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1. A negative feedback loop between fibroadipogenic progenitors and muscle fibres involving endothelin promotes human muscle fibrosis

Author

Mona Bensalah, Laura Muraine, Alexis Boulinguiez, Lorenzo Giordani, Victorine Albert, Victor Ythier, Jamila Dhiab, Alison Oliver, Valentine Hanique, Teresa Gidaro, Sophie Perié, Jean Lacau St‐Guily, Aurélien Corneau, Gillian Butler‐Browne, Anne Bigot, Vincent Mouly, Elisa Negroni, and Capucine Trollet

Subjects
Human, FAPs, Skeletal muscle, Pharyngeal muscle, Fibrosis, ECM, Diseases of the musculoskeletal system, RC925-935, Human anatomy, QM1-695
Abstract

Abstract Background Fibrosis is defined as an excessive accumulation of extracellular matrix (ECM) components. Many organs are subjected to fibrosis including the lung, liver, heart, skin, kidney, and muscle. Muscle fibrosis occurs in response to trauma, aging, or dystrophies and impairs muscle function. Fibrosis represents a hurdle for the treatment of human muscular dystrophies. While data on the mechanisms of fibrosis have mostly been investigated in mice, dystrophic mouse models often do not recapitulate fibrosis as observed in human patients. Consequently, the cellular and molecular mechanisms that lead to fibrosis in human muscle still need to be identified. Methods Combining mass cytometry, transcriptome profiling, in vitro co‐culture experiments, and in vivo transplantation in immunodeficient mice, we investigated the role and nature of nonmyogenic cells (fibroadipogenic progenitors, FAPs) from human fibrotic muscles of healthy individuals (FibMCT) and individuals with oculopharyngeal muscular dystrophy (OPMD; FibMOP), as compared with nonmyogenic cells from human nonfibrotic muscle (MCT). Results We found that the proliferation rate of FAPs from fibrotic muscle is 3–4 times higher than those of FAPs from nonfibrotic muscle (population doubling per day: MCT 0.2 ± 0.1, FibMCT 0.7 ± 0.1, and FibMOP 0.8 ± 0.3). When cocultured with muscle cells, FAPs from fibrotic muscle impair the fusion index unlike MCT FAPs (myoblasts alone 57.3 ± 11.1%, coculture with MCT 43.1 ± 8.9%, with FibMCT 31.7 ± 8.2%, and with FibMOP 36.06 ± 10.29%). We also observed an increased proliferation of FAPs from fibrotic muscles in these co‐cultures in differentiation conditions (FibMCT +17.4%, P

Published
2022
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2. Upper limb disease evolution in exon 53 skipping eligible patients with Duchenne muscular dystrophy

Author

Charlotte Lilien, Harmen Reyngoudt, Andreea Mihaela Seferian, Teresa Gidaro, Mélanie Annoussamy, Virginie Chê, Valérie Decostre, Isabelle Ledoux, Julien Le Louër, Eric Guemas, Francesco Muntoni, Jean‐Yves Hogrel, Pierre Georges Carlier, Laurent Servais, and and the PreU7 Study Group

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Objective To understand the natural disease upper limb progression over 3 years of ambulatory and non‐ambulatory patients with Duchenne muscular dystrophy (DMD) using functional assessments and quantitative magnetic resonance imaging (MRI) and to exploratively identify prognostic factors. Methods Forty boys with DMD (22 non‐ambulatory and 18 ambulatory) with deletions in dystrophin that make them eligible for exon 53‐skipping therapy were included. Clinical assessments, including Brooke score, motor function measure (MFM), hand grip and key pinch strength, and upper limb distal coordination and endurance (MoviPlate), were performed every 6 months and quantitative MRI of fat fraction (FF) and lean muscle cross sectional area (flexor and extensor muscles) were performed yearly. Results In the whole population, there were strong nonlinear correlations between outcome measures. In non‐ambulatory patients, annual changes over the course of 3 years were detected with high sensitivity standard response mean (|SRM| ≥0.8) for quantitative MRI‐based FF, hand grip and key pinch, and MFM. Boys who presented with a FF27% were able to bring a glass to their mouth and retained this ability in the following 3 years. Ambulatory patients with grip strength >35% of predicted value and FF

Published
2021
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3. Natural history of Type 2 and 3 spinal muscular atrophy: 2‐year NatHis‐SMA study

Author

Mélanie Annoussamy, Andreea M. Seferian, Aurore Daron, Yann Péréon, Claude Cances, Carole Vuillerot, Liesbeth De Waele, Vincent Laugel, Ulrike Schara, Teresa Gidaro, Charlotte Lilien, Jean‐Yves Hogrel, Pierre Carlier, Emmanuel Fournier, Linda Lowes, Ksenija Gorni, Myriam Ly‐Le Moal, Nicole Hellbach, Timothy Seabrook, Christian Czech, Ricardo Hermosilla, Laurent Servais, and the NatHis‐SMA study group

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Objective To characterize the natural history of spinal muscular atrophy (SMA) over 24 months using innovative measures such as wearable devices, and to provide evidence for the sensitivity of these measures to determine their suitability as endpoints in clinical trials. Methods Patients with Type 2 and 3 SMA (N = 81) with varied functional abilities (sitters, nonsitters, nonambulant, and ambulant) who were not receiving disease‐modifying treatment were assessed over 24 months: motor function (Motor Function Measure [MFM]), upper limb strength (MyoGrip, MyoPinch), upper limb activity (ActiMyo®), quantitative magnetic resonance imaging (fat fraction [FFT2] mapping and contractile cross‐sectional area [C‐CSA]), pulmonary function (forced vital capacity [FVC], peak cough flow, maximum expiratory pressure, maximum inspiratory pressure, and sniff nasal inspiratory pressure), and survival of motor neuron (SMN) protein levels. Results MFM32 scores declined significantly over 24 months, but not 12 months. Changes in upper limb activity could be detected over 6 months and continued to decrease significantly over 12 months, but not 24 months. Upper limb strength decreased significantly over 12 and 24 months. FVC declined significantly over 12 months, but not 24 months. FFT2 increased over 12 and 24 months, although not with statistical significance. A significant increase in C‐CSA was observed at 12 but not 24 months. Blood SMN protein levels were stable over 12 and 24 months. Interpretation These data demonstrate that the MFM32, MyoGrip, MyoPinch, and ActiMyo® enable the detection of a significant decline in patients with Type 2 and 3 SMA over 12 or 24 months.

Published
2021
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4. Prospective and longitudinal natural history study of patients with Type 2 and 3 spinal muscular atrophy: Baseline data NatHis-SMA study.

Author

Aurélie Chabanon, Andreea Mihaela Seferian, Aurore Daron, Yann Péréon, Claude Cances, Carole Vuillerot, Liesbeth De Waele, Jean-Marie Cuisset, Vincent Laugel, Ulrike Schara, Teresa Gidaro, Stéphanie Gilabert, Jean-Yves Hogrel, Pierre-Yves Baudin, Pierre Carlier, Emmanuel Fournier, Linda Pax Lowes, Nicole Hellbach, Timothy Seabrook, Elie Toledano, Mélanie Annoussamy, Laurent Servais, and NatHis-SMA study group

Subjects
Medicine, Science
Abstract

Spinal muscular atrophy (SMA) is a monogenic disorder caused by loss of function mutations in the survival motor neuron 1 gene, which results in a broad range of disease severity, from neonatal to adult onset. There is currently a concerted effort to define the natural history of the disease and develop outcome measures that accurately capture its complexity. As several therapeutic strategies are currently under investigation and both the FDA and EMA have recently approved the first medical treatment for SMA, there is a critical need to identify the right association of responsive outcome measures and biomarkers for individual patient follow-up. As an approved treatment becomes available, untreated patients will soon become rare, further intensifying the need for a rapid, prospective and longitudinal study of the natural history of SMA Type 2 and 3. Here we present the baseline assessments of 81 patients aged 2 to 30 years of which 19 are non-sitter SMA Type 2, 34 are sitter SMA Type 2, 9 non-ambulant SMA Type 3 and 19 ambulant SMA Type 3. Collecting these data at nine sites in France, Germany and Belgium established the feasibility of gathering consistent data from numerous and demanding assessments in a multicenter SMA study. Most assessments discriminated between the four groups well. This included the Motor Function Measure (MFM), pulmonary function testing, strength, electroneuromyography, muscle imaging and workspace volume. Additionally, all of the assessments showed good correlation with the MFM score. As the untreated patient population decreases, having reliable and valid multi-site data will be imperative for recruitment in clinical trials. The pending two-year study results will evaluate the sensitivity of the studied outcomes and biomarkers to disease progression. TRIAL REGISTRATION:ClinicalTrials.gov (NCT02391831).

Published
2018
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5. Mitochondrial dysfunction reveals the role of mRNA poly(A) tail regulation in oculopharyngeal muscular dystrophy pathogenesis.

Author

Aymeric Chartier, Pierre Klein, Stéphanie Pierson, Nicolas Barbezier, Teresa Gidaro, François Casas, Steven Carberry, Paul Dowling, Laurie Maynadier, Maëlle Bellec, Martine Oloko, Claude Jardel, Bodo Moritz, George Dickson, Vincent Mouly, Kay Ohlendieck, Gillian Butler-Browne, Capucine Trollet, and Martine Simonelig

Subjects
Genetics, QH426-470
Abstract

Oculopharyngeal muscular dystrophy (OPMD), a late-onset disorder characterized by progressive degeneration of specific muscles, results from the extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Here, we show, using Drosophila and mouse models, that OPMD pathogenesis depends on affected poly(A) tail lengths of specific mRNAs. We identify a set of mRNAs encoding mitochondrial proteins that are down-regulated starting at the earliest stages of OPMD progression. The down-regulation of these mRNAs correlates with their shortened poly(A) tails and partial rescue of their levels when deadenylation is genetically reduced improves muscle function. Genetic analysis of candidate genes encoding RNA binding proteins using the Drosophila OPMD model uncovers a potential role of a number of them. We focus on the deadenylation regulator Smaug and show that it is expressed in adult muscles and specifically binds to the down-regulated mRNAs. In addition, the first step of the cleavage and polyadenylation reaction, mRNA cleavage, is affected in muscles expressing alanine-expanded PABPN1. We propose that impaired cleavage during nuclear cleavage/polyadenylation is an early defect in OPMD. This defect followed by active deadenylation of specific mRNAs, involving Smaug and the CCR4-NOT deadenylation complex, leads to their destabilization and mitochondrial dysfunction. These results broaden our understanding of the role of mRNA regulation in pathologies and might help to understand the molecular mechanisms underlying neurodegenerative disorders that involve mitochondrial dysfunction.

Published
2015
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6. Upper limb strength and function changes during a one-year follow-up in non-ambulant patients with Duchenne Muscular Dystrophy: an observational multicenter trial.

Author

Andreea Mihaela Seferian, Amélie Moraux, Mélanie Annoussamy, Aurélie Canal, Valérie Decostre, Oumar Diebate, Anne-Gaëlle Le Moing, Teresa Gidaro, Nicolas Deconinck, Frauke Van Parys, Wendy Vereecke, Sylvia Wittevrongel, Michèle Mayer, Kim Maincent, Isabelle Desguerre, Christine Thémar-Noël, Jean-Marie Cuisset, Vincent Tiffreau, Severine Denis, Virginie Jousten, Susana Quijano-Roy, Thomas Voit, Jean-Yves Hogrel, and Laurent Servais

Subjects
Medicine, Science
Abstract

INTRODUCTION:Upper limb evaluation of patients with Duchenne Muscular Dystrophy is crucially important to evaluations of efficacy of new treatments in non-ambulant patients. In patients who have lost ambulation, there are few validated and informative outcome measures. In addition, longitudinal data demonstrating sensitivity to clinical evolution of outcome measures over short-term periods are lacking. PATIENTS AND METHODS:We report here the results of a one-year multicenter study using specifically designed tools to assess grip, pinch strength, and hand function in wheelchair-bound patients. Our study assessed 53 non-ambulant patients with Duchenne muscular dystrophy aged 17.1 ± 4.8 years (range: 9 - 28.1 years). The average Brooke functional score of these patients was 4.6 ± 1.1. The average forced vital capacity was 44.5% predicted and 19 patients used non-invasive ventilation. Patients were assessed at baseline, 6 months, and one year using the Motor Function Measure and innovative devices (namely the MyoSet composed of MyoGrip, MyoPinch, and MoviPlate). RESULTS:Our study confirmed preliminary data previously reported regarding feasibility of use and of reliability of the MyoSet and the correlation at baseline between distal strength and clinical outcomes such as FVC, Brooke score, age, and duration since loss of ambulation. A significant correlation was observed between the distal upper limb strength and clinical variables. The sensitive dynamometers (MyoGrip and MyoPinch) and MoviPlate captured a 12-month change in non-ambulant Duchenne muscular dystrophy patients of all ages. TRIAL REGISTRATION:ClinicalTrials.gov NCT00993161 NCT00993161.

Published
2015
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7. Upper limb evaluation and one-year follow up of non-ambulant patients with spinal muscular atrophy: an observational multicenter trial.

Author

Andreea Mihaela Seferian, Amélie Moraux, Aurélie Canal, Valérie Decostre, Oumar Diebate, Anne Gaëlle Le Moing, Teresa Gidaro, Nicolas Deconinck, Frauke Van Parys, Wendy Vereecke, Sylvia Wittevrongel, Mélanie Annoussamy, Michèle Mayer, Kim Maincent, Jean-Marie Cuisset, Vincent Tiffreau, Severine Denis, Virginie Jousten, Susana Quijano-Roy, Thomas Voit, Jean-Yves Hogrel, and Laurent Servais

Subjects
Medicine, Science
Abstract

Assessment of the upper limb strength in non-ambulant neuromuscular patients remains challenging. Although potential outcome measures have been reported, longitudinal data demonstrating sensitivity to clinical evolution in spinal muscular atrophy patients are critically lacking. Our study recruited 23 non-ambulant patients, 16 patients (males/females = 6/10; median age 15.4 years with a range from 10.7 to 31.1 years) with spinal muscular atrophy type II and 7 patients (males/females = 2/5; median age 19.9 years with a range from 8.3 to 29.9 years) with type III. The Brooke functional score was on median 3 with a range from 2 to 6. The average total vital capacity was 46%, and seven patients required non-invasive ventilation at night. Patients were assessed at baseline, 6 months, and 1 year using the Motor Function Measure and innovative devices MyoGrip, MyoPinch, and MoviPlate, which assess handgrip strength, key pinch strength, and hand/finger extension-flexion function, respectively. The study demonstrated the feasibility and reliability of these measures for all patients, and sensitivity to negative changes after the age of 14 years. The younger patients showed an increase of the distal force in the follow-up period. The distal force measurements and function were correlated to different functional scales. These data represent an important step in the process of validating these devices as potential outcome measures for future clinical trials.

Published
2015
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8. Mesoangioblasts from Facioscapulohumeral Muscular Dystrophy Display in Vivo a Variable Myogenic Ability Predictable by their in Vitro Behavior

Author

Roberta Morosetti M.D., Teresa Gidaro, Aldobrando Broccolini, Carla Gliubizzi, Cristina Sancricca, Pietro Attilio Tonali, Enzo Ricci, and Massimiliano Mirabella M.D., Ph.D.

Subjects
Medicine
Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is the third most frequent inherited myopathy. We previously demonstrated that mesoangioblasts can be efficiently isolated from FSHD muscles, although their differentiation ability into skeletal muscle was variably impaired. This correlates with overall disease severity and degree of histopathologic abnormalities, since mesoangioblasts from morphologically normal muscles did not show any myogenic differentiation block. The aim of our present study was to verify whether mesoangioblasts from differentially affected FSHD muscles reproduce in vivo the same differentiation ability shown in vitro by studying their capability to form new muscle fibers during muscle regeneration of experimentally damaged muscles. We show that a diverse ability of FSHD mesoangioblasts to engraft and differentiate into skeletal muscle of SCID mice is strictly related to the characteristics of the muscle of origin, closely replicating in vivo what was previously observed in vitro. Moreover, we demonstrate that mesoangioblasts obtained from severely affected muscles scarcely integrate into muscle fibers, remaining mainly localized in the connective tissue. This suggests a defective migration in response to chemoattractants released by damaged fibers, as indicated by cell migration assays in response to HMGB1 and very low levels of RAGE expression, along with a decreased ability to fuse or to appropriately trigger the myogenic program. Our study indicates that FSHD mesoangioblasts from unaffected muscles can be used as selective treatment to halt muscle degeneration in severely affected muscles, and suggests that pharmacological and molecular interventions aimed to ameliorate homing and engraftment of transplanted autologous mesoangioblasts may open the way to cell therapy for FSHD patients, without requiring immunosuppression or genetic correction in vitro.

Published
2011
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9. Safety, tolerability and pharmacokinetics of eteplirsen in young boys aged 6–48 months with Duchenne muscular dystrophy amenable to exon 51 skipping

Author

E. Mercuri, A.M. Seferian, L. Servais, N. Deconinck, H. Stevenson, X. Ni, W. Zhang, L. East, S. Yonren, F. Muntoni, Nicolas Deconinck, Rudy Van Coster, Arnaud Vanlander, Andreea Seferian, Silvana De Lucia, Teresa Gidaro, Laura Vanden Brande, Laurent Servais, Janbernd Kirschner, Sabine Borell, Eugenio Mercuri, Claudia Brogna, Marika Pane, Lavinia Fanelli, Giulia Norcia, Francesco Muntoni, Chiara Brusa, Mary Chesshyre, Kate Maresh, Jaqueline Pitchforth, Lucia Schottlaender, Mariacristina Scoto, Arpana Silwal, and Fedrica Trucco

Subjects
Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Genetics (clinical)
Published
2023

12. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial

Author

Eugenio Mercuri, Nicolas Deconinck, Elena S Mazzone, Andres Nascimento, Maryam Oskoui, Kayoko Saito, Carole Vuillerot, Giovanni Baranello, Odile Boespflug-Tanguy, Nathalie Goemans, Janbernd Kirschner, Anna Kostera-Pruszczyk, Laurent Servais, Marianne Gerber, Ksenija Gorni, Omar Khwaja, Heidemarie Kletzl, Renata S Scalco, Hannah Staunton, Wai Yin Yeung, Carmen Martin, Paulo Fontoura, John W Day, Joseph J. Volpe, John Posner, Ulrich Kellner, Rosaline Quinlivan, Aurore Daron, Stéphanie Delstanche, Romain Bruninx, Fabian Dal Farra, Olivier Schneider, Irina Balikova, Patricia Delbeke, Inge Joniau, Valentine Tahon, Sylvia Wittevrongel, Elke De Vos, Ingele Casteels, Liesbeth De Waele, Catherine Cassiman, Lies Prové, David Kinoo, Lisa Vancampenhout, Marleen Van Den Hauwe, Annelies Van Impe, Alexandra Prufer de Queiroz Campos Araujo, Aline Chacon Pereira, Flávia Nardes, Lorena Haefeli, Julia Rossetto, Marcos Ferreira Rebel, Jaqueline Almeida Pereira, Craig Campbell, Sapna Sharan, Wendy McDonald, Cheryl Scholtes, Jean Mah, Maria Sframeli, Angela Chiu, Jane Hagel, Raquel Beneish, Gaela Cariou-Palmer, Connie Pham, Daniela Toffoli, Stephanie Arpin, Sarah Turgeon Desilets, Yi Wang, Chaoping Hu, Jianfeng Huan, Chen Qian, Li Shen, Ying Xiao, Zhenxuan Zhou, Hui Li, Sujuan Wang, Hui Xiong, Xingzhi Chang, Hui Dong, Ying Liu, Tian Sang, Cuijie Wei, Jing Wen, Yiwen Cao, Xingyao Ly, Jingjing Zhao, Wenzhu Li, Lun Qin, Nina Barisic, Martina Galiot Delic, Petra Kristina Ivkic, Nenad Vukojevic, Ivana Kern, Boris Najdanovic, Marin Skugor, Teresa Gidaro, Andreea Seferian, Silvana De Lucia, Emmanuel Barreau, Nabila Mnafek, Marta Milkova Momtchilova, Helene Peche, Carole Valherie, Allison Grange, Charlotte Lilien, Darko Milascevic, Shotaro Tachibana, Claudia Ravelli, Ruxandra Cardas, Jessica Taytard, Guillaume Aubertin, Laure Vanden Brande, Jean-Baptiste Davion, Stephanie Coopman, Ikram Bouacha, Philippe Debruyne, Sabine Defoort, Gilles Derlyn, Florian Leroy, Loïc Danjoux, Julie Guilbaud, Isabelle Desguerre, Christine Barnérias, Michaela Semeraro, Dominique Bremond-Gignac, Lenaic Bruere, Maxence Rateaux, Élodie Deladrière, Virginie Germa, Yann Pereon, Sandra Mercie, Fanny Billaud, Lucie Le Goff, Guy Letellier, Aurélie Portefaix, Camille De-Montferrand, Laure Le-Goff, Stephanie Fontaine, Manel Saidi, Nabil Bouzid, Aurélie Barriere, Marie Tinat, Michelle Dreesbach, Wolf Lagréze, Bettina Michaelis, Fanni Molnar, Dorina Seger, Sibylle Vogt, Enrico Bertini, Adele D'Amico, Sergio Petroni, Anna Maria Bonetti, Adelina Carlesi, Irene Mizzoni, Claudio Bruno, Enrico Priolo, Giuseppe Rao, Simone Morando, Paola Tacchetti, Ambra Zuffi, Giacomo Pietro Comi, Roberta Brusa, Stefania Corti, Velardo Daniele, Alessandra Govoni, Francesca Magri, Valeria Minorini, Silvia Gabriella Osnaghi, Francesca Abbati, Federica Fassini, Michaela Foa, Amaqlia Lopopolo, Megi Meneri, Francesca Zoppas, Valeria Parente, Riccardo Masson, Stefania Bianchi Marzoli, Diletta Santarsiero, Myriam Garcia Sierra, Gemma Tremolada, Maria Teresa Arnoldi, Marta Vigano, Riccardo Zanin, Laura Antonaci, Roberto de Sanctis, Marika Pane, Maria Carmela Pera, Giulia Maria Amorelli, Costanza Barresi, Gugliemo D'Amico, Lorenzo Orazi, Giorgia Coratti, Kazuhiro Haginoya, Atsuko Kato, Yuko Morishita, Ryutaro Kira, Kiyomu Akiyama, Miwako Goto, Yujiro Mori, Misato Okamoto, Saki Tsutsui, Yuta Takatsuji, Aya Tanaka, Hirofumi Komaki, Miina Omori, Ippei Suzuki, Mizuki Takeuchi, Daisuke Todoroki, Seji Watanabe, Tomoko Matsubayashi, Emi Inakazu, Hiroe Nagura, Akira Suzuki, Manami Usui, Nobutsune Ishikawa, Yousuke Harada, Kenishi Fudeyasu, Kazuhiko Hirata, Kana Michiue, Kazuyuki Ueda, Junko Fujitani, Reiko Arakawa, Kozue Takano, Shigeko Yashiro, Maiko Seki, Nozomi Sano, Koji Fukuyama, Yuki Matsumoto, Hirofumi Miyazaki, Minoru Shibata, Kyoko Kobayashi, Yukie Nakamura, Yasuhiro Takeshima, Moe Kuma, Anna Fraczek, Maria Jedrzejowska, Anna Lusakowska, Agnieszka Czeszyk-Piotrowicz, Wojciech Hautz, Klaudia Rakusiewicz, Malgorzata Burlewicz, Zuzanna Gierlak-Wojcicka, Malwina Kepa, Adam Sikorski, Marcin Sobieraj, Maria Mazurkiewicz-Beldzinska, Anna Lemska, Sandra Modrzejewska, Mateusz Koberda, Urszula Stodolska-Koberda, Agnieszka Waskowska, Jagoda Kolendo, Agnieszka Sobierajska-Rek, Barbara Steinborn, Magdalena Dalz, Julia Grabowska, Wojciech Hajduk, Justyna Janasiewicz-Karachitos, Monika Klimas, Marcin Stopa, Ewa Gajewska, Beata Pusz, Dmitry Vlodavets, Evgenia Melnik, Natalya Leppenen, Nataliya Yupatova, Anastasya Monakhova, Yulia Papina, Olga Shidlovsckaia, Vedrana Milic Rasic, Vesna Brankovic, Ana Kosac, Olivera Djokic, Vesna Jakšic, Ana Pepic, Jelena Martinovic, Francina Munell Casadesus, Eduardo Tizzano, Nieves Martín Begué, Charlotte Wolley Dod, Olaia Subira, Bernat Planas Pascual, Esther Toro Tamargo, Marcos Madruga Garrido, José David Medina Romero, Marta Peña Salinas, Andrés Nascimento Osorio, Ana Díaz Cortés, Enrique Jiménez Gañan, Simone Dowon Suh, Julita Medina Cantillo, Obdulia Moya, Nuria Padros, Sandra Roca Urraca, Hugo Gonzalez Valdivia, Samuel Pascual Pascual, Sofía de Manuel, Susana Noval Martin, Paul Burnham, Sandra Espinosa, Mercedes Martinez Moreno, Haluk Topaloglu, Ibrahim Oncel, Nesibe Eroglu Ertugru, Bahadir Konuskan, Bora Eldem, Sibel Kadayifçilar, Ipek Alemdaroglu, Aynur Ayse Karaduman, Oznur Tunca Yilmaz, Neslihan Bilgin, Seher Sari, Claudia Chiriboga, John J. Lee, Donnielle Rome-Martin, John W. Day, Shannon Beres, Tina Duong, Richard Gee, Sally Dunaway Young, Sabine Fuerst-Recktenwald, Anne Marquet, Nicoletta Muelhardt, and Dylan Trundell

Subjects
Adult, Risdiplam, spinal muscular atrophy, Adolescent, Spinal Muscular Atrophies of Childhood, Settore MED/26 - NEUROLOGIA, Young Adult, Pyrimidines, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Double-Blind Method, Child, Preschool, Humans, Neurology (clinical), Child, Preschool, Azo Compounds, Aged
Abstract

BACKGROUND: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing =20 kg) or 0·25 mg/kg (for individuals weighing

Published
2022

13. Leveraging Natural History Data in One- and Two-Arm Hierarchical Bayesian Studies of Rare Disease Progression

Author

A. Daron, James J. Dowling, Carole Vuillerot, Severine Denis, Bruno Boulanger, Rémi Bellance, Jean-Michel Arnal, Carina Wallgren-Pettersson, Kimberly Amburgey, Etsuko Tsuchiya, A. Hernandez, Jean-Marie Cuisset, Bradley P. Carlin, Enrico Bertini, Andrea Gangfuß, Barbara Andres, Arnaud Monseur, E. Gargaun, Dominique Duchene, Ruxandra Cardas, Virginie Latournerie, Ana Buj-Bello, Ulrike Schara, Basil T. Darras, H. Landy, V. Chê, Chris Freitag, Laurent Servais, S. Fontaine, Adele D'Amico, Jean-Yves Hogrel, Teresa Gidaro, Nacera Reguiba, Andreea Mihaela Seferian, L. Thielemans, Valérie Biancalana, Michèle Mayer, and Capucine de Lattre

Subjects
Statistics and Probability, medicine.medical_specialty, Clinical study design, Bayesian probability, Context (language use), Disease, Placebo, Biochemistry, Genetics and Molecular Biology (miscellaneous), Natural history, Physical medicine and rehabilitation, medicine, Biostatistics, Psychology, Type I and type II errors
Abstract

The small sample sizes inherent in rare and pediatric disease settings offer significant challenges for clinical trial design. In such settings, Bayesian adaptive trial methods can often pay dividends, allowing the sensible incorporation of auxiliary data and other relevant information to bolster that collected by the trial itself. Previous work has also included the use of one-arm trials augmented by the participants’ own natural history data, from which the future course of the disease in the absence of intervention can be predicted. Patient response can then be defined by the degree to which post-intervention observations are inconsistent with the predicted “natural” trajectory. While such trials offer obvious advantages in efficiency and ethical hazard (since they expose no new patients to a placebo, anathema to patients or their parents and caregivers), they can offer no protection against bias arising from the presence of any “placebo effect,” the tendency of patients to improve merely by being in the trial. In this paper, we investigate the impact of both static and transient placebo effects on one-arm responder studies of this type, as well as two-arm versions that incorporate a small concurrent placebo group but still borrow strength from the natural history data. We also propose more traditional Bayesian changepoint models that specify a parametric functional form for the patient’s post-intervention trajectory, which in turn allow quantification of the treatment benefit in terms of the model parameters, rather than semi-parametrically in terms of a response relative to some “null” model. We compare the operating characteristics of our designs in the context of an ongoing investigation of centronuclear myopathies (CNMs), a group of congenital neuromuscular diseases whose most common and severe form is X-linked, affecting approximately 1 in 50,000 newborn boys. Our results indicate our two-arm responder and changepoint methods can offer protection against placebo effects, improving power while protecting the trial’s Type I error rate. However, further research into innovative trial designs as well as ongoing dialog with regulatory authorities remain critically important in rare disease research.

Published
2021

14. Natural history of Type 2 and 3 spinal muscular atrophy: 2‐year NatHis‐SMA study

Author

Jean-Yves Hogrel, Myriam Ly-Le Moal, A. Daron, Teresa Gidaro, Timothy Seabrook, Laurent Servais, Carole Vuillerot, Vincent Laugel, Emmanuel Fournier, Pierre G. Carlier, Ulrike Schara, Yann Péréon, Nicole Hellbach, Andreea Mihaela Seferian, Claude Cances, Ksenija Gorni, M. Annoussamy, Linda Lowes, C. Lilien, Ricardo Hermosilla, Christian Czech, Liesbeth De Waele, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), SYSNAV, Centre Hospitalier Universitaire de Liège (CHU-Liège), Centre de reference des maladies neuromusculaires Nantes-Angers, CHU d'Angers et Nantes, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University Hospitals Leuven [Leuven], KU Leuven Campus Kulak Kortrijk [Belgium], CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], University of Duisburg-Essen, University of Oxford, Nationwide Children's Hospital, Hoffman-La Roche Ltd, Translational Medicine, Neuroscience, Institut ROCHE [Boulogne-Billancourt], Roche S.A.S, Roche Innovation Center [Basel, Switzerland], Pfizer, Gestionnaire, Hal Sorbonne Université, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), CHU Toulouse [Toulouse], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, University of Oxford [Oxford], and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]

Subjects
0301 basic medicine, Vital capacity, Time Factors, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Medizin, MESH: Respiratory Function Tests, NASAL INSPIRATORY PRESSURE, Severity of Illness Index, Pulmonary function testing, MESH: Magnetic Resonance Imaging, Disability Evaluation, 0302 clinical medicine, MESH: Muscular Atrophy, Spinal, MESH: Child, Longitudinal Studies, MESH: Nerve Tissue Proteins, Child, MESH: Longitudinal Studies, Research Articles, VALUES, General Neuroscience, MESH: Muscle Strength, MESH: Disability Evaluation, RNA-Binding Proteins, SMA, Magnetic Resonance Imaging, MESH: Motor Activity, Respiratory Function Tests, medicine.anatomical_structure, MESH: Young Adult, Child, Preschool, Anesthesia, Disease Progression, Upper limb, MESH: Disease Progression, Erratum, Life Sciences & Biomedicine, RC321-571, Research Article, Adult, Adolescent, Clinical Neurology, Neurosciences. Biological psychiatry. Neuropsychiatry, Nerve Tissue Proteins, Motor Activity, Muscular Atrophy, Spinal, Upper Extremity, Young Adult, 03 medical and health sciences, FEV1/FVC ratio, Statistical significance, MESH: Severity of Illness Index, medicine, Humans, Muscle Strength, RC346-429, MESH: Adolescent, Science & Technology, MESH: Humans, business.industry, MESH: Time Factors, MESH: Child, Preschool, Neurosciences, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Survival of motor neuron, MESH: Adult, Spinal muscular atrophy, MESH: Upper Extremity, medicine.disease, 030104 developmental biology, MESH: RNA-Binding Proteins, Neurology. Diseases of the nervous system, Neurology (clinical), Neurosciences & Neurology, business, 030217 neurology & neurosurgery
Abstract

OBJECTIVE: To characterize the natural history of spinal muscular atrophy (SMA) over 24 months using innovative measures such as wearable devices, and to provide evidence for the sensitivity of these measures to determine their suitability as endpoints in clinical trials. METHODS: Patients with Type 2 and 3 SMA (N = 81) with varied functional abilities (sitters, nonsitters, nonambulant, and ambulant) who were not receiving disease-modifying treatment were assessed over 24 months: motor function (Motor Function Measure [MFM]), upper limb strength (MyoGrip, MyoPinch), upper limb activity (ActiMyo® ), quantitative magnetic resonance imaging (fat fraction [FFT2 ] mapping and contractile cross-sectional area [C-CSA]), pulmonary function (forced vital capacity [FVC], peak cough flow, maximum expiratory pressure, maximum inspiratory pressure, and sniff nasal inspiratory pressure), and survival of motor neuron (SMN) protein levels. RESULTS: MFM32 scores declined significantly over 24 months, but not 12 months. Changes in upper limb activity could be detected over 6 months and continued to decrease significantly over 12 months, but not 24 months. Upper limb strength decreased significantly over 12 and 24 months. FVC declined significantly over 12 months, but not 24 months. FFT2 increased over 12 and 24 months, although not with statistical significance. A significant increase in C-CSA was observed at 12 but not 24 months. Blood SMN protein levels were stable over 12 and 24 months. INTERPRETATION: These data demonstrate that the MFM32, MyoGrip, MyoPinch, and ActiMyo® enable the detection of a significant decline in patients with Type 2 and 3 SMA over 12 or 24 months. ispartof: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY vol:8 issue:2 pages:359-373 ispartof: location:United States status: published

Published
2020

15. Relationship between markers of disease activity and progression in skeletal muscle of GNE myopathy patients using quantitative nuclear magnetic resonance imaging and 31P nuclear magnetic resonance spectroscopy

Author

Pierre G. Carlier, Benjamin Marty, Laurent Servais, Harmen Reyngoudt, Julien Le Louër, Ericky C. A. Araujo, Teresa Gidaro, P. Baudin, Anthony Behin, and Jean-Marc Boisserie

Subjects
Surrogate endpoint, business.industry, Disease progression, Skeletal muscle, GNE MYOPATHY, Nuclear magnetic resonance spectroscopy, 030218 nuclear medicine & medical imaging, Disease activity, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Nuclear magnetic resonance, Forearm, medicine, Radiology, Nuclear Medicine and imaging, business, Hamstring
Abstract

Background Quantitative nuclear magnetic resonance imaging (NMRI) is an objective and precise outcome measure for evaluating disease progression in neuromuscular disorders. We aimed to investigate predictive 'disease activity' NMR indices, including water T2 and 31P NMR spectroscopy (NMRS), and its relation to NMR markers of 'disease progression', such as the changes in fat fraction (ΔFat%) and contractile cross-sectional area (ΔcCSA), in GNE myopathy (GNEM) patients. Methods NMR was performed on a 3T clinical scanner, at baseline and at a 1-year interval, in 10 GNEM patients and 29 age-matched controls. Dixon-based fat-water imaging and water T2 mapping were acquired in legs and thighs, and in the dominant forearm. 31P NMRS was performed at the level of quadriceps and hamstring. Water T2 and 31P NMRS indices were determined for all muscle groups and visits. Correlations were performed with 'disease progression' indices ΔFat%, ΔcCSA and the muscle fat transformation rate (Rmuscle_transf). Results In quadriceps, known to be relatively preserved in GNEM, water T2 at baseline was significantly higher compared to controls, and correlated strongly with the one-year evolution of Fat% and cCSA and Rmuscle_transf. Various 31P NMRS indices showed significant differences in quadriceps and hamstring compared to controls and correlations existed between these indices and ΔFat%, ΔcCSA and Rmuscle_transf. Conclusions This study demonstrates that disease activity indices such as water T2 and 31P NMRS may predict disease progression in skeletal muscles of GNEM patients, and suggests that these measures may be considered to be valuable surrogate endpoints in the assessment of GNEM disease progression.

Published
2020

16. ASC‐1 Is a Cell Cycle Regulator Associated with Severe and Mild Forms of Myopathy

Author

Teresa Gidaro, Julien Durigneux, Emma Pierce-Hoffman, Fabio Catervi, Johann Böhm, Alan H. Beggs, Adnan Yuksel, Montse Olivé, Casie A. Genetti, Raul Juntas-Morales, Isabelle Duband-Goulet, Nicolas Deconinck, Norma B. Romero, Eva Cabet, Rocío-Nur Villar-Quiles, Asuman Koparir, Ana Ferreiro, Jocelyn Laporte, Xavière Lornage, Mireille Cossée, John Rendu, Sandra Coppens, Lara Servais, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Biruni University, Children's University Hospital Queen Fabiola [Bruxelles, Belgium], Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA, Partenaires INRAE, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des Maladies Neuromusculaires AOC, Groupe d'imagerie neurofonctionnelle (GIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Children's Hospital and Harvard Medical School, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Mühendislik ve Doğa Bilimleri Fakültesi

Subjects
Male, TRANSCRIPTION COACTIVATOR, 0301 basic medicine, Pathology, animal diseases, [SDV]Life Sciences [q-bio], Cardiomyopathy, Muscle Proteins, medicine.disease_cause, SIGNAL COINTEGRATOR 1, 0302 clinical medicine, Fibroblasts -- physiology, Amyotrophic lateral sclerosis, Child, Cells, Cultured, Mutation, ABNORMALITIES, Cell Cycle -- physiology, Cell Cycle, PROLIFERATION, hemic and immune systems, Sciences bio-médicales et agricoles, Middle Aged, MUSCLE, Pedigree, 3. Good health, Phenotype, Neurology, Child, Preschool, Female, Transcription Factors -- genetics, medicine.symptom, tissues, D3, G1 phase, Adult, endocrine system, medicine.medical_specialty, Amino Acid Transport System y+, DISORDERS, Muscle Proteins -- genetics, Muscle, Skeletal -- pathology -- physiopathology, Article, 03 medical and health sciences, Muscular Diseases, Neurologie, medicine, Humans, Amino Acid Transport System y+ -- metabolism -- physiology, Muscle, Skeletal, Cell Cycle Protein, Myopathy, business.industry, Infant, Spinal muscular atrophy, Fibroblasts, medicine.disease, GENE, Congenital myopathy, eye diseases, MUSCULAR-DYSTROPHY, ADIPOGENESIS, 030104 developmental biology, Muscular Diseases -- genetics -- physiopathology, Neurology (clinical), business, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Objective: Recently, the ASC-1 complex has been identified as a mechanistic link between amyotrophic lateral sclerosis and spinal muscular atrophy (SMA), and 3 mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations. Methods: Clinical, molecular, histological, and magnetic resonance imaging studies were made in 5 families with 7 novel TRIP4 mutations. Fluorescence activated cell sorting and Western blot were performed in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells. Results: All mutations caused ASC-1 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure, and in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers, and/or mild endomysial fibrosis. ASC-1 depletion in C2C12 and in patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins, and/or shortening of the G0/G1 cell cycle phase leading to cell size reduction. Interpretation: Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with isolated primary muscle involvement, and establish TRIP4 as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic-body myopathies. They also identify ASC-1 as a novel cell cycle regulator with a key role in cell proliferation, and underline transcriptional coregulation defects as a novel pathophysiological mechanism. ANN NEUROL 2020;87:217–232., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2019

17. Home-based gait analysis as an exploratory endpoint during a multicenter phase 1 trial in limb girdle muscular dystrophy type R2 and facioscapulohumeral muscular dystrophy

Author

Erwan Gasnier, David Vissiere, Laurent Servais, Tahseen Mozaffar, Gennyne Walker, Kathryn R. Wagner, John Vissing, Teresa Gidaro, M. Annoussamy, Sanjay S. Shukla, Stanley Iyadurai, and Shahram Attarian

Subjects
musculoskeletal diseases, medicine.medical_specialty, Physiology, STRIDE, Walking, Cellular and Molecular Neuroscience, Physical medicine and rehabilitation, Physiology (medical), medicine, Facioscapulohumeral muscular dystrophy, Humans, Gait, business.industry, Stride length, medicine.disease, Home based, Muscular Dystrophy, Facioscapulohumeral, Clinical trial, Muscular Dystrophies, Limb-Girdle, Gait analysis, Neurology (clinical), business, Gait Analysis, human activities, Limb-girdle muscular dystrophy
Abstract

INTRODUCTION/AIMS Limb girdle muscular dystrophy type 2B (LGMDR2) and facioscapulohumeral muscular dystrophy (FSHD) are genetic muscular dystrophies with an increasing number of potential therapeutic approaches. The aim of this study is to report the data of exploratory digital outcomes extracted from wearable magneto-inertial sensors used in a non-controlled environment for ambulant patients with FSHD and LGMDR2 in a short-term, multicenter clinical study. METHODS Digital outcomes (stride length, stride speed, and walk parameters in a non-controlled environment) were used as exploratory outcomes in the open-label study ATYR1940-C-004 in ambulant patients during the 3 mo of ATYR1940 treatment and 1 mo of follow-up. Activity and gait variables were calculated from the data recorded in 30-day sub-periods using the sensors. For each sub-period, activity and gait parameters were compared between FSHD and LGMDR2 patients. Change from baseline over the 4-mo study period was assessed. RESULTS Ten patients (5 FSHD, 5 LGMDR2) were ambulant and compliant for analysis. Gait parameters, but not activity variables, were significantly lower in LGMDR2 compared to FSHD patients at baseline. Longitudinal analyses showed a slight but significant decrease in stride speed at month 4 for all subjects. Activity variables such as total number of strides per day were highly variable from month to month in individual patients, and no visit effects were found for this variable. DISCUSSION The present study suggests that home-recorded stride speed constitutes a precise and sensitive outcome in ambulant patients with FSHD and LGMDR2.

Published
2021

18. Quantitative nuclear magnetic resonance imaging detects subclinical changes over 1 year in skeletal muscle of GNE myopathy

Author

Harmen Reyngoudt, Anthony Behin, Ericky C. A. Araujo, Benjamin Marty, Ferial Toumi, M. Annoussamy, Jean-Yves Hogrel, Melanie Villeret, Laurent Servais, Teresa Gidaro, P. Baudin, Julien Le Louër, and Pierre G. Carlier

Subjects
Adult, Male, medicine.medical_specialty, Neurology, Thigh, 03 medical and health sciences, 0302 clinical medicine, Nuclear magnetic resonance, Forearm, medicine, Humans, 030212 general & internal medicine, Muscle, Skeletal, Neuroradiology, Subclinical infection, Surrogate endpoint, business.industry, Skeletal muscle, Middle Aged, Magnetic Resonance Imaging, Distal Myopathies, medicine.anatomical_structure, Disease Progression, Upper limb, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

BACKGROUND AND OBJECTIVE: To identify the most responsive and sensitive clinical outcome measures in GNE myopathy. METHODS: ClinBio-GNE is a natural history study in GNE myopathy. Patients were assessed prospectively by clinical, functional and quantitative nuclear magnetic resonance imaging (qNMRI) evaluations. Strength and functional tests included Myogrip, Myopinch, MoviPlate and Brooke assessments for upper limb and the 6-min walk distance for lower limb. qNMRI was performed for determining the degree of fatty infiltration and trophicity in leg, thigh, forearm and hand skeletal muscles. Ten GNE myopathy patients were included. Three patients were non-ambulant. Age and gender-matched healthy subjects were used as controls. RESULTS: Fatty infiltration and contractile cross-sectional area changed inversely and significantly in lower distal limbs and in proximal lower and distal upper limbs over 1 year. qNMRI indices and functional assessment results were strongly correlated. CONCLUSIONS: Even in a limited number of patients, qNMRI could detect a significant change over a 1-year period in GNE myopathy, which suggests that qNMRI could constitute a surrogate endpoint in this slowly progressive disease. Quantitative NMRI outcome measures can monitor intramuscular fat accumulation with high responsiveness. Longer follow-up should improve our understanding of GNE myopathy evolution and also lead to the identification of non-invasive outcome measures with the highest discriminant power for upcoming clinical trials.

Published
2019

19. Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls

Author

Darras, Basil T, Masson, Riccardo, Mazurkiewicz-Bełdzińska, Maria, Rose, Kristy, Xiong, Hui, Zanoteli, Edmar, Baranello, Giovanni, Bruno, Claudio, Vlodavets, Dmitry, Wang, Yi, El-Khairi, Muna, Gerber, Marianne, Gorni, Ksenija, Khwaja, Omar, Kletzl, Heidemarie, Scalco, Renata S, Fontoura, Paulo, Servais, Laurent, Joseph J, Volpe, John, Posner, Armin, Koch, Ulrich, Kellner, Rosaline, Quinlivan, Nicolas, Deconinck, Irina, Balikova, Patricia, Delbeke, Inge, Joniau, Valentine, Tahon, Sylvia, Wittevrongel, Elke De Vos, Rodrigo de Holanda Mendonça, Ciro Matsui Jr, Ana Letícia Fornazieri Darcie, Cleide, Machado, Maria Kiyoko Oyamada, Daniel de Souza Costa, Joyce, Martini, Graziela, Polido, Juliana Rodrigues Iannicelli, Juliana Caires de Oliveira Achili Ferreira, Chaoping, Hu, Yiyun, Shi, Shuizhen, Zhou, Xiaomei, Zhu, Chen, Qian, Shen, Li, Ying, Xiao, Zhenxuan, Zhou, Hui, Li, Sujuan, Wang, Tian, Sang, Cuijie, Wei, Jing, Wen, Yiwen, Cao, Wenzhu, Li, Lun, Qin, Nina, Barisic, Ivan, Celovec, Martina, Martina, Galiot, Delic, Petra Kristina Ivkić, Nenad, Vukojević, Ivana, Kern, Boris, Najdanovic, Marin, Skugor, Odile, Boespflug-Tanguy, Teresa, Gidaro, Andrea, Seferian, Emmanuel, Barreau, Elodie Da Cunha, Céline, Lambotin, Nabila, Mnafek, Helene, Peche, Stephanie, Gilabert, Allison, Grange, Charlotte, Lilien, Darko, Milascevic, Ariadna, Perticari, Shotaro, Tachibana, Emanuela, Pagliano, Stefania Bianchi Marzoli, Diletta, Santarsiero, Myriam Garcia Sierra, Gemma, Tremolada, Maria Teresa Arnoldi, Marta, Vigano, Riccardo, Zanin, Noemi, Brolatti, Marina, Pedemonte, Enrico, Priolo, Giuseppe, Rao, Enrica, Spaletra, Lorenza, Sposetti, Elisa, Tassara, Simone, Morando, Paola, Tacchetti, Giacomo Pietro Comi, Alessandra, Govoni, Silvia Gabriella Osnaghi, Valeria, Minorini, Francesca, Abbati, Federica, Fassini, Michaela, Foa, Amalia, Lopopolo, Elisa, Minuti, Mercuri, Eugenio Maria, Pane, Marika, Concetta, Palermo, Pera, Maria Carmela, Amorelli, Giulia Maria, Costanza, Barresi, Gugliemo, D'Amico, Orazi, Lorenzo, Coratti, Giorgia, De Sanctis, Roberto, Yasuhiro, Takeshima, Fumi, Gomi, Naoki, Kimura, Takanobu, Morimatsu, Mana, Okamoto, Toru, Furukawa, Mateusz, Koberda, Natalia, Kubiak, Urszula, Stodolska-Koberda, Agnieszka, Waśkowska, Jagoda, Kolendo, Agnieszka, Sobierajska-Rek, Svetlana, Artemyeva, Evgenia, Melnik, Natalya, Leppenen, Nataliya, Yupatova, Elena, Litvinova, Anastasya, Monakhova, Yulia, Papina, Olga, Shidlovsckaia, Andrea, Klein, Cornelia, Enzmann, Elea, Galiart, Konstantin, Gugleta, Patricia, Siems, Verena, Kreiliger, Christine Wondrusch Haschke, Haluk, Topaloglu, Ibrahim, Oncel, Didem, Ardicli, Nesibe Eroglu Ertugrul, Hizal, Gharibzadeh, Ceren, Gunbey, Bahadir, Konuskan, Selen Serel Arslan, Elams Ebru Yalcin, Fatma Gokcem Yildiz Sarikaya, Bora, Eldem, Sibel, Kadayıfçılar, Ipek, Alemdaroglu, Aynur Ayse Karaduman, Oznur Tunca Yilmaz, Robert, J Graham, Partha, Ghosh, David, Casavant, Brian, Snyder, Alexis, Levine, Rachael, Titus, Amanda, Engelbrekt, Lucia, Ambrosio, Anne, Fulton, Anna Maria Baglieri, Courtney, Dias, Elizabeth, Maczek, Elizabeth, Mirek, Amy, Pasternak, John, W Day, Shannon, Beres, Tina, Duong, Richard, Gee, Sally, Young, Darras, Basil T, Masson, Riccardo, Mazurkiewicz-Bełdzińska, Maria, Rose, Kristy, Xiong, Hui, Zanoteli, Edmar, Baranello, Giovanni, Bruno, Claudio, Vlodavets, Dmitry, Wang, Yi, El-Khairi, Muna, Gerber, Marianne, Gorni, Ksenija, Khwaja, Omar, Kletzl, Heidemarie, Scalco, Renata S, Fontoura, Paulo, Servais, Laurent, and Ambrosio, Lucia

Subjects
Male, medicine.medical_specialty, Neuromuscular disease, Risdiplam, Type 1 Spinal Muscular Atrophy, treated infants, historical controls, MEDLINE, Spinal Muscular Atrophies of Childhood, Severity of Illness Index, Text mining, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Internal medicine, Severity of illness, medicine, Humans, Progression-free survival, 610 Medicine & health, business.industry, Historically Controlled Study, Infant, General Medicine, Spinal muscular atrophy, SMA, medicine.disease, Progression-Free Survival, Settore MED/26 - NEUROLOGIA, Pyrimidines, Neuromuscular Agents, Motor Skills, Female, business, Azo Compounds
Abstract

BACKGROUND Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein in blood. METHODS We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA. RESULTS A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P

Published
2021

20. Risdiplam in Type 1 Spinal Muscular Atrophy

Author

Baranello, Giovanni, Darras, Basil T, Day, John W, Deconinck, Nicolas, Klein, Andrea, Masson, Riccardo, Mercuri, Eugenio Maria, Rose, Kristy, El-Khairi, Muna, Gerber, Marianne, Gorni, Ksenija, Khwaja, Omar, Kletzl, Heidemarie, Scalco, Renata S, Seabrook, Timothy, Fontoura, Paulo, Servais, Laurent, FIREFISH Working Group: Joseph, J Volpe, John, Posner, Armin, Koch, Ulrich, Kellner, Rosaline, Quinlivan, Irina, Balikova, Patricia, Delbeke, Inge, Joniau, Valentine, Tahon, Sylvia, Wittevrongel, Elke De Vos, Edmar, Zanoteli, Rodrigo de Holanda Mendonça, Ciro Matsui Jr, Ana Letícia Fornazieri Darcie, Cleide, Machado, Maria Kiyoko Oyamada, Daniel de Souza Costa, Joyce, Martini, Graziela, Polido, Juliana Rodrigues Iannicelli, Juliana Caires de Oliveira Achili Ferreira, Wang, Yi, Chaoping, Hu, Yiyun, Shi, Shuizhen, Zhou, Xiaomei, Zhu, Chen, Qian, Shen, Li, Ying, Xiao, Zhenxuan, Zhou, Hui, Li, Sujuan, Wang, Hui, Xiong, Tian, Sang, Cuijie, Wei, Jing, Wen, Yiwen, Cao, Wenzhu, Li, Lun, Qin, Nina, Barisic, Ivan, Celovec, Martina Galiot Delic, Petra Kristina Ivkić, Nenad, Vukojević, Ivana, Kern, Boris, Najdanovic, Marin, Skugor, Odile, Boespflug-Tanguy, Teresa, Gidaro, Andrea, Seferian, Emmanuel, Barreau, Elodie Da Cunha, Céline, Lambotin, Nabila, Mnafek, Helene, Peche, Stephanie, Gilabert, Allison, Grange, Charlotte, Lilien, Darko, Milascevic, Ariadna, Perticari, Shotaro, Tachibana, Emanuela, Pagliano, Bianchi Marzoli, Stefania, Diletta, Santarsiero, Myriam Garcia Sierra, Gemma, Tremolada, Maria Teresa Arnoldi, Marta, Vigano, Riccardo, Zanin, Bissoli, Claudio Bruno, Noemi, Brolatti, Marina, Pedemonte, Enrico, Priolo, Giuseppe, Rao, Enrica, Spaletra, Lorenza, Sposetti, Elisa, Tassara, Simone, Morando, Paola, Tacchetti, Giacomo Pietro Comi, Alessandra, Govoni, Silvia Gabriella Osnaghi, Valeria, Minorini, Francesca, Abbati, Federica, Fassini, Michaela, Foa, Amalia, Lopopolo, Elisa, Minuti, Pane, Marika, Concetta, Palermo, Pera, Maria Carmela, Amorelli, Giulia Maria, Costanza, Barresi, Gugliemo, D'Amico, Orazi, Lorenzo, Coratti, Giorgia, De Sanctis, Roberto, Yasuhiro, Takeshima, Fumi, Gomi, Naoki, Kimura, Takanobu, Morimatsu, Mana, Okamoto, Toru, Furukawa, Maria, Mazurkiewicz-Bełdzińska, Mateusz, Koberda, Natalia, Kubiak, Urszula, Stodolska-Koberda, Agnieszka, Waśkowska, Jagoda, Kolendo, Agnieszka, Sobierajska-Rek, Dmitry, Vlodavets, Svetlana, Artemyeva, Evgenia, Melnik, Natalya, Leppenen, Nataliya, Yupatova, Elena, Litvinova, Anastasya, Monakhova, Yulia, Papina, Olga, Shidlovsckaia, Cornelia, Enzmann, Elea, Galiart, Konstantin, Gugleta, Patricia, Siems, Verena, Kreiliger, Christine Wondrusch Haschke, Haluk, Topaloglu, Ibrahim, Oncel, Didem, Ardicli, Nesibe Eroglu Ertugrul, Hizal, Gharibzadeh, Ceren, Gunbey, Bahadir, Konuskan, Selen Serel Arslan, Elams Ebru Yalcin, Fatma Gokcem Yildiz Sarikaya, Bora, Eldem, Sibel, Kadayıfçılar, Ipek, Alemdaroglu, Aynur Ayse Karaduman, Oznur Tunca Yilmaz, Lucia, Ambrosio, Anne, Fulton, Anna Maria Baglieri, Courtney, Dias, Elizabeth, Maczek, Elizabeth, Mirek, Amy, Pasternak, Shannon, Beres, Tina, Duong, Richard, Gee, Sally, Young, Giovanni, Baranello, Basil T, Darra, John W, Day, Nicolas, Deconinck, Andrea, Klein, Riccardo, Masson, Eugenio, Mercuri, Kristy, Rose, Muna, El-Khairi, Marianne, Gerber, Ksenija, Gorni, Omar, Khwaja, Heidemarie, Kletzl, Renata S, Scalco, Timothy, Seabrook, Paulo, Fontoura, Laurent, Servai, and Ambrosio, Lucia

Subjects
Male, Oral, Neuromuscular disease, RNA Splicing, Administration, Oral, 030204 cardiovascular system & hematology, Spinal Muscular Atrophies of Childhood, Bioinformatics, Dose-Response Relationship, 03 medical and health sciences, 0302 clinical medicine, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, medicine, Humans, Risdiplam, Type 1 Spinal Muscular Atrophy, 030212 general & internal medicine, Progression-free survival, 610 Medicine & health, Respiratory Tract Infections, Dose-Response Relationship, Drug, business.industry, Infant, Survival of motor neuron, General Medicine, Spinal muscular atrophy, medicine.disease, Survival of Motor Neuron 1 Protein, Progression-Free Survival, Clinical trial, Dose–response relationship, Settore MED/26 - NEUROLOGIA, Pyrimidines, nervous system, Neuromuscular Agents, RNA splicing, Administration, Female, Drug, business, Respiratory Insufficiency, Azo Compounds
Abstract

Background: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. Methods: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. Results: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. Conclusions: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).

Published
2021

21. Relationship between markers of disease activity and progression in skeletal muscle of GNE myopathy patients using quantitative nuclear magnetic resonance imaging and

Author

Harmen, Reyngoudt, Benjamin, Marty, Ericky, Caldas de Almeida Araújo, Pierre-Yves, Baudin, Julien, Le Louër, Jean-Marc, Boisserie, Anthony, Béhin, Laurent, Servais, Teresa, Gidaro, and Pierre G, Carlier

Subjects
Original Article
Abstract

BACKGROUND: Quantitative nuclear magnetic resonance imaging (NMRI) is an objective and precise outcome measure for evaluating disease progression in neuromuscular disorders. We aimed to investigate predictive ‘disease activity’ NMR indices, including water T(2) and (31)P NMR spectroscopy (NMRS), and its relation to NMR markers of ‘disease progression’, such as the changes in fat fraction (ΔFat%) and contractile cross-sectional area (ΔcCSA), in GNE myopathy (GNEM) patients. METHODS: NMR was performed on a 3T clinical scanner, at baseline and at a 1-year interval, in 10 GNEM patients and 29 age-matched controls. Dixon-based fat-water imaging and water T(2) mapping were acquired in legs and thighs, and in the dominant forearm. (31)P NMRS was performed at the level of quadriceps and hamstring. Water T(2) and (31)P NMRS indices were determined for all muscle groups and visits. Correlations were performed with ‘disease progression’ indices ΔFat%, ΔcCSA and the muscle fat transformation rate (R(muscle_transf)). RESULTS: In quadriceps, known to be relatively preserved in GNEM, water T(2) at baseline was significantly higher compared to controls, and correlated strongly with the one-year evolution of Fat% and cCSA and R(muscle_transf). Various (31)P NMRS indices showed significant differences in quadriceps and hamstring compared to controls and correlations existed between these indices and ΔFat%, ΔcCSA and R(muscle_transf). CONCLUSIONS: This study demonstrates that disease activity indices such as water T(2) and (31)P NMRS may predict disease progression in skeletal muscles of GNEM patients, and suggests that these measures may be considered to be valuable surrogate endpoints in the assessment of GNEM disease progression.

Published
2020

22. Global versus individual muscle segmentation to assess quantitative MRI-based fat fraction changes in neuromuscular diseases

Author

Olivier Benveniste, Benjamin Marty, Julien Le Louër, Brenda L. Wong, Yves Allenbach, Teresa Gidaro, P. Baudin, Jean-Marc Boisserie, Harmen Reyngoudt, Pierre G. Carlier, Cedi Koumako, Anthony Behin, Laurent Servais, Tanya Stojkovic, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire RMN AIM-CEA, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Division of Pediatric Neurology, Cincinnati Children's Hospital Medical Center, CHU Pitié-Salpêtrière [AP-HP], Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and University of Oxford

Subjects
medicine.medical_specialty, Dysferlinopathy, Neuromuscular disease, [SDV]Life Sciences [q-bio], Duchenne muscular dystrophy, Thigh, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Muscular dystrophy, Muscle, Skeletal, business.industry, Muscles, Skeletal muscle, General Medicine, Spinal muscular atrophy, Neuromuscular Diseases, medicine.disease, Magnetic Resonance Imaging, medicine.anatomical_structure, Adipose Tissue, Muscular Dystrophies, Limb-Girdle, 030220 oncology & carcinogenesis, Cardiology, Radiology, Inclusion body myositis, business
Abstract

Magnetic resonance imaging (MRI) constitutes a powerful outcome measure in neuromuscular disorders, yet there is a broad diversity of approaches in data acquisition and analysis. Since each neuromuscular disease presents a specific pattern of muscle involvement, the recommended analysis is assumed to be the muscle-by-muscle approach. We, therefore, performed a comparative analysis of different segmentation approaches, including global muscle segmentation, to determine the best strategy for evaluating disease progression. In 102 patients (21 immune-mediated necrotizing myopathy/IMNM, 21 inclusion body myositis/IBM, 10 GNE myopathy/GNEM, 19 Duchenne muscular dystrophy/DMD, 12 dysferlinopathy/DYSF, 7 limb-girdle muscular dystrophy/LGMD2I, 7 Pompe disease, 5 spinal muscular atrophy/SMA), two MRI scans were obtained at a 1-year interval in thighs and lower legs. Regions of interest (ROIs) were drawn in individual muscles, muscle groups, and the global muscle segment. Standardized response means (SRMs) were determined to assess sensitivity to change in fat fraction (ΔFat%) in individual muscles, muscle groups, weighted combinations of muscles and muscle groups, and in the global muscle segment. Global muscle segmentation gave high SRMs for ΔFat% in thigh and lower leg for IMNM, DYSF, LGMD2I, DMD, SMA, and Pompe disease, and only in lower leg for GNEM and thigh for IBM. Global muscle segment Fat% showed to be sensitive to change in most investigated neuromuscular disorders. As compared to individual muscle drawing, it is a faster and an easier approach to assess disease progression. The use of individual muscle ROIs, however, is still of interest for exploring selective muscle involvement. • MRI-based evaluation of fatty replacement in muscles is used as an outcome measure in the assessment of 1-year disease progression in 8 different neuromuscular diseases. • Different segmentation approaches, including global muscle segmentation, were evaluated for determining 1-year fat fraction changes in lower limb skeletal muscles. • Global muscle segment fat fraction has shown to be sensitive to change in lower leg and thigh in most of the investigated neuromuscular diseases.

Published
2020

23. Mild clinical presentation in KLHL40-related nemaline myopathy (NEM 8)

Author

John Rendu, Julien Fauré, Laurent Pelletier, Pierre G. Carlier, Laurent Servais, Norma B. Romero, Andreea Mihaela Seferian, Véronique Forin, Edoardo Malfatti, Teresa Gidaro, Jessica Taytard, E. Gargaun, C Bosson, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de réhabilitation pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), NMR Laboratory, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Institut de Myologie (U153 Inserm - IM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Centre de référence des maladies rares neuromusculaires [CHU Pitié-Salpétriêre], and HAL-UPMC, Gestionnaire

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Muscle Proteins, KLHL40, Biology, medicine.disease_cause, Myopathies, Nemaline, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Nemaline myopathy, medicine, Humans, Nemaline bodies, Child, Muscle, Skeletal, Genetics (clinical), Sanger sequencing, Mutation, Muscle biopsy, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, Genetic heterogeneity, medicine.disease, Hypotonia, 3. Good health, 030104 developmental biology, Phenotype, Neurology, Pediatrics, Perinatology and Child Health, symbols, Female, Neurology (clinical), Presentation (obstetrics), medicine.symptom, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Nemaline myopathies are clinically and genetically heterogeneous muscle diseases characterized by the presence of nemaline bodies (rods) in muscle fibers. Mutations in the KLHL40 (kelch-like family member 40) gene (NEM 8) are common cause of severe/lethal nemaline myopathy. We report an 8-year-old girl born to consanguineous Moroccan parents, who presented with hypotonia and poor sucking at birth, delayed motor development, and further mild difficulties in walking and fatigability. A muscle biopsy revealed the presence of nemaline bodies. KLHL40 gene Sanger sequencing disclosed a never before reported pathogenic homozygous mutation which resulted in absent KLHL40 protein expression in the muscle. This further expands the phenotypical spectrum of KLHL40 related nemaline myopathy.

Published
2020

24. Targeted exomes reveal simultaneous MFN2 and GDAP1 mutations in a severe Charcot‐Marie‐Tooth disease type 2 phenotype

Author

Ruxandra Cardas, Teresa Gidaro, A. Guiochon-Mantel, C. Anghelescu, Laurent Servais, P. Aubourg, and Bruno Francou

Subjects
0301 basic medicine, 030102 biochemistry & molecular biology, business.industry, MFN2, Bioinformatics, Phenotype, 03 medical and health sciences, Tooth disease, 0302 clinical medicine, Neurology, Medicine, Neurology (clinical), business, Exome, 030217 neurology & neurosurgery, Exome sequencing
Published
2020

25. DMD and West syndrome

Author

N. Butoianu, Teresa Gidaro, E. Gargaun, Svetlana Gataullina, Ruxandra Cardas, Laurent Servais, Thierry Bienvenu, Dana Craiu, Juliette Nectoux, Catrinel Iliescu, and Andreea Mihaela Seferian

Subjects
musculoskeletal diseases, Central Nervous System, Male, Pediatrics, medicine.medical_specialty, Duchenne muscular dystrophy, Dystrophin, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Seizures, 030225 pediatrics, medicine, Humans, Protein Isoforms, Muscular dystrophy, Genetics (clinical), biology, Seizure types, business.industry, Infant, West Syndrome, medicine.disease, Hypsarrhythmia, Muscular Dystrophy, Duchenne, Epileptic spasms, Neurology, Child, Preschool, Pediatrics, Perinatology and Child Health, Mutation, biology.protein, Neurology (clinical), medicine.symptom, business, Spasms, Infantile, 030217 neurology & neurosurgery
Abstract

Duchenne Muscular Dystrophy (DMD) is the most frequent muscular dystrophy in childhood, with a worldwide incidence of one in 5000 live male births. It is due to mutations in the dystrophin gene leading to absence of full-length dystrophin protein. Central nervous system involvement is well-known in Duchenne Muscular Dystrophy. The multiple dystrophin isoforms expressed in brain have important roles in cerebral development and functioning. The association of Duchenne Muscular Dystrophy with seizures has been reported, and there is a higher prevalence of epilepsy in Duchenne Muscular Dystrophy patients (between 6.3% and 12.3%) than in the general pediatric population (0.5–1%). Duchenne Muscular Dystrophy patients may present with focal seizures, generalized tonic-clonic seizures or absences. We report on two boys in whom Duchenne Muscular Dystrophy is associated with epileptic spasms and hypsarrhythmia that fulfil the criteria for West syndrome, thus extending the spectrum of seizure types described in Duchenne Muscular Dystrophy patients.

Published
2020

26. Normalized grip strength is a sensitive outcome measure through all stages of Duchenne muscular dystrophy

Author

Volker Straub, Valeria Ricotti, Jean-Yves Hogrel, Laurent Servais, Thomas Voit, Andreea Mihaela Seferian, Imelda J. M. de Groot, Marie De Antonio, Teresa Gidaro, Valérie Decostre, Erik H. Niks, Francesco Muntoni, Isabelle Ledoux, Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Leiden University Medical Center (LUMC), Radboud University Medical Center [Nijmegen], University College of London [London] (UCL), Centre Hospitalier Universitaire de Liège (CHU-Liège), University of Oxford [Oxford], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universiteit Leiden, University of Oxford, and Gestionnaire, Hal Sorbonne Université

Subjects
Duchenne muscular dystrophy, Adult, Male, medicine.medical_specialty, Adolescent, Normal values, Muscle Strength Dynamometer, Outcome measures, 03 medical and health sciences, Grip strength, Young Adult, 0302 clinical medicine, Physical medicine and rehabilitation, [SPI.MECA.BIOM] Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph], Outcome Assessment, Health Care, medicine, Humans, In patient, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030212 general & internal medicine, Child, Glucocorticoids, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Hand Strength, business.industry, [SPI.MECA.BIOM]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph], Reproducibility of Results, medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Muscular Dystrophy, Duchenne, Neurology, Child, Preschool, Cohort, Ambulatory, Disease Progression, Ceiling effect, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

Contains fulltext : 220816.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The main aim was to explore the changes in hand-grip strength in patients with Duchenne muscular dystrophy (DMD) aged 5-29 years. Secondary aims were to test the effect of mutation, ambulatory status and glucocorticoid use on grip strength and its changes over time and to compute the number of subjects needed for a clinical trial to stabilize grip strength. METHODS: The analysis was performed on data collected during five international natural history studies on a cohort of DMD patients. Two hundred and two patients with genetically proven DMD were pooled from five different natural history studies. Excepting 13 patients with only one visit, the mean duration of follow-up was 2.2 +/- 1.6 years. A total of 977 measurement points were collected. Grip strength was measured on the dominant side with a high precision dynamometer. The analysis was performed using absolute values and normalized values expressed in percentage of predicted values for age. RESULTS: For absolute values, grip strength typically increased in ambulatory boys and decreased in non-ambulatory patients. However, when normalized, grip strength was already reduced at age 5 years and thereafter continued to fall away from normal values. The weaker the patients, the less strength they are prone to lose over again. INTERPRETATION: Grip strength constitutes a sensitive and continuous outcome measure that can be used across all stages of DMD. Its measurement is easy to standardized, can be used in ambulatory and non-ambulatory patients and does not present any floor or ceiling effect. It is thus attractive as an outcome measure in therapeutic trials.

Published
2020

27. Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy

Author

Joana Domingos, Delphine Labolle, Teresa Gidaro, Francesco Muntoni, Florence Porte Thomé, Camilla Johansson, Stefano C. Previtali, Jordi Díaz-Manera, Pietro Spitali, Julian Gray, Mirko Signorelli, Stephanie Carnesecchi, Jacqueline Pitchforth, Alberto Zambon, Cristina Al-Khalili Szigyarto, Pascale Roux-Lombard, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hospital de la Santa Creu i Sant Pau, CIBER de Enfermedades Raras (CIBERER), Université de Genève (UNIGE), Geneva University Hospital (HUG), Leiden University Medical Center (LUMC), Royal Institute of Technology [Stockholm] (KTH ), Science for Life Laboratory [Solna], University College of London [London] (UCL), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université de Genève = University of Geneva (UNIGE), and Universiteit Leiden

Subjects
Male, 0301 basic medicine, musculoskeletal diseases, Cardiomyopathy, Duchenne muscular dystrophy, Administration, Oral, Pharmacokinetic, Duchenne Muscular Dystrophy, Pharmacology, ddc:616.07, Models, Biological, Drug Administration Schedule, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, Rimeporide, medicine, Humans, In patient, Child, Muscle, Skeletal, NHE-1, ComputingMethodologies_COMPUTERGRAPHICS, ddc:616, Sodium-Hydrogen Exchanger 1, business.industry, medicine.disease, Pathophysiology, 3. Good health, Europe, Muscular Dystrophy, Duchenne, Treatment Outcome, 030104 developmental biology, Neuromuscular Agents, chemistry, 030220 oncology & carcinogenesis, Pharmacodynamics, Heart failure, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Safety, business
Abstract

Graphical abstract, Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide’s anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6–11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies.

Published
2020

28. Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps

Author

Teresa Gidaro and Laurent Servais

Subjects
030506 rehabilitation, Pediatrics, medicine.medical_specialty, Oligonucleotides, MEDLINE, SMN1, Approved drug, Muscular Atrophy, Spinal, 03 medical and health sciences, 0302 clinical medicine, Developmental Neuroscience, medicine, Milestone (project management), Animals, Humans, Drug Approval, business.industry, Spinal muscular atrophy, medicine.disease, SMA, Expanded access, Pediatrics, Perinatology and Child Health, Nusinersen, Neurology (clinical), 0305 other medical science, business, 030217 neurology & neurosurgery, Central Nervous System Agents
Abstract

Spinal muscular atrophy (SMA) is a recessive disorder caused by a mutation in the survival motor neuron 1 gene (SMN1); it affects 1 in 11 000 newborn infants. The most severe and most common form, type 1 SMA, is associated with early mortality in most cases and severe disability in survivors. Nusinersen, an antisense oligonucleotide, promotes production of full-length protein from the pseudogene SMN2. Nusinersen treatment prolongs survival of patients with type 1 SMA and allows motor milestone acquisition. Patients with type 2 SMA also show progress on different motor scales after nusinersen treatment. Nusinersen was recently approved by the European Medicines Agency and the US Food and Drug Administration; it is now reimbursed in several European countries and in the USA. In Australia, the transition from expanded access programme to commercial availability is coming soon. In New Zealand, an expanded access programme is opened, and in Canada price negotiation for the treatment is in progress. In this review we exemplify the clinical benefit of nusinersen in subgroups of patients with SMA. Nusinersen represents the first efficacious marked approved drug in type 1 and type 2 SMA. Different knowledge gaps, such as results in older patients, in patients with permanent ventilation, in patients with neonatal forms, or in patients after spinal fusion, still need to be addressed. WHAT THIS PAPER ADDS: Identifies gaps in knowledge about the efficacy of nusinersen in broader populations of patients with spinal muscular atrophy. Identifies open questions in populations of patients where proof of efficacy is available.

Published
2018

29. Home-Based Monitor for Gait and Activity Analysis

Author

Marc Grelet, Teresa Gidaro, David Vissiere, C. Lilien, Andreea Mihaela Seferian, Erwan Gasnier, and Laurent Servais

Subjects
Male, medicine.medical_specialty, Computer science, General Chemical Engineering, STRIDE, Wearable computer, Accelerometer, General Biochemistry, Genetics and Molecular Biology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Wheelchair, Gait (human), law, medicine, Humans, Gait, Monitoring, Physiologic, General Immunology and Microbiology, General Neuroscience, Gyroscope, Barometer, House Calls, 030220 oncology & carcinogenesis, Female, Docking station, 030217 neurology & neurosurgery
Abstract

Current outcomes in neuromuscular disorder clinical trials include motor function scales, timed tests, and strength measures performed by trained clinical evaluators. These measures are slightly subjective and are performed during a visit to a clinic or hospital and constitute therefore a point assessment. Point assessments can be influenced by daily patient condition or factors such as fatigue, motivation, and intercurrent illness. To enable home-based monitoring of gait and activity, a wearable magneto-inertial sensor (WMIS) has been developed. This device is a movement monitor composed of two very light watch-like sensors and a docking station. Each sensor contains a tri-axial accelerometer, gyroscope, magnetometer, and a barometer that record linear acceleration, angular velocity, the magnetic field of the movement in all directions, and barometric altitude, respectively. The sensors can be worn on the wrist, ankle, or wheelchair to record the subject's movements during the day. The docking station enables data uploading and recharging of sensor batteries during the night. Data are analyzed using proprietary algorithms to compute parameters representative of the type and intensity of the performed movement. This WMIS can record a set of digital biomarkers, including cumulative variables, such as total number of meters walked, and descriptive gait variables, such as the percentage of the most rapid or longest stride that represents the top performance of patient over a predefined period of time.

Published
2019

30. X-linked myotubular myopathy: A prospective international natural history study

Author

A. Hernandez, Andrea Gangfuß, V. Chê, Adele D'Amico, Rémi Bellance, Laurent Servais, Capucine de Lattre, Basil T. Darras, E. Gargaun, James J. Dowling, Teresa Gidaro, C. Lilien, Ulrike Schara, A. Daron, Ana Buj-Bello, H. Landy, Jean-Marie Cuisset, Carole Vuillerot, Jean-Yves Hogrel, S. Fontaine, Jean-Michel Arnal, Valérie Biancalana, Michèle Mayer, M. Annoussamy, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Advanced BC.org, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Neuromuscular Physiology and Evaluation Laboratory, Service of Clinical Trials and Databases, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Adult, Male, Vital capacity, medicine.medical_specialty, Neuromuscular disease, Adolescent, [SDV]Life Sciences [q-bio], Population, Medizin, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Humans, Longitudinal Studies, Prospective Studies, education, Prospective cohort study, Child, education.field_of_study, business.industry, Exhalation, Infant, Middle Aged, medicine.disease, X-linked myotubular myopathy, 3. Good health, 030104 developmental biology, Phenotype, Child, Preschool, Breathing, Disease Progression, Neurology (clinical), business, 030217 neurology & neurosurgery, Natural history study, Follow-Up Studies, Myopathies, Structural, Congenital
Abstract

ObjectivesBecause X-linked myotubular myopathy (XLMTM) is a rare neuromuscular disease caused by mutations in the MTM1 gene with a large phenotypic heterogeneity, to ensure clinical trial readiness, it was mandatory to better quantify disease burden and determine best outcome measures.MethodsWe designed an international prospective and longitudinal natural history study in patients with XLMTM and assessed muscle strength and motor and respiratory functions over the first year of follow-up. The humoral immunity against adeno-associated virus serotype 8 was also monitored.ResultsForty-five male patients aged 3.5 months to 56.8 years were enrolled between May 2014 and May 2017. Thirteen patients had a mild phenotype (no ventilation support), 7 had an intermediate phenotype (ventilation support less than 12 hours a day), and 25 had a severe phenotype (ventilation support 12 or more hours a day). Most strength and motor function assessments could be performed even in very weak patients. Motor Function Measure 32 total score, grip and pinch strengths, and forced vital capacity, forced expiratory volume in the first second of exhalation, and peak cough flow measures discriminated the 3 groups of patients. Disease history revealed motor milestone loss in several patients. Longitudinal data on 37 patients showed that the Motor Function Measure 32 total score significantly decreased by 2%. Of the 38 patients evaluated, anti–adeno-associated virus type 8 neutralizing activity was detected in 26% with 2 patients having an inhibitory titer >1:10.ConclusionsOur data confirm that XLMTM is slowly progressive for male survivors regardless of their phenotype and provide outcome validation and natural history data that can support clinical development in this population.ClinicalTrials.gov identifierNCT02057705.

Published
2019

31. P.200 Feasibility and baseline values of continuous movement measurement in patients with centronuclear myopathy by using ActiMyo®

Author

J.Y. Hogrel, H. Landy, Ulrike Schara, V. Chê, Teresa Gidaro, Alessandra D'Amico, Andreea Mihaela Seferian, C. Lilien, L. Servais, M. Annoussamy, Jonathan Baets, Chris Freitag, M. Grelet, Anna Buj-Bello, A. Hernandez, Dominique Duchene, C. de Lattre, Anthony Behin, A. Grangé, and E. Gasnier

Subjects
Baseline values, medicine.medical_specialty, business.industry, Movement measurement, Medizin, medicine.disease, Neurology, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, Cardiology, In patient, Neurology (clinical), Centronuclear myopathy, business, Genetics (clinical)
Published
2019

32. Longitudinal functional and NMR assessment of upper limbs in Duchenne muscular dystrophy

Author

Gwenn Ollivier, Aurélie Canal, Laurent Servais, Jean-Yves Hogrel, Valérie Decostre, Noura Azzabou, Teresa Gidaro, Isabelle Ledoux, Anne Gaelle Le Moing, C. Lilien, Pierre G. Carlier, M. Annoussamy, Nacera Reguiba, Thomas Voit, Amélie Moraux, Ruxandra Cardas, Claire Wary, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and DESSAIVRE, Louise

Subjects
Male, medicine.medical_specialty, Magnetic Resonance Spectroscopy, Adolescent, [SDV]Life Sciences [q-bio], Duchenne muscular dystrophy, Fat infiltration, Article, 030218 nuclear medicine & medical imaging, Phosphocreatine, Upper Extremity, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, Longitudinal Studies, Muscular dystrophy, Sensitivity to change, Child, business.industry, Nuclear magnetic resonance spectroscopy, medicine.disease, [SDV] Life Sciences [q-bio], Muscular Dystrophy, Duchenne, medicine.anatomical_structure, chemistry, Ambulatory, Cardiology, Upper limb, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

International audience; Objective:To explore the value of nuclear magnetic resonance (NMR) and functional assessments for follow-up of ambulatory and nonambulatory patients with Duchenne muscular dystrophy (DMD).Methods:Twenty-five 53-skippable patients with DMD were included in this study; 15 were nonambulatory at baseline. All patients underwent clinical and functional assessments every 6 months using the Motor Function Measure (MFM), hand grip and key pinch strength, MoviPlate, and NMR spectroscopy and imaging studies.Results:Upper limb distal strength decreased in nonambulatory patients over the period of 1 year; ambulatory patients showed improvement during the same period. The same applied for several NMRS indices, such as phosphocreatine/adenosine triphosphate, which decreased in older patients but increased in younger ambulatory patients. Fat infiltration in the upper limbs increased linearly with age. Almost all NMR and functional assessment results correlated.Conclusions:Our results underscore complementarity of functional and NMR assessments in patients with DMD. Sensitivity to change of various indices may differ according to disease stage.

Published
2016

33. Nusinersen in patients older than 7 months with spinal muscular atrophy type 1: A cohort study

Author

Juliette Ropars, Karolina Aragon-Gawinska, Andreea Mihaela Seferian, Jessica Taytard, Laurent Servais, Jerome Rambaud, Carole Vuillerot, Chiara Marini-Bettolo, Teresa Gidaro, Claude Cances, M. Annoussamy, Mariacristina Scoto, Mondher Chouchane, Inge Cuppen, A. Daron, E. Gargaun, Imelda Hughes, and Marjorie Illingworth

Subjects
0301 basic medicine, Male, Pediatrics, medicine.medical_specialty, DNA Copy Number Variations, Movement, Oligonucleotides, Phases of clinical research, Spinal Muscular Atrophies of Childhood, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Severity of illness, medicine, Humans, Longitudinal Studies, Stage (cooking), Child, Injections, Spinal, business.industry, Respiration, Infant, Spinal muscular atrophy, medicine.disease, Clinical trial, Survival of Motor Neuron 2 Protein, 030104 developmental biology, Treatment Outcome, Expanded access, Child, Preschool, Nusinersen, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Cohort study
Abstract

ObjectiveTo evaluate the safety and clinical efficacy of nusinersen in patients older than 7 months with spinal muscular atrophy type 1 (SMA1).MethodsPatients with SMA1 were treated with nusinersen by intrathecal injections as a part of the Expanded Access Program (EAP; NCT02865109). We evaluated patients before treatment initiation (M0) and at 2 months (M2) and 6 months (M6) after treatment initiation. Survival, respiratory, and nutritional data were collected. Motor function was assessed with the modified Hammersmith Infant Neurologic Examination Part 2 (HINE-2) and physiotherapist scales adjusted to patient age (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and the Motor Function Measure 20 or 32).ResultsWe treated 33 children ranging in age from 8.3 to 113.1 months between December 2016 and May 2017. All patients were alive and were continuing treatment at M6. Median progress on the modified HINE-2 score was 1.5 points after 6 months of treatment (p < 0.001). The need for respiratory support significantly increased over time. There were no statistically significant differences between patients presenting with 2 and those presenting with 3 copies of the survival motor neuron 2 (SMN2) gene.ConclusionsOur results are in line with the phase 3 study for nusinersen in patients with SMA1 treated before 7 months of age and indicate that patients benefit from nusinersen even at a later stage of the disease.ClinicalTrials.gov identifier:NCT02865109.Classification of evidenceThis study provides Class IV evidence that for patients with SMA1 who are older than 7 months, nusinersen is beneficial.

Published
2018

34. MRI – MUSCLE IMAGING

Author

Anthony Behin, Y. Allenbach, Teresa Gidaro, P. Baudin, Benjamin Marty, L. Servais, Cedi Koumako, Jean-Marc Boisserie, Olivier Benveniste, Harmen Reyngoudt, Pierre G. Carlier, J. Le Louër, Brenda Wong, and T. Stojkovic

Subjects
Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Genetics (clinical)
Published
2019

35. P.107Clinical changes over time in patients with centronuclear myopathy due to mutations in DNM2 gene enrolled in a European prospective natural history study

Author

C. Lilien, Nicol C. Voermans, A. Grangé, Teresa Gidaro, L. Servais, V. Chê, Andreea Mihaela Seferian, Jonathan Baets, Anthony Behin, W. De Ridder, M. Annoussamy, C. Freitag, L. Thielemans, Marc Bitoun, K. Paradis, J.Y. Hogrel, S. Van Rooijen, and D. Duchene

Subjects
medicine.medical_specialty, business.industry, medicine.disease, DNM2, Neurology, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, In patient, Neurology (clinical), Centronuclear myopathy, business, Gene, Genetics (clinical), Natural history study
Published
2019

36. P.240ASC-1 related myopathy: phenotypic spectrum and pathophysiology of an emerging congenital myopathy

Author

L. Servais, Nicolas Deconinck, Teresa Gidaro, Montse Olivé, Johann Böhm, E. Pierce-Hoffman, A. Koparir, Ana Ferreiro, R. Juntas-Morales, Casie A. Genetti, Isabelle Duband-Goulet, L. Davignon, Alan H. Beggs, Eva Cabet, A. Yuksel, Rocío-Nur Villar-Quiles, Mireille Cossée, and Sandra Coppens

Subjects
Pathology, medicine.medical_specialty, business.industry, medicine.disease, Congenital myopathy, Phenotype, Pathophysiology, Neurology, Pediatrics, Perinatology and Child Health, Medicine, Neurology (clinical), medicine.symptom, business, Myopathy, Genetics (clinical)
Published
2019

37. Invited review: Stem cells and muscle diseases: advances in cell therapy strategies

Author

Vincent Mouly, Gillian Butler-Browne, Anne Bigot, Elisa Negroni, Capucine Trollet, and Teresa Gidaro

Subjects
Histology, Cell, Biology, medicine.disease, Embryonic stem cell, 3. Good health, Pathology and Forensic Medicine, Transplantation, Cell therapy, medicine.anatomical_structure, Neurology, Physiology (medical), Immunology, medicine, Myocyte, Neurology (clinical), Stem cell, Muscular dystrophy, Induced pluripotent stem cell, Neuroscience
Abstract

Despite considerable progress to increase our understanding of muscle genetics, pathophysiology, molecular and cellular partners involved in muscular dystrophies and muscle ageing, there is still a crucial need for effective treatments to counteract muscle degeneration and muscle wasting in such conditions. This review focuses on cell-based therapy for muscle diseases. We give an overview of the different parameters that have to be taken into account in such a therapeutic strategy, including the influence of muscle ageing, cell proliferation and migration capacities, as well as the translation of preclinical results in rodent into human clinical approaches. We describe recent advances in different types of human myogenic stem cells, with a particular emphasis on myoblasts but also on other candidate cells described so far [CD133+ cells, aldehyde dehydrogenase-positive cells (ALDH+), muscle-derived stem cells (MuStem), embryonic stem cells (ES) and induced pluripotent stem cells (iPS)]. Finally, we provide an update of ongoing clinical trials using cell therapy strategies.

Published
2015

38. EGR2 mutation enhances phenotype spectrum of Dejerine–Sottas syndrome

Author

Cécile Masson, Isabelle Nelson, Ruxandra Cardas, Marie-Thérèse Bihoreau, Laurent Servais, Catherine Delanoe, Jean-François Deleuze, E. Gargaun, Gisèle Bonne, Anne Boland, Andreea Mihaela Seferian, Teresa Gidaro, Juliette Nectoux, Anne-Gaëlle Le Moing, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unité de Neurophysiologie [AP-HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Sorbonne Université (SU), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)

Subjects
0301 basic medicine, Genetics, education.field_of_study, Early Growth Response Protein 2, business.industry, [SDV]Life Sciences [q-bio], Phenotype, DEJERINE-SOTTAS SYNDROME, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, Mutation (genetic algorithm), DNA Mutational Analysis, Medicine, Neurology (clinical), education, business, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery
Abstract

International audience

Published
2016

39. New myotubular myopathy classification

Author

L. Servais, C. deLattre, V. Chê, Jean-Marie Cuisset, J.Y. Hogrel, A. Hernandez, E. Gargaun, Teresa Gidaro, Rémi Bellance, A. Daron, C. Lilien, S. Fontaine, M. Mayer, Ulrike Schara, H. Landy, Valérie Biancalana, Carole Vuillerot, Anna Buj-Bello, Alessandra D'Amico, M. Annoussamy, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, and Généthon

Subjects
0303 health sciences, Pathology, medicine.medical_specialty, business.industry, Medizin, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 03 medical and health sciences, 0302 clinical medicine, Neurology, Pediatrics, Perinatology and Child Health, Medicine, Myotubular Myopathy, Neurology (clinical), business, 030217 neurology & neurosurgery, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2017

40. Longitudinal data of the European prospective natural history study of patients with type 2 and 3 spinal muscular atrophy

Author

Claude Cances, Jean-Marie Cuisset, Linda Lowes, Vincent Laugel, Laurent Servais, Teresa Gidaro, A. Chabanon, M. Annoussamy, Ulrike Schara, A. Daron, Omar Khwaja, Carole Vuillerot, Ricardo Hermosilla, J.Y. Hogrel, Andreea Mihaela Seferian, Nathalie Goemans, E. Gargaun, Yann Péréon, Pierre G. Carlier, and Christian Czech

Subjects
0301 basic medicine, medicine.medical_specialty, Longitudinal data, business.industry, Medizin, Spinal muscular atrophy, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Physical medicine and rehabilitation, Neurology, Pediatrics, Perinatology and Child Health, Physical therapy, medicine, Neurology (clinical), business, 030217 neurology & neurosurgery, Genetics (clinical), Natural history study
Published
2017

41. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

Author

S. Richardson, E. Kimber, H. Kim, Diana Castro, H. Johnson, A. C. Tesi Rocha, Matthias Eckenweiler, C. Manzitti, John W. Day, R. De Sanctis, M. Gormley, Mar Tulinius, Mirac Yildirim, C. M. Temucin, M. Gratacos Vinola, S. Matsumaru, F. Weber-Guzman, J. Kitsuwa-Lowe, Lavinia Fanelli, T. Sato, W. C. Virginia, J. H. Hsu, S. Nagata, A. Michoulas, Sally Dunaway, Mariacristina Scoto, R. Shell, R. Laine, D. DiBella, C. King, Jacqueline Montes, Haluk Topaloglu, Maryam Oskoui, Didem Ardicli, K. Rupprich, C. Stella, F. Dorban, Alan C Farrow-Gillespie, S. A. Choi, T. Ikai, W. C. Liang, N. Matsushima, PH Lister, Arnaud Vanlander, N. Rausch, T. T. Duong, Marika Pane, Melissa Gibbons, M. M. Homi, A. K. Kroksmark, B. Andres, Kristin J. Krosschell, S. Patnaik, L. Welsh, Eduardo F. Tizzano, M. Gallardo, Michèle Mayer, Sarada Sakamuri, W. Liew, T. Spain, M. Yang, Kayoko Saito, Edward C. Smith, L. Sanabria, Astrid Pechmann, H. Kaneko, Leslie Nelson, Basil T. Darras, C. Milleson, Janbernd Kirschner, R. Arakawa, Margot Morrison, Y. Kaburagi, P. Dinunzio, C. K.W. Joseph, M. Chadehumbe, Craig M. Zaidman, S. Nicolarsen, Hyung Ik Shin, Alberto Garaventa, James J. Dowling, J. S. Lee, K. Booker, A. Takeshita, D. McElroy, K. Carroll, D. Vens, Y. Chiba, L. Wand, C. Kelly, Luke Smith, H. Shimomura, M. Srour, J. B. Bodensteriner, B. Rippberger, A. Herbert, Eugenio Mercuri, H. Jo, J. Turner, A. Camuto, N. Parziale, J. O'Brien, N. Nelson, E. Serdaroglu, Jong-Hee Chae, V. Tahon, E. Toro Tamargo, L. Weimer, T. Voit, L. W.M. Wendy, J. Rambaud, G. Gilbert, C. Zimmerman, S. Kramer, D. McFall, Jennifer Perez, N. Berthon-Jones, Jessica Taytard, Marco Luigetti, J. Pisco Domingos, R. Van Der Looven, Genevieve D'Souza, C. Berde, E. Roland, M. de Los Angeles Tormos Munoz, J. Zigmont, S. Baily, S. Gilabert, H. Nakatsukasa, S. Trest, Bahadır Konuşkan, H. A. Ferreira Sampaio, Z. John Zhong, G. VanderVeen, V. Allen, C. Aguilar, N. Taniguchi, G. Ordonez, Elizabeth Kichula, F. Shu, M. N. Chui-San, M. Zinn, Anne M. Connolly, Ian R. Woodcock, Ayşe Karaduman, R. Haldenby, K. Hirasawa, F. Munell Casadesus, L.D.M. Peña, Vamshi K. Rao, Allan M. Glanzman, Claudia A. Chiriboga, A. Martinez Bermejo, John F. Brandsema, S. Epinosa Garcia, M. K. Schroth, T. Shibano, Richard Gee, Valeria Ricotti, Y. Ito, Y. Tanaka, S. Arpin, C. S. Yan, L. Schottlaender, Marco Piastra, M. Kauk, Francesco Muntoni, K. Sugimoto, Öznur Yilmaz, K. DeCock, Kathryn Selby, T. Yanagishita, Concetta Palermo, H. W. Chung, B. Taicher, Jiri Vajsar, K. Zilke, R. Gadeken, A. Yamauchi, Marta Bertoli, Nancy L. Kuntz, T. Tachikawa, C. Johnson, A. Mayhew, Jahannaz Dastgir, Y. J. Jong, P. C. Chou, G. Rivera, T. N. Shun, Y. H. Ju, N. Holuba La Marca, M. Toms, Matthew Civitello, Eugene Schneider, C. Lilien, S. Ito, C. Skura, Y. Yvonne, K. O'Reardon, Barry S. Russman, Janet Quigley, J. W. Said, B. Planas Pascual, R. J. Ramamurthi, Wildon Farwell, V. Selby, W. Y. Connie, M. Souris, Nicholas E. Johnson, M. Miki, N. Sponemann, Andrei Constantinescu, K. Mayne, H. H. Shih, B. Sanjanwala, Teresa Gidaro, D. Berry, Gihan Tennekoon, A. G. Le Moing, Danielle Ramsey, C. Poulin, S. Goldman, K. Watson, H. L. Teoh, N. J. Palacios, Tai-Heng Chen, A. C. Chung, Terri Carry, J. Coates, D. Zielinski, R. Vialle, F. G. Yildiz Sarikaya, Marcus Krüger, M. del Mar Garcia Romero, E. Michael, E. D. Austin, J. Janas, K. Engelstad, S. Y. Kim, M. Alavarez Molinero, Leon G. Epstein, Monique M. Ryan, Jean Flickinger, D. Benjamin, S. Wider, C. S. Davis, Jena M. Krueger, I. J.K. Janice, Darryl C. De Vivo, M. del Mar Melendez Plumed, Y. Takeshima, C. Gunbey, Serena Sivo, A. Christiaens, Q. Ollievier, Elizabeth Mirek, D. Stanford, Susan T. Iannaccone, Jonathan E. Kurz, D. Cook, C. S. Ng, A. Koka, V. Chau, M. del Pilar Tirado Requero, M. B. Gomez Garcia de la Banda, E. M. Yiu, Amy Pasternak, Rosangel Cruz, S. So, S. I. Pascual Pascual, V. G. Haliloglu, E. S. Schroers, P. Jachertz, C. Ortiz-Miller, Sandra Coppens, J. Lee, M. Popolizio, Michael Doumit, Rachel Salazar, Michelle A. Farrar, Peter G. Fuhr, M. Pedermonte, L. S. Lord-Halvorson, W. Leon, Y. S. Zeng, L. D'Argenzio, Russell J. Butterfield, C. Blomgren, Erika Finanger, S. Shea, Paola Tacchetti, N. Y. Ki, H. W. Choi, K. Oriyama, S. Wittevrongel, Catherine Siener, K. Mizuochi, M. Cowie, R. Van Coster, E. Gargaun, S. M. Scuplak, Sibylle Vogt, S. Stein, Tim Harrington, P. M. Ingelmo, J. Wootton, M. Tanyildiz, A. F. Rucian, Jonathan Marra, C. Frank Bennett, Claire L Wood, Nicolas Deconinck, Adnan Y. Manzur, Helene Verhelst, B. Purse, P. L. Léger, J. Cappell, S. Aziz-Zaman, H. Y. Wang, Claudio Bruno, S. Garcia Guixot, Robert Muni Lofra, Federica Trucco, S. M. Chun, Catherine E. Roberts, Ulrike Schara, Walter G. Bradley, K. L. De Valle, E. De Vos voor, S. Borell, A. Lim, Sophelia H. S. Chan, L. Rao, M. Shichiji, S. Rooze, T. M. Newcomb, Fouad Al-Ghamdi, Chiara Fiorillo, J. D. Endsley, L. Y. Sigurdardottir, Pallavi Anand, A. Zuffi, Julie A. Parsons, M. Kasper, A. Nishikawa, Sarah Gheuens, S. Turgeon-Desilet, T. Fujino, L. Staudt, Y. C. Wu, Jacinda B. Sampson, Paola Lanteri, Stephanie DeArmey, Partha S. Ghosh, Alexandra C. Ross, L. Adang, Laurent Servais, V. Tran, Alan Bielsky, Y. Otani, Navil F. Sethna, J. Hen, Perry B. Shieh, N. Fukuda, N. Miller, K. Eto, S. Paulose, Niklas Darin, C. Sabapathy, Robert J. Graham, Christopher Proud, Richard S. Finkel, Alexander G. Khandji, A. Della Marina, Adrian Murphy, Kathie M. Bishop, Tejaswi Kandula, Valentina Lanzillotta, Heather Szelag, Kalliopi Sofou, Y. H. Chou, Heike Koelbel, J. Eldblom, T. Lee, M. M. Martinez Moreno, Volker Straub, Laura E. Case, A. Lindstedt, G. Gili, A. Frank, H. C.C. Alvin, A. Ganfuss, Karen Herbert, Paul T. Golumbek, D. Villano, B. Wenderickx, B. C. Lim, W. S. Son, Schara, Ulrike (Beitragende*r), Ganfuss, Andrea (Beitragende*r), Koelbel, Heike (Beitragende*r), Rupprich, Katrin (Beitragende*r), Schroers, Ester Sarah (Beitragende*r), Sponemann, Nina (Beitragende*r), and Çocuk Sağlığı ve Hastalıkları

Subjects
Male, 0301 basic medicine, Pathology, Movement disorders, animal diseases, Messenger, Oligonucleotides, Medizin, Spinal Muscular Atrophies of Childhood, 0302 clinical medicine, Age of Onset, Disease-Free Survival, Double-Blind Method, Female, Humans, Infant, Injections, Spinal, Motor Skills, Oligonucleotides, Antisense, RNA, Messenger, Respiration, Artificial, Survival Analysis, Survival of Motor Neuron 2 Protein, Medicine (all), Respiration, General Medicine, Settore MED/26 - NEUROLOGIA, medicine.anatomical_structure, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Artificial, Nusinersen, medicine.symptom, medicine.medical_specialty, Spinal, Injections, 03 medical and health sciences, Atrophy, General & Internal Medicine, Settore MED/41 - ANESTESIOLOGIA, medicine, Antisense, Survival analysis, business.industry, Spinal muscular atrophy, Motor neuron, medicine.disease, nervous system diseases, 030104 developmental biology, nervous system, RNA, Infantile onset, Age of onset, business, 030217 neurology & neurosurgery
Abstract

Background: Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre–messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. Methods: We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. Results: In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P Conclusions: Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug.

Published
2017

42. Congenital muscular dystrophy phenotype with neuromuscular spindles excess in a 5-year-old girl caused by HRAS mutation

Author

Anamaria Bolocan, Dominique P. Germain, Susana Quijano-Roy, Michel Fardeau, Teresa Gidaro, Nathalie Blin, Brigitte Estournet, Anne-Gaëlle Le Moing, Robert Carlier, Laurent Servais, Andreea Mihaela Seferian, Valérie Allamand, Hélène Cavé, Pascale Richard, C. Gartioux, Thomas Voit, Norma B. Romero, and Clarisse Baumann

Subjects
Ullrich congenital muscular dystrophy, DNA Mutational Analysis, Muscular Dystrophies, Amino Acyl-tRNA Synthetases, medicine, Humans, Missense mutation, HRAS, Muscle Spindles, Kyphoscoliosis, Genetics (clinical), Muscle biopsy, medicine.diagnostic_test, business.industry, Skeletal muscle, Anatomy, medicine.disease, Magnetic Resonance Imaging, medicine.anatomical_structure, Neurology, Child, Preschool, Mutation, Pediatrics, Perinatology and Child Health, Congenital muscular dystrophy, Female, Neurology (clinical), Differential diagnosis, business
Abstract

We report on a 5-year-old girl who presented with an association of symptoms reminiscent of an Ullrich-like congenital muscular dystrophy including congenital hypotonia, proximal joint contractures, hyperlaxity of distal joints, normal cognitive development, and kyphoscoliosis. There was an excess of neuromuscular spindles on the skeletal muscle biopsy. This very peculiar feature on muscle biopsy has been reported only in patients with mutations in the HRAS gene. Sequence analysis of the subject's HRAS gene from blood leukocytes and skeletal muscle revealed a previously described heterozygous missense mutation (c.187G>A, p. Glu63Lys). The present report thus extends the differential diagnosis of congenital muscular dystrophy with major "retractile" phenotypes and adds congenital muscular dystrophy to the clinical spectrum of HRAS-related disorders.

Published
2014

43. Nuclear poly(A)-binding protein aggregates misplace a pre-mRNA outside of SC35 speckle causing its abnormal splicing

Author

Bruno Bastide, Alberto Malerba, Vincent Mouly, George Dickson, Capucine Trollet, Fanny Roth, Sophie Périé, Jean Lacau St Guily, Teresa Gidaro, Linda Popplewell, Gillian Butler-Browne, Valérie Montel, Pierre Klein, Susan Jarmin, Michael Antoniou, Martine Oloko, Pierre de la Grange, Univ. Littoral Côte d’Opale, Univ. Artois, Université de Lille, Université Pierre et Marie Curie - Paris 6 [UPMC], Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 [URePSSS], Royal Holloway [University of London] [RHUL], CHU Pitié-Salpêtrière [AP-HP], Guy's Hospital [London], Centre de recherche en myologie, University of London [London], HAL UPMC, Gestionnaire, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 (URePSSS), Université d'Artois (UA)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille, Royal Holloway, School of Biological Sciences (ROYAL HOLLOWAY), Queen Mary University of London (QMUL), Oto-Rhino-Laryngologie Chirurgie cervico-faciale [CHU Tenon], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), GenoSplice technology, Incubateur et Pépinière d'Entreprises Paris-Salpêtrière (iPEPS-ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université d'Artois (UA)-Université de Lille-Université du Littoral Côte d'Opale (ULCO), Service d’ORL et de chirurgie cervico-faciale [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and GenoSplice [Paris]

Subjects
Adult, Male, 0301 basic medicine, Exonic splicing enhancer, Mice, Transgenic, RNA-binding protein, Biology, Splicing, Poly(A)-Binding Protein I, RNA Transport, Mice, Protein Aggregates, 03 medical and health sciences, Splicing factor, Exon, 0302 clinical medicine, SR protein, Muscular Dystrophy, Oculopharyngeal, Troponin T, Protein splicing, RNA Precursors, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Muscle, Skeletal, Aged, Aged, 80 and over, Aggregate, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Serine-Arginine Splicing Factors, Alternative splicing, Middle Aged, Molecular biology, Cell biology, Alternative Splicing, HEK293 Cells, 030104 developmental biology, Case-Control Studies, OPMD, RNA splicing, RNA, TNNT3, Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, 80 and over, Transgenic, Muscle, Skeletal, Muscular Dystrophy, Oculopharyngeal
Abstract

International audience; A short abnormal polyalanine expansion in the polyadenylate-binding protein nuclear-1 (PABPN1) protein causes oculopharyngeal muscular dystro-phy (OPMD). Mutated PABPN1 proteins accumulate as insoluble intranuclear aggregates in muscles of OPMD patients. While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice have been established, the molecular mechanisms which trigger pathological defects in OPMD and the role of aggregates remain to be determined. Using exon array, for the first time we have identified several splicing defects in OPMD. In particular, we have demonstrated a defect in the splicing regulation of the muscle-specific Troponin T3 (TNNT3) mutually exclusive exons 16 and 17 in OPMD samples compared to controls. This splicing defect is directly linked to the SC35 (SRSF2) splicing factor and to the presence of nuclear aggregates. As reported here, PABPN1 aggregates are able to trap TNNT3 pre-mRNA, driving it outside nuclear speck-les, leading to an altered SC35-mediated splicing. This results in a decreased calcium sensitivity of muscle fibers, which could in turn plays a role in muscle pathology. We thus report a novel mechanism of alternative splicing deregulation that may play a role in various other diseases with nuclear inclusions or foci containing an RNA binding protein.

Published
2016

44. SMA THERAPIES I

Author

Imelda Hughes, A. Daron, Karen L. White, Chiara Marini-Bettolo, Teresa Gidaro, Ana Ulinici, Andreea Mihaela Seferian, M. Chouchane, Mariacristina Scoto, M. Annoussamy, Juliette Ropars, L. Vanden Brande, M. Illingworth, Z. Balintova, I. Cuppen, L. Servais, Claude Cances, Nicolas Deconinck, S. Modrzejewska, Carole Vuillerot, and Karolina Aragon-Gawinska

Subjects
Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), SMA, Genetics (clinical)
Published
2018

45. O.28Safety and tolerability of suvodirsen (WVE-210201) in patients with Duchenne muscular dystrophy: results from a phase 1 clinical trial

Author

S. Schmitz, Teresa Gidaro, F. Muntoni, V. Straub, L. Servais, L. Cripe, X. Hu, S. Lake, M. Eagle, H. Phan, Kathryn R. Wagner, M. Panzara, and P. Lonkar

Subjects
medicine.medical_specialty, business.industry, Duchenne muscular dystrophy, Phases of clinical research, medicine.disease, Neurology, Tolerability, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, In patient, Neurology (clinical), business, Genetics (clinical)
Published
2019

46. PABPN1 (GCN)11 as a Dominant Allele in Oculopharyngeal Muscular Dystrophy -Consequences in Clinical Diagnosis and Genetic Counselling

Author

Xavier Ferrer-Monasterio, Guy Brochier, Marie-Laure Martin-N, Jean Lacau Saint-Guily, Bruno Eymard, Norma B. Romero, Teresa Gidaro, Capucine Trollet, Michel Fardeau, L. Demay, Guilhem Sol, Pascal Lafor, Pascale Richard, Fernando Ms Tom, Edoardo Malfatti, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institute of Myology Paris France, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and CHU Bordeaux [Bordeaux]

Subjects
Genetics, Research Report, Muscle biopsy, medicine.diagnostic_test, Oculopharyngeal muscular dystrophy, [SDV]Life Sciences [q-bio], PABPN1 gene, Biology, medicine.disease, Penetrance, Phenotype, Neurology, Ptosis, Polymorphism (computer science), medicine, genetics, Neurology (clinical), medicine.symptom, Allele, Gene
Abstract

Oculopharyngeal muscular dystrophy (OPMD) is mainly characterized by ptosis and dysphagia. The genetic cause is a short expansion of a (GCN)10 repeat encoding for polyalanine in the poly(A) binding protein nuclear 1 (PABPN1) gene to (GCN)12–17 repeats. The (GCN)11/Ala11 allele has so far been described to be either a polymorphism or a recessive allele with no effect on the phenotype in the heterozygous state. Here we report the clinical and histopathological phenotype of a patient carrying a single (GCN)11/Ala11 heterozygous allele and presenting an atypical form of OPMD with dysphagia and late and mild oculomotor symptoms. Intranuclear inclusions were observed in his muscle biopsy. This suggests a dominant mode of expression of the (GCN)11/Ala11 allele associated with a partial penetrance of OPMD.

Published
2016

47. X-linked myotubular myopathy in ambulant patients

Author

J.Y. Hogrel, Jean-Michel Arnal, V. Chê, M. Annoussamy, Teresa Gidaro, A. Daron, M. Mayer, Jocelyn Laporte, C. Lilien, Valérie Biancalana, L. Servais, D. Ramsdell, Carina Wallgren-Pettersson, H. Landy, Anna Buj-Bello, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, and Généthon

Subjects
0303 health sciences, Pathology, medicine.medical_specialty, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, X-linked myotubular myopathy, 03 medical and health sciences, 0302 clinical medicine, Neurology, Pediatrics, Perinatology and Child Health, medicine, Neurology (clinical), business, 030217 neurology & neurosurgery, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2016

48. Baseline data from patients with myotubular myopathy enrolled in a European prospective and longitudinal natural history study

Author

J.Y. Hogrel, H. Landy, Teresa Gidaro, Ulrike Schara, E. Gargaun, A. Daron, A. Hernandez, Laurent Servais, S. Fontaine, Carole Vuillerot, Jean-Michel Arnal, Valérie Biancalana, Anna Buj-Bello, M. Annoussamy, Michèle Mayer, V. Chê, C. Lilien, A. Gangfuss, Jean-Marie Cuisset, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, and Généthon

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, business.industry, Medizin, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Baseline data, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, Pediatrics, Perinatology and Child Health, medicine, Physical therapy, Myotubular Myopathy, Neurology (clinical), business, 030217 neurology & neurosurgery, Genetics (clinical), Natural history study, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2016

49. Feasibility of magneto-inertial motion analysis in non-ambulant patients with spinal muscular atrophy

Author

Andreea Mihaela Seferian, Ulrike Schara, Teresa Gidaro, E. Gargaun, A. Chabanon, E. Gasnier, Carole Vuillerot, Nathalie Goemans, Y. Pereon, D. Vissiere, A. Daron, M. Annoussamy, Claude Cances, G. Quicke, Anne Marquet, Jean-Marie Cuisset, Vincent Laugel, and Laurent Servais

Subjects
Physics, medicine.medical_specialty, Physical medicine and rehabilitation, Neurology, Pediatrics, Perinatology and Child Health, medicine, Medizin, Inertial motion, Neurology (clinical), Spinal muscular atrophy, medicine.disease, Magneto, Genetics (clinical)
Published
2016

50. TWEAK in Inclusion-Body Myositis Muscle

Author

Massimiliano Mirabella, Matteo Lucchini, Aldobrando Broccolini, Carla Gliubizzi, Teresa Gidaro, Cristina Sancricca, and Roberta Morosetti

Subjects
musculoskeletal diseases, Mesoangioblast, Myogenesis, Cellular differentiation, medicine.medical_treatment, education, Biology, medicine.disease, Polymyositis, Muscle atrophy, Pathology and Forensic Medicine, Cytokine, parasitic diseases, Immunology, Cancer research, medicine, Stem cell, Inclusion body myositis, medicine.symptom
Abstract

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 exert pleiotropic effects, including regulation of myogenesis. Sporadic inclusion-body myositis (IBM) is the most common muscle disease of the elderly population and leads to severe disability. IBM mesoangioblasts, different from mesoangioblasts in other inflammatory myopathies, display a myogenic differentiation defect. The objective of the present study was to investigate TWEAK-Fn14 expression in IBM and other inflammatory myopathies and explore whether TWEAK modulation affects myogenesis in IBM mesoangioblasts. TWEAK, Fn14, and NF-κB expression was assessed by immunohistochemistry and Western blot in cell samples from both muscle biopsies and primary cultures. Mesoangioblasts isolated from samples of IBM, dermatomyositis, polymyositis, and control muscles were treated with recombinant human TWEAK, Fn14-Fc chimera, and anti-TWEAK antibody. TWEAK-RNA interference was performed in IBM and dermatomyositis mesoangioblasts. TWEAK levels in culture media were determined by enzyme-linked immunosorbent assay. In IBM muscle, we found increased TWEAK-Fn14 expression. Increased levels of TWEAK were found in differentiation medium from IBM mesoangioblasts. Moreover, TWEAK inhibited myogenic differentiation of mesoangioblasts. Consistent with this evidence, TWEAK inhibition by Fn14-Fc chimera or short interfering RNA induced myogenic differentiation of IBM mesoangioblasts. We provide evidence that TWEAK is a negative regulator of human mesoangioblast differentiation. Dysregulation of the TWEAK-Fn14 axis in IBM muscle may induce progressive muscle atrophy and reduce activation and differentiation of muscle precursor cells.

Published
2012

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