a range of neurodevelopmental diseases including idiopathic/genetic generalized epilepsy (IGE/GGE), childhood focal epilepsy, and self-limited childhood benign epilepsy with centrotemporal spikes (BECTS, rolandic epilepsy), and autism. The protein regulates alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. Herein, we examined whether structural deletions affecting RBFOX1 exons confer susceptibility to common forms of juvenile and adult focal epilepsy syndromes. We screened 807 unrelated patients with sporadic focal epilepsy, and we identified seven hemizygous exonic RBFOX1 deletions in patients with sporadic focal epilepsy (0.9%) in comparison to one deletion found in 1,502 controls. The phenotypes of the patients carrying RBFOX1 deletions comprise magnetic resonance imaging (MRI)–negative epilepsy of unknown etiology with frontal and temporal origin (n = 5) and two patients with temporal lobe epilepsy with hippocampal sclerosis. The epilepsies were largely pharmacoresistant but not associated with intellectual disability. Our study extends the phenotypic spectrum of RBFOX1 deletions as a risk factor for focal epilepsy and suggests that exonic RBFOX1 deletions are involved in the broad spectrum of focal and generalized epilepsies.

Published
2015

41. Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells

Author

Bernd O. Evert, Ullrich Wüllner, Holger Lutz, Eduard A. Struys, Thomas Klockgether, Eva Jarre, Cornelis Jakobs, Wolfram S. Kunz, Stefan Vielhaber, Carmen Noelker, and Michael Linnebank

Subjects
inorganic chemicals, medicine.medical_specialty, Hyperhomocysteinemia, Programmed cell death, Homocysteine, Cytochrome-c Oxidase Deficiency, Apoptosis, PC12 Cells, lcsh:RC321-571, Electron Transport Complex IV, chemistry.chemical_compound, Internal medicine, medicine, Animals, Humans, Cytochrome c oxidase, Menkes Kinky Hair Syndrome, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Cells, Cultured, Chelating Agents, Neurons, chemistry.chemical_classification, Reactive oxygen species, Dose-Response Relationship, Drug, biology, Neurodegeneration, Neurotoxicity, COX, Brain, Neurodegenerative Diseases, Menkes disease, medicine.disease, Rats, Neuroprotective Agents, Endocrinology, Animals, Newborn, Neurology, chemistry, biology.protein, Homocystinuria, Copper
Abstract

Children with hereditary severe hyperhomocysteinemia present with a variety of neurological impairment, and mild hyperhomocysteinemia has been associated with neurodegeneration in the elderly. The link of hyperhomocysteinemia to neurological dysfunction is unknown. We investigated mitochondrial mechanisms of homocysteine (HCys) neurotoxicity in rat dopaminergic pheochromocytoma cells, human neuroblastoma cells and primary rat cerebellar granule neurons. HCys dose dependently impaired cytochrome c oxidase (COX) activity as well as stability and induced reactive oxygen species and apoptotic cell death. We found that HCys binds the COX cofactor Cu(2+), and Cu(2+) supplementation prior to HCys treatment preserved COX activity and prevented cell death. The Cu(2+) chelating action of HCys and impairement of COX activity represent novel mechanisms of HCys neurotoxicity, which might be preventable by supplementation of Cu(2+).

Published
2006

42. Bedeutung der mitochondrialen DNA-Analyse in der Diagnostik der chronisch-progressiven externen Ophthalmoplegie (CPEO)

Author

Cornelia Kornblum, Thomas Klockgether, P. Roggenkämper, Wolfram S. Kunz, and Rolf Schröder

Subjects
Mitochondrial DNA, Pathology, medicine.medical_specialty, medicine.diagnostic_test, Mitochondrial disease, Respiratory chain, Skeletal muscle, Biology, medicine.disease, Ophthalmoparesis, Ophthalmology, medicine.anatomical_structure, Ptosis, Biopsy, medicine, medicine.symptom, Chronic progressive external ophthalmoplegia
Abstract

Background Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial cytopathy presenting with ptosis and external ophthalmoparesis. Mitochondrial disorders are characterized by a broad clinical spectrum and genetic background with marked genotype/phenotype variability. The routine diagnostic work-up usually includes clinical and laboratory examinations as well as histological and histochemical analysis of skeletal muscle biopsy. In our case only an additional molecular biological examination allowed the diagnosis of CPEO. Patient and methods We report a 35-year-old woman with a 7-years history of slowly progressive diplopia due to impaired ocular motility and bilateral ptosis. We performed ophthalmological and neurological examinations, laboratory testing, lower limb skeletal muscle biopsy including histological and histochemical investigations, biochemical analysis of respiratory chain enzymes in skeletal muscle homogenate and molecular genetic testing of skeletal muscle DNA. Results Although clinical, laboratory, histological and biochemical analyses did not give any hints suggesting a mitochondrial cytopathy, molecular genetic testing of total DNA from skeletal muscle tissue by Southern blot analysis finally revealed a 3.8 kb mitochondrial DNA deletion with a degree of heteroplasmy of 45 %. Conclusions In patients with unexplained binocular diplopia , oculomotor deficits and/or acquired ptosis, an underlying mitochondrial cytopathy should be considered. Even in the case of inconspicuous skeletal muscle histology and biochemistry, molecular genetic testing of skeletal muscle DNA is advisable in order to establish the diagnosis.

Published
2004
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43. Re-evaluation of the dysfunction of mitochondrial respiratory chain in skeletal muscle of patients with Parkinson?s disease

Author

Falk R. Wiedemann, Elmar Kirches, Claus-W. Wallesch, C. Mawrin, Kirstin Winkler-Stuck, Wolfram S. Kunz, Hartmut Lins, and Knut Dietzmann

Subjects
Adult, Male, medicine.medical_specialty, Mitochondrial DNA, Mitochondrial Diseases, Parkinson's disease, Free Radicals, Cell Respiration, DNA Mutational Analysis, Respiratory chain, Oxidative phosphorylation, Biology, DNA, Mitochondrial, Oxidative Phosphorylation, Electron Transport, Internal medicine, medicine, Humans, Point Mutation, Muscle, Skeletal, Biological Psychiatry, Aged, Point mutation, Skeletal muscle, Parkinson Disease, Middle Aged, medicine.disease, Mitochondria, Oxidative Stress, Psychiatry and Mental health, Mitochondrial respiratory chain, Endocrinology, medicine.anatomical_structure, Neurology, Biochemistry, Metabolic control analysis, Female, Neurology (clinical)
Abstract

The origin and tissue distribution of the mitochondrial dysfunction in Parkinson's disease (PD) remains still a matter of controversy. To re-evaluate a probably free radical-born, generalized mitochondrial impairment in PD, we applied optimized enzymatic assays, high resolution oxygraphic measurements of permeabilized muscle fibers, and application of metabolic control analysis to skeletal muscle samples of 19 PD patients and 36 age-matched controls. We detected decreased activities of respiratory chain complexes I and IV being accompanied by increased flux control coefficients of complexes I and IV on oxygen consumption of muscle fibers. We further investigated if randomly distributed point mutations in two discrete regions of the mitochondrial DNA are increased in PD muscle, and if they could contribute to the mitochondrial impairment. Our data confirm the previously debated presence of a mild mitochondrial defect in skeletal muscle of patients with PD which is accompanied with an about 1.5 to 2-fold increase of point mutated mtDNA.

Published
2004
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44. Effect of coenzyme Q10 on the mitochondrial function of skin fibroblasts from Parkinson patients

Author

Kirstin Winkler-Stuck, Falk R. Wiedemann, Wolfram S. Kunz, and Claus-W. Wallesch

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Parkinson's disease, Ubiquinone, Coenzymes, Respiratory chain, Glutamic Acid, Oxidative phosphorylation, Mitochondrion, Pharmacology, Biology, Antioxidants, chemistry.chemical_compound, Pyruvic Acid, medicine, Humans, Drug Interactions, Fibroblast, Cells, Cultured, Aged, Skin, Coenzyme Q10, Parkinson Disease, Fibroblasts, Middle Aged, NAD, medicine.disease, Mitochondria, Adenosine Diphosphate, Oxygen, medicine.anatomical_structure, Neurology, chemistry, Coenzyme Q – cytochrome c reductase, Amobarbital, Female, Neurology (clinical), NAD+ kinase
Abstract

Several lines of evidence suggest an impairment of mitochondrial function in the brain of patients with Parkinson's disease (PD). However, the presence of a detectable mitochondrial defect in extracerebral tissue of these patients remains a matter of dispute. Therefore, we investigated mitochondrial function in fibroblasts of 18 PD patients applying biochemical micromethods. Putative beneficial effects of coenzyme Q(10) (CoQ(10)), a potent antioxidant, on the mitochondrial function of skin fibroblast cultures were evaluated. Applying inhibitor titrations of the mitochondrial respiration to calculate flux control coefficients of respiratory chain complexes I and IV, we observed deficiencies of both complexes in cultivated skin fibroblasts of PD patients. Cultivation of fibroblasts in the presence of 5 microM CoQ(10) restored the activity of impaired respiratory chain complexes in the fibroblast cultures of 9 out of 18 PD patients. Our data support the presence of a generalised mitochondrial defect in at least a subgroup of patients with PD that can be partially ameliorated in vitro by coenzyme Q(10) treatment.

Published
2004
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45. Mitochondrial dysfunction in myofibrillar myopathy

Author

Jens Reimann, Stefan Vielhaber, Rolf Schröder, Wolfram S. Kunz, and Karin Kappes-Horn

Subjects
Mitochondrial encephalomyopathy, Pathology, medicine.medical_specialty, Histology, Respiratory chain, Skeletal muscle, Neuropathology, Mitochondrion, Biology, medicine.disease, Pathology and Forensic Medicine, medicine.anatomical_structure, Neurology, Physiology (medical), Lactic acidosis, medicine, Desmin, Neurology (clinical), Intermediate filament
Abstract

J. Reimann, W. S. Kunz, S. Vielhaber, K. Kappes-Horn and R. Schroder (2003) Neuropathology and Applied Neurobiology 29, 45–51 Mitochondrial dysfunction in myofibrillar myopathy ‘Myofibrillar myopathy’ defines a myopathic condition with focal myofibrillar destruction and accumulation of degraded myofibrillar elements. Despite the fact that a number of mutations in different genes as well as cytotoxic agents lead to the disease, abnormal accumulation of desmin is a typical, common feature. Pathological changes of mitochondrial morphology and function have been observed in animal models with intermediate filament pathology. Therefore, in the present study we tested for mitochondrial pathology in skeletal muscle of five patients with the pathohistological diagnosis of myofibrillar myopathy. Screening for large-scale mtDNA deletions and the frequent MERRF (myoclonic epilepsy; ragged red fibres) and MELAS (mitochondrial encephalomyopathy; lactic acidosis; stroke) point mutations was negative in all patients. Histologically, all muscle biopsies showed nonspecific abnormalities of the oxidative/mitochondrial enzyme stainings (histochemistry for reduced nicotinamide adenine dinucleotide, succinic dehydrogenase, cytochrome c oxidase), only one of them had ragged red fibres and a significant number of cytochrome c oxidase-negative fibres. Upon biochemical investigation, four of our patients showed pathologically low respiratory chain complex I activities. Only one of our patients had a pathologically low complex IV activity, while the measurements of the others were within low normal range. The single patient with pathological values for both complex I and IV was the one with the clear histological hallmarks (ragged red and cytochrome c oxidase-negative fibres) of mitochondrial pathology. She also was the only patient with clinical signs hinting at a mitochondrial disorder. Together with data from observations in desmin- and plectin-deficient mice, our results support the view that desmin intermediate filament pathology in these cases is closely linked to mitochondrial dysfunction in skeletal muscle.

Published
2003
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46. Correlation of Hippocampal Glucose Oxidation Capacity and Interictal FDG‐PET in Temporal Lobe Epilepsy

Author

Christian E. Elger, Ariel Schoenfeld, Stefan Vielhaber, Wolfram S. Kunz, Joachim von Oertzen, Hans‐Juergen Biersack, Christian Menzel, Alexei Kudin, and Thomas Kral

Subjects
Adult, Blood Glucose, Male, Adolescent, Hippocampus, Apoptosis, Hippocampal formation, Temporal lobe, Epilepsy, Fluorodeoxyglucose F18, Hexokinase, Image Processing, Computer-Assisted, Humans, Medicine, Ictal, Fluorodeoxyglucose, Sclerosis, medicine.diagnostic_test, business.industry, Dentate gyrus, Middle Aged, medicine.disease, Epilepsy, Temporal Lobe, nervous system, Neurology, Positron emission tomography, Female, Neurology (clinical), Energy Metabolism, business, Oxidation-Reduction, Neuroscience, Tomography, Emission-Computed, medicine.drug
Abstract

Summary: Purpose: Interictal [ 18 F]fluorodeoxyglucose (FDG) positron emission tomography (PET) demonstrates temporal hypometabolism in the epileptogenic zone of 60–90% of patients with temporal lobe epilepsy. The pathophysiology of this finding is still unknown. Several studies failed to show a correlation between hippocampal FDG-PET hypometabolism and neuronal cell loss. Because FDG is metabolized by hexokinase bound to the outer mitochondrial membrane, we correlated the glucose-oxidation capacity of hippocampal subfields obtained after surgical resection with the corresponding hippocampal presurgical FDG-PET activity. Methods: In 16 patients with electrophysiologically confirmed temporal lobe epilepsy, we used high-resolution respirometry to determine the basal and maximal glucose-oxidation rates in 400-m-thick hippocampal subfields obtained after dissection of human hippocampal slices into the CA1 and CA3 pyramidal subfields and the dentate gyrus. Results: We observed a correlation of the FDG-PET activity with the maximal glucose-oxidation rate of the CA3 pyramidal subfields (rp 0.7, p 0.003) but not for the regions CA1 and dentate gyrus. In accordance with previous studies, no correlation of the FDG-PET to the neuronal cell density of CA1, CA3, and dentate gyrus was found. Conclusions: The interictal hippocampal FDG-PET hypometabolism in patients with temporal lobe epilepsy is correlated to the glucose-oxidation capacity of the CA3 hippocampal subfield as result of impaired oxidative metabolism. Key Words: Temporal lobe epilepsy—FDG-PET—Mitochondrial oxidative phosphorylation.

Published
2003
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47. Mitochondrial Diseases - An Expanding Spectrum of Disorders and Affected Genes

Author

Jürgen-Christoph von Kleist-Retzow, Dietrich Michalk, Wolfram S. Kunz, and Ulrike Schauseil-Zipf

Subjects
Genetics, Mitochondrial DNA, Mitochondrial Diseases, Heterogeneous group, Nuclear gene, Mitochondrial disease, General Medicine, Oxidative phosphorylation, Biology, medicine.disease, DNA, Mitochondrial, Phenotype, Human mitochondrial genetics, Oxidative Phosphorylation, Mutation, medicine, Animals, Humans, Oxidoreductases, Gene
Abstract

Mitochondrial diseases are a heterogeneous group of disorders caused by the impairment of the mitochondrial oxidative phosphorylation system which have been associated with various mutations of the mitochondrial DNA (mtDNA) and nuclear gene mutations. The clinical phenotypes are very diverse and the spectrum is still expanding. This review gives an overview of the principal clinical phenotypes and the molecular genetic basis of mitochondrial disorders identified so far.

Published
2003
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48. Expression Pattern of Mitochondrial Respiratory Chain Enzymes in Skeletal Muscle of Patients Harboring the A3243G Point Mutation or Large-Scale Deletions of Mitochondrial DNA

Author

Stefan Vielhaber, Martina Seibel, Tatiana A. Kudina, Wolfram S. Kunz, Karin Kappes-Horn, Rolf Schröder, Peter Seibel, Christian E. Elger, and Dmitry A. Varlamov

Subjects
Male, Respiratory chain, Citrate (si)-Synthase, Gene mutation, Biology, medicine.disease_cause, MELAS syndrome, DNA, Mitochondrial, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, MELAS Syndrome, medicine, Humans, Point Mutation, Cytochrome c oxidase, Muscle, Skeletal, Sequence Deletion, Mutation, Base Sequence, Point mutation, General Medicine, medicine.disease, Molecular biology, Heteroplasmy, Mitochondria, Muscle, Neurology, Biochemistry, Coenzyme Q – cytochrome c reductase, biology.protein, Cytochromes, Female, Neurology (clinical)
Abstract

To assess the detailed expression pattern of mitochondrial-encoded proteins in skeletal muscle of patients with mitochondrial diseases we performed determinations of cytochrome content and enzyme activities of respiratory chain complexes of 12 patients harboring large-scale deletions and of 10 patients harboring the A3243G mutation. For large-scale deletions we observed a mutation gene dose-dependent linear decline of cytochrome aa 3 content, cytochrome c oxidase (COX) activity, and complex I activity. The content of cytochromes b and the complex III activity was either not affected or only weakly affected by the deletion mutation and did not correlate to the degree of heteroplasmy. In contrast, in skeletal muscle harboring the A3243G mutation all investigated enzymes containing mitochondrial-encoded subunits were equally affected by the mutation, but we observed milder enzyme deficiencies at a comparable mutation gene dose. The results of single fiber analysis of selected biopsies supported these findings but revealed differences in the distribution of COX deficiency. Whereas predominantly type 1 fibers were affected in A3243G and deletion CPEO biopsies, we observed in MELAS and KSS biopsies higher quantities of COX-deficient type 2 fibers. Our findings indicate different pathomechanisms of deletion and A3243G mutations.

Published
2002
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49. Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy

Author

Berghuis, Bianca, van der Palen, Job, de Haan, Gerrit-Jan, Lindhout, Dick, Koeleman, Bobby P.C., Sander, Josemir W., Møller, Rikke S., Nikanorova, Marina, Ingason, Andrés, Depondt, Chantal, Johnson, Michael R., Langley, Sarah R, Klein, Karl Martin, McCormack, Mark, Delanty, Norman, Cavalleri, Gianpiero L., van Zijl, Janic, Muhle, Hiltrud, Borghei, Mojgansadat, Donatello, Simona, Willis, Joseph, Leu, Costin, Heggeli, Kristin, Avbersek, Andreja, Sisodiya, Sanjay M., Gamberdella, Antonio, Weckhuysen, Sarah, Kunz, Wolfram S., Striano, Pasquale, Zara, Federico, Brodie, Martin J., Stefánsson, Kári, Marson, Anthony G., Jorgensen, Andrea, Auce, Pauls, Francis, Ben, Srivastava, Prashant, Sills, Graeme J., Primec, Zvonka Rener, Krause, Roland, Wolking, Stefan, Weber, Yvonne G., Rau, Sarah, Hengsbach, Christian, Lerche, Holger, Sonsma, Anja, Krenn, Martin, Zimprich, Fritz, Pataraia, Ekaterina, and The EpiPGX Consortium

Subjects
Male, Cohort Studies, Epilepsy, Electrolytes, 0302 clinical medicine, Risk Factors, Sodium levels, 030212 general & internal medicine, Oxcarbazepine, media_common, Middle Aged, 3. Good health, Carbamazepine, Neurology, Adverse effects, Antiepileptic drugs, Anesthesia, Anticonvulsants, Drug Therapy, Combination, Female, Hyponatremia, medicine.drug, Cohort study, Drug, Adult, medicine.medical_specialty, media_common.quotation_subject, Clinical Neurology, 03 medical and health sciences, Sex Factors, Internal medicine, medicine, Journal Article, Humans, Adverse effect, business.industry, Sodium, nutritional and metabolic diseases, medicine.disease, n/a OA procedure, Concomitant, Human medicine, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

OBJECTIVE: To ascertain possible determinants of carbamazepine (CBZ)- and oxcarbazepine (OXC)-induced hyponatremia in a large cohort of people with epilepsy.METHODS: We collected data on serum sodium levels in people with epilepsy who were attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L and severe hyponatremia as Na+ ≤128 mEq/L.RESULTS: We identified 1,782 people who had used CBZ (n = 1,424) or OXC (n = 358), of whom 50 were treated with both drugs. Data on sodium level measurements were available in 1,132 on CBZ and in 289 on OXC. Hyponatremia occurred in 26% of those taking CBZ and 46% of those taking OXC. This was severe in 7% in the CBZ group and 22% in the OXC group. Hyponatremia was symptomatic in 48% and led to admissions in 3%. Age over 40 years, high serum levels of CBZ and OXC, and concomitant use of other antiepileptic drugs were the main risk factors for hyponatremia in both treatment groups. Female patients on OXC were at a higher risk than male patients of hyponatremia. The risk of hyponatremia on CBZ was significantly associated with the risk of hyponatremia on OXC within a subgroup that used both drugs consecutively.SIGNIFICANCE: Hyponatremia is a common problem in people taking CBZ or OXC. Regular ascertainment of sodium levels in those taking either drug is recommended and results should be acted on.

Published
2017
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50. A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy

Author

Ann-Kathrin Ruppert, Wolfram S. Kunz, Peter Nürnberg, Janbernd Kirschner, Felicitas Becker, Yvonne G. Weber, Holger Thiele, Christian E. Elger, Holger Lerche, Gábor Zsurka, Kerstin Hallmann, Susanna Moskau-Hartmann, Özkan Özdemir, Rudolf Korinthenberg, and Thomas Sander

Subjects
Adult, Male, Mitochondrial DNA, RNA Splicing, Epilepsies, Myoclonic, Progressive myoclonus epilepsy, Biology, DNA, Mitochondrial, Amino Acyl-tRNA Synthetases, Exon, symbols.namesake, Young Adult, medicine, Humans, Gene, Genetics, Sanger sequencing, Splice site mutation, Homozygote, MERRF syndrome, medicine.disease, MERRF Syndrome, Mitochondria, Pedigree, Mutation, symbols, Myoclonic epilepsy, Female, Neurology (clinical)
Abstract

Objective: We report a consanguineous family with 2 affected individuals whose clinical symptoms closely resembled MERRF (myoclonus epilepsy with ragged red fibers) syndrome including severe myoclonic epilepsy, progressive spastic tetraparesis, progressive impairment of vision and hearing, as well as progressive cognitive decline. Methods: After excluding the presence of pathogenic mitochondrial DNA mutations, whole-exome sequencing of blood DNA from the index patient was performed. Detected homozygous mutations and their cosegregation were confirmed by Sanger sequencing. CARS2 (cysteinyl-tRNA synthetase 2, mitochondrial) messenger RNA analysis was performed by reverse transcription PCR and sequencing. Results: We identified a homozygous c.655G>A mutation in the CARS2 gene cosegregating in the family. The mutation is localized at the last nucleotide of exon 6 and thus is predicted to cause aberrant splicing. Analysis of the CARS2 messenger RNA showed that the presence of the mutation resulted in removal of exon 6. This leads to an in-frame deletion of 28 amino acids in a conserved sequence motif of the protein involved in stabilization of the acceptor end hairpin of tRNA Cys . Conclusion: CARS2 is a novel disease gene associated with a severe progressive myoclonic epilepsy most resembling MERRF syndrome.

Published
2014

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