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201. 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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202. No Evidence For A Brd2 Promoter Hypermethylation Inblood Leukocytes Of Europeans With Juvenile Myoclonic Epilepsy

Author

Schulz, Herbert, Ruppert, Ann-Kathrin, Zara, Federico, Madia, Francesca, Iacomino, Michele, Vari, Maria S., Balagura, Ganna, Minetti, Carlo, Striano, Pasquale, Blanche, Amedeo, Marini, Carla, Guerrini, Renzo, Weber, Yvonne G., Becker, Felicitas, Lerche, Holger, Kapser, Claudia, Schankin, Christoph J., Kunz, Wolfram S., Moller, Rikke S., and Oliver, Karen L.

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

203. 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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207. High-Resolution Monitored Data Analysis of EV Public Charging Stations for Modelled Grid Impact Validation

Author

Aaron Estrada Poggio, Giuseppe Rotondo, Matteo Giacomo Prina, Alyona Zubaryeva, and Wolfram Sparber

Subjects
electric mobility, charging infrastructure, charging behavior, energy consumption, grid impact, public charging stations, Technology, Engineering (General). Civil engineering (General), TA1-2040, Biology (General), QH301-705.5, Physics, QC1-999, Chemistry, QD1-999
Abstract

As electric vehicle adoption grows, understanding the impact of electric vehicle charging on electricity grids becomes increasingly important. Accurate grid impact modelling requires high-quality charging infrastructure data. This study examined the electric vehicle recharging infrastructure and usage patterns in a region of the Italian Alps over a three-year period from 2021 to 2023. The primary objectives were to analyze the growth and distribution of electric vehicle charging stations, assess energy consumption, and evaluate charging behaviours across various recharging points. The research involved collecting empirical data from 411,800 recharging sessions and simulated data using the emobpy tool to model energy consumption and charging behavior. Key findings reveal a substantial increase in the number of recharging points, from 673 in 2021 to 970 in 2023, with the total energy delivered increasing from 938 MWh in 2021 to 4133 MWh in 2023. The data showed distinct temporal trends: AC points were primarily used during the day, while DC points saw higher usage during morning and late afternoon peaks, aligning with travelling times. The study’s validation of simulation results against empirical data emphasized the importance of high-quality input for accurate grid impact assessments. These findings suggest the necessity for strategic placement of recharging infrastructure and provide practical insights for policymakers, urban planners, and utility companies to support sustainable electric vehicle integration.

Published
2024
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208. Reference Architecture for the Integration of Prescriptive Analytics Use Cases in Smart Factories

Author

Julian Weller, Nico Migenda, Yash Naik, Tim Heuwinkel, Arno Kühn, Martin Kohlhase, Wolfram Schenck, and Roman Dumitrescu

Subjects
prescriptive analytics, reference architecture, smart factory, decision theory, data driven decision making, Mathematics, QA1-939
Abstract

Prescriptive analytics plays an important role in decision making in smart factories by utilizing the available data to gain actionable insights. The planning, integration and development of such use cases still poses manifold challenges. Use cases are still being implemented as standalone versions; the existing IT-infrastructure is not fit for integrative bidirectional decision communication, and implementations only reach low technical readiness levels. We propose a reference architecture for the integration of prescriptive analytics use cases in smart factories. The method for the empirically grounded development of reference architectures by Galster and Avgeriou serves as a blueprint. Through the development and validation of a specific IoT-Factory use case, we demonstrate the efficacy of the proposed reference architecture. We expand the given reference architecture for one use case to the integration of a smart factory and its application to multiple use cases. Moreover, we identify the interdependency among multiple use cases within dynamic environments. Our prescriptive reference architecture provides a structured way to improve operational efficiency and optimize resource allocation.

Published
2024
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209. Improvement of Breast Cancer Detection Using Dual-Layer Spectral CT

Author

Felix Christian Hasse, Athanasios Giannakis, Eckhard Wehrse, Wolfram Stiller, Markus Wallwiener, Hans-Ulrich Kauczor, Tim F. Weber, Jörg Heil, and Theresa Mokry

Subjects
thorax, breast neoplasms, multidetector computed tomography, Medicine (General), R5-920
Abstract

This study aimed to investigate the diagnostic performance of breast mass detection on monoenergetic image data at 40 keV (MonoE40) and on iodine maps (IM) compared with conventional image data (CI). In this prospective single-center case-control study, 50 breast cancer patients were examined using contrast-enhanced dual-layer spectral CT. For qualitative and quantitative comparison of MonoE40 and IM with CI image data, four blinded, independent readers assessed 300 randomized single slices (two slices for each imaging type per case) with or without cancerous lesions for the presence of a breast mass. Detection sensitivity and specificity were calculated and readers rated their subjective diagnostic certainty. For statistical analysis of sensitivity and specificity, a paired t-test and ANOVA were used (significance level p = 0.05). A total of 50 female patients (median age 51 years, range 28–83 years) participated. IM had the highest overall scores in sensitivity and specificity for breast cancer detection, with 0.97 ± 0.06 and 0.95 ± 0.07, respectively, compared with 0.90 ± 0.04 and 0.92 ± 0.06 in CI. MonoE40 yielded a sensitivity of 0.96 ± 0.02 and specificity of 0.94 ± 0.08. All differences in sensitivity and specificity between MonoE or IM and CI were statistically significant (p < 0.001). The superiority of IM sensitivity and specificity was most pronounced in patients with dense breasts. Spectral CT improved the detection of breast cancer with higher sensitivity and specificity compared to conventional image data in our study.

Published
2024
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215. Elongation differences between the sub-tendons of gastrocnemius medialis and lateralis during plantarflexion in different frontal plane position of the foot

Author

Wolfram, S, Hodson-Tole, EF, Morse, CI, Winwood, KL, McEwan, IM, Wolfram, S, Hodson-Tole, EF, Morse, CI, Winwood, KL, and McEwan, IM

Abstract

© 2019 Background: Gastrocnemius medialis (GM) and lateralis (GL) act at the ankle complex in the sagittal and frontal planes and there is evidence that their actions can be somewhat uncoupled from each other. Some independence of GM and GL from each other could be advantageous, e.g. to stabilise the ankle complex in unstable walking conditions. Given the compartmentalised structure of the Achilles tendon, the sub-tendons of GM and GL may exhibit different elongation during plantarflexion contractions, particularly with the foot in different frontal plane positions. Research Questions: • Is elongation within a sub-tendon affected by frontal plane foot position? • Does elongation between the two sub-tendons differ? • Are elongation differences between the sub-tendons affected by frontal plane foot position? Methods: Sub-tendon elongation was determined from 18 participants during ramped isometric plantarflexion contractions to 70% of their maximum voluntary contraction (MVC) level with the foot in neutral, inversion and eversion. One-dimensional statistical parametric mapping was applied to determine elongation differences. Results: Elongation within a sub-tendon did not differ in the three foot positions. Elongation was similar between both sub-tendons at very low contraction levels, but GM sub-tendon elongation exceeded GL sub-tendon displacement significantly from 30% MVC. The elongation differences between the sub-tendons were not affected by foot position. Significance: Greater GM sub-tendon elongation is likely caused by the greater force production capability of GM but may also indicate that the sub-tendons of GM and GL have different mechanical properties, which is currently unknown. Elongation differences were contraction level dependent suggesting that contributions of GM and GL to plantarflexion torque may also be contraction level dependent.

Published
2019

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

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L., Dhindsa, Ryan S., Stanley, Kate E., Cavalleri, Gianpiero L., Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, 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., Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, 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, Baalen, Andreas Van, Spiczak, Sarah Von, 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., Barišić, 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, 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, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Yis, Uluc, Topaloglu, Pınar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Uğur-İşeri, Sibel, Baykan, Betül, Salman, Barış, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yeşim, Özkara, Çiğdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, 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, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, 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., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Fanous, Ayman H., 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., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea, Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Heinzen, Erin L., Dhindsa, Ryan S., Stanley, Kate E., Cavalleri, Gianpiero L., Hakonarson, Hakon, Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, 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., Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, 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, Baalen, Andreas Van, Spiczak, Sarah Von, 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., Barišić, 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, 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, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Yis, Uluc, Topaloglu, Pınar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Uğur-İşeri, Sibel, Baykan, Betül, Salman, Barış, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yeşim, Özkara, Çiğdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, 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, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, 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., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Fanous, Ayman H., 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., and Neale, Benjamin M.

Abstract

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), 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; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas 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 DEEs 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 lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.

Published
2019

217. Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy

Author

Silvennoinen, Katri, de Lange, Nikola Maria, Zagaglia, Sara, Balestrini, Simona, Androsova, Ganna, Wassenaar, Merel, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Berghuis, Bianca, Campbell, Ellen, Coppola, Antonietta, Francis, Ben, Wolking, Stefan, Cavalleri, Gianpiero L., Craig, John, Delanty, Norman, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., O’Brien, Terence J., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, van der Palen, Job, Krause, Roland, Depondt, Chantal, Sisodiya, Sanjay M., Consortium, The Epipgx, Silvennoinen, Katri, de Lange, Nikola Maria, Zagaglia, Sara, Balestrini, Simona, Androsova, Ganna, Wassenaar, Merel, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Berghuis, Bianca, Campbell, Ellen, Coppola, Antonietta, Francis, Ben, Wolking, Stefan, Cavalleri, Gianpiero L., Craig, John, Delanty, Norman, Johnson, Michael R., Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., O’Brien, Terence J., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, van der Palen, Job, Krause, Roland, Depondt, Chantal, Sisodiya, Sanjay M., and Consortium, The Epipgx

Abstract

Objective To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. Results We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7\%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1\%) was not significant. The rates of ADRs were highest for topiramate (45.5\%) and valproate (37.5\%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2 vs 92.6\%, P = 0.001). Significance In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place

Published
2019

220. Recombination of Human Mitochondrial DNA

Author

Kraytsberg, Yevgenya, Schwartz, Marianne, Brown, Timothy A., Ebralidse, Konstantin, Kunz, Wolfram S., Clayton, David A., Vissing, John, and Khrapko, Konstantin

Published
2004

227. Disorganization of the Desmin Cytoskeleton and Mitochondrial Dysfunction in Plectin-Related Epidermolysis Bullosa Simplex with Muscular Dystrophy

Author

SCHRÖDER, ROLF, KUNZ, WOLFRAM S., ROUAN, FATIMA, PFENDNER, ELLEN, TOLKSDORF, KAREN, KAPPES-HORN, KARIN, ALTENSCHMIDT-MEHRING, MANUELA, KNOBLICH, RUPERT, VAN DER VEN, PETER F.M., REIMANN, JENS, FÜRST, DIETER O., BLÜMCKE, INGMAR, VIELHABER, STEFAN, ZILLIKENS, DETLEF, EMING, SABINE, KLOCKGETHER, THOMAS, UITTO, JOUNI, WICHE, GERHARD, and ROLFS, ARNDT

Published
2002

229. The NMR core analyzing tomograph: a multi-functional tool for non-destructive testing of building materials

Author

Sabine Kruschwitz, Sarah Munsch, Melissa Telong, Wolfram Schmidt, Thilo Bintz, Matthias Fladt, and Ludwig Stelzner

Subjects
Natural stone, Concrete, Sensitivity, Moisture transport, Cement hydration, Supplementary cementitious materials, Physical and theoretical chemistry, QD450-801, Analytical chemistry, QD71-142
Abstract

NMR is becoming increasingly popular for the investigation of building materials as it is a non-invasive technology that does not require any sample preparation nor causes damage to the material. Depending on the specific application it can offer insights into properties like porosity and spatial saturation degree as well as pore structure. Moreover it enables the determination of moisture transport properties and the (re-)distribution of internal moisture into different reservoirs or chemical phases upon damage and curing. However, as yet most investigations were carried out using devices originally either designed for geophysical applications or the analysis of rather homogeneous small scale (< 10 mL) samples. This paper describes the capabilities of an NMR tomograph, which has been specifically optimized for the investigation of larger, heterogeneous building material samples (diameters of up to 72 mm, length of up to 700 mm) with a high flexibility due to interchangeable coils allowing for a high SNR and short echo times (50–80 μs).

Published
2023
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230. Chirality control of a single carbene molecule by tip-induced van der Waals interactions

Author

Yunjun Cao, Joel Mieres-Perez, Julien Frederic Rowen, Elsa Sanchez-Garcia, Wolfram Sander, and Karina Morgenstern

Subjects
Science
Abstract

Abstract Non-covalent interactions such as van der Waals interactions and hydrogen bonds are crucial for the chiral induction and control of molecules, but it remains difficult to study them at the single-molecule level. Here, we report a carbene molecule on a copper surface as a prototype of an anchored molecule with a facile chirality change. We examine the influence of the attractive van der Waals interactions on the chirality change by regulating the tip-molecule distance, resulting in an excess of a carbene enantiomer. Our model study provides insight into the change of molecular chirality controlled by van der Waals interactions, which is fundamental for understanding the mechanisms of chiral induction and amplification.

Published
2023
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231. Pancreatic CT perfusion: quantitative meta-analysis of disease discrimination, protocol development, and effect of CT parameters

Author

Stephan Skornitzke, Neha Vats, Philipp Mayer, Hans-Ulrich Kauczor, and Wolfram Stiller

Subjects
X-ray computed tomography, Perfusion imaging, Pancreas, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract

Abstract Background This study provides a quantitative meta-analysis of pancreatic CT perfusion studies, investigating choice of study parameters, ability for quantitative discrimination of pancreatic diseases, and influence of acquisition and reconstruction parameters on reported results. Methods Based on a PubMed search with key terms ‘pancreas’ or ‘pancreatic,’ ‘dynamic’ or ‘perfusion,’ and ‘computed tomography’ or ‘CT,’ 491 articles published between 1982 and 2020 were screened for inclusion in the study. Inclusion criteria were: reported original data, human subjects, five or more datasets, measurements of pancreas or pancreatic pathologies, and reported quantitative perfusion parameters. Study parameters and reported quantitative measurements were extracted, and heterogeneity of study parameters and trends over time are analyzed. Pooled data were tested with weighted ANOVA and ANCOVA models for differences in perfusion results between normal pancreas, pancreatitis, PDAC (pancreatic ductal adenocarcinoma), and non-PDAC (e.g., neuroendocrine tumors, insulinomas) and based on study parameters. Results Reported acquisition parameters were heterogeneous, except for contrast agent amount and injection rate. Tube potential and slice thickness decreased, whereas tube current time product and scan coverage increased over time. Blood flow and blood volume showed significant differences between pathologies (both p

Published
2023
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232. Bilateral vocal cord palsy as complication of CNS tuberculosis

Author

Liesa Regner-Nelke, Bendix Labeit, Christopher Nelke, Wolfram Schwindt, Rainer Dziewas, and Sonja Suntrup-Krueger

Subjects
Bilateral vocal cord palsy, Tuberculous meningitis, CNS tuberculosis, Cranial nerves, Case report, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Tuberculous meningitis, a rare but severe form of extrapulmonary tuberculosis, frequently affects cranial nerves. While nerves III, VI and VII are commonly involved, involvement of caudal cranial nerves is rarely described. Here, we report a rare case of bilateral vocal cord palsy secondary to caudal cranial nerve involvement in tuberculous meningoencephalitis, that occurred in Germany, a country with low tuberculosis incidence. Case presentation A 71-year-old woman was transferred for further treatment of hydrocephalus as a complication of presumed bacterial meningitis with unknown pathogen at that time. Because of decreased consciousness, intubation was performed and an empiric antibiotic therapy with ampicillin, ceftriaxone and acyclovir was initiated. Upon admission to our hospital, an external ventricular drainage was placed. Cerebrospinal fluid analysis revealed Mycobacterium tuberculosis as the causative pathogen, and antitubercular treatment was initiated. Extubation was possible one week after admission. Eleven days later, the patient developed inspiratory stridor that worsened within a few hours. Flexible endoscopic evaluation of swallowing (FEES) revealed new-onset bilateral vocal cord palsy as the cause of respiratory distress, which required re-intubation and tracheostomy. The bilateral vocal cord palsy persisted despite continued antitubercular therapy on the follow-up examination. Conclusion Considering the aetiology of infectious meningitis, cranial nerve palsies may be suggestive for tuberculous meningitis as underlying disease given their rarity in other bacterial forms of meningitis. Nevertheless, intracranial involvement of inferior cranial nerves is rare even in this specific entity, as only extracranial lesions of inferior cranial nerves have been reported in tuberculosis. With this report of a rare case of bilateral vocal cord palsy due to intracranial involvement of the vagal nerves, we emphasize the importance of timely initiation of treatment for tuberculous meningitis. This may help to prevent serious complications and associated poor outcome since the response to anti-tuberculosis therapy may be limited.

Published
2023
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233. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2Pathogenic Variants

Author

Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brünger, Tobias, Hedrich, Ulrike B.S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Lejla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Phillip S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M., Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, and Weber, Yvonne

Published
2022
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234. Neoadjuvant ipilimumab plus nivolumab therapy as a potential organ preservation strategy in mucosal melanoma: case report

Author

Claire V. Ong and Wolfram Samlowski

Subjects
neoadjuvant therapy, checkpoint inhibitors, sinonasal melanoma, rectal melanoma, organ preservation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Mucosal melanoma represents an uncommon melanoma subtype. Wide excision has long represented the standard therapeutic approach. Unfortunately, there is a high relapse rate and mortality. Neoadjuvant therapy with ipilimumab plus nivolumab has shown significant activity in cutaneous melanoma. We present two cases of mucosal melanoma, each with potential regional dissemination, who were treated with neoadjuvant immunotherapy with minimal toxicity. Both patients were closely monitored and achieved radiologic and pathologic complete responses. These patients were able to avoid radical surgery and related functional consequences. Both patients remain recurrence-free with protracted follow-up. The potential usefulness of neoadjuvant immunotherapy as an organ preservation strategy in mucosal melanoma deserves further evaluation in prospective clinical trials.

Published
2024
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236. Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue

Author

Christoph S. Clemen, Viktoriya Peeva, Harald Herrmann, Britta Eggers, Carolin Berwanger, Lilli Winter, Cornelia Kornblum, Wolfram S. Kunz, Katalin Barkovits, Valentina Strecker, Rolf Schröder, Ilka Wittig, Rudolf A. Kley, Juliana Heidler, Katrin Marcus, and Frédéric Chevessier

Subjects
0301 basic medicine, Mitochondrial DNA, Proteome, Intermediate Filaments, Clinical Neurology, Respiratory chain, Myofibrillar myopathy, Mice, Transgenic, macromolecular substances, Mitochondrion, Biology, medicine.disease_cause, Desmin, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Muscular Diseases, medicine, Animals, Humans, Intermediate Filament Protein, Muscle, Skeletal, Cytoskeleton, Intermediate filament, Original Paper, Mutation, Desmin knock-out, mtDNA, Desminopathy, Protein aggregate myopathy, Molecular biology, Mitochondria, 030104 developmental biology, R350P desmin, Neurology (clinical), R349P desmin knock-in, 030217 neurology & neurosurgery
Abstract

Secondary mitochondrial dysfunction is a feature in a wide variety of human protein aggregate diseases caused by mutations in different proteins, both in the central nervous system and in striated muscle. The functional relationship between the expression of a mutated protein and mitochondrial dysfunction is largely unknown. In particular, the mechanism how this dysfunction drives the disease process is still elusive. To address this issue for protein aggregate myopathies, we performed a comprehensive, multi-level analysis of mitochondrial pathology in skeletal muscles of human patients with mutations in the intermediate filament protein desmin and in muscles of hetero- and homozygous knock-in mice carrying the R349P desmin mutation. We demonstrate that the expression of mutant desmin causes disruption of the extrasarcomeric desmin cytoskeleton and extensive mitochondrial abnormalities regarding subcellular distribution, number and shape. At the molecular level, we uncovered changes in the abundancy and assembly of the respiratory chain complexes and supercomplexes. In addition, we revealed a marked reduction of mtDNA- and nuclear DNA-encoded mitochondrial proteins in parallel with large-scale deletions in mtDNA and reduced mtDNA copy numbers. Hence, our data demonstrate that the expression of mutant desmin causes multi-level damage of mitochondria already in early stages of desminopathies. Electronic supplementary material The online version of this article (doi:10.1007/s00401-016-1592-7) contains supplementary material, which is available to authorized users.

Published
2016
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240. 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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241. Signaling pathways targeting mitochondrial potassium channels

Author

Daria Rotko, Adam Szewczyk, Bogusz Kulawiak, and Wolfram S. Kunz

Subjects
0301 basic medicine, Cell type, Potassium Channels, Biochemistry, Potassium Channels, Calcium-Activated, 03 medical and health sciences, Adenosine Triphosphate, Potassium Channels, Tandem Pore Domain, 0302 clinical medicine, Animals, Humans, Inner mitochondrial membrane, chemistry.chemical_classification, Membrane potential, Reactive oxygen species, Kinase, Chemistry, Cell Biology, Potassium channel, Mitochondria, Cell biology, 030104 developmental biology, Potassium Channels, Voltage-Gated, 030220 oncology & carcinogenesis, Mitochondrial Membranes, Phosphorylation, Calcium, Signal transduction, Reactive Oxygen Species, Oxidation-Reduction, Signal Transduction
Abstract

In this review, we describe key signaling pathways regulating potassium channels present in the inner mitochondrial membrane. The signaling cascades covered here include phosphorylation, redox reactions, modulation by calcium ions and nucleotides. The following types of potassium channels have been identified in the inner mitochondrial membrane of various tissues: ATP-sensitive, Ca2+-activated, voltage-gated and two-pore domain potassium channels. The direct roles of these channels involve regulation of mitochondrial respiration, membrane potential and synthesis of reactive oxygen species (ROS). Changes in channel activity lead to diverse pro-life and pro-death responses in different cell types. Hence, characterizing the signaling pathways regulating mitochondrial potassium channels will facilitate understanding the physiological role of these proteins. Additionally, we describe in this paper certain regulatory mechanisms, which are unique to mitochondrial potassium channels.

Published
2020
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242. Heme is required for carbon monoxide activation of mitochondrial BKCa channel

Author

Piotr Koprowski, Bogusz Kulawiak, Wolfram S. Kunz, Piotr Bednarczyk, Daria Rotko, and Adam Szewczyk

Subjects
0301 basic medicine, Pharmacology, Hemeprotein, Heme binding, Cell, Mitochondrion, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Membrane, medicine.anatomical_structure, chemistry, medicine, Biophysics, Inner mitochondrial membrane, Heme, 030217 neurology & neurosurgery, Carbon monoxide
Abstract

Carbon monoxide (CO) is an endogenously synthesized gaseous mediator and is involved in the regulation of numerous physiological processes. Mitochondria, in which hemoproteins are abundant, are among the targets for CO action. Large-conductance calcium-activated (mitoBKCa) channels in the inner mitochondrial membrane share multiple biophysical similarities with the BKCa channels of the plasma membrane and could be a potential target for CO. To test this hypothesis, the activity of the mitoBKCa channels in human astrocytoma U-87 MG cell mitochondria was assessed with the patch-clamp technique. The effects of CO-releasing molecules (CORMs), such as CORM-2, CORM-401, and CORM-A1, were compared to the application of a CO-saturated solution to the mitoBKCa channels in membrane patches. The applied CORMs showed pleiotropic effects including channel inhibition, while the CO-containing solution did not significantly modulate channel activity. Interestingly, CO applied to the mitoBKCa channels, which were inhibited by exogenously added heme, stimulated the channel. To summarize, our findings indicate a requirement of heme binding to the mitoBKCa channel for channel modulation by CO and suggest that CORMs might have complex unspecific effects on mitoBKCa channels.

Published
2020
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243. Reply to Rutter et al.: The roles of cytosolic and intramitochondrial Ca2+ and the mitochondrial Ca2+-uniporter (MCU) in the stimulation of mammalian oxidative phosphorylation

Author

Michael Schwarzer, Volkmar Lessmann, Wolfram S. Kunz, Torsten Doenst, Marten Szibor, Frank N. Gellerich, Stefan Vielhaber, and Zemfira Gizatullina

Subjects
metabolism [Pyruvic Acid], Malates, Glutamic Acid, Stimulation, Oxidative phosphorylation, Biochemistry, Oxidative Phosphorylation, Substrate Specificity, Mice, Cytosol, Pyruvic Acid, Animals, metabolism [Calcium], ddc:610, Letters to the Editor, Uniporter, Molecular Biology, Membrane Potential, Mitochondrial, Mice, Knockout, Aspartic Acid, Chemistry, Myocardium, metabolism [Calcium Channels], Brain, Heart, Cell Biology, metabolism [Mitochondria], Mitochondria, Rats, Cell biology, Mice, Inbred C57BL, Calcium, Calcium Channels, Synaptosomes
Abstract

Each model used in the work referred to by Rutter et al. (1) addressed certain aspects of mitochondrial biology, and together, they fully support the conclusions made. Please note that we describe Ca2+-mediated regulation of oxidative phosphorylation (OXPHOS) fluxes (2, 3) and do not question Ca2+-responsiveness of pyruvate dehydrogenase en-zyme activity (4). To address concerns such as those raised by Rutter et al. (1), we studied glutamate/malate-dependent OXPHOS in the absence of exogenous pyruvate in mitochondria, omitted pyruvate from cell experiments, and implemented the working rat heart model perfused by Krebs–Henseleit (glucose) buffer. This unequivocally demonstrates in a broad range of models that MAS (malate-aspartate shuttle) inhibition induces a state of mitochondrial pyruvate starvation (3).An unresolved observation is that mitochondria of MCU knockout mice show negligible activity of Ca2+-uptake (5), which we confirm (3). We attributed this activity to residual expression of wild-type Mcu transcripts (3) as the result of a rare event of gene-trap excision during mRNA splicing, since this activity was sensitive to ruthenium red, an inhibitor of the MCU. Besides, please also note the low MCU Ca2+ affinity (6). In vivo, the endoplasmic reticulum is thought to facilitate the generation of microcompartments of high Ca2+ concentration to allow Ca2+ uptake via MCU (6). This mechanism is compromised in MCU knockout mice and can be ruled out in isolated mitochondria. Thus, our data support the notion that, depending on tissue, model system and pathophysiological status, a combination of mechanisms (e.g., mitochondrial gas pedal and MCU) control OXPHOS substrate supply.Notably, the viability of MCU knockout mice (3, 5), albeit living in a laboratory cage, indicates that MCU-dependent pathways are dispensable for a sedentary life. It remains interestingto elucidate, however, why MCU-dependent activation of matrix dehydrogenases is indispensable for high activity states (7) and how this may allow stressful life in the wild.

Published
2020
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246. 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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247. Distinct segregation of the pathogenic m.5667GA mitochondrial tRNA

Author

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

Subjects
Electron Transport Complex IV, Male, Ophthalmoplegia, Chronic Progressive External, Adolescent, Electron Transport Chain Complex Proteins, RNA, Transfer, Asn, Oculomotor Muscles, Muscle Fibers, Skeletal, Cytochrome-c Oxidase Deficiency, Humans, Muscle, Skeletal, Immunohistochemistry, Quadriceps Muscle
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.5667GA mutation in the mitochondrial tRNA

Published
2018

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

Author

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

Subjects
Adult, ultrastructure [Axons], Male, Progranulins, diagnostic imaging [Amyotrophic Lateral Sclerosis], diagnostic imaging [Peripheral Nervous System Diseases], diagnostic imaging [Forearm], Humans, ddc:610, Prospective Studies, Ulnar Nerve, cerebrospinal fluid [Progranulins], Aged, Ultrasonography, Anatomy, Cross-Sectional, Amyotrophic Lateral Sclerosis, Peripheral Nervous System Diseases, Middle Aged, diagnostic imaging [Median Nerve], Axons, innervation [Forearm], Median Nerve, Electrophysiological Phenomena, Forearm, Cross-Sectional Studies, diagnostic imaging [Ulnar Nerve], cerebrospinal fluid [Amyotrophic Lateral Sclerosis], Female, Atrophy, Biomarkers
Abstract

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).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 × CSF PGRN interaction effects on various measures.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.In ALS, the constellation of peripheral nerve atrophy together with higher CSF PGRN levels indicates pronounced axonal damage. Muscle Nerve 57: 273-278, 2018.

Published
2018
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249. P.79Malignant cardiac phenotype after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous R349P desmin knock-in mice

Author

Tobias Radecke, J W Schrickel, Carolin Berwanger, Viktoriya Peeva, Christoph S. Clemen, Lars Eichhorn, Thomas Beiert, Wolfram S. Kunz, Florian Stöckigt, Georg Nickenig, Vincent Knappe, Rolf Schröder, and Martin Steinmetz

Subjects
Pressure overload, medicine.medical_specialty, Endocrinology, Neurology, Gene knockin, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, Desmin, Neurology (clinical), Biology, Cardiac phenotype, Genetics (clinical)
Published
2019
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250. Genotypes and phenotypes of patients with Lafora disease living in Germany

Author

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

Published
2019
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