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185 results on '"Wilichowski, Ekkehard"'

1. 5qSMA: standardised retrospective natural history assessment in 268 patients with four copies of SMN2

Author

Vill, Katharina, Tacke, Moritz, König, Anna, Baumann, Matthias, Baumgartner, Manuela, Steinbach, Meike, Bernert, Guenther, Blaschek, Astrid, Deschauer, Marcus, Flotats-Bastardas, Marina, Friese, Johannes, Goldbach, Susanne, Gross, Martin, Günther, René, Hahn, Andreas, Hagenacker, Tim, Hauser, Erwin, Horber, Veronka, Illsinger, Sabine, Johannsen, Jessika, Kamm, Christoph, Koch, Jan C., Koelbel, Heike, Koehler, Cornelia, Kolzter, Kirsten, Lochmüller, Hanns, Ludolph, Albert, Mensch, Alexander, Meyer zu Hoerste, Gerd, Mueller, Monika, Mueller-Felber, Wolfgang, Neuwirth, Christoph, Petri, Susanne, Probst-Schendzielorz, Kristina, Pühringer, Manuel, Steinbach, Robert, Schara-Schmidt, Ulrike, Schimmel, Mareike, Schrank, Bertold, Schwartz, Oliver, Schlachter, Kurt, Schwerin-Nagel, Annette, Schreiber, Gudrun, Smitka, Martin, Topakian, Raffi, Trollmann, Regina, Tuerk, Matthias, Theophil, Manuela, Rauscher, Christian, Vorgerd, Mathias, Walter, Maggie C., Weiler, Markus, Weiss, Claudia, Wilichowski, Ekkehard, Wurster, Claudia D., Wunderlich, Gilbert, Zeller, Daniel, Ziegler, Andreas, Kirschner, Janbernd, and Pechmann, Astrid

Published
2024
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2. Improved upper limb function in non-ambulant children with SMA type 2 and 3 during nusinersen treatment: a prospective 3-years SMArtCARE registry study

Author

Pechmann, Astrid, Behrens, Max, Dörnbrack, Katharina, Tassoni, Adrian, Wenzel, Franziska, Stein, Sabine, Vogt, Sibylle, Zöller, Daniela, Bernert, Günther, Hagenacker, Tim, Schara-Schmidt, Ulrike, Walter, Maggie C., Bertsche, Astrid, Vill, Katharina, Baumann, Matthias, Baumgartner, Manuela, Cordts, Isabell, Eisenkölbl, Astrid, Flotats-Bastardas, Marina, Friese, Johannes, Günther, René, Hahn, Andreas, Horber, Veronka, Husain, Ralf A., Illsinger, Sabine, Jahnel, Jörg, Johannsen, Jessika, Köhler, Cornelia, Kölbel, Heike, Müller, Monika, von Moers, Arpad, Schwerin-Nagel, Annette, Reihle, Christof, Schlachter, Kurt, Schreiber, Gudrun, Schwartz, Oliver, Smitka, Martin, Steiner, Elisabeth, Trollmann, Regina, Weiler, Markus, Weiß, Claudia, Wiegand, Gert, Wilichowski, Ekkehard, Ziegler, Andreas, Lochmüller, Hanns, and Kirschner, Janbernd

Published
2022
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3. A checklist for clinical trials in rare disease: obstacles and anticipatory actions-lessons learned from the FOR-DMD trial.

Author

Crow, Rebecca, Hart, Kimberly, McDermott, Michael, Tawil, Rabi, Martens, William, Herr, Barbara, McColl, Elaine, Wilkinson, Jennifer, Kirschner, Janbernd, King, Wendy, Eagle, Michele, Brown, Mary, Hirtz, Deborah, Lochmuller, Hanns, Straub, Volker, Ciafaloni, Emma, Shieh, Perry, Spinty, Stefan, Childs, Anne-Marie, Manzur, Adnan, Morandi, Lucia, Butterfield, Russell, Horrocks, Iain, Roper, Helen, Flanigan, Kevin, Kuntz, Nancy, Mah, Jean, Morrison, Leslie, Darras, Basil, von der Hagen, Maja, Schara, Ulrike, Wilichowski, Ekkehard, Mongini, Tiziana, Vita, Giuseppe, Barohn, Richard, Finkel, Richard, Wicklund, Matthew, McMillan, Hugh, Hughes, Imelda, Pegoraro, Elena, Bryan Burnette, W, Howard, James, Thangarajh, Mathula, Campbell, Craig, Griggs, Robert, Bushby, Kate, Guglieri, Michela, and McDonald, Craig

Subjects
Academic-led clinical trial, Clinical trial, Clinical trial regulations, Duchenne muscular dystrophy, Rare disease, Budgets, Checklist, Clinical Trials as Topic, Contracts, Humans, International Cooperation, Multicenter Studies as Topic, Muscular Dystrophy, Duchenne, Patient Selection, Rare Diseases, Research Design, Research Support as Topic, Steroids, Time Factors, Treatment Outcome
Abstract

BACKGROUND: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. METHOD: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. RESULTS: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. CONCLUSION: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.

Published
2018

4. Health related quality of life in young, steroid-naïve boys with Duchenne muscular dystrophy

Author

Straub, Volker, Childs, Anne-Marie, Ciafaloni, Emma, Shieh, Perry B., Spinty, Stefan, Butterfield, Russell J., Horrocks, Iain, Roper, Helen, Maggi, Lorenzo, Baranello, Giovanni, Flanigan, Kevin M., Kuntz, Nancy L., Manzur, Adnan Y., Darras, Basil T., Kang, Peter, Mah, Jean K., Mongini, Tiziana, Ricci, Federica, Morrison, Leslie, Krzesniak-Swinarska, Monika, von der Hagen, Maja, Finkel, Richard S., Kumar, Ashutosh, Wicklund, Matthew, McDonald, Craig M., Henricson, Erik K., Schara-Schmidt, Ulrike, Wilichowski, Ekkehard, Barohn, Richard J., Statland, Jeffrey, Kirschner, Janbernd, Vita, Giuseppe, Vita, Gian Luca, Howard, James F., Jr., Hughes, Imelda, McMillan, Hugh J., Pegoraro, Elena, Bello, Luca, Burnette, W. Bryan, Thangarajh, Mathula, Chang, Taeun, Campbell, Craig, McColl, Elaine, McDermott, Michael P., Martens, William B., Guglieri, Michela, and Griggs, Robert C.

Published
2021
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5. Developing standardized corticosteroid treatment for Duchenne muscular dystrophy.

Author

Guglieri, Michela, Bushby, Kate, McDermott, Michael, Hart, Kimberly, Tawil, Rabi, Martens, William, Herr, Barbara, McColl, Elaine, Wilkinson, Jennifer, Kirschner, Janbernd, King, Wendy, Eagle, Michele, Brown, Mary, Willis, Tracey, Hirtz, Deborah, Shieh, Perry, Straub, Volker, Childs, Anne-Marie, Ciafaloni, Emma, Butterfield, Russell, Horrocks, Iain, Spinty, Stefan, Flanigan, Kevin, Kuntz, Nancy, Baranello, Giovanni, Roper, Helen, Morrison, Leslie, Mah, Jean, Manzur, Adnan, Schara, Ulrike, von der Hagen, Maja, Barohn, Richard, Campbell, Craig, Darras, Basil, Finkel, Richard, Vita, Giuseppe, Hughes, Imelda, Mongini, Tiziana, Pegoraro, Elena, Wicklund, Matthew, Wilichowski, Ekkehard, Bryan Burnette, W, Howard, James, McMillan, Hugh, Thangarajh, Mathula, Griggs, Robert, and McDonald, Craig

Subjects
Deflazacort, Duchenne muscular dystrophy, Prednisolone, Randomized, Standards of care, Child, Child, Preschool, Disability Evaluation, Double-Blind Method, Drug Administration Schedule, Heart Function Tests, Humans, Immunosuppressive Agents, Male, Muscle Strength, Muscular Dystrophy, Duchenne, Patient Satisfaction, Prednisone, Pregnenediones, Range of Motion, Articular, Research Design, Vital Capacity
Abstract

Despite corticosteroids being the only treatment documented to improve strength and function in boys with Duchenne muscular dystrophy (DMD) corticosteroid prescription is inconsistent and in some countries, corticosteroids are not prescribed. We are conducting a clinical trial that (1) compares the 3 most frequently prescribed corticosteroid regimes; (2) standardizes treatment of DMD complications; and (3) standardizes prevention of corticosteroid side effects. Investigators at 38 sites in 5 countries plan to recruit 300 boys aged 4-7 who are randomly assigned to one of three regimens: daily prednisone; daily deflazacort; or intermittent prednisone (10days on/10days off). Boys are followed for a minimum of 3years to assess the relative effectiveness and adverse event profiles of the different regimens. The primary outcome is a 3-dimensional variable consisting of log-transformed time to rise from the floor, forced vital capacity, and subject/parent satisfaction with treatment, each averaged over all post-baseline visits. The study protocol includes evidence- and consensus-based treatment of DMD complications and of corticosteroid side effects. This study seeks to establish a standard corticosteroid regimen for DMD. Since all new interventions for DMD are being developed as add-on therapies to corticosteroids, defining the optimum regimen is of importance for all new treatments.

Published
2017

6. Clinical Effectiveness of Newborn Screening for Spinal Muscular Atrophy: A Nonrandomized Controlled Trial.

Author

Schwartz, Oliver, Vill, Katharina, Pfaffenlehner, Michelle, Behrens, Max, Weiß, Claudia, Johannsen, Jessika, Friese, Johannes, Hahn, Andreas, Ziegler, Andreas, Illsinger, Sabine, Smitka, Martin, von Moers, Arpad, Kölbel, Heike, Schreiber, Gudrun, Kaiser, Nadja, Wilichowski, Ekkehard, Flotats-Bastardas, Marina, Husain, Ralf A., Baumann, Matthias, and Köhler, Cornelia

Published
2024
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9. Handlungsempfehlungen zur Gentherapie der spinalen Muskelatrophie mit Onasemnogene Abeparvovec – AVXS-101: Konsensuspapier der deutschen Vertretung der Gesellschaft für Neuropädiatrie (GNP) und der deutschen Behandlungszentren unter Mitwirkung des Medizinisch-Wissenschaftlichen Beirates der Deutschen Gesellschaft für Muskelkranke (DGM) e. V.

Author

Ziegler, Andreas, Wilichowski, Ekkehard, Schara, Ulrike, Hahn, Andreas, Müller-Felber, Wolfgang, Johannsen, Jessika, von der Hagen, Maja, von Moers, Arpad, Stoltenburg, Corinna, Saffari, Afshin, Walter, Maggie C., Husain, Ralf A., Pechmann, Astrid, Köhler, Cornelia, Horber, Veronka, Schwartz, Oliver, and Kirschner, Janbernd

Published
2020
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10. Adressen

Author

Bernhard, Matthias K., primary, Blank, Rainer, additional, Dulz, Simon, additional, Ebinger, Friedrich, additional, Ebinger, Martin, additional, Friedrich, Reinhard E., additional, Frölich, Jan, additional, Gärtner, Jutta, additional, Hagel, Christian, additional, Häusler, Martin, additional, Hömberg, Volker, additional, Hornung, Dagmar, additional, Jorch, Gerhard, additional, Jaite, Charlotte, additional, Jung, Nikolai, additional, Kammler, Gertrud, additional, Klein, Christine, additional, Kohlschütter, Alfried, additional, Kordes, Uwe, additional, Korinthenberg, Rudolf, additional, Krägeloh-Mann, Ingeborg, additional, Krause, Matthias, additional, Kunde-Trommer, Jutta, additional, Lehmkuhl, Gerd, additional, Lehmkuhl, Ulrike, additional, Linhart, Dieter, additional, Löbel, Ulrike, additional, Mall, Volker, additional, Mautner, Victor-Felix, additional, Mehlan, Juliane, additional, Merkenschlager, Andreas, additional, von Moers, Arpad, additional, Müller, Kristina, additional, Müller-Felber, Wolfgang, additional, Münchau, Alexander, additional, Müther, Silvia, additional, Muschol, Nicole, additional, Nestler, Ulf, additional, Omran, Heymut, additional, Panteliadis, Christos P., additional, Ramantani, Georgia, additional, Roessner, Veit, additional, Röhling, Dagmar, additional, Rosenbaum, Thorsten, additional, Rothenberger, Aribert, additional, Rudolf, Jobst, additional, Rutkowski, Stefan, additional, Rutz, Erich, additional, Salbach, Harriet, additional, Schlößer, Rolf L., additional, Schneider, Markus, additional, Schneider, Susanne A., additional, Schöls, Ludger, additional, Schönweiler, Rainer, additional, Schüller, Ulrich, additional, Sinzig, Judith, additional, Schüttauf, Frank, additional, Spiekerkötter, Ute, additional, Spitzer, Martin, additional, Steinfeld, Robert, additional, Stephani, Ulrich, additional, von Suchodoletz, Waldemar, additional, Synofzik, Matthis, additional, Thiel, Christian, additional, Tischler, Tanja, additional, Trinka, Eugen, additional, Unterberger, Iris, additional, Velthoven, Vera van, additional, and Wilichowski, Ekkehard, additional

Published
2020
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11. The clinical, histological, and genotypic spectrum of SEPN1-related myopathy: A case series

Author

Villar-Quiles, Rocio N, von der Hagen, Maja, Métay, Corinne, Gonzalez, Victoria, Donkervoort, Sandra, Bertini, Enrico, Castiglioni, Claudia, Chaigne, Denys, Colomer, Jaume, Cuadrado, Maria Luz, Visser, Marianne, de, Desguerre, Isabelle, Eymard, Bruno, Goemans, Nathalie, Kaindl, Angela, Lagrue, Emmanuelle, Lütschg, Jürg, Malfatti, Edoardo, Mayer, Michèle, Merlini, Luciano, Orlikowski, David, Reuner, Ulrike, Salih, Mustafa A, Schlotter-Weigel, Beate, Stoetter, Mechthild, Straub, Volker, Topaloglu, Haluk, Urtizberea, J. Andoni, van der Kooi, Anneke, Wilichowski, Ekkehard, Romero, Norma B, Fardeau, Michel, Bönnemann, Carsten G, Estournet, Brigitte, Richard, Pascale, Quijano-Roy, Susana, Schara, Ulrike, and Ferreiro, Ana

Published
2020
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12. Effect and safety of treatment with ACE-inhibitor Enalapril and β-blocker metoprolol on the onset of left ventricular dysfunction in Duchenne muscular dystrophy - a randomized, double-blind, placebo-controlled trial

Author

Dittrich, Sven, Graf, Erika, Trollmann, Regina, Neudorf, Ulrich, Schara, Ulrike, Heilmann, Antje, von der Hagen, Maja, Stiller, Brigitte, Kirschner, Janbernd, Pozza, Robert Dalla, Müller-Felber, Wolfgang, Weiss, Katja, von Au, Katja, Khalil, Markus, Motz, Reinald, Korenke, Christoph, Lange, Martina, Wilichowski, Ekkehard, Pattathu, Joseph, Ebinger, Friedrich, Wiechmann, Nicola, Schröder, Rolf, and on behalf of the German Competence Network for Congenital Heart Defects and the Treat-NMD Neuromuscular Network Investigators list of additional local Investigators and co-workers of the German Competence Network for Congenital Heart Defects and the Treat-NMD Neuromuscular Network

Published
2019
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13. Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations

Author

Huemer, Martina, Karall, Daniela, Schossig, Anna, Abdenur, Jose E., Al Jasmi, Fatma, Biagosch, Caroline, Distelmaier, Felix, Freisinger, Peter, Graham, Brett H., Haack, Tobias B., Hauser, Natalie, Hertecant, Jozef, Ebrahimi-Fakhari, Darius, Konstantopoulou, Vassiliki, Leydiker, Karen, Lourenco, Charles M., Scholl-Bürgi, Sabine, Wilichowski, Ekkehard, Wolf, Nicole I., Wortmann, Saskia B., Taylor, Robert W., Mayr, Johannes A., Bonnen, Penelope E., Sperl, Wolfgang, Prokisch, Holger, and McFarland, Robert

Published
2015
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14. Cathepsin D as biomarker in cerebrospinal fluid of nusinersen-treated patients with spinal muscular atrophy

Author

Schorling, David C., Kölbel, Heike, Hentschel, Andreas, Pechmann, Astrid, Meyer, Nancy, Wirth, Brunhilde, Rombo, Roman, Sickmann, Albert, Kirschner, Janbernd, Schara‐Schmidt, Ulrike, Lochmüller, Hanns, Roos, Andreas, Abele, Thea Beatrice, Andres, Barbara, Angelova‐Toshkina, Daniela, Baum, Petra, Baum, Tobias, Baumann, Matthias, Baumgartner, Manuela, Baur, Ute, Becker, Benedikt, Behring, Bettina, Bernert, Günther, Birsak, Theresa, Bellut, Julia, Bertsche, Astrid, Blankenburg, Markus, Blaschek, Astrid, Braun, Nathalie, Braun, Sarah, Burgenmeister, Nadine, Claus, Nicole, Cordts, Isabell, de Vries, Heike, Deba, Timo, Marina, Adela Della, Denecke, Jonas, Deschauer, Marcus, Dörnbrack, Katharina, Driemeyer, Joenna, Eckenweiler, Matthias, Eisenkölbl, Astrid, Fiedler, Barbara, Fischer, Michal, Flotats‐Bastardas, Marina, Freigang, Maren, Friese, Johannes, Gaiser, Philippa, Gebert, Axel, Geitmann, Stephanie, Goldhahn, Klaus, Grässl, Michael, Gröning, Kristina, Grosskreutz, Julian, Gruber‐Sedlmayr, Ursula, Guillemot, Helene, Günther, René, von der Hagen, Maja, Hagenacker, Tim, Hahn, Andreas, Hartmann, Hans, Hiebeler, Miriam, Hobbiebrunken, Elke, Friedrich Hoffmann, Georg, Holtkamp, Britta, Holzwarth, Dorothea, Horber, Veronka, Husain, Ralf A., Illsinger, Sabine, Jansen, Eva, Johannsen, Jessika, Kaindl, Angela, Kaiser, Nadja, Klamroth, Jennifer, Christoph Koch, Jan, Köhler, Cornelia, Koelker, Stefan, Kolzter, Kirsten, Korschinsky, Brigitte, Küpper, Hanna, Langer, Thorsten, Lehnert, Ilka, Lingor, Paul, Löscher, Wolfgang N., LoudoviciüKrug, Dana, Martakis, Kyriakos, Mayer, Iris, Metelmann, Moritz, Meyer, Sascha, von Moers, Arpad, Mueller‐Kaempffer, Katharina, Müller, Monika, Müller, Petra, Müller‐Felber, Wolfgang, Neuwirth, Christoph, Niederschweiberer, Johanna, Nolte, Anja, Odorfer, Thorsten, Omran, Heymut, Pauschek, Josefine, Pickrodt, Katrin, Plecko, Barbara, Pühringer, Manuel, Quinten, Anna Lisa, Rappold, Mika, Reihle, Christof, Reinhardt, Tabea, Rödiger, Annekathrin, Roetmann, Gerda, Saffari, Afshin, Schimmel, Mareike, Schlachter, Kurt, Schneider, Joanna, Schoene‐Bake, Christoph, Schreiber, Gudrun, Schwartz, Oliver, Schwerin‐Nagel, Anette, Schwersenz, Inge, Smitka, Martin, Stein, Sabine, Steinbach, Robert, Steiner, Elisabeth, Steuernagel, Daniela, Stögmann, Eva, Stolte, Benjamin, Stoltenburg, Corinna, Stüve, Burkhard, Tassoni, Adrian, Theophil, Manuela, Thiele, Simone, Topakian, Raffi, Trollmann, Regina, Türk, Matthias, van der Stam, Lieske, Vill, Katharina, Vogt, Sibylle, Vollmann, Peter, Walter, Maggie C., Warken, Birgit, Weber, Markus, Weiler, Markus, Weiß, Claudia, Weiss, Deike, Weiss, Simone, Wenzel, Franziska, Wider, Sabine, Wiebe, Nils, Wiegand, Gert, Wilichowski, Ekkehard, Wilken, Bernd, Wochner, Katarzyna, Zeiner, Fiona, Zeisler, Daniela, Zeller, Daniel, Zemlin, Michael, and Ziegler, Andreas

Subjects
Adult, Proteomics, Adolescent, Oligonucleotides, Medizin, Cathepsin D, Atròfia muscular espinal -- Tractament, Muscular Atrophy, Spinal, Neurology, Humans, Neurology (clinical), Child, Biomarkers, Aged
Abstract

Data de publicació electrònica: 23-03-2022 Background and purpose: The therapeutic landscape of spinal muscular atrophy (SMA) has changed dramatically during the past 4 years, but treatment responses differ remarkably between individuals, and therapeutic decision-making remains challenging, underlining the persistent need for validated biomarkers. Methods: We applied untargeted proteomic analyses to determine biomarkers in cerebrospinal fluid (CSF) samples of SMA patients under treatment with nusinersen. Identified candidate proteins were validated in CSF samples of SMA patients by Western blot and enzyme-linked immunosorbent assay. Furthermore, levels of peripheral neurofilament heavy and light chain were determined. Results: Untargeted proteomic analysis of CSF samples of three SMA type 1 patients revealed the lysosomal protease cathepsin D as a candidate biomarker. Subsequent validation analysis in a larger cohort of 31 pediatric SMA patients (type 1, n = 12; type 2, n = 9; type 3, n = 6; presymptomatically treated, n = 4; age = 0-16 years) revealed a significant decline of cathepsin D levels in SMA patients aged ≥2 months at the start of treatment. Although evident in all older age categories, this decline was only significant in the group of patients who showed a positive motor response. Moreover, downregulation of cathepsin D was evident in muscle biopsies of SMA patients. Conclusions: We identified a decline of cathepsin D levels in CSF samples of SMA patients under nusinersen treatment that was more pronounced in the group of "treatment responders" than in "nonresponders." We believe that our results indicate a suitability of cathepsin D levels as a possible biomarker in SMA also in older patients, in combination with analysis of peripheral neurofilament light chain in adolescents or alone in adult patients. Funding: H.L. receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). This work was also supported by a grant of the French Muscular Dystrophy Association (AFM-Téléthon;#21466) to A.R. The work of B.W. is supported by the German Research Foundation (Wi945/17-1, SFB 1451 [project-ID 431549029–A01] and GRK1960 [project ID 233886668]), the European Research Council under the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement 956185 (SMABEYOND), and the Center for Molecular Medicine Cologne (project No C18)

Published
2022

16. Treatment of Duchenne muscular dystrophy with ciclosporin A: a randomised, double-blind, placebo-controlled multicentre trial

Author

Kirschner, Janbernd, Schessl, Joachim, Schara, Ulrike, Reitter, Bernd, Stettner, Georg M, Hobbiebrunken, Elke, Wilichowski, Ekkehard, Bernert, Günther, Weiss, Simone, Stehling, Florian, Wiegand, Gert, Müller-Felber, Wolfgang, Thiele, Simone, Grieben, Ulrike, von der Hagen, Maja, Lütschg, Jürg, Schmoor, Claudia, Ihorst, Gabriele, and Korinthenberg, Rudolf

Published
2010
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17. Health related quality of life in young, steroid-naïve boys with Duchenne muscular dystrophy

Author

Campbell, Craig, primary, McColl, Elaine, additional, McDermott, Michael P., additional, Martens, William B., additional, Guglieri, Michela, additional, Griggs, Robert C., additional, Straub, Volker, additional, Childs, Anne-Marie, additional, Ciafaloni, Emma, additional, Shieh, Perry B., additional, Spinty, Stefan, additional, Butterfield, Russell J., additional, Horrocks, Iain, additional, Roper, Helen, additional, Maggi, Lorenzo, additional, Baranello, Giovanni, additional, Flanigan, Kevin M., additional, Kuntz, Nancy L., additional, Manzur, Adnan Y., additional, Darras, Basil T., additional, Kang, Peter, additional, Mah, Jean K., additional, Mongini, Tiziana, additional, Ricci, Federica, additional, Morrison, Leslie, additional, Krzesniak-Swinarska, Monika, additional, von der Hagen, Maja, additional, Finkel, Richard S., additional, Kumar, Ashutosh, additional, Wicklund, Matthew, additional, McDonald, Craig M., additional, Henricson, Erik K., additional, Schara-Schmidt, Ulrike, additional, Wilichowski, Ekkehard, additional, Barohn, Richard J., additional, Statland, Jeffrey, additional, Kirschner, Janbernd, additional, Vita, Giuseppe, additional, Vita, Gian Luca, additional, Howard, James F., additional, Hughes, Imelda, additional, McMillan, Hugh J., additional, Pegoraro, Elena, additional, Bello, Luca, additional, Burnette, W. Bryan, additional, Thangarajh, Mathula, additional, and Chang, Taeun, additional

Published
2021
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19. Autorenverzeichnis

Author

Bernhard, Matthias K., primary, Blank, Rainer, additional, Ebinger, Friedrich, additional, Ebinger, Martin, additional, Eysholdt, Ulrich, additional, Fricke-Oerkermann, Leonie, additional, Friedrich, Reinhard E., additional, Gärtner, Jutta, additional, Göderer, Lisa, additional, Graham, Herbert Kerr, additional, Hagel, Christian, additional, Häusler, Martin, additional, Hömberg, Volker, additional, Hornung, Dagmar, additional, Jandeck, Claudia, additional, Jorch, Gerhard, additional, Jung, Nikolai, additional, Kammler, Gertrud, additional, Klein, Christine, additional, Kohlschütter, Alfried, additional, Kordes, Uwe, additional, Körner, Christian, additional, Korinthenberg, Rudolf, additional, Krägeloh-Mann, Ingeborg, additional, Kunde-Trommer, Jutta, additional, Lehmkuhl, Gerd, additional, Lehmkuhl, Ulrike, additional, Linhart, Dieter, additional, Löbel, Ulrike, additional, Mall, Volker, additional, Mautner, Victor-Felix, additional, Merkenschlager, Andreas, additional, Mitschke, Alexander, additional, Müller, Kristina, additional, Müller-Felber, Wolfgang, additional, Münchau, Alexander, additional, Muschol, Nicole, additional, Nestler, Ulf, additional, Omran, Heymut, additional, Panteliadis, Christos P., additional, Preuß, Matthias, additional, Ramantani, Georgia, additional, Resch, Anika, additional, Roessner, Veit, additional, Röhling, Dagmar, additional, Rosenbaum, Thorsten, additional, Rössler, Jochen, additional, Rothenberger, Aribert, additional, Rudolf, Jobst, additional, Rüther, Klaus, additional, Rutkowski, Stefan, additional, Salbach-Andrae, Harriet, additional, Schlößer, Rolf, additional, Schneider, Susanne A., additional, Schöls, Ludger, additional, Schulz, Elisabeth, additional, Sinzig, Judith, additional, Spiekerkötter, Ute, additional, Steinfeld, Robert, additional, Stephani, Ulrich, additional, Suchodoletz, Waldemar von, additional, Synofzik, Matthis, additional, Thiel, Christian, additional, Trinka, Eugen, additional, Unterberger, Iris, additional, Velthoven, Vera van, additional, Wiater, Alfred, additional, and Wilichowski, Ekkehard, additional

Published
2014
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20. Neurometabolische und neurodegenerative Krankheiten

Author

Gärtner, Jutta, primary, Körner, Christian, additional, Kohlschütter, Alfried, additional, Muschol, Nicole, additional, Schneider, Susanne A., additional, Spiekerkötter, Ute, additional, Steinfeld, Robert, additional, Thiel, Christian, additional, and Wilichowski, Ekkehard, additional

Published
2014
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21. Diagnosing pediatric mitochondrial disease: lessons from 2,000 exomes

Author

Stenton, Sarah L., primary, Shimura, Masaru, additional, Piekutowska-Abramczuk, Dorota, additional, Freisinger, Peter, additional, Distelmaier, Felix, additional, Mayr, Johannes A., additional, Makowski, Christine, additional, Büchner, Boriana, additional, Alhaddad, Bader, additional, Alston, Charlotte L., additional, Ardissone, Anna, additional, Ban, Rui, additional, Barić, Ivo, additional, Berutti, Riccardo, additional, Brunet, Theresa, additional, Ciara, Elżbieta, additional, Deen, Dasha, additional, Gagneur, Julien, additional, Ghezzi, Daniele, additional, Gusic, Mirjana, additional, Haack, Tobias B., additional, Hempel, Maja, additional, Husain, Ralf A., additional, Karall, Daniela, additional, Kölker, Stefan, additional, Kotzaeridou, Urania, additional, Klopstock, Thomas, additional, Kopajtich, Robert, additional, Konstantopoulou, Vassiliki, additional, Liez, Steffen, additional, Lenz, Dominic, additional, Lim, Albert Z., additional, Mandel, Hanna, additional, McFarland, Robert, additional, Müller-Felber, Wolfgang, additional, Muñoz-Pujol, Gerard, additional, Ohtake, Akira, additional, Okazaki, Yasushi, additional, Olsen, Rikke, additional, Pronicka, Ewa, additional, Pyle, Angela, additional, Ribes, Antonia, additional, Rokicki, Dariusz, additional, Santer, René, additional, Schiff, Manuel, additional, Schuelke, Markus, additional, Smirnov, Dmitrii, additional, Sperl, Wolfgang, additional, Strom, Tim, additional, Tort, Frederic, additional, Tsygankova, Polina, additional, van Coster, Rudy, additional, Verloo, Patrick, additional, von Kleist-Retzow, Jürgen-Christoph, additional, Wilichowski, Ekkehard, additional, Wolstein, Tekla, additional, Xu, Manting, additional, Yépez, Vicente, additional, Zech, Michael, additional, Wortmann, Saskia, additional, Wagner, Matias, additional, Lamperti, Costanza, additional, Taylor, Robert W., additional, Fang, Fang, additional, Rötig, Agnés, additional, Murayama, Kei, additional, Meitinger, Thomas, additional, and Prokisch, Holger, additional

Published
2021
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22. Additional file 2 of Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes

Author

Yap, Zheng Yie, Park, Yo Han, Wortmann, Saskia B., Gunning, Adam C., Ezer, Shlomit, Sukyeong Lee, Duraine, Lita, Wilichowski, Ekkehard, Wilson, Kate, Mayr, Johannes A., Wagner, Matias, Li, Hong, Kini, Usha, Black, Emily Davis, Monaghan, Kristin G., Lupski, James R., Ellard, Sian, Westphal, Dominik S., Harel, Tamar, and Yoon, Wan Hee

Abstract

Additional file 2 : Table S2. Primers used for breakpoint junction analyses: Primers used to define breakpoint junctions in families 1-4. Table S3. Missense variants identified in ATAD3A: Bioinformatic predictions of missense variants identified in this study. Figure S1. Homozygous variant in Family 8: Visualization of exome sequencing reads showing the homozygous variant c.980G>C, p.(Arg327Pro). Figure S2. Segregation analysis in Family 7: Data showing that the c.150C>G variant is de novo, whereas the c.1703_1705del variant is maternally inherited. Figure S3. Compound heterozygous deletion affecting ATAD3A in Family 1: Visualization of exome sequencing read alignments indicating two overlapping deletions inherited in trans. Figure S4. Breakpoint junction sequencing of paternally inherited ATAD3B/ATAD3A deletion in Family 1: Alignment to ATAD3B and ATAD3A shows that the breakpoint occurred within a region of identity between the paralogs. Figure S5. Read depth analysis of exome sequencing data in Family 2: The compound heterozygous deletion can be appreciated. Figure S6. Breakpoint junction sequencing of first ATAD3B/ATAD3A deletion in Family 2: Alignment to ATAD3B and ATAD3A shows that the breakpoint occurred within a region of identity between the paralogs. Figure S7. Breakpoint junction sequencing of second inherited ATAD3B/ATAD3A deletion in Family 2: Alignment to ATAD3B and ATAD3A shows that the breakpoint occurred within a region of identity between the paralogs. Figure S8. Confirmatory array data from Family 3: The heterozygous deletion can be appreciated in the proband and mother’s samples, but not in the father’s sample. Figure S9. Breakpoint junction sequencing of maternally inherited ATAD3B/ATAD3A deletion in Family 3: Alignment to ATAD3B and ATAD3A shows that the breakpoint occurred within a region of identity between the paralogs. Figure S10. Breakpoint junction sequencing of paternally inherited 2-exon deletion in ATAD3A (Family 4): Delineation of the breakpoint junction by Sanger sequencing spanning the deletion, and evolutionary conservation of the skipped exons. Figure S11. Schematic diagram of all CNVs identified in this study: Diagram of the six CNVs studied; five of six were resolved at the breakpoint junction level. Figure S12. dAtad3a is expressed ubiquitously in embryos: Confocal micrographs of an embryo expressing GFP protein under the control of dAtad3a-T2A-Gal4 showed that dAtad3a is expressed ubiquitously. Figure S13. R176W and L83V did not affect mitochondria content and morphology in larvae muscles: Mitochondria content and morphology of dAtad3a mutant muscles expressing dAtad3aR176W, or dAtad3aL83V are comparable to those in wildtype controls. Figure S14. dAtad3a null, F56L, G242V, and R333P cause increased mitochondrial content in embryos: Mitochondrial content in dAtad3a null mutant embryo and those expressing dAtad3aF56L, dAtad3aG242V, or dAtad3aR333P is higher than those in wild type control embryos. Figure S15. dAtad3a null, F56L, G242V, and R333P cause increased mitochondrial numbers and size in embryos: In embryo VNC, dAtad3a null mutant and those expressing dAtad3aF56L, dAtad3aG242V, or dAtad3aR333P exhibited an increase in the mitochondrial size and numbers compared to those in wild type controls. Figure S16. R176W causes small mitochondria in adult muscles: dAtad3a mutant muscles expressing dAtad3aR176W exhibited smaller size of mitochondria compared to those expressing dAtad3aWT, or dAtad3aL83V. Figure S17. R176W and L83V cause various defects in mitochondria in adult muscles: dAtad3a mutant muscles expressing dAtad3aR176W, or dAtad3aL83V exhibited small, and membrane-defective mitochondria compared to those expressing dAtad3aL83V.

Published
2021
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23. Making sense of missense variants in TTN-related congenital myopathies

Author

Rees, Martin, Nikoopour, Roksana, Fukuzawa, Atsushi, Kho, Ay Lin, Fernandez-Garcia, Miguel A., Wraige, Elizabeth, Bodi, Istvan, Deshpande, Charu, Oezdemir, Oezkan, Daimagueler, Hulya-Sevcan, Pfuhl, Mark, Holt, Mark, Brandmeier, Birgit, Grover, Sarah, Fluss, Joel, Longman, Cheryl, Farrugia, Maria Elena, Matthews, Emma, Hanna, Michael, Muntoni, Francesco, Sarkozy, Anna, Phadke, Rahul, Quinlivan, Ros, Oates, Emily C., Schroeder, Rolf, Thiel, Christian, Reimann, Jens, Voermans, Nicol, Erasmus, Corrie, Kamsteeg, Erik-Jan, Konersman, Chaminda, Grosmann, Carla, McKee, Shane, Tirupathi, Sandya, Moore, Steven A., Wilichowski, Ekkehard, Hobbiebrunken, Elke, Dekomien, Gabriele, Richard, Isabelle, Van den Bergh, Peter, Dominguez-Gonzalez, Cristina, Cirak, Sebahattin, Ferreiro, Ana, Jungbluth, Heinz, Gautel, Mathias, Rees, Martin, Nikoopour, Roksana, Fukuzawa, Atsushi, Kho, Ay Lin, Fernandez-Garcia, Miguel A., Wraige, Elizabeth, Bodi, Istvan, Deshpande, Charu, Oezdemir, Oezkan, Daimagueler, Hulya-Sevcan, Pfuhl, Mark, Holt, Mark, Brandmeier, Birgit, Grover, Sarah, Fluss, Joel, Longman, Cheryl, Farrugia, Maria Elena, Matthews, Emma, Hanna, Michael, Muntoni, Francesco, Sarkozy, Anna, Phadke, Rahul, Quinlivan, Ros, Oates, Emily C., Schroeder, Rolf, Thiel, Christian, Reimann, Jens, Voermans, Nicol, Erasmus, Corrie, Kamsteeg, Erik-Jan, Konersman, Chaminda, Grosmann, Carla, McKee, Shane, Tirupathi, Sandya, Moore, Steven A., Wilichowski, Ekkehard, Hobbiebrunken, Elke, Dekomien, Gabriele, Richard, Isabelle, Van den Bergh, Peter, Dominguez-Gonzalez, Cristina, Cirak, Sebahattin, Ferreiro, Ana, Jungbluth, Heinz, and Gautel, Mathias

Abstract

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.

Published
2021

24. Making sense of missense variants in TTN-related congenital myopathies

Author

UCL - (SLuc) Centre de référence neuromusculaire, Rees, Martin, Nikoopour, Roksana, Fukuzawa, Atsushi, Kho, Ay Lin, Fernandez-Garcia, Miguel A., Wraige, Elizabeth, Bodi, Istvan, Deshpande, Charu, Özdemir, Özkan, Daimagüler, Hülya-Sevcan, Pfuhl, Mark, Holt, Mark, Brandmeier, Birgit, Grover, Sarah, Fluss, Joël, Longman, Cheryl, Farrugia, Maria Elena, Matthews, Emma, Hanna, Michael, Muntoni, Francesco, Sarkozy, Anna, Phadke, Rahul, Quinlivan, Ros, Oates, Emily C., Schröder, Rolf, Thiel, Christian, Reimann, Jens, Voermans, Nicol, Erasmus, Corrie, Kamsteeg, Erik-Jan, Konersman, Chaminda, Grosmann, Carla, McKee, Shane, Tirupathi, Sandya, Moore, Steven A., Wilichowski, Ekkehard, Hobbiebrunken, Elke, Dekomien, Gabriele, Richard, Isabelle, Van den Bergh, Peter, Domínguez-González, Cristina, Cirak, Sebahattin, Ferreiro, Ana, Jungbluth, Heinz, Gautel, Mathias, UCL - (SLuc) Centre de référence neuromusculaire, Rees, Martin, Nikoopour, Roksana, Fukuzawa, Atsushi, Kho, Ay Lin, Fernandez-Garcia, Miguel A., Wraige, Elizabeth, Bodi, Istvan, Deshpande, Charu, Özdemir, Özkan, Daimagüler, Hülya-Sevcan, Pfuhl, Mark, Holt, Mark, Brandmeier, Birgit, Grover, Sarah, Fluss, Joël, Longman, Cheryl, Farrugia, Maria Elena, Matthews, Emma, Hanna, Michael, Muntoni, Francesco, Sarkozy, Anna, Phadke, Rahul, Quinlivan, Ros, Oates, Emily C., Schröder, Rolf, Thiel, Christian, Reimann, Jens, Voermans, Nicol, Erasmus, Corrie, Kamsteeg, Erik-Jan, Konersman, Chaminda, Grosmann, Carla, McKee, Shane, Tirupathi, Sandya, Moore, Steven A., Wilichowski, Ekkehard, Hobbiebrunken, Elke, Dekomien, Gabriele, Richard, Isabelle, Van den Bergh, Peter, Domínguez-González, Cristina, Cirak, Sebahattin, Ferreiro, Ana, Jungbluth, Heinz, and Gautel, Mathias

Abstract

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.

Published
2021

25. Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations

Author

Huemer, Martina, Karall, Daniela, Schossig, Anna, Abdenur, Jose, Al Jasmi, Fatma, Biagosch, Caroline, Distelmaier, Felix, Freisinger, Peter, Graham, Brett, Haack, Tobias, Hauser, Natalie, Hertecant, Jozef, Ebrahimi-Fakhari, Darius, Konstantopoulou, Vassiliki, Leydiker, Karen, Lourenco, Charles, Scholl-Bürgi, Sabine, Wilichowski, Ekkehard, Wolf, Nicole, Wortmann, Saskia, Taylor, Robert, Mayr, Johannes, Bonnen, Penelope, Sperl, Wolfgang, Prokisch, Holger, McFarland, Robert, Huemer, Martina, Karall, Daniela, Schossig, Anna, Abdenur, Jose, Al Jasmi, Fatma, Biagosch, Caroline, Distelmaier, Felix, Freisinger, Peter, Graham, Brett, Haack, Tobias, Hauser, Natalie, Hertecant, Jozef, Ebrahimi-Fakhari, Darius, Konstantopoulou, Vassiliki, Leydiker, Karen, Lourenco, Charles, Scholl-Bürgi, Sabine, Wilichowski, Ekkehard, Wolf, Nicole, Wortmann, Saskia, Taylor, Robert, Mayr, Johannes, Bonnen, Penelope, Sperl, Wolfgang, Prokisch, Holger, and McFarland, Robert

Abstract

FBXL4 deficiency is a recently described disorder of mitochondrial maintenance associated with a loss of mitochondrial DNA in cells. To date, the genetic diagnosis of FBXL4 deficiency has been established in 28 individuals. This paper retrospectively reviews proxy-reported clinical and biochemical findings and evaluates brain imaging, morphological and genetic data in 21 of those patients. Neonatal/early-onset severe lactic acidosis, muscular hypotonia, feeding problems and failure to thrive is the characteristic pattern at first presentation. Facial dysmorphic features are present in 67% of cases. Seven children died (mean age 37months); 11 children were alive (mean age at follow-up 46months), three children were lost to follow-up. All survivors developed severe psychomotor retardation. Brain imaging was non-specific in neonates but a later-onset, rapidly progressive brain atrophy was noted. Elevated blood lactate and metabolic acidosis were observed in all individuals; creatine kinase was elevated in 45% of measurements. Diagnostic workup in patient tissues and cells revealed a severe combined respiratory chain defect with a general decrease of enzymes associated with mitochondrial energy metabolism and a relative depletion of mitochondrial DNA content. Mutations were detected throughout the FBXL4 gene albeit with no clear delineation of a genotype-phenotype correlation. Treatment with "mitochondrial medications” did not prove effective. In conclusion, a clinical pattern of early-onset encephalopathy, persistent lactic acidosis, profound muscular hypotonia and typical facial dysmorphism should prompt initiation of molecular genetic analysis of FBXL4. Establishment of the diagnosis permits genetic counselling, prevents patients undergoing unhelpful diagnostic procedures and allows for accurate prognosis.

Published
2021

26. Mutation Update and Genotype–Phenotype Correlations of Novel and Previously Described Mutations in TPM2 and TPM3 Causing Congenital Myopathies

Author

Marttila, Minttu, Lehtokari, Vilma-Lotta, Marston, Steven, Nyman, Tuula A., Barnerias, Christine, Beggs, Alan H., Bertini, Enrico, Ceyhan-Birsoy, Özge, Cintas, Pascal, Gerard, Marion, Gilbert-Dussardier, Brigitte, Hogue, Jacob S., Longman, Cheryl, Eymard, Bruno, Frydman, Moshe, Kang, Peter B., Klinge, Lars, Kolski, Hanna, Lochmüller, Hans, Magy, Laurent, Manel, Véronique, Mayer, Michèle, Mercuri, Eugenio, North, Kathryn N., Peudenier-Robert, Sylviane, Pihko, Helena, Probst, Frank J., Reisin, Ricardo, Stewart, Willie, Taratuto, Ana Lia, de Visser, Marianne, Wilichowski, Ekkehard, Winer, John, Nowak, Kristen, Laing, Nigel G., Winder, Tom L., Monnier, Nicole, Clarke, Nigel F., Pelin, Katarina, Grönholm, Mikaela, and Wallgren-Pettersson, Carina

Published
2014
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28. Making sense of missense variants in TTN-related congenital myopathies

Author

Rees, Martin, primary, Nikoopour, Roksana, additional, Fukuzawa, Atsushi, additional, Kho, Ay Lin, additional, Fernandez-Garcia, Miguel A., additional, Wraige, Elizabeth, additional, Bodi, Istvan, additional, Deshpande, Charu, additional, Özdemir, Özkan, additional, Daimagüler, Hülya-Sevcan, additional, Pfuhl, Mark, additional, Holt, Mark, additional, Brandmeier, Birgit, additional, Grover, Sarah, additional, Fluss, Joël, additional, Longman, Cheryl, additional, Farrugia, Maria Elena, additional, Matthews, Emma, additional, Hanna, Michael, additional, Muntoni, Francesco, additional, Sarkozy, Anna, additional, Phadke, Rahul, additional, Quinlivan, Ros, additional, Oates, Emily C., additional, Schröder, Rolf, additional, Thiel, Christian, additional, Reimann, Jens, additional, Voermans, Nicol, additional, Erasmus, Corrie, additional, Kamsteeg, Erik-Jan, additional, Konersman, Chaminda, additional, Grosmann, Carla, additional, McKee, Shane, additional, Tirupathi, Sandya, additional, Moore, Steven A., additional, Wilichowski, Ekkehard, additional, Hobbiebrunken, Elke, additional, Dekomien, Gabriele, additional, Richard, Isabelle, additional, Van den Bergh, Peter, additional, Domínguez-González, Cristina, additional, Cirak, Sebahattin, additional, Ferreiro, Ana, additional, Jungbluth, Heinz, additional, and Gautel, Mathias, additional

Published
2021
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30. Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing

Author

Haack, Tobias B, Haberberger, Birgit, Frisch, Eva-Maria, Wieland, Thomas, Iuso, Arcangela, Gorza, Matteo, Strecker, Valentina, Graf, Elisabeth, Mayr, Johannes A, Herberg, Ulrike, Hennermann, Julia B, Klopstock, Thomas, Kuhn, Klaus A, Ahting, Uwe, Sperl, Wolfgang, Wilichowski, Ekkehard, Hoffmann, Georg F, Tesarova, Marketa, Hansikova, Hana, Zeman, Jiri, Plecko, Barbara, Zeviani, Massimo, Wittig, Ilka, Strom, Tim M, Schuelke, Markus, Freisinger, Peter, Meitinger, Thomas, and Prokisch, Holger

Published
2012
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31. Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes

Author

Yap, Zheng Yie, primary, Park, YoHan, additional, Wortmann, Saskia B., additional, Gunning, Adam C., additional, Lee, Sukyoung, additional, Duraine, Lita, additional, Wilichowski, Ekkehard, additional, Wilson, Kate, additional, Mayr, Johannes A., additional, Wagner, Matias, additional, Li, Hong, additional, Kini, Usha, additional, Black, Emily Davis, additional, Lupski, James R., additional, Ellard, Sian, additional, Westphal, Dominik S., additional, Harel, Tamar, additional, and Yoon, Wan Hee, additional

Published
2020
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32. Treatment with Nusinersen – Challenges Regarding the Indication for Children with SMA Type 1

Author

Pechmann, Astrid, primary, Baumann, Matthias, additional, Bernert, Günther, additional, Flotats-Bastardas, Marina, additional, Gruber-Sedlmayr, Ursula, additional, von der Hagen, Maja, additional, Hasselmann, Oswald, additional, Hobbiebrunken, Elke, additional, Horber, Veronka, additional, Johannsen, Jessika, additional, Kellersmann, Anna, additional, Köhler, Cornelia, additional, von Moers, Arpad, additional, Müller-Felber, Wolfgang, additional, Plecko, Barbara, additional, Reihle, Christof, additional, Schlachter, Kurt, additional, Schreiber, Gudrun, additional, Schwartz, Oliver, additional, Smitka, Martin, additional, Steiner, Elisabeth, additional, Stoltenburg, Corinna, additional, Stüve, Burkhard, additional, Theophil, Manuela, additional, Weiß, Claudia, additional, Wiegand, Gert, additional, Wilichowski, Ekkehard, additional, Winter, Benedikt, additional, Wittmann, Wolfgang, additional, Schara, Ulrike, additional, and Kirschner, Janbernd, additional

Published
2020
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34. Additional file 1: of Effect and safety of treatment with ACE-inhibitor Enalapril and β-blocker metoprolol on the onset of left ventricular dysfunction in Duchenne muscular dystrophy - a randomized, double-blind, placebo-controlled trial

Author

Dittrich, Sven, Graf, Erika, Trollmann, Regina, Neudorf, Ulrich, Schara, Ulrike, Heilmann, Antje, Hagen, Maja, Stiller, Brigitte, Janbernd Kirschner, Pozza, Robert, Müller-Felber, Wolfgang, Weiss, Katja, Au, Katja, Khalil, Markus, Motz, Reinald, Korenke, Christoph, Lange, Martina, Wilichowski, Ekkehard, Pattathu, Joseph, Ebinger, Friedrich, Wiechmann, Nicola, and Schröder, Rolf

Abstract

Table S1A. Outcomes before and after run-in medication (all patients, additional measurements). Table S2A. Baseline characteristics by randomized treatment (additional measurements). Figure S1A. Results from KINDL-questionnaire. (DOCX 72 kb)

Published
2019
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35. Paralog Studies Augment Gene Discovery: DDX and DHX Genes

Author

Paine, Ingrid, primary, Posey, Jennifer E., additional, Grochowski, Christopher M., additional, Jhangiani, Shalini N., additional, Rosenheck, Sarah, additional, Kleyner, Robert, additional, Marmorale, Taylor, additional, Yoon, Margaret, additional, Wang, Kai, additional, Robison, Reid, additional, Cappuccio, Gerarda, additional, Pinelli, Michele, additional, Magli, Adriano, additional, Coban Akdemir, Zeynep, additional, Hui, Joannie, additional, Yeung, Wai Lan, additional, Wong, Bibiana K.Y., additional, Ortega, Lucia, additional, Bekheirnia, Mir Reza, additional, Bierhals, Tatjana, additional, Hempel, Maja, additional, Johannsen, Jessika, additional, Santer, René, additional, Aktas, Dilek, additional, Alikasifoglu, Mehmet, additional, Bozdogan, Sevcan, additional, Aydin, Hatip, additional, Karaca, Ender, additional, Bayram, Yavuz, additional, Ityel, Hadas, additional, Dorschner, Michael, additional, White, Janson J., additional, Wilichowski, Ekkehard, additional, Wortmann, Saskia B., additional, Casella, Erasmo B., additional, Kitajima, Joao Paulo, additional, Kok, Fernando, additional, Monteiro, Fabiola, additional, Muzny, Donna M., additional, Bamshad, Michael, additional, Gibbs, Richard A., additional, Sutton, V. Reid, additional, Van Esch, Hilde, additional, Brunetti-Pierri, Nicola, additional, Hildebrandt, Friedhelm, additional, Brautbar, Ariel, additional, Van den Veyver, Ignatia B., additional, Glass, Ian, additional, Lessel, Davor, additional, Lyon, Gholson J., additional, and Lupski, James R., additional

Published
2019
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38. Identification of subtelomeric genomic imbalances and breakpoint mapping with quantitative PCR in 296 individuals with congenital defects and/or mental retardation

Author

Brockmann Knut, Liehr Thomas, Boehm Detlef, Burfeind Peter, Zoll Barbara, Bruemmer Verena, Auber Bernd, Wilichowski Ekkehard, Argyriou Loukas, and Bartels Iris

Subjects
Genetics, QH426-470
Abstract

Abstract Background Submicroscopic imbalances in the subtelomeric regions of the chromosomes are considered to play an important role in the aetiology of mental retardation (MR). The aim of the study was to evaluate a quantitative PCR (qPCR) protocol established by Boehm et al. (2004) in the clinical routine of subtelomeric testing. Results 296 patients with MR and a normal karyotype (500–550 bands) were screened for subtelomeric imbalances by using qPCR combined with SYBR green detection. In total, 17 patients (5.8%) with 20 subtelomeric imbalances were identified. Six of the aberrations (2%) were classified as causative for the symptoms, because they occurred either de novo in the patients (5 cases) or the aberration were be detected in the patient and an equally affected parent (1 case). The extent of the deletions ranged from 1.8 to approximately 10 Mb, duplications were 1.8 to approximately 5 Mb in size. In 6 patients, the copy number variations (CNVs) were rated as benign polymorphisms, and the clinical relevance of these CNVs remains unclear in 5 patients (1.7%). Therefore, the overall frequency of clinically relevant imbalances ranges between 2% and 3.7% in our cohort. Conclusion This study illustrates that the qPCR/SYBR green technique represents a rapid and versatile method for the detection of subtelomeric imbalances and the option to map the breakpoint. Thus, this technique is highly suitable for genotype/phenotype studies in patients with MR/developmental delay and/or congenital defects.

Published
2009
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41. Survival among children with “Lethal” congenital contracture syndrome 11 caused by novel mutations in the gliomedin gene ( GLDN )

Author

Wambach, Jennifer A., primary, Stettner, Georg M., additional, Haack, Tobias B., additional, Writzl, Karin, additional, Škofljanec, Andreja, additional, Maver, Aleš, additional, Munell, Francina, additional, Ossowski, Stephan, additional, Bosio, Mattia, additional, Wegner, Daniel J., additional, Shinawi, Marwan, additional, Baldridge, Dustin, additional, Alhaddad, Bader, additional, Strom, Tim M., additional, Grange, Dorothy K., additional, Wilichowski, Ekkehard, additional, Troxell, Robin, additional, Collins, James, additional, Warner, Barbara B., additional, Schmidt, Robert E., additional, Pestronk, Alan, additional, Cole, F. Sessions, additional, and Steinfeld, Robert, additional

Published
2017
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42. Developing standardized corticosteroid treatment for Duchenne muscular dystrophy

Author

Guglieri, Michela, primary, Bushby, Kate, additional, McDermott, Michael P., additional, Hart, Kimberly A., additional, Tawil, Rabi, additional, Martens, William B., additional, Herr, Barbara E., additional, McColl, Elaine, additional, Wilkinson, Jennifer, additional, Kirschner, Janbernd, additional, King, Wendy M., additional, Eagle, Michele, additional, Brown, Mary W., additional, Willis, Tracey, additional, Hirtz, Deborah, additional, Shieh, Perry B., additional, Straub, Volker, additional, Childs, Anne-Marie, additional, Ciafaloni, Emma, additional, Butterfield, Russell J., additional, Horrocks, Iain, additional, Spinty, Stefan, additional, Flanigan, Kevin M., additional, Kuntz, Nancy L., additional, Baranello, Giovanni, additional, Roper, Helen, additional, Morrison, Leslie, additional, Mah, Jean K., additional, Manzur, Adnan Y., additional, McDonald, Craig M., additional, Schara, Ulrike, additional, von der Hagen, Maja, additional, Barohn, Richard J., additional, Campbell, Craig, additional, Darras, Basil T., additional, Finkel, Richard S., additional, Vita, Giuseppe, additional, Hughes, Imelda, additional, Mongini, Tiziana, additional, Pegoraro, Elena, additional, Wicklund, Matthew, additional, Wilichowski, Ekkehard, additional, Bryan Burnette, W., additional, Howard, James F., additional, McMillan, Hugh J., additional, Thangarajh, Mathula, additional, and Griggs, Robert C., additional

Published
2017
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44. Functional Consequences of Mitochondrial DNA Deletions in Human Skin Fibroblasts : Increased Contractile Strength in Collagen Lattices Is Due to Oxidative Stress-Induced Lysyl Oxidase Activity

Author

Majora, Marc, Wittkampf, Tanja, Schuermann, Bianca, Schneider, Maren, Franke, Susanne, Grether-Beck, Susanne, Wilichowski, Ekkehard, Bernerd, Françoise, Schroeder, Peter, and Krutmann, Jean

Subjects
musculoskeletal diseases, integumentary system, Kearns-Sayre Syndrome, Fibroblasts, DNA, Mitochondrial, Mitochondria, Skin Aging, Cyclic N-Oxides, Enzyme Activation, Protein-Lysine 6-Oxidase, Mice, Oxidative Stress, Aminopropionitrile, Animals, Humans, Collagen, Enzyme Inhibitors, Reactive Oxygen Species, Oxidation-Reduction, Cells, Cultured, Regular Articles, DNA Damage, Sequence Deletion, Skin
Abstract

Deletions within the mitochondrial DNA (mtDNA) are thought to contribute to extrinsic skin aging. To study the translation of mtDNA deletions into functional and structural changes in the skin, we seeded human skin fibroblasts into collagen gels to generate dermal equivalents. These cells were either derived from Kearns-Sayre syndrome (KSS) patients, who constitutively carry large amounts of the UV-inducible mitochondrial common deletion, or normal human volunteers. We found that KSS fibroblasts, in comparison with normal human fibroblasts, contracted the gels faster and more strongly, an effect that was dependent on reactive oxygen species. Gene expression and Western blot analysis revealed significant upregulation of lysyl oxidase (LOX) in KSS fibroblasts. Treatment with the specific LOX inhibitor beta-aminopropionitrile decreased the contraction difference between KSS and normal human fibroblast equivalents. Also, addition of the antioxidant N-tert-butyl-alpha-phenylnitrone reduced the contraction difference by inhibiting collagen gel contraction in KSS fibroblasts, and both beta-aminopropionitrile and N-tert-butyl-alpha-phenylnitrone diminished LOX activity. These data suggest a causal relationship between mtDNA deletions, reactive oxygen species production, and increased LOX activity that leads to increased contraction of collagen gels. Accordingly, increased LOX expression was also observed in vivo in photoaged human and mouse skin. Therefore, mtDNA deletions in human fibroblasts may lead to functional and structural alterations of the skin.

Published
2009

45. Mutation Update and Genotype-Phenotype Correlations of Novel and Previously Described Mutations inTPM2andTPM3Causing Congenital Myopathies

Author

Marttila, Minttu, primary, Lehtokari, Vilma-Lotta, additional, Marston, Steven, additional, Nyman, Tuula A., additional, Barnerias, Christine, additional, Beggs, Alan H., additional, Bertini, Enrico, additional, Ceyhan-Birsoy, Özge, additional, Cintas, Pascal, additional, Gerard, Marion, additional, Gilbert-Dussardier, Brigitte, additional, Hogue, Jacob S., additional, Longman, Cheryl, additional, Eymard, Bruno, additional, Frydman, Moshe, additional, Kang, Peter B., additional, Klinge, Lars, additional, Kolski, Hanna, additional, Lochmüller, Hans, additional, Magy, Laurent, additional, Manel, Véronique, additional, Mayer, Michèle, additional, Mercuri, Eugenio, additional, North, Kathryn N., additional, Peudenier-Robert, Sylviane, additional, Pihko, Helena, additional, Probst, Frank J., additional, Reisin, Ricardo, additional, Stewart, Willie, additional, Taratuto, Ana Lia, additional, de Visser, Marianne, additional, Wilichowski, Ekkehard, additional, Winer, John, additional, Nowak, Kristen, additional, Laing, Nigel G., additional, Winder, Tom L., additional, Monnier, Nicole, additional, Clarke, Nigel F., additional, Pelin, Katarina, additional, Grönholm, Mikaela, additional, and Wallgren-Pettersson, Carina, additional

Published
2014
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46. Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening

Author

Haack, Tobias B., primary, Gorza, Matteo, additional, Danhauser, Katharina, additional, Mayr, Johannes A., additional, Haberberger, Birgit, additional, Wieland, Thomas, additional, Kremer, Laura, additional, Strecker, Valentina, additional, Graf, Elisabeth, additional, Memari, Yasin, additional, Ahting, Uwe, additional, Kopajtich, Robert, additional, Wortmann, Saskia B., additional, Rodenburg, Richard J., additional, Kotzaeridou, Urania, additional, Hoffmann, Georg F., additional, Sperl, Wolfgang, additional, Wittig, Ilka, additional, Wilichowski, Ekkehard, additional, Schottmann, Gudrun, additional, Schuelke, Markus, additional, Plecko, Barbara, additional, Stephani, Ulrich, additional, Strom, Tim M., additional, Meitinger, Thomas, additional, Prokisch, Holger, additional, and Freisinger, Peter, additional

Published
2014
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47. Cytochrome c Oxidase Partial Deficiency-Associated Leigh Disease Presenting as an Extrapyramidal Syndrome

Author

Čačić, Melita, Wilichowski, Ekkehard, Mejaški-Bošnjak, Vlatka, Fumić, Ksenija, Lujić, Lucija, Marušić Della Marina, Branka, and Hanefeld, Folker

Subjects
Cytochrome c Oxydase, Partial Deficiency, Leigh Disease, Extrapyramidal Syndrome
Abstract

Leigh disease is a subacute neurodegenerative disorder characterized by simmetric necrotic lesions i the basal ganglia, cerebellum, thalamus, brain stem, and optical nerves and caused by altered oxidative phosphorylation. We dwscribe the clinical, biochemical, neuroimaging, and molecular studies of a 19-year-old boy with early-onset Leigh Disease manifesting as severe extrapyramidal disorder with generalized dystonia and choreoathetosis. He was born of healthy parents after an uneventful pregnancy and delivery. At the age of 2, 5 years, after a minor respiratory infection, he developed unstable, broad-based gait and tremor of the hands. These symptoms persisted for the next several years, when ataxia became more prominent. Difficulty in swallowing, dysarthria, trunk dystonia, and marked dyskinesia of the arms and hands gradually-developed. Nystagmus, transient ptosis, and strabismus alse appeared. Abnormal laboratory findings included elevated plasma and cereblospinal fluid lactate and pyruvate, with an abnormal lactate/pyruvate ratio. Cranial computed tomography and magnetic resonance imaging demonstrated signs of cerebelar atrophy, bilateral and symmetric hypodensities in the lentiform nucleus and thalamus, and transient hyperintensities of cerebral peduncles in T2-weighted sequences suggestive of Leigh disease. Mescle biopsy revealed isolated fiber atrophy, necrotic fibers undergoing phagocytosis, and no ragged-red fibers. The measured catalytic activity of cytochrome c oxidase in skeletal muscle homogenates demonstrated a partial cytochrome c oxidase defficiency. No abnormalities in the mitochondrial genome and in the SURF-1 gene were found. The boy is currently recieving levodopa therapy, creatine monohydrate, and a high dosage of thiamine and lipoic acid, his condition is stabilized, and extrapyramidal symptoms are less pronounced.

Published
2001

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