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1. Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings

Author

Schmidt, Axel, Danyel, Magdalena, Grundmann, Kathrin, Brunet, Theresa, Klinkhammer, Hannah, Hsieh, Tzung-Chien, Engels, Hartmut, Peters, Sophia, Knaus, Alexej, Moosa, Shahida, Averdunk, Luisa, Boschann, Felix, Sczakiel, Henrike Lisa, Schwartzmann, Sarina, Mensah, Martin Atta, Pantel, Jean Tori, Holtgrewe, Manuel, Bösch, Annemarie, Weiß, Claudia, Weinhold, Natalie, Suter, Aude-Annick, Stoltenburg, Corinna, Neugebauer, Julia, Kallinich, Tillmann, Kaindl, Angela M., Holzhauer, Susanne, Bührer, Christoph, Bufler, Philip, Kornak, Uwe, Ott, Claus-Eric, Schülke, Markus, Nguyen, Hoa Huu Phuc, Hoffjan, Sabine, Grasemann, Corinna, Rothoeft, Tobias, Brinkmann, Folke, Matar, Nora, Sivalingam, Sugirthan, Perne, Claudia, Mangold, Elisabeth, Kreiss, Martina, Cremer, Kirsten, Betz, Regina C., Mücke, Martin, Grigull, Lorenz, Klockgether, Thomas, Spier, Isabel, Heimbach, André, Bender, Tim, Brand, Fabian, Stieber, Christiane, Morawiec, Alexandra Marzena, Karakostas, Pantelis, Schäfer, Valentin S., Bernsen, Sarah, Weydt, Patrick, Castro-Gomez, Sergio, Aziz, Ahmad, Grobe-Einsler, Marcus, Kimmich, Okka, Kobeleva, Xenia, Önder, Demet, Lesmann, Hellen, Kumar, Sheetal, Tacik, Pawel, Basin, Meghna Ahuja, Incardona, Pietro, Lee-Kirsch, Min Ae, Berner, Reinhard, Schuetz, Catharina, Körholz, Julia, Kretschmer, Tanita, Di Donato, Nataliya, Schröck, Evelin, Heinen, André, Reuner, Ulrike, Hanßke, Amalia-Mihaela, Kaiser, Frank J., Manka, Eva, Munteanu, Martin, Kuechler, Alma, Cordula, Kiewert, Hirtz, Raphael, Schlapakow, Elena, Schlein, Christian, Lisfeld, Jasmin, Kubisch, Christian, Herget, Theresia, Hempel, Maja, Weiler-Normann, Christina, Ullrich, Kurt, Schramm, Christoph, Rudolph, Cornelia, Rillig, Franziska, Groffmann, Maximilian, Muntau, Ania, Tibelius, Alexandra, Schwaibold, Eva M. C., Schaaf, Christian P., Zawada, Michal, Kaufmann, Lilian, Hinderhofer, Katrin, Okun, Pamela M., Kotzaeridou, Urania, Hoffmann, Georg F., Choukair, Daniela, Bettendorf, Markus, Spielmann, Malte, Ripke, Annekatrin, Pauly, Martje, Münchau, Alexander, Lohmann, Katja, Hüning, Irina, Hanker, Britta, Bäumer, Tobias, Herzog, Rebecca, Hellenbroich, Yorck, Westphal, Dominik S., Strom, Tim, Kovacs, Reka, Riedhammer, Korbinian M., Mayerhanser, Katharina, Graf, Elisabeth, Brugger, Melanie, Hoefele, Julia, Oexle, Konrad, Mirza-Schreiber, Nazanin, Berutti, Riccardo, Schatz, Ulrich, Krenn, Martin, Makowski, Christine, Weigand, Heike, Schröder, Sebastian, Rohlfs, Meino, Vill, Katharina, Hauck, Fabian, Borggraefe, Ingo, Müller-Felber, Wolfgang, Kurth, Ingo, Elbracht, Miriam, Knopp, Cordula, Begemann, Matthias, Kraft, Florian, Lemke, Johannes R., Hentschel, Julia, Platzer, Konrad, Strehlow, Vincent, Abou Jamra, Rami, Kehrer, Martin, Demidov, German, Beck-Wödl, Stefanie, Graessner, Holm, Sturm, Marc, Zeltner, Lena, Schöls, Ludger J., Magg, Janine, Bevot, Andrea, Kehrer, Christiane, Kaiser, Nadja, Turro, Ernest, Horn, Denise, Grüters-Kieslich, Annette, Klein, Christoph, Mundlos, Stefan, Nöthen, Markus, Riess, Olaf, Meitinger, Thomas, Krude, Heiko, Krawitz, Peter M., Haack, Tobias, Ehmke, Nadja, and Wagner, Matias

Published
2024
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4. Efficacy and safety of gene therapy with onasemnogene abeparvovec in children with spinal muscular atrophy in the D-A-CH-region: a population-based observational studyResearch in context

Author

Claudia Weiß, Lena-Luise Becker, Johannes Friese, Astrid Blaschek, Andreas Hahn, Sabine Illsinger, Oliver Schwartz, Günther Bernert, Maja von der Hagen, Ralf A. Husain, Klaus Goldhahn, Janbernd Kirschner, Astrid Pechmann, Marina Flotats-Bastardas, Gudrun Schreiber, Ulrike Schara, Barbara Plecko, Regina Trollmann, Veronka Horber, Ekkehard Wilichowski, Matthias Baumann, Andrea Klein, Astrid Eisenkölbl, Cornelia Köhler, Georg M. Stettner, Sebahattin Cirak, Oswald Hasselmann, Angela M. Kaindl, Sven F. Garbade, Jessika Johannsen, Andreas Ziegler, Petra Baum, Manuela Baumgartner, Astrid Bertsche, Markus Blankenburg, Jonas Denecke, Marcus Deschauer, Matthias Eckenweiler, Tobias Geis, Martin Groß, René Günther, Tim Hagenacker, Eckard Hamelmann, Christoph Kamm, Birgit Kauffmann, Jan Christoph Koch, Wolfgang Löscher, Albert Ludolph, Pascal Martin, Alexander Mensch, Gerd Meyer zu Hörste, Christoph Neuwirth, Susanne Petri, Manuel Pühringer, Imke Rathmann, Dorothee Schäfer, Mareike Schimmel, Bertold Schrank, Olivia Schreiber-Katz, Anette Schwerin-Nagel, Martin Smitka, Meike Steinbach, Elisabeth Steiner, Johannes Stoffels, Manuela Theophil, Raffi Topakian, Matthias Türk, Matthias Vorgerd, Maggie C. Walter, Markus Weiler, Gert Wiegand, Gilbert Wunderlich, Claudia Diana Wurster, Daniel Zeller, Moritz Metelmann, Fiona Zeiner, Veronika Pilshofer, Mika Rappold, Josefine Pauschek, Christof Reihle, Annette Karolin Homma, Paul Lingor, Bettina Henzi, Tabea Reinhardt, Dorothea Holzwarth, Wolfgang Wittmann, Stefan Kappel, Maren Freigang, Benjamin Stolte, Kyriakos Martakis, Georg Classen, Doris Roland-Schäfer, Daniela Steuernagel, Hans Hartmann, Sophie Fischer, Marieke Wermuth, Mohamad Tareq Muhandes, Anna Hotter, Zeljko Uzelac, Steffen Naegel, Sarah Wiethoff, Nathalie Braun, Bogdan Bjelica, Heike Kölbel, Daniela Angelova-Toshkina, Bernd Wilken, Alma Osmanovic, Barbara Fiedler, Maike Tomforde, Thomas Voelkl, Arpad von Moers, Petra Müller, Bettina Behring, Anne Güttsches, Peter Reilich, Wolfgang Wick, Corinna Stoltenburg, Simon Witzel, Julia Bellut, Georg Friedrich Hoffmann, Kathrin Mörtlbauer, Alexandra Ille, Michael Schroth, Joenna Driemeyer, Luisa Semmler, Cornelia Müller, Katharina Dörnbrack, Michael Zemlin, Stephanie Geitmann, Hanna Sophie Lapp, Svenja Brakemeier, Tascha Gehrke, Klearchos Ntemiris, Nadja Kaiser, Sabine Borowski, Barbara Ramadan, Ulf Hustedt, Tobias Baum, Ilka Schneider, Esra Akova-Oztürk, Katharina Vill, Zylfie Dibrani, Camilla Wohnrade, Adela Della-Marina, Lisa Jung, Timo Deba, Joachim Zobel, Jens Schallner, Christina Kraut, Peter Vollmann, Stephanie Schüssler, Melanie Roeder, Miriam Hiebeler, Nicole Berberich, Joanna Schneider, Brigitte Brauner, Stefan Kölker, Elke Pernegger, Magdalena Gosk-Tomek, Sarah Braun, Deike Weiss, Gerrit Machetanz, Thorsten Langer, Christina Saier, Sandra Baumann, Sabine Hettrich, Gabriel Dworschak, Katharina Müller-Kaempffer, Isabelle Dittes, Andreas Thimm, Lisa Quinten, Kristina Albers, Andrea Bevot, Christa Bretschneider, Johannes Dorst, Thomas Kendzierski, Iris Hannibal, Jasmin Bischofberger, Tilman Riesmeier, Andrea Gangfuß, Eva Johann to Settel, Michael Grässl, Susan Fiebig, Carmen Hollerauer, Lea Seeber, Ina Krahwinkler, Irene Lange, Federica Montagnese, Marcel Mann-Richter, Alexandra Wagner, Christine Leypold, Afshin Saffari, Elmecker Anna, Anna Wiesenhofer, Eva-Maria Wendel, Paula-Sophie Steffens, Sabine Wider, Adrian Tassoni, Andrea Dall, Franziska Busch, Daniela Zeisler, Maria Wessel, Jaqueline Lipka, Andrea Hackemer, Loreen Plugge, Eva Jansen, Erdmute Roth, Joachim Schuster, Anna Koelsch, Birgit Warken-Madelung, Michaela Schwippert, Britta Holtkamp, Katja Köbbing, Sander Claeys, Sandy Foerster, Simone Thiele, Heidi Rochau-Trumpp, Annette George, Moritz Niesert, Tanja Neimair, Katia Vettori, Julia Haverkamp, Jila Taherpour, Juliane Hug, Franziska Wenzel, Christina Bant, Ute Baur, Kathrin Bühner, Melina Schlag, Lena Ruß, Hanna Küpper, Anja Müller, Kurt Wollinsky, Therese Well, Antonia Leinert, Barbara Andres, Heymut Omran, Nicole Claus, Anna Hagenmeyer, Marion Schnurr, Vladimir Dukic, Albert Christian Ludolph, Sabine Specht, Verena Angermair, Anna Hüpper, Daniela Banholzer, Sabine Stein, Tim Kampowski, Marion Richmann, Sylke Nicolai, Omar Atta, Birgit Meßmer, Heike de Vries, Elisabeth Rotenfusser, Alma Oscmanovic, Isabelle Renger, Hélène Guillemot, Ilka Lehnert, Mike Grünwedel, Laura Grimm, Guido Stocker, Annegret Hoevel, Theresa Stadler, Michal Fischer, Sibylle Vogt, Axel Gebert, Susanne Goldbach, Hanns Lochmüller, Wolfgang Müller-Felber, Ulrike Schara-Schmidt, Kristina Probst-Schendzielorz, Annina Lang, Maren Nitzsche, Julie Hammer, Katharina Müller-Kaempfer, Corinna Wirner-Piotrowski, Lieske van der Stam, Anke Bongartz, Cornelia Enzmann, Joël Fluss, Elea Galiart, David Jacquier, Dominique Baumann Metzler, and Anne Tscherter

Subjects
Spinal muscular atrophy, Gene addition therapy, SMA, Onasemnogene abeparvovec, Gene therapy, Zolgensma, Public aspects of medicine, RA1-1270
Abstract

Summary: Background: Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH). Methods: This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status. Findings: 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0–90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups. Interpretation: Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio. Funding: The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).

Published
2024
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7. Influence of sex and disease etiology on the development of papilledema and optic nerve sheath extension in the setting of intracranial pressure elevation in children

Author

Susanne Regina Kerscher, Jonas Tellermann, Julian Zipfel, Andrea Bevot, Karin Haas-Lude, and Martin Ulrich Schuhmann

Subjects
Optic nerve sheath diameter, ONSD, Fundoscopy, Sex-specificity, Etiology-specificity, ICP, Neurology. Diseases of the nervous system, RC346-429
Abstract

Introduction: Dilatation of the optic nerve sheath diameter and swelling of the optic disc are known phenomena associated with intracranial pressure elevation. Research question: Do sex and disease etiology have an impact on the development of optic disc elevation and optic nerve sheath extension in children in the setting of ICP elevation? Fundoscopic papilledema and point-of-care-ultrasound techniques-optic nerve sheath diameter (US-ONSD) and optic disc elevation (US-ODE) - were compared in this regard. Material and methods: 72 children were included in this prospective study; 50 with proven pathology (e.g. pseudotumor cerebri, tumor), 22 with pathology excluded. Bilateral US-ONSD and US-ODE were quantified by US using a 12-MHz-linear-array-transducer. This was compared with fundoscopic optic disc findings and in 28 patients with invasive ICP values, stratified for sex and etiology. Results: In patients with proven disease, significant more girls (69%) had fundoscopic papilledema compared with boys (37%, p

Published
2024
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8. Botulinum neurotoxin type A in the interdisciplinary treatment of sialorrhea in adults and children—update and practice recommendations

Author

Wolfgang H. Jost, Tobias Bäumer, Andrea Bevot, Ulrich Birkmann, Carsten Buhmann, Maria Grosheva, Orlando Guntinas-Lichius, Rainer Laskawi, Sebastian Paus, Christina Pflug, A. Sebastian Schroeder, Björn Spittau, Armin Steffen, Bernd Wilken, Martin Winterholler, and Steffen Berweck

Subjects
sialorrhea, botulinum toxin, botulinum neurotoxin type A, BoNT/A, IncobotulinumtoxinA, hypersalivation, Neurology. Diseases of the nervous system, RC346-429
Abstract

Sialorrhea is defined as a chronic excessive flow of saliva from the mouth, often with adverse consequences for health and quality of life of patients. In addition to currently used non-drug treatment and systemic drugs, intraglandular Botulinum Neurotoxin A (BoNT/A) injections have been examined in case studies, controlled trials and clinical practice. Two pivotal Phase III trials recently led to market approval in the USA and EU for IncobotulinumtoxinA [Xeomin®, IncoBoNT/A, Clostridium botulinum neurotoxin type A (150 kD), free from complexing proteins, Merz Pharmaceuticals GmbH] for treatment of chronic sialorrhea in adults and pediatric patients. This review provides a multidisciplinary approach to discuss the current state of sialorrhea therapy as well as benefits and current limitations of BoNT/A injections. A consensus regarding treatment recommendations made available to physicians in Germany in 2022 has now been updated here for presentation to an international audience. This review provides a framework including a flow chart for patient selection, recommendations for dosing and the injection process, as well as a discussion of therapeutic goals, long-term benefits and safety aspects. This review is aimed at supporting physicians in developing multidisciplinary and individualized treatment approaches to achieve optimal benefits for patients.

Published
2023
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11. Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders

Author

Langhammer, Franziska, Maroofian, Reza, Badar, Rueda, Gregor, Anne, Rochman, Michelle, Ratliff, Jeffrey B., Koopmans, Marije, Herget, Theresia, Hempel, Maja, Kortüm, Fanny, Heron, Delphine, Mignot, Cyril, Keren, Boris, Brooks, Susan, Botti, Christina, Ben-Zeev, Bruria, Argilli, Emanuela, Sherr, Elliot H., Gowda, Vykuntaraju K., Srinivasan, Varunvenkat M., Bakhtiari, Somayeh, Kruer, Michael C., Salih, Mustafa A., Kuechler, Alma, Muller, Eric A., Blocker, Karli, Kuismin, Outi, Park, Kristen L., Kochhar, Aaina, Brown, Kathleen, Ramanathan, Subhadra, Clark, Robin D., Elgizouli, Magdeldin, Melikishvili, Gia, Tabatadze, Nazhi, Stark, Zornitza, Mirzaa, Ghayda M., Ong, Jinfon, Grasshoff, Ute, Bevot, Andrea, von Wintzingerode, Lydia, Jamra, Rami A., Hennig, Yvonne, Goldenberg, Paula, Al Alam, Chadi, Charif, Majida, Boulouiz, Redouane, Bellaoui, Mohammed, Amrani, Rim, Al Mutairi, Fuad, Tamim, Abdullah M., Abdulwahab, Firdous, Alkuraya, Fowzan S., Khouj, Ebtissal M., Alvi, Javeria R., Sultan, Tipu, Hashemi, Narges, Karimiani, Ehsan G., Ashrafzadeh, Farah, Imannezhad, Shima, Efthymiou, Stephanie, Houlden, Henry, Sticht, Heinrich, and Zweier, Christiane

Published
2023
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12. Non-Invasive Quantitative Approximation of Intracranial Pressure in Pediatric Idiopathic Intracranial Hypertension Based on Point-of-Care Ultrasound of the Optic Nerve Sheath Diameter

Author

Susanne Regina Kerscher, Julian Zipfel, Andrea Bevot, Nico Sollmann, Karin Haas-Lude, Jonas Tellermann, and Martin Ulrich Schuhmann

Subjects
optic nerve sheath diameter, ONSD, ultrasound, idiopathic intracranial hypertension, ICP, mathematical approach, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Background: To investigate whether ultrasound-based optic nerve sheath diameter (US-ONSD) is a reliable measure to follow up children with idiopathic intracranial hypertension (IIH). In addition, to analyze the inter- and intra-individual relationships between US-ONSD and intracranial pressure (ICP), and to investigate whether an individualized mathematical regression equation obtained from two paired US-ONSD/ICP values can be used to approximate ICP from US-ONSD values. Methods: 159 US examinations and 53 invasive ICP measures via lumbar puncture (LP) were performed in 28 children with IIH. US-ONSD was measured using a 12 Mhz linear transducer and compared to ICP values. In 15 children, a minimum of 2 paired US-ONSD/ICP determinations were performed, and repeated-measures correlation (rmcorr) and intra-individual correlations were analyzed. Results: The cohort correlation between US-ONSD and ICP was moderate (r = 0.504, p < 0.01). Rmcorr (r = 0.91, p < 0.01) and intra-individual correlations (r = 0.956–1) of US-ONSD and ICP were excellent. A mathematical regression equation can be calculated from two paired US-ONSD/ICP values and applied to the individual patient to approximate ICP from US-ONSD. Conclusions: Related to excellent intra-individual correlations between US-ONSD and ICP, an individualized regression formula, created from two pairs of US-ONSD/ICP values, may be used to directly approximate ICP based on US-ONSD values. Hence, US-ONSD may become a non-invasive and reliable measure to control treatment efficacy in pediatric IIH.

Published
2023
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16. Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia

Author

Schröder, Simone, Li, Yun, Yigit, Gökhan, Altmüller, Janine, Bader, Ingrid, Bevot, Andrea, Biskup, Saskia, Dreha-Kulaczewski, Steffi, Christoph Korenke, G., Kottke, Raimund, Mayr, Johannes A., Preisel, Martin, Toelle, Sandra P., Wente-Schulz, Sarah, Wortmann, Saskia B., Hahn, Heidi, Boltshauser, Eugen, Uhmann, Anja, Wollnik, Bernd, and Brockmann, Knut

Published
2021
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18. Botulinum neurotoxin type A in the interdisciplinary treatment of sialorrhea in adults and children—update and practice recommendations

Author

Jost, Wolfgang H., primary, Bäumer, Tobias, additional, Bevot, Andrea, additional, Birkmann, Ulrich, additional, Buhmann, Carsten, additional, Grosheva, Maria, additional, Guntinas-Lichius, Orlando, additional, Laskawi, Rainer, additional, Paus, Sebastian, additional, Pflug, Christina, additional, Schroeder, A. Sebastian, additional, Spittau, Björn, additional, Steffen, Armin, additional, Wilken, Bernd, additional, Winterholler, Martin, additional, and Berweck, Steffen, additional

Published
2023
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26. Evaluating the safety of perioperative dexamethasone treatment: A retrospective analysis of a single center pediatric low‐grade glioma cohort

Author

David Gorodezki, Julian Zipfel, Manon Queudeville, Ursula Holzer, Andrea Bevot, Jens Schittenhelm, Thomas Nägele, Martin U. Schuhmann, and Martin Ebinger

Subjects
Cancer Research, Oncology
Abstract

In addition to surgical management, corticosteroids have proven to be beneficial in the management of acute symptoms related to CNS tumors, and have been widely used for many decades, with dexamethasone (DM) representing the most commonly used agent. However, lately published in vitro data possibly indicates a DM-induced suppression of oncogene-induced senescence (OIS) in a preclinical pediatric low-grade glioma (pLGG) model, which, alongside data associating perioperative DM treatment with reduced event-free survival in adult glioma, raises questions concerning the safety of DM treatment in pLGG. A total of 172 patients with pLGG were retrospectively analyzed concerning the impact of perioperative DM application on postoperative short- and long-term tumor growth velocity and progression-free survival (PFS). Three-dimensional volumetric analyses of sequential MRI follow-up examinations were used for assessment of tumor growth behavior. Mean follow-up period accounted for 60.1 months. Sixty-five patients (45%) were perioperatively treated with DM in commonly used doses. Five-year PFS accounted for 93% following gross-total resection (GTR) and 57% post incomplete resection (IR). Comparison of short- and long-term postoperative tumor growth rates in patients with vs without perioperative DM application showed no significant difference (short-term: 0.022 vs 0.023 cm

Published
2022

29. Resection extent and BRAF V600E mutation status determine postoperative tumor growth velocity in pediatric low-grade glioma: results from a single-center cohort analysis

Author

David Gorodezki, Julian Zipfel, Manon Queudeville, Jordana Sosa, Ursula Holzer, Jan Kern, Andrea Bevot, Jens Schittenhelm, Thomas Nägele, Martin Ebinger, and Martin U. Schuhmann

Subjects
Proto-Oncogene Proteins B-raf, Cohort Studies, Cancer Research, Neoplasm, Residual, Neurology, Oncology, Brain Neoplasms, Mutation, Humans, Glioma, Neurology (clinical), Child, Retrospective Studies
Abstract

Purpose Despite excellent long-term overall survival rates, pediatric low-grade gliomas (pLGG) show high variety of clinical behavior regarding progress or senescence post incomplete resection (IR). This study retrospectively analyzes tumor growth velocity (TGV) of pLGG before surgery and after IR to investigate the impact of surgical extent, tumor location and molecular BRAF status on postoperative residual tumor growth behavior. Methods Of a total of 172 patients with pLGG receiving surgical treatment, 107 underwent IR (66%). Fifty-three vs 94 patients could be included in the pre- and post-operative cohort, respectively, and were observed over a mean follow-up time of 40.2 vs 60.1 months. Sequential three-dimensional MRI-based tumor volumetry of a total of 407 MRI scans was performed to calculate pre- and postoperative TGV. Results Mean preoperative TGV of 0.264 cm3/month showed significant deceleration of tumor growth to 0.085 cm3/month, 0.024 cm3/month and −0.016 cm3/month after 1st, 2nd, and 3rd IR, respectively (p 2.03 cm3 associated with a higher risk of progress post IR (sensitivity 78,6%, specificity 76.3%, AUC 0.88). Postoperative TGV of BRAF V600E-mutant LGG was significantly higher than of BRAF wild-type LGG (0.123 cm3/month vs. 0.016 cm3/month, p = 0.047). Conclusion This data suggests that extensive surgical resection may impact pediatric LGG growth kinetics post incomplete resection by inducing a significant deceleration of tumor growth. BRAF-V600E mutation may be a risk factor for higher postoperative TGV.

Published
2022

30. Non-Invasive Quantitative Approximation of Intracranial Pressure in Pediatric Idiopathic Intracranial Hypertension Based on Point-of-Care Ultrasound of the Optic Nerve Sheath Diameter.

Author

Kerscher, Susanne Regina, Zipfel, Julian, Bevot, Andrea, Sollmann, Nico, Haas-Lude, Karin, Tellermann, Jonas, and Schuhmann, Martin Ulrich

Subjects
INTRACRANIAL hypertension, OPTIC nerve, INTRACRANIAL pressure, ULTRASONIC imaging, POINT-of-care testing
Abstract

Background: To investigate whether ultrasound-based optic nerve sheath diameter (US-ONSD) is a reliable measure to follow up children with idiopathic intracranial hypertension (IIH). In addition, to analyze the inter- and intra-individual relationships between US-ONSD and intracranial pressure (ICP), and to investigate whether an individualized mathematical regression equation obtained from two paired US-ONSD/ICP values can be used to approximate ICP from US-ONSD values. Methods: 159 US examinations and 53 invasive ICP measures via lumbar puncture (LP) were performed in 28 children with IIH. US-ONSD was measured using a 12 Mhz linear transducer and compared to ICP values. In 15 children, a minimum of 2 paired US-ONSD/ICP determinations were performed, and repeated-measures correlation (rmcorr) and intra-individual correlations were analyzed. Results: The cohort correlation between US-ONSD and ICP was moderate (r = 0.504, p < 0.01). Rmcorr (r = 0.91, p < 0.01) and intra-individual correlations (r = 0.956–1) of US-ONSD and ICP were excellent. A mathematical regression equation can be calculated from two paired US-ONSD/ICP values and applied to the individual patient to approximate ICP from US-ONSD. Conclusions: Related to excellent intra-individual correlations between US-ONSD and ICP, an individualized regression formula, created from two pairs of US-ONSD/ICP values, may be used to directly approximate ICP based on US-ONSD values. Hence, US-ONSD may become a non-invasive and reliable measure to control treatment efficacy in pediatric IIH. [ABSTRACT FROM AUTHOR]

Published
2024
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31. A further case of AFG2B‐related neurodevelopmental disorder with hearing loss and microcephaly allows further clarification of pathogenicity of the variant c.1313T>C, p.(Leu438Pro).

Author

Grosch, Sarah, Kehrer, Martin, Riess, Olaf, Bevot, Andrea, and Haack, Tobias B.

Subjects
HEARING disorders, EXOMES, SENSORINEURAL hearing loss, NEURAL development, MICROCEPHALY, GENETIC variation, AGENESIS of corpus callosum
Abstract

Background: Bi‐allelic variants in AFG2B (previously known as SPATA5L1) have recently been associated with a neurodevelopmental disorder with hearing loss and spasticity, as well as isolated hearing loss. We report on a 6 1/2‐year‐old girl with a history of global developmental delay, subsequent intellectual disability without relevant language acquisition, sensorineural hearing loss, muscular hypotonia and microcephaly. Methods: We performed trio exome sequencing on the patient and her parents. Results: Trio exome sequencing revealed likely pathogenic compound heterozygous missense variants in AFG2B [c.527G>T, p.(Gly176Val) and c.1313T>C, p.(Leu438Pro)] in the patient. Conclusion: Of note, the change c.1313T>C, p.(Leu438Pro) has been observed in a previously published patient as part of a complex disease allele along with a second homozygous missense change, so the exact contribution of the two alterations to this patient's disease had initially remained unclear. Our results support the pathogenic relevance of the c.1313T>C, p.(Leu438Pro) allele while providing detailed insights into the disease manifestation of a further patient. [ABSTRACT FROM AUTHOR]

Published
2024
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32. Long-Term Follow-Up of Pediatric Patients with Dyskinetic Cerebral Palsy and Deep Brain Stimulation

Author

Koy, Anne, Kühn, Andrea A, Schiller, Petra, Huebl, Julius, Schneider, Gerd-Helge, Eckenweiler, Matthias, Rensing-Zimmermann, Cornelia, Coenen, Volker Arnd, Krauss, Joachim K, Saryyeva, Assel, Hartmann, Hans, Lorenz, Delia, Volkmann, Jens, Matthies, Cordula, Schnitzler, Alfons, Vesper, Jan, Gharabaghi, Alireza, Weiss, Daniel, Bevot, Andrea, Marks, Warren, Howser, Angela, Monbaliu, Elegast, Mueller, Joerg, Prinz-Langenohl, Reinhild, Visser-Vandewalle, Veerle, Timmermann, Lars, and STIM-CP investigators

Subjects
dyskinetic cerebral palsy, children, prospective, trial, long-term effects, deep brain stimulation
Abstract

BACKGROUND: Deep brain stimulation (DBS) has been increasingly used in the management of dyskinetic cerebral palsy (DCP). Data on long-term effects and the safety profile are rare. OBJECTIVES: We assessed the efficacy and safety of pallidal DBS in pediatric patients with DCP. METHODS: The STIM-CP trial was a prospective, single-arm, multicenter study in which patients from the parental trial agreed to be followed-up for up to 36 months. Assessments included motor and non-motor domains. RESULTS: Of the 16 patients included initially, 14 (mean inclusion age 14 years) were assessed. There was a significant change in the (blinded) ratings of the total Dyskinesia Impairment Scale at 36 months. Twelve serious adverse events (possibly) related to treatment were documented. CONCLUSION: DBS significantly improved dyskinesia, but other outcome parameters did not change significantly. Investigations of larger homogeneous cohorts are needed to further ascertain the impact of DBS and guide treatment decisions in DCP. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. ispartof: Mov Disord ispartof: location:United States status: Published online

Published
2023

35. Genotype–phenotype correlation and treatment effects in young patients withGNAO1-associated disorders

Author

Thiel, Moritz, primary, Bamborschke, Daniel, additional, Janzarik, Wibke G., additional, Assmann, Birgit, additional, Zittel, Simone, additional, Patzer, Steffi, additional, Auhuber, Andrea, additional, Opp, Joachim, additional, Matzker, Eva, additional, Bevot, Andrea, additional, Seeger, Juergen, additional, van Baalen, Andreas, additional, Stüve, Burkhard, additional, Brockmann, Knut, additional, Cirak, Sebahattin, additional, and Koy, Anne, additional

Published
2023
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36. Next-generation phenotyping integrated in a national framework for patients with ultra-rare disorders improves genetic diagnostics and yields new molecular findings

Author

Schmidt, Axel, primary, Danyel, Magdalena, additional, Grundmann, Kathrin, additional, Brunet, Theresa, additional, Klinkhammer, Hannah, additional, Hsieh, Tzung-Chien, additional, Engels, Hartmut, additional, Peters, Sophia, additional, Knaus, Alexej, additional, Moosa, Shahida, additional, Averdunk, Luisa, additional, Boschann, Felix, additional, Sczakiel, Henrike, additional, Schwartzmann, Sarina, additional, Mensah, Martin Atta, additional, Pantel, Jean Tori, additional, Holtgrewe, Manuel, additional, Boesch, Annemarie, additional, Weiss, Claudia, additional, Weinhold, Natalie, additional, Suter, Aude-Annick, additional, Stoltenburg, Corinna, additional, Neugebauer, Julia, additional, Kallinich, Tillmann, additional, Kaindl, Angela M., additional, Holzhauer, Susanne, additional, Buehrer, Christoph, additional, Bufler, Philip, additional, Kornak, Uwe, additional, Ott, Claus-Eric, additional, Schuelke, Markus, additional, Nguyen, Hoa Huu Phuc, additional, Hoffjan, Sabine, additional, Grasemann, Corinna, additional, Rothoeft, Tobias, additional, Brinkmann, Folke, additional, Matar, Nora, additional, Sivalingam, Sugirthan, additional, Perne, Claudia, additional, Mangold, Elisabeth, additional, Kreiss, Martina, additional, Cremer, Kirsten, additional, Betz, Regina C., additional, Bender, Tim, additional, Muecke, Martin, additional, Grigull, Lorenz, additional, Klockgether, Thomas, additional, Isabel, Spier, additional, Heimbach, Andre, additional, Tim, Bender, additional, Brand, Fabian, additional, Stieber, Christiane, additional, Morawiec, Alexandra Marzena, additional, Karakostas, Pantelis, additional, Schaefer, Valentin S., additional, Bernsen, Sarah, additional, Weydt, Patrick, additional, Castro-Gomez, Sergio, additional, Aziz, Ahmad, additional, Grobe-Einsler, Marcus, additional, Kimmich, Okka, additional, Kobeleva, Xenia, additional, oender, Demet, additional, Lesmann, Hellen, additional, Kumar, Sheetal, additional, Tacik, Pawel, additional, Lee-Kirsch, Min Ae, additional, Berner, Reinhard, additional, Schuetz, Catharina, additional, Koerholz, Julia, additional, Kretschmer, Tanita, additional, Di Donato, Nataliya, additional, Schroeck, Evelin, additional, Heinen, Andre, additional, Reuner, Ulrike, additional, Hansske, Amalia-Mihaela, additional, Kaiser, Frank J., additional, Manka, Eva, additional, Munteanu, Martin, additional, Kuechler, Alma, additional, Cordula, Kiewert, additional, Hirtz, Raphael, additional, Schlapakow, Elena, additional, Schlein, Christian, additional, Lisfeld, Jasmin, additional, Kubisch, Christian, additional, Herget, Theresia, additional, Hempel, Maja, additional, Weiler-Normann, Christina, additional, Ullrich, Kurt, additional, Schramm, Christoph, additional, Rudolph, Cornelia, additional, Rillig, Franziska, additional, Groffmann, Maximilian, additional, Muntau, Ania, additional, Tibelius, Alexandra, additional, Schwaibold, Eva M. C., additional, Schaaf, Christian P., additional, Zawada, Michal, additional, Kaufmann, Lilian, additional, Hinderhofer, Katrin, additional, Okun, Pamela M., additional, Kotzaeridou, Urania, additional, Hoffmann, Georg F., additional, Choukair, Daniela, additional, Bettendorf, Markus, additional, Spielmann, Malte, additional, Ripke, Annekatrin, additional, Pauly, Martje, additional, Muenchau, Alexander, additional, Lohmann, Katja, additional, Huening, Irina, additional, Hanker, Britta, additional, Baeumer, Tobias, additional, Herzog, Rebecca, additional, Hellenbroich, Yorck, additional, Westphal, Dominik S., additional, Strom, Tim, additional, Kovacs, Reka, additional, Riedhammer, Korbinian M., additional, Mayerhanser, Katharina, additional, Graf, Elisabeth, additional, Brugger, Melanie, additional, Hoefele, Julia, additional, Oexle, Konrad, additional, Mirza-Schreiber, Nazanin, additional, Berutti, Riccardo, additional, Schatz, Ulrich, additional, Krenn, Martin, additional, Makowski, Christine, additional, Weigand, Heike, additional, Schroeder, Sebastian, additional, Rohlfs, Meino, additional, Katharina, Vill, additional, Hauck, Fabian, additional, Borggraefe, Ingo, additional, Mueller-Felber, Wolfgang, additional, Kurth, Ingo, additional, Elbracht, Miriam, additional, Knopp, Cordula, additional, Begemann, Matthias, additional, Kraft, Florian, additional, Lemke, Johannes, additional, Hentschel, Julia, additional, Platzer, Konrad, additional, Strehlow, Vincent, additional, Abou Jamra, Rami, additional, Kehrer, Martin, additional, Demidov, German, additional, Beck-Woedl, Stefanie, additional, Graessner, Holm, additional, Sturm, Marc, additional, Zeltner, Lena, additional, Schoels, Ludger J., additional, Magg, Janine, additional, Bevot, Andrea, additional, Kehrer, Christiane, additional, Kaiser, Nadja, additional, Horn, Denise, additional, Grueters-Kieslich, Annette, additional, Klein, Christoph, additional, Mundlos, Stefan, additional, Noethen, Markus, additional, Riess, Olaf, additional, Meitinger, Thomas, additional, Krude, Heiko, additional, Krawitz, Peter M., additional, Haack, Tobias, additional, Ehmke, Nadja, additional, and Wagner, Matias, additional

Published
2023
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38. Next-generation phenotyping integrated in a national framework for patients with ultra-rare disorders improves genetic diagnostics and yields new molecular findings

Author

Axel Schmidt, Magdalena Danyel, Kathrin Grundmann, Theresa Brunet, Hannah Klinkhammer, Tzung-Chien Hsieh, Hartmut Engels, Sophia Peters, Alexej Knaus, Shahida Moosa, Luisa Averdunk, Felix Boschann, Henrike Sczakiel, Sarina Schwartzmann, Martin Atta Mensah, Jean Tori Pantel, Manuel Holtgrewe, Annemarie Bösch, Claudia Weiß, Natalie Weinhold, Aude-Annick Suter, Corinna Stoltenburg, Julia Neugebauer, Tillmann Kallinich, Angela M. Kaindl, Susanne Holzhauer, Christoph Bührer, Philip Bufler, Uwe Kornak, Claus-Eric Ott, Markus Schülke, Hoa Huu Phuc Nguyen, Sabine Hoffjan, Corinna Grasemann, Tobias Rothoeft, Folke Brinkmann, Nora Matar, Sugirthan Sivalingam, Claudia Perne, Elisabeth Mangold, Martina Kreiss, Kirsten Cremer, Regina C. Betz, Tim Bender, Martin Mücke, Lorenz Grigull, Thomas Klockgether, Spier Isabel, Heimbach André, Bender Tim, Fabian Brand, Christiane Stieber, Alexandra Marzena Morawiec, Pantelis Karakostas, Valentin S. Schäfer, Sarah Bernsen, Patrick Weydt, Sergio Castro-Gomez, Ahmad Aziz, Marcus Grobe-Einsler, Okka Kimmich, Xenia Kobeleva, Demet Önder, Hellen Lesmann, Sheetal Kumar, Pawel Tacik, Min Ae Lee-Kirsch, Reinhard Berner, Catharina Schuetz, Julia Körholz, Tanita Kretschmer, Nataliya Di Donato, Evelin Schröck, André Heinen, Ulrike Reuner, Amalia-Mihaela Hanßke, Frank J. Kaiser, Eva Manka, Martin Munteanu, Alma Kuechler, Kiewert Cordula, Raphael Hirtz, Elena Schlapakow, Christian Schlein, Jasmin Lisfeld, Christian Kubisch, Theresia Herget, Maja Hempel, Christina Weiler-Normann, Kurt Ullrich, Christoph Schramm, Cornelia Rudolph, Franziska Rillig, Maximilian Groffmann, Ania Muntau, Alexandra Tibelius, Eva M. C. Schwaibold, Christian P. Schaaf, Michal Zawada, Lilian Kaufmann, Katrin Hinderhofer, Pamela M. Okun, Urania Kotzaeridou, Georg F. Hoffmann, Daniela Choukair, Markus Bettendorf, Malte Spielmann, Annekatrin Ripke, Martje Pauly, Alexander Münchau, Katja Lohmann, Irina Hüning, Britta Hanker, Tobias Bäumer, Rebecca Herzog, Yorck Hellenbroich, Dominik S. Westphal, Tim Strom, Reka Kovacs, Korbinian M. Riedhammer, Katharina Mayerhanser, Elisabeth Graf, Melanie Brugger, Julia Hoefele, Konrad Oexle, Nazanin Mirza-Schreiber, Riccardo Berutti, Ulrich Schatz, Martin Krenn, Christine Makowski, Heike Weigand, Sebastian Schröder, Meino Rohlfs, Vill Katharina, Fabian Hauck, Ingo Borggraefe, Wolfgang Müller-Felber, Ingo Kurth, Miriam Elbracht, Cordula Knopp, Matthias Begemann, Florian Kraft, Johannes R. Lemke, Julia Hentschel, Konrad Platzer, Vincent Strehlow, Rami Abou Jamra, Martin Kehrer, German Demidov, Stefanie Beck-Wödl, Holm Graessner, Marc Sturm, Lena Zeltner, Ludger J. Schöls, Janine Magg, Andrea Bevot, Christiane Kehrer, Nadja Kaiser, Denise Horn, Annette Grüters-Kieslich, Christoph Klein, Stefan Mundlos, Markus Nöthen, Olaf Riess, Thomas Meitinger, Heiko Krude, Peter M. Krawitz, Tobias Haack, Nadja Ehmke, and Matias Wagner

Abstract

Most individuals with rare diseases initially consult their primary care physician. For a subset of rare diseases, efficient diagnostic pathways are available. However, ultra-rare diseases often require both expert clinical knowledge and comprehensive genetic diagnostics, which poses structural challenges for public healthcare systems. To address these challenges within Germany, a novel structured diagnostic concept, based on multidisciplinary expertise at established university hospital centers for rare diseases (CRDs), was evaluated in the three year prospective study TRANSLATE NAMSE. A key goal of TRANSLATE NAMSE was to assess the clinical value of exome sequencing (ES) in the ultra-rare disease population. The aims of the present study were to perform a systematic investigation of the phenotypic and molecular genetic data of TRANSLATE NAMSE patients who had undergone ES in order to determine the yield of both ultra-rare diagnoses and novel gene-disease associations; and determine whether the complementary use of machine learning and artificial intelligence (AI) tools improved diagnostic effectiveness and efficiency.ES was performed for 1,577 patients (268 adult and 1,309 pediatric). Molecular genetic diagnoses were established in 499 patients (74 adult and 425 pediatric). A total of 370 distinct molecular genetic causes were established. The majority of these concerned known disorders, most of which were ultra-rare. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were delineated, mainly in individuals with neurodevelopmental disorders.To determine the likelihood that ES will lead to a molecular diagnosis in a given patient, based on the respective clinical features only, we developed a statistical framework called YieldPred. The genetic data of a subcohort of 224 individuals that also gave consent to the computer-assisted analysis of their facial images were processed with the AI tool Prioritization of Exome Data by Image Analysis (PEDIA) and showed superior performance in variant prioritization.The present analyses demonstrated that the novel structured diagnostic concept facilitated the identification of ultra-rare genetic disorders and novel gene-disease associations on a national level and that the machine learning and AI tools improved diagnostic effectiveness and efficiency for ultra-rare genetic disorders.

Published
2023

39. Chronic Pleural Effusion in Ventriculoperitoneal Shunt due to Diaphragmatic CSF Fistula. Report of a case treated by Endoscopic Choroid Plexus Coagulation and literature review

Author

Simon Schmid, Andrea Bevot, Felix Neunhoeffer, Jörg Michel, Matthias Kumpf, Matthias Reimold, Michael Hofbeck, and Martin Schuhmann

Subjects
Pediatrics, Perinatology and Child Health, Surgery, Neurology (clinical), General Medicine
Abstract

Chronic pleural cerebrospinal fluid (CSF) effusion is a rare complication after ventriculoperitoneal (VP) shunt insertion and only 18 cases in children and adults have been described so far without catheter dislocation to the intrathoracic cavity. We report on a 4-year-old girl with a complex history of underlying neurogenetic disorder, a hypoxic ischemic encephalopathy after influenza A Infection with septic shock and severe acute respiratory distress syndrome, followed by meningitis at the age of 10 months. In consequence she developed a severe cerebral atrophy and postmeningitic hydrocephalus requiring placement of a VP shunt. At age 4 she was admitted with community acquired mycoplasma pneumonia and developed increasing pleural effusions leading to severe respiratory distress and requiring continuous chest tube drainage (up to 1000 -1400 ml/day), that could not be weaned. ß trace protein, in CSF present at concentrations > 6 mg/l, was found in the pleural fluid at low concentrations of 2.7 mg/l. An abdomino-thoracic CSF fistula was finally proven by single photon emission computerized tomography combined with low dose computer tomography. After shunt externalization, the pleural effusion stopped and the chest tube was removed. CSF production rate remain high above 500 ml/24h. An atrial CSF shunt could not be placed, since a hemodynamically relevant atrial septum defect with frail circulatory balance would not have tolerated the large CSF volumes. Therefore, she underwent a total bilateral endoscopic choroid plexus laser coagulation (CPC) within the lateral ventricles via bi-occipital burr holes. Postoperatively CSF production rate went close to 0 ml and after external ventricular drain removal no signs and symptoms of hydrocephalus developed during a follow-up of now 2.5 years. In summary, pleural effusions in patients with VP shunt can rarely be caused by an abdomino-thoracic fistula, with non-elevated ß trace protein in the pleural fluid. The majority of reported cases in literature were treated by ventriculo-atrial shunt. This is the 2nd reported case, which has been successfully treated by radical CPC alone including the temporal horn choroid plexus, making the child shunt independent.

Published
2023

40. Behandlung der Sialorrhoe mit Botulinum Neurotoxin Typ A – Konsentierte Praxisempfehlungen für Kinder und Erwachsene

Author

Wolfgang H. Jost, Tobias Bäumer, Andrea Bevot, Ulrich Birkmann, Carsten Buhmann, Maria Grosheva, Orlando Guntinas-Lichius, Ute Mlynczak, Sebastian Paus, Christina Pflug, Sebastian Schröder, Armin Steffen, Bernd Wilken, and Steffen Berweck

Subjects
Psychiatry and Mental health, Neurology, Neurology (clinical)
Abstract

ZusammenfassungSialorrhoe, ein unkontrollierter, übermäßiger Speichelfluss aus dem Mund und in den Schlund, tritt als Begleitsymptom bei verschiedenen, v. a. neurologischen Erkrankungen im Kindes- und Erwachsenenalter auf. Mit IncobotulinumtoxinA (Xeomin, IncoBoNT/A, Merz Pharmaceuticals GmbH) steht seit 2019 ein zugelassenes Medikament für die Behandlung der Sialorrhoe zur Verfügung. Indikationsstellung, mögliche Therapieziele, Praxis der Behandlung und Management in besonderen Behandlungssituationen bilden den Schwerpunkt dieser konsentierten Praxis-Empfehlungen, die in interdisziplinärer Zusammenarbeit erfahrener Anwender entwickelt wurden. Ziel ist, den Zugang zur Therapie zu erleichtern und einen Beitrag zu einer qualifizierten Botulinumtoxin-Therapie zu leisten.

Published
2022

41. Genotype-phenotype correlation and treatment effects in young patients with GNAO1-associated disorders.

Author

Thiel, Moritz, Bamborschke, Daniel, Janzarik, Wibke G., Assmann, Birgit, Zittel, Simone, Patzer, Steffi, Auhuber, Andrea, Opp, Joachim, Matzker, Eva, Bevot, Andrea, Seeger, Juergen, van Baalen, Andreas, Stüve, Burkhard, Brockmann, Knut, Cirak, Sebahattin, and Koy, Anne

Subjects
EPILEPSY, MEDICAL ethics, AMINO acid sequence, CELLULAR signal transduction, NASOENTERAL tubes, PROTEIN structure prediction
Published
2023
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44. Solving unsolved rare neurological diseases-a Solve-RD viewpoint

Author

Schüle, Rebecca, Timmann, Dagmar, Erasmus, Corrie E., Reichbauer, Jennifer, Wayand, Melanie, Solve-RD-DITF-RND Baets Jonathan Balicza Peter Chinnery Patrick Dürr Alexandra Haack Tobias Hengel Holger Horvath Rita Houlden Henry Kamsteeg Erik-Jan Kamsteeg Christoph Lohmann Katja Macaya Alfons Marcé-Grau Anna Maver Ales Molnar Judit Münchau Alexander Peterlin Borut Riess Olaf Schöls Ludger European Reference Network for Rare Neurological Diseases, Tübingen, Germany Schüle Rebecca European Reference Network for Rare Neurological Diseases, Tübingen, Germany Stevanin Giovanni Synofzik Matthis European Reference Network for Rare Neurological Diseases, Tübingen, Germany Timmerman Vincent van de Warrenburg Bart Department of Neurology, Donders Centre for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands van Os Nienke Vandrovcova Jana Wayand Melanie German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany Wilke Carlo German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany, Baets, Jonathan, Balicza, Peter, Chinnery, Patrick, Dürr, Alexandra, Haack, Tobias, Hengel, Holger, Horvath, Rita, Houlden, Henry, Kamsteeg, Erik-Jan, Kamsteeg, Christoph, Lohmann, Katja, Macaya, Alfons, Marcé-Grau, Anna, Maver, Ales, Molnar, Judit, Münchau, Alexander, Peterlin, Borut, Riess, Olaf, Schöls, Ludger, Stevanin, Giovanni, Synofzik, Matthis, Timmerman, Vincent, van de Warrenburg, Bart, van Os, Nienke, Vandrovcova, Jana, Wilke, Carlo, Bevot, Andrea, Zuchner, Stephan, Beltran, Sergi, Laurie, Steven, Matalonga, Leslie, Graessner, Holm, The Solve-RD Consortium Graessner Holm Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany Zurek Birte Ellwanger Kornelia Ossowski Stephan Demidov German Sturm Marc Schulze-Hentrich Julia M. Heutink Peter Brunner Han Scheffer Hans Hoogerbrugge Nicoline Hoischen Alexander ’t Hoen Peter A. C. Vissers Lisenka E. L. M. Gilissen Christian Steyaert Wouter Sablauskas Karolis de Voer Richarda M. Janssen Erik de Boer Elke Steehouwer Marloes Yaldiz Burcu Kleefstra Tjitske Brookes Anthony J. Veal Colin Gibson Spencer Wadsley Marc Mehtarizadeh Mehdi Riaz Umar Warren Greg Dizjikan Farid Yavari Shorter Thomas Töpf Ana Straub Volker Bettolo Chiara Marini Specht Sabine Clayton-Smith Jill Banka Siddharth Alexander Elizabeth Jackson Adam Faivre Laurence Thauvin Christel Vitobello Antonio Denommé-Pichon Anne-Sophie Duffourd Yannis Tisserant Emilie Bruel Ange-Line Peyron Christine Pélissier Aurore Beltran Sergi Facultat de Biologia, Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona (UB), Barcelona, Spain Gut Ivo Glynne Laurie Steven CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain Piscia Davide Matalonga Leslie CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain Papakonstantinou Anastasios Bullich Gemma Corvo Alberto Garcia Carles Fernandez-Callejo Marcos Hernández Carles Picó Daniel Paramonov Ida Lochmüller Hanns Gumus Gulcin Bros-Facer Virginie Rath Ana Hanauer Marc Olry Annie Lagorce David Havrylenko Svitlana Izem Katia Rigour Fanny Durr Alexandra Davoine Claire-Sophie Guillot-Noel Léna Heinzmann Anna Coarelli Giulia Bonne Gisèle Evangelista Teresinha Allamand Valérie Nelson Isabelle Yaou Rabah Ben Metay Corinne Eymard Bruno Cohen Enzo Atalaia Antonio Stojkovic Tanya Macek Milan Jr. Turnovec Marek Thomasová Dana Kremliková Radka Pourová Franková Vera Havlovicová Markéta Kremlik Vlastimil Parkinson Helen Keane Thomas Spalding Dylan Senf Alexander Robinson Peter Danis Daniel Robert Glenn Costa Alessia Patch Christine Hanna Mike Houlden Henry Reilly Mary Vandrovcova Jana Muntoni Francesco Zaharieva Irina Sarkozy Anna de Jonghe Peter Nigro Vincenzo Banfi Sandro Torella Annalaura Musacchia Francesco Piluso Giulio Ferlini Alessandra Selvatici Rita Rossi Rachele Neri Marcella Aretz Stefan Spier Isabel Sommer Anna Katharina Peters Sophia Oliveira Carla Pelaez Jose Garcia Matos Ana Rita José Celina São Ferreira Marta Gullo Irene Fernandes Susana Garrido Luzia Ferreira Pedro Carneiro Fátima Swertz Morris A. Johansson Lennart van der Velde Joeri K. van der Vries Gerben Neerincx Pieter B. Roelofs-Prins Dieuwke Köhler Sebastian Metcalfe Alison Verloes Alain Drunat Séverine Rooryck Caroline Trimouille Aurelien Castello Raffaele Morleo Manuela Pinelli Michele Varavallo Alessandra De la Paz Manuel Posada Sánchez Eva Bermejo Martín Estrella López Delgado Beatriz Martínez de la Rosa F. Javier Alonso García Ciolfi Andrea Dallapiccola Bruno Pizzi Simone Radio Francesca Clementina Tartaglia Marco Renieri Alessandra Benetti Elisa Balicza Peter Molnar Maria Judit Maver Ales Peterlin Borut Münchau Alexander Lohmann Katja Herzog Rebecca Pauly Martje Macaya Alfons Marcé-Grau Anna Osorio Andres Nascimiento de Benito Daniel Natera Lochmüller Hanns Thompson Rachel Polavarapu Kiran Beeson David Cossins Judith Cruz Pedro M. Rodriguez Hackman Peter Johari Mridul Savarese Marco Udd Bjarne Horvath Rita Capella Gabriel Valle Laura Holinski-Feder Elke Laner Andreas Steinke-Lange Verena Schröck Evelin Rump Andreas, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, Hoischen, Alexander, ’t Hoen, Peter A. C., Vissers, Lisenka E. L. M., Gilissen, Christian, Steyaert, Wouter, Sablauskas, Karolis, de Voer, Richarda M., Janssen, Erik, de Boer, Elke, Steehouwer, Marloes, Yaldiz, Burcu, Kleefstra, Tjitske, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Wadsley, Marc, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Töpf, Ana, Straub, Volker, Bettolo, Chiara Marini, Specht, Sabine, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Vitobello, Antonio, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Tisserant, Emilie, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Gut, Ivo Glynne, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Garcia, Carles, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Paramonov, Ida, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Olry, Annie, Lagorce, David, Havrylenko, Svitlana, Izem, Katia, Rigour, Fanny, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Cohen, Enzo, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Kremlik, Vlastimil, Parkinson, Helen, Keane, Thomas, Spalding, Dylan, Senf, Alexander, Robinson, Peter, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Reilly, Mary, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, de Jonghe, Peter, Nigro, Vincenzo, Banfi, Sandro, Torella, Annalaura, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Velde, Joeri K., van der Vries, Gerben, Neerincx, Pieter B., Roelofs-Prins, Dieuwke, Köhler, Sebastian, Metcalfe, Alison, Verloes, Alain, Drunat, Séverine, Rooryck, Caroline, Trimouille, Aurelien, Castello, Raffaele, Morleo, Manuela, Pinelli, Michele, Varavallo, Alessandra, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F. Javier Alonso García, Ciolfi, Andrea, Dallapiccola, Bruno, Pizzi, Simone, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Benetti, Elisa, Molnar, Maria Judit, Herzog, Rebecca, Pauly, Martje, Osorio, Andres Nascimiento, de Benito, Daniel Natera, Thompson, Rachel, Polavarapu, Kiran, Beeson, David, Cossins, Judith, Cruz, Pedro M. Rodriguez, Hackman, Peter, Johari, Mridul, Savarese, Marco, Udd, Bjarne, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Solve-RD-DITF-RND, Solve-RD Consortium, Schule, R., Timmann, D., Erasmus, C. E., Reichbauer, J., Wayand, M., van de Warrenburg, B., Schols, L., Wilke, C., Bevot, A., Zuchner, S., Beltran, S., Laurie, S., Matalonga, L., Graessner, H., Synofzik, M., Nigro, V., Banfi, S., Torella, A., Piluso, G., Medicum, University of Helsinki, Department of Medical and Clinical Genetics, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Wilke, Carlo [0000-0002-7250-8597], Beltran, Sergi [0000-0002-2810-3445], Laurie, Steven [0000-0003-3913-5829], Graessner, Holm [0000-0001-9803-7183], Synofzik, Matthis [0000-0002-2280-7273], and Apollo - University of Cambridge Repository

Subjects
genetics [Rare Diseases], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Medizin, Datasets as Topic, 0302 clinical medicine, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Medicine, Genetics (clinical), 0303 health sciences, methods [Genomics], Management science, Neurodevelopmental disorders, Neurodegenerative diseases, 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Genomics, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], genetics [Nervous System Diseases], 3. Good health, Chemistry, Practice Guidelines as Topic, Malalties rares, pathology [Rare Diseases], methods [Genetic Testing], Movement disorders, Other Research Donders Center for Medical Neuroscience [Radboudumc 0], Socio-culturale, standards [Exome Sequencing], standards [Genetic Testing], pathology [Nervous System Diseases], 03 medical and health sciences, Rare Diseases, Viewpoint, Exome Sequencing, Genetics, Humans, Genetic Testing, ddc:610, Biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Sistema nerviós -- Malalties, methods [Exome Sequencing], standards [Genomics], 3111 Biomedicine, Human medicine, Nervous System Diseases, business, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], 030217 neurology & neurosurgery
Abstract

Rare genetic neurological disorders (RND; ORPHA:71859) are a heterogeneous group of disorders comprising >1700 distinct genetic disease entities. However, genetic discoveries have not yet translated into dramatic increases of diagnostic yield and indeed rates of molecular genetic diagnoses have been stuck at about 30–50% across NGS modalities and RND phenotypes [1, 2]. Existence of yet unknown disease genes as well as shortcomings of commonly employed NGS technologies and analysis pipelines in detecting certain variant types are typically cited to explain the low diagnosis rates. To increase the diagnostic yield in RNDs - one of the four focus disease groups in Solve-RD - we follow two major approaches, that we will here present and exemplify: (i) systematic state-of the art re-analysis of large cohorts of unsolved whole-exome/genome sequencing (WES/WGS) RND datasets; and (ii) novel-omics approaches. Based on the way Solve-RD systematically organizes researchers’ expertise to channel this approach [3], the European Reference Network for Rare Neurological Diseases (ERN-RND) has established its own Data Interpretation Task Force (DITF) within SOLVE-RD, which is currently composed of clinical and genetic experts from 29 sites in 15 European countries. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 779257. Data were analysed using the RD‐Connect Genome‐Phenome Analysis Platform, which received funding from EU projects RD‐Connect, Solve-RD and EJP-RD (Grant Numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (Grant Numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática, INB) and ELIXIR Implementation Studies. The study was further funded by the Federal Ministry of Education and Research, Germany, through the TreatHSP network (01GM1905 to RS and LS), the National Institute of Neurological Diseases and Stroke (R01NS072248 to SZ and RS), the European Joint Program on Rare Diseases-EJP-RD COFUND-EJP N° 825575 through funding for the PROSPAX consortium (441409627 to MS, RS and BvW). CW was supported by the PATE program of the Medical Faculty, University of Tübingen. CEE received support from the Dutch Princess Beatrix Muscle Fund and the Dutch Spieren voor Spieren Muscle fund. Authors on this paper are members of the European Reference Network for Rare Neurological Diseases (ERN-RND, Project ID 739510)

Published
2021

45. 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, Kirschner, Janbernd, Ameshofer, Lisa, Andres, Barbara, Angelova-Toshkina, Daniela, Banholzer, Daniela, Bant, Christina, Baum, Petra, Baumann, Sandra, Baur, Ute, Becker, Benedikt, Behring, Bettina, Bellut, Julia, Bevot, Andrea, Bischofberger, Jasmin, Bitzan, Lisa, Bjelica, Bogdan, Blankenburg, Markus, Böger, Sandra, Bonetti, Friederike, Bongartz, Anke, Brakemeier, Svenja, Bratka, Lisa, Braun, Nathalie, Braun, Sarah, Brauner, Brigitte, Bretschneider, Christa, Burgenmeister, Nadine, Burke, Bea, Cirak, Sebahattin, Dall, Andrea, de Vries, Heike, Marina, Adela Della, Denecke, Jonas, Deschauer, Marcus, Dibrani, Zylfie, Diebold, Uta, Dondit, Lutz, Drebes, Jessica, Driemeyer, Joenna, Dukic, Vladimir, Eckenweiler, Matthias, Eminger, Mirjam, Fischer, Michal, Fischer, Cornelia, Freigang, Maren, Gaiser, Philippa, Gangfuß, Andrea, Geitmann, Stephanie, George, Annette, Gosk-Tomek, Magdalena, Grinzinger, Susanne, Gröning, Kristina, Groß, Martin, Güttsches, Anne-Katrin, Hagenmeyer, Anna, Hartmann, Hans, Haverkamp, Julia, Hiebeler, Miriam, Hoevel, Annegret, Hoffmann, Georg Friedrich, Holtkamp, Britta, Holzwarth, Dorothea, Homma, Annette, Horneff, Viola, Hörnig, Carolin, Hotter, Anna, Hubert, Andrea, Huppke, Peter, Jansen, Eva, Jung, Lisa, Kaiser, Nadja, Kappel, Stefan, Katharina, Bolte, Koch, Johannes, Kölke, Stefan, Korschinsky, Brigitte, Kostede, Franziska, Krause, Karsten, Küpper, Hanna, Lang, Annina, Lange, Irene, Langer, Thorsten, Lechner, Yvonne, Lehmann, Helmar, Leypold, Christine, Lingor, Paul, Lipka, Jaqueline, Löscher, Wolfgang, Luiking, Antje, Machetanz, Gerrit, Malm, Eva, Martakis, Kyriakos, Menzen, Bettina, Metelmann, Moritz, Meyer zu Hörste, Gerd, Montagnese, Federica, Mörtlbauer, Kathrin, Müller, Petra, Müller, Anne, Müller, Anja, Müschen, Lars, Neuwirth, Christoph, Niesert, Moritz, Pauschek, Josefine, Pernegger, Elke, Petri, Susanne, Pilshofer, Veronika, Plecko, Barbara, Pollok, Jürgen, Preisel, Martin, Pühringer, Manuel, Quinten, Anna Lisa, Raffler, Sabine, Ramadan, Barbara, Rappold, Mika, Rauscher, Christian, Reckmann, Kerstin, Reinhardt, Tabea, Röder, Melanie, Roland-Schäfer, Doris, Roth, Erdmute, Ruß, Lena, Saffari, Afshin, Schimmel, Mareike, Schlag, Melina, Schlotter-Weigel, Beate, Schneider, Joanna, Schöne-Bake, Jan-Christoph, Schorling, David, Schreiner, Isabella, Schüssler, Stephanie, Schwarzbach, Michaela, Schwippert, Michaela, Semmler, Luisa, Smuda, Karin, Sprenger-Svacina, Alina, Stadler, Theresa, Steffens, Paula, Steuernagel, Daniela, Stolte, Benjamin, Stoltenburg, Corinna, Tasch, Gehrke, Thimm, Andreas, Tiefenthaler, Elke, Topakian, Raffi, Türk, Matthias, van der Stam, Lieske, Vettori, Katia, Vollmann, Peter, Vorgerd, Matthias, Weiss, Deike, Wenninger, Stephan, Werring, Svea, Wessel, Maria, Weyen, Ute, Wider, Sabine, Wiebe, Nils Ole, Wiesenhofer, Anna, Wiethoff, Sarah, Wirner, Corinna, Wohnrade, Camilla, Wunderlich, Gilbert, Zeller, Daniel, Zemlin, Michael, and Zobel, Joachim

Subjects
Medizin, Pharmacology (medical), General Medicine, ddc:610, Genetics (clinical)
Abstract

Background The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months. Methods SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Results Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score. Conclusion Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity.

Published
2022

47. ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies

Author

Morava, Eva, Tiemes, Vera, Thiel, Christian, Seta, Nathalie, de Lonlay, Pascale, de Klerk, Hans, Mulder, Margot, Rubio-Gozalbo, Estela, Visser, Gepke, van Hasselt, Peter, Horovitz, Dafne D. G., de Souza, Carolina Fischinger Moura, Schwartz, Ida V. D., Green, Andrew, Al-Owain, Mohammed, Uziel, Graciella, Sigaudy, Sabine, Chabrol, Brigitte, van Spronsen, Franc-Jan, Steinert, Martin, Komini, Eleni, Wurm, Donald, Bevot, Andrea, Ayadi, Addelkarim, Huijben, Karin, Dercksen, Marli, Witters, Peter, Jaeken, Jaak, Matthijs, Gert, Lefeber, Dirk J., and Wevers, Ron A.

Published
2016
Full Text
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48. LGG-51. Resection extent and BRAF V600E mutation status determine postoperative growth velocity in pediatric Low-grade glioma: Results from a single-center cohort analysis

Author

Gorodezki, David, primary, Sosa, Jordana, additional, Holzer, Ursula, additional, Queudeville, Manon, additional, Zipfel, Julian, additional, Bevot, Andrea, additional, Schittenhelm, Jens, additional, Nägele, Thomas, additional, Ebinger, Martin, additional, and Schuhmann, Martin, additional

Published
2022
Full Text
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49. Genotype–phenotype correlation and treatment effects in young patients withGNAO1-associated disorders

Author

Moritz Thiel, Daniel Bamborschke, Wibke G. Janzarik, Birgit Assmann, Simone Zittel, Steffi Patzer, Andrea Auhuber, Joachim Opp, Eva Matzker, Andrea Bevot, Juergen Seeger, Andreas van Baalen, Burkhard Stüve, Knut Brockmann, Sebahattin Cirak, and Anne Koy

Subjects
Psychiatry and Mental health, Surgery, Neurology (clinical)
Abstract

BackgroundPatients carrying pathogenic variants inGNAO1often present with early-onset central hypotonia and global developmental delay, with or without epilepsy. As the disorder progresses, a complex hypertonic and hyperkinetic movement disorder is a common phenotype. A genotype–phenotype correlation has not yet been described and there are no evidence-based therapeutic recommendations.MethodsTo improve understanding of the clinical course and pathophysiology of this ultra-rare disorder, we built up a registry forGNAO1patients in Germany. In this retrospective, multicentre cohort study, we collected detailed clinical data, treatment effects and genetic data for 25 affected patients.ResultsThe main clinical features were symptom onset within the first months of life, with central hypotonia or seizures. Within the first year of life, nearly all patients developed a movement disorder comprising dystonia (84%) and choreoathetosis (52%). Twelve (48%) patients suffered life-threatening hyperkinetic crises. Fifteen (60%) patients had epilepsy with poor treatment response. Two patients showed an atypical phenotype and seven novel pathogenic variants inGNAO1were identified. Nine (38%) patients were treated with bilateral deep brain stimulation of the globus pallidus internus. Deep brain stimulation reduced hyperkinetic symptoms and prevented further hyperkinetic crises. The in silico prediction programmes did not predict the phenotype by the genotype.ConclusionThe broad clinical spectrum and genetic findings expand the phenotypical spectrum ofGNAO1-associated disorder and therefore disprove the assumption that there are only two main phenotypes. No specific overall genotype–phenotype correlation was identified. We highlight deep brain stimulation as a useful treatment option in this disorder.

Published
2023

50. Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders

Author

Franziska Langhammer, Reza Maroofian, Rueda Badar, Anne Gregor, Michelle Rochman, Jeffrey B. Ratliff, Marije Koopmans, Theresia Herget, Maja Hempel, Fanny Kortüm, Delphine Heron, Cyril Mignot, Boris Keren, Susan Brooks, Christina Botti, Bruria Ben-Zeev, Emanuela Argilli, Elliot H. Sherr, Vykuntaraju K. Gowda, Varunvenkat M. Srinivasan, Somayeh Bakhtiari, Michael C. Kruer, Mustafa A. Salih, Alma Kuechler, Eric A. Muller, Karli Blocker, Outi Kuismin, Kristen L. Park, Aaina Kochhar, Kathleen Brown, Subhadra Ramanathan, Robin Dawn Clark, Magdeldin Elgizouli, Gia Melikishvili, Nazhi Tabatadze, Zornitza Stark, Ghayda M. Mirzaa, Jinfon Ong, Ute Grasshoff, Andrea Bevot, Lydia von Wintzingerode, Rami Abou Jamra, Yvonne Hennig, Paula Goldenberg, Chadi Al Alam, Majida Charif, Redouane Boulouiz, Mohammed Bellaoui, Rim Amrani, Fuad Al Mutairi, Abdullah M. Tamim, Firdous Abdulwahab, Fowzan S. Alkuraya, Ebtissal Mohammad Khouj, Javeria Raza Alvi, Tipu Sulta, Narges Hashemi, Ehsan Ghayoor Karimiani, Farah Ashrafzadeh, Shima Imannezhad, Stephanie Efthymiou, Henry Houlden, Heinrich Sticht, and Christiane Zweier

Subjects
Medizin, 610 Medizin und Gesundheit, Genetics (clinical)
Abstract

PURPOSE Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy (DEE) with early-onset seizures and severe intellectual disability. METHODS By international collaboration we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders (NDDs). By western blotting we investigated the consequences of missense variants in vitro. RESULTS In accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe DEE in 16 individuals. We now identified also de novo missense variants in the GTPase domain in six individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences.Furthermore, we observed bi-allelic splice-site and truncating variants in nine families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well. CONCLUSION By identifying phenotype-genotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying bi-allelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2 related disorders including both autosomal dominant and recessive NDDs.

Published
2023

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