Author: "Aleksandra Nadaj-Pakleza" - Searchworks@Jio Institute Digital Library Search Results

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1. The FLNC Ala1186Val Variant Linked to Cytoplasmic Body Myopathy and Cardiomyopathy Causes Protein Instability

Author: Marion Onnée, Audrey Bénézit, Sultan Bastu, Aleksandra Nadaj-Pakleza, Béatrice Lannes, Flavie Ader, Corinne Thèze, Pascal Cintas, Claude Cances, Robert-Yves Carlier, Corinne Metay, Mireille Cossée, and Edoardo Malfatti
Subjects: cardiomyopathy, myopathy, FLNC, mutation, Biology (General), QH301-705.5
Abstract: Filamin C-related disorders include myopathies and cardiomyopathies linked to variants in the FLNC gene. Filamin C belongs to a family of actin-binding proteins involved in sarcomere stability. This study investigates the pathogenic impact of the FLNC c.3557C > T (p.Ala1186Val) pathogenic variant associated with an early-onset cytoplasmic body myopathy and cardiomyopathy in three unrelated patients. We performed clinical imaging and myopathologic and genetic characterization of three patients with an early-onset myopathy and cardiomyopathy. Bioinformatics analysis, variant interpretation, and protein structure analysis were performed to validate and assess the effects of the filamin C variant. All patients presented with a homogeneous clinical phenotype marked by a severe contractural myopathy, leading to loss of gait. There was prominent respiratory involvement and restrictive or hypertrophic cardiomyopathies. The Ala1186Val variant is located in the interstrand loop involved in intradomain stabilization and/or interdomain interactions with neighbor Ig-like domains. 3D modeling highlights local structural changes involving nearby residues and probably impacts the protein stability, causing protein aggregation in the form of cytoplasmic bodies. Myopathologic studies have disclosed the prominent aggregation and upregulation of the aggrephagy-associated proteins LC3B and p62. As a whole, the Ala1186Val variant in the FLNC gene provokes a severe myopathy with contractures, respiratory involvement, and cardiomyopathy due to protein aggregation in patients’ muscles.
Published: 2024
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2. In inflammatory myopathies, dropped head/bent spine syndrome is associated with scleromyositis: an international case–control study

Author: Jérémie Sellam, Laurent Arnaud, Marta Mosca, Florenzo Iannone, Luca Diamanti, Luca Iaccarino, Aurélien Guffroy, Jacques-Eric Gottenberg, Veronica Codullo, Alain Meyer, Simone Barsotti, Jelena Blagojevic, Lorenzo Cavagna, François Séverac, Bernard Geny, Jean Sibilia, Marie Hudson, François Maurier, Benjamin Terrier, Silvia Bellando-Randone, Emanuelle Dernis, Carlotta Nannini, Marion Couderc, Anne Tournadre, Jean Jacques Dubost, Albert Selva-O'Callaghan, Claire de Moreuil, Giacomo Emmi, Baptiste Hervier, Guilhem Sole, Philippe Guilpain, Jean-François Viallard, Aleksandra Nadaj-Pakleza, Enrico Marchioni, Monica Groza, Sergio Prieto-González, Nicolas Poursac, Isabelle Guichard, Kubéraka Mariampillai, Yves Troyanov, Luc Pijnenburg, Antoine Soulages, Jean-Marc Galempoix, Margherita Giannini, Maude Bouchard-Marmen, Livio Bernardi, Paola Bini, Fanny Duval, Delphine Lebrun, Jean-Maxime Piot, Eglantine Rouanet, Nathalie Vernier, Veronique Vesperini, and Rahima Ziane
Subjects: Medicine
Abstract: Background Some myopathies can lead to dropped head or bent spine syndrome (DH/BS). The significance of this symptom has not been studied in inflammatory myopathies (IM).Objectives To assess the significance of DH/BS in patients with IM.Methods Practitioners from five IM networks were invited to report patients with IM suffering from DH/BS (without other known cause than IM). IM patients without DH/BS, randomly selected in each participating centre, were included as controls at a ratio of 2 to 1.Results 49 DH/BS-IM patients (DH: 57.1%, BS: 42.9%) were compared with 98 control-IM patients. DH/BS-IM patients were older (65 years vs 53 years, p
Published: 2023
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3. Convergence of patient- and physician-reported outcomes in the French National Registry of Facioscapulohumeral Dystrophy

Author: Benoît Sanson, Caroline Stalens, Céline Guien, Luisa Villa, Catherine Eng, Sitraka Rabarimeriarijaona, Rafaëlle Bernard, Pascal Cintas, Guilhem Solé, Vincent Tiffreau, Andoni Echaniz-Laguna, Armelle Magot, Raul Juntas Morales, François Constant Boyer, Aleksandra Nadaj-Pakleza, Agnès Jacquin-Piques, Christophe Béroud, Sabrina Sacconi, and The French FSHD registry collaboration group
Subjects: Medicine
Abstract: Abstract Background Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent muscular dystrophies and currently has no treatment. Clinical and genetic heterogeneity are the main challenges to a full comprehension of the physiopathological mechanism. Improving our knowledge of FSHD is crucial to the development of future therapeutic trials and standards of care. National FSHD registries have been set up to this end. The French National Registry of FSHD combines a clinical evaluation form (CEF) and a self-report questionnaire (SRQ), filled out by a physician with expertise in neuromuscular dystrophies and by the patient, respectively. Aside from favoring recruitment, our strategy was devised to improve data quality. Indeed, the pairwise comparison of data from 281 patients for 39 items allowed for evaluating data accuracy. Kappa or intra-class coefficient (ICC) values were calculated to determine the correlation between answers provided in both the CEF and SRQ. Results Patients and physicians agreed on a majority of questions common to the SRQ and CEF (24 out of 39). Demographic, diagnosis- and care-related questions were generally answered consistently by the patient and the medical practitioner (kappa or ICC values of most items in these groups were greater than 0.8). Muscle function-related items, i.e. FSHD-specific signs, showed an overall medium to poor correlation between data provided in the two forms; the distribution of agreements in this section was markedly spread out and ranged from poor to good. In particular, there was very little agreement regarding the assessment of facial motricity and the presence of a winged scapula. However, patients and physicians agreed very well on the Vignos and Brooke scores. The report of symptoms not specific to FSHD showed general poor consistency. Conclusions Patient and physician answers are largely concordant when addressing quantitative and objective items. Consequently, we updated collection forms by relying more on patient-reported data where appropriate. We hope the revised forms will reduce data collection time while ensuring the same quality standard. With the advent of artificial intelligence and automated decision-making, high-quality and reliable data are critical to develop top-performing algorithms to improve diagnosis, care, and evaluate the efficiency of upcoming treatments.
Published: 2022
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4. A multicenter cross-sectional French study of the impact of COVID-19 on neuromuscular diseases

Author: Lucie Isoline Pisella, Sara Fernandes, Guilhem Solé, Tanya Stojkovic, Céline Tard, Jean-Baptiste Chanson, Françoise Bouhour, Emmanuelle Salort-Campana, Guillemette Beaudonnet, Louise Debergé, Fanny Duval, Aude-Marie Grapperon, Marion Masingue, Aleksandra Nadaj-Pakleza, Yann Péréon, Frédérique Audic, Anthony Behin, Diane Friedman, Armelle Magot, Jean-Baptiste Noury, Sarah Souvannanorath, Karim Wahbi, Jean-Christophe Antoine, Kévin Bigaut, Jean-Philippe Camdessanché, Pascal Cintas, Rabab Debs, Caroline Espil-Taris, Laurent Kremer, Thierry Kuntzer, Pascal Laforêt, Vincent Laugel, Martial Mallaret, Maud Michaud, Sylvain Nollet, Juliette Svahn, Savine Vicart, Rocio Nur Villar-Quiles, Isabelle Desguerre, David Adams, Sandrine Segovia-Kueny, Géraldine Merret, Elhadi Hammouda, Annamaria Molon, and Shahram Attarian
Subjects: Neuromuscular diseases, COVID-19, Risk factor, Prognosis, Medicine
Abstract: Abstract Background Due to their health condition, patients with neuromuscular diseases (NMD) are at greater risk of developing serious complications with COVID-19. The objective of this study was to analyze the prevalence of COVID-19 among NMD patients and the risk factors for its impact and severity during the first wave of the pandemic. Clinical data were collected from NMD-COVID-19 patients, between March 25, 2020 and May 11, 2020 in an anonymous survey carried out by expert physicians from the French Health Care Network Filnemus. Results Physicians reported 84 patients, including: 34 with myasthenia gravis, 27 with myopathy and 23 with neuropathy. COVID-19 had no effect on NMD for 48 (58%) patients and 48 (58%) patients developed low COVID-19 severity. COVID-19 caused the death of 9 (11%) NMD patients. Diabetic patients were at greater risk of dying. Patients with diabetes, hypertension or severe forms of NMD had a higher risk of developing a moderate or severe form of COVID-19. In our cohort, corticosteroids and other immunosuppressants were not significantly associated with higher COVID-19 severity for acquired NMD. Conclusion During this period, a small percentage of French NMD patients was affected by COVID-19 compared to the general French population and COVID-19 had a limited short-term effect on them. Diabetes, hypertension and a severe degree of NMD were identified as risk factors of unfavorable outcome following COVID-19. Conversely, in our cohort of patients with acquired NMD, corticosteroids or other immunosuppressants did not appear to be risk factors for more severe COVID-19.
Published: 2021
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5. Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment

Author: Pascal Laforêt, Michio Inoue, Evelyne Goillot, Claire Lefeuvre, Umut Cagin, Nathalie Streichenberger, Sarah Leonard-Louis, Guy Brochier, Angeline Madelaine, Clemence Labasse, Carola Hedberg-Oldfors, Thomas Krag, Louisa Jauze, Julien Fabregue, Philippe Labrune, Jose Milisenda, Aleksandra Nadaj-Pakleza, Sabrina Sacconi, Federico Mingozzi, Giuseppe Ronzitti, François Petit, Benedikt Schoser, Anders Oldfors, John Vissing, Norma B. Romero, Ichizo Nishino, and Edoardo Malfatti
Subjects: Glycogen storage disease III, Muscle glycogenosis, Metabolic myopathies, Myopathology, Autophagy, Autophagic impairment, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene. In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large non-membrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model. In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples. These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.
Published: 2019
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6. Sporadic late-onset nemaline myopathy: clinico-pathological characteristics and review of 76 cases

Author: Lukas J. Schnitzler, Tobias Schreckenbach, Aleksandra Nadaj-Pakleza, Werner Stenzel, Elisabeth J. Rushing, Philip Van Damme, Andreas Ferbert, Susanne Petri, Christian Hartmann, Antje Bornemann, Andreas Meisel, Jens A. Petersen, Thomas Tousseyn, Dietmar R. Thal, Jens Reimann, Peter De Jonghe, Jean-Jacques Martin, Peter Y. Van den Bergh, Jörg B. Schulz, Joachim Weis, and Kristl G. Claeys
Subjects: SLONM, Muscle biopsy, HIV-associated nemaline myopathy, HIV-NM, Monoclonal gammopathy, MGUS, Medicine
Abstract: Abstract Background Sporadic late-onset nemaline myopathy (SLONM) is a rare, late-onset muscle disorder, characterized by the presence of nemaline rods in muscle fibers. Phenotypic characterization in a large cohort and a comprehensive overview of SLONM are lacking. Methods We studied the clinico-pathological features, treatment and outcome in a large cohort of 76 patients with SLONM, comprising 10 new patients and 66 cases derived from a literature meta-analysis (PubMed, 1966–2016), and compared these with 15 reported HIV-associated nemaline myopathy (HIV-NM) cases. In 6 SLONM patients, we performed a targeted next-generation sequencing (NGS) panel comprising 283 myopathy genes. Results SLONM patients had a mean age at onset of 52 years. The predominant phenotype consisted of weakness and atrophy of proximal upper limbs in 84%, of proximal lower limbs in 80% and both in 67%. Other common symptoms included axial weakness in 68%, as well as dyspnea in 55% and dysphagia in 47% of the patients. In 53% a monoclonal gammopathy of unknown significance (MGUS) was detected in serum. The mean percentage of muscle fibers containing rods was 28% (range 1–63%). In 2 cases ultrastructural analysis was necessary to detect the rods. The most successful treatment in SLONM patients (all with MGUS) was autologous peripheral blood stem cell therapy. A targeted NGS gene panel in 6 SLONM patients (without MGUS) did not reveal causative pathogenic variants. In a comparison of SLONM patients with and without MGUS, the former comprised significantly more males, had more rapid disease progression, and more vacuolar changes in muscle fibers. Interestingly, the muscle biopsy of 2 SLONM patients with MGUS revealed intranuclear rods, whereas this feature was not seen in any of the biopsies from patients without paraproteinemia. Compared to the overall SLONM cohort, significantly more HIV-NM patients were male, with a lower age at onset (mean 34 years). In addition, immunosuppression was more frequently applied with more favorable outcome, and muscle biopsies revealed a significantly higher degree of inflammation and necrosis in this cohort. Similar to SLONM, MGUS was present in half of the HIV-NM patients. Conclusions SLONM presents a challenging, but important differential diagnosis to other neuromuscular diseases of adult onset. Investigations for MGUS and HIV should be performed, as they require distinct but often effective therapeutic approaches. Even though SLONM and HIV-NM show some differences, there exists a large clinico-pathological overlap between the 2 entities.
Published: 2017
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7. Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study.

Author: Celine Dogan, Marie De Antonio, Dalil Hamroun, Hugo Varet, Marianne Fabbro, Felix Rougier, Khadija Amarof, Marie-Christine Arne Bes, Anne-Laure Bedat-Millet, Anthony Behin, Remi Bellance, Françoise Bouhour, Celia Boutte, François Boyer, Emmanuelle Campana-Salort, Françoise Chapon, Pascal Cintas, Claude Desnuelle, Romain Deschamps, Valerie Drouin-Garraud, Xavier Ferrer, Helene Gervais-Bernard, Karima Ghorab, Pascal Laforet, Armelle Magot, Laurent Magy, Dominique Menard, Marie-Christine Minot, Aleksandra Nadaj-Pakleza, Sybille Pellieux, Yann Pereon, Marguerite Preudhomme, Jean Pouget, Sabrina Sacconi, Guilhem Sole, Tanya Stojkovich, Vincent Tiffreau, Andoni Urtizberea, Christophe Vial, Fabien Zagnoli, Gilbert Caranhac, Claude Bourlier, Gerard Riviere, Alain Geille, Romain K Gherardi, Bruno Eymard, Jack Puymirat, Sandrine Katsahian, and Guillaume Bassez
Subjects: Medicine, Science
Abstract: Myotonic Dystrophy type 1 (DM1) is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity.We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18 y) from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Téléthon DM1 survey (n = 970), and morbidity and mortality using the French National Health Service Database (n = 3301).Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate.Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials.
Published: 2016
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8. Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study

Author: James F Howard, Saskia Bresch, Angela Genge, Channa Hewamadduma, John Hinton, Yessar Hussain, Raul Juntas-Morales, Henry J Kaminski, Angelina Maniaol, Renato Mantegazza, Masayuki Masuda, Kumaraswamy Sivakumar, Marek Śmiłowski, Kimiaki Utsugisawa, Tuan Vu, Michael D Weiss, Małgorzata Zajda, Babak Boroojerdi, Melissa Brock, Guillemette de la Borderie, Petra W Duda, Romana Lowcock, Mark Vanderkelen, M Isabel Leite, Dylan Sembinelli, Jeanne Teitelbaum, Michael Nicolle, Emilien Bernard, Juliette Svahn, Marco Spinazzi, Tanya Stojkovic, Sophie Demeret, Nicolas Weiss, Loïc Le Guennec, Sihame Messai, Christine Tranchant, Aleksandra Nadaj-Pakleza, Jean-Baptiste Chanson, Muhtadi Suliman, Leila Zaidi, Celine Tard, Peggy Lecointe, Jana Zschüntzsch, Jens Schmidt, Stefanie Glaubitz, Rachel Zeng, Matthias Scholl, Markus Kowarik, Ulf Ziemann, Markus Krumbholz, Pascal Martin, Christoph Ruschil, Jutta Dünschede, Roswitha Kemmner, Natalie Rumpel, Benjamin Berger, Andreas Totzeck, Tim Hagenacker, Benjamin Stolte, Raffaele Iorio, Amelia Evoli, Silvia Falso, Carlo Antozzi, Rita Frangiamore, Fiammetta Vanoli, Elena Rinaldi, Kazushi Deguchi, Naoya Minami, Yuriko Nagane, Yasushi Suzuki, Sayaka Ishida, Shigeaki Suzuki, Jin Nakahara, Astushi Nagaoka, Shunsuke Yoshimura, Shingo Konno, Youko Tsuya, Akiyuki Uzawa, Tomoya Kubota, Masanori Takahashi, Tatsusada Okuno, Hiroyuki Murai, Nils Erik Gilhus, Marion Boldingh, Tone Hakvåg Rønning, Urszula Chyrchel-Paszkiewicz, Klaudiusz Kumor, Tomasz Zielinski, Krzysztof Banaszkiewicz, Michał Błaż, Agata Kłósek, Mariola Świderek-Matysiak, Andrzej Szczudlik, Aneta Paśko, Lech Szczechowski, Marta Banach, Jan Ilkowski, Solange Kapetanovic Garcia, Patricia Ortiz Bagan, Ana Belén Cánovas Segura, Joana Turon Sans, Nuria Vidal Fernandez, Elena Cortes Vicente, Patricia Rodrigo Armenteros, Mohammad Ashraghi, Ana Cavey, Liam Haslam, Anna Emery, Kore Liow, Sharon Yegiaian, Alexandru Barboi, Rosa Maria Vazquez, Joshua Lennon, Robert M Pascuzzi, Cynthia Bodkin, Sandra Guingrich, Adam Comer, Mark Bromberg, Teresa Janecki, Sami Saba, Marco Tellez, Bakri Elsheikh, Miriam Freimer, Sarah Heintzman, Raghav Govindarajan, Jeffrey Guptill, Janice M Massey, Vern Juel, Natalia Gonzalez, Ali A Habib, Tahseen Mozaffar, Manisha Korb, Namita Goyal, Hannah Machemehl, Georgios Manousakis, Jeffrey Allen, Emily Harper, Constantine Farmakidis, Lilli Saavedra, Mazen Dimachkie, Mamatha Pasnoor, Salma Akhter, Said Beydoun, Courtney McIlduff, Joan Nye, Bhaskar Roy, Bailey Munro Sheldon, Richard Nowak, Benjamin Barnes, Michael Rivner, Niraja Suresh, Jessica Shaw, Brittany Harvey, Lucy Lam, Nikki Thomas, Manisha Chopra, Rebecca E Traub, Sarah Jones, Mary Wagoner, Sejla Smajic, Radwa Aly, Jonathan Katz, Henry Chen, Robert G Miller, Liberty Jenkins, Shaida Khan, Bhupendra Khatri, Lisa Sershon, Pantelis Pavlakis, Shara Holzberg, Yuebing Li, Irys B Caristo, Robert Marquardt, Debbie Hastings, Jacob Rube, Robert P Lisak, Aparna Choudhury, Katherine Ruzhansky, Amit Sachdev, Susan Shin, Joan Bratton, Mary Fetter, Naya McKinnon, Jonathan McKinnon, Laura Sissons-Ross, Amos Sahu, and B Jane Distad
Subjects: Neurology (clinical)
Published: 2023

9. Safety and efficacy of rozanolixizumab in patients with generalised myasthenia gravis (MycarinG): a randomised, double-blind, placebo-controlled, adaptive phase 3 study

Author: Vera Bril, Artur Drużdż, Julian Grosskreutz, Ali A Habib, Renato Mantegazza, Sabrina Sacconi, Kimiaki Utsugisawa, John Vissing, Tuan Vu, Marion Boehnlein, Ali Bozorg, Maryam Gayfieva, Bernhard Greve, Franz Woltering, Henry J Kaminski, Angela Genge, Rami Massie, Maxime Berube, Lubna Daniyal, Shabber Mannan, Eduardo Ng, Ritesh Rohan Raghu Raman, Evelyn Sarpong, Monica Alcantara, Annie Dionne, Zaeem Siddiqi, Derrick Blackmore, Faraz Hussain, Genevieve Matte, Stephan Botez, Michaela Tyblova, Michala Jakubikova, Jana Junkerova, Nanna Witting, Sonja Holm-Yildiz, Mads Stemmerik, Henning Andersen, Izabella Obál, Guilhem Solé, Stéphane Mathis, Marie-Hélène Violleau, Christine Tranchant, Sihame Messai, Jean-Baptiste Chanson, Aleksandra Nadaj-Pakleza, Arnaud Verloes, Leila Zaidi, Manuela Gambella, Michele Cavalli, Tanya Stojkovic, Sophie Demeret, Loic Le Guennec, Giorgia Querin, Nicolas Weiss, Marion Masingue, Laurent Magy, Karima Ghorab, Ia Rukhadze, Alexander Tsiskaridze, Marina Janelidze, Temur Margania, Florian Then Bergh, Eike Hänsel, Andrea Kalb, Bianca Meilick, Mandy Reuschel, Lars-Malte Teußer, Astrid Unterlauft, Clemens Goedel, Tim Hagenacker, Andreas Totzeck, Benjamin Stolte, Franz Blaes, Christine Bindler, Vasilios Tsoutsikas, Annekathrin Roediger, Christian Geis, Jens Schmidt, Jana Zschüntzsch, Margret Schwarz, Stefanie Meyer, Karsten Kummer, Stefanie Glaubitz, Rachel Zeng, Heinz Wiendl, Luisa Klotz, Anna Lammerskitten, Jan Lünemann, Péter Diószeghy, Lorenzo Maggi, Elena Rinaldi, Matteo Gastaldi, Federico Mazzacane, Pietro Businaro, Raffaele Iorio, Giovanni Antonini, Laura Fionda, Rita Rinaldi, Simone Rossi, Francesco Habetswallner, Francesco Tuccillo, Haruna Umehara, Eiko Uenaka, Masanori Takahashi, Keiko Higashi, Makoto Kinoshita, Emika Yoneda, Noriko Nakamura, Saeka Fujita, Tomoya Kubota, Masami Ono, Sana Yamamoto, Taku Hatano, Kazuki Oikoshi, Kazumasa Yokoyama, Yutaka Oji, Yuji Tomizawa, Akiyuki Uzawa, Manato Yasuda, Sachiko Akita, Yukiko Ozawa, Yosuke Onishi, Miki Takaki, Hiromi Yamada, Kanako Minemoto, Miki Sanko, Nanae Izawa, Mayumi Nakayama, Masayuki Masuda, Rune Tsuji, Nobuhiro Ido, Yumi Hyodo, Yoshihiko Okubo, Akiko Minohara, Nana Haraguchi, Makiko Naito, Seiko Yoshida, Yuri Fukushige, Akira Tsujino, Atsushi Nagaoka, Teiichiro Miyazaki, Shunsuke Yoshimura, Takuro Hirayama, Tomoaki Shima, Naoko Okamoto, Riki Matsumoto, Kenji Sekiguchi, Takehiro Ueda, Norio Chihara, Mari Kirimura, Emi Sunagawa, Ayaka Suzuki, Shigeaki Suzuki, Aozora Wada, Kei Ishizuchi, Yasushi Suzuki, Mitsuo Yata, Yuka Komatsu, Kenichi Tsukita, Genya Watanabe, Kazuki Sato, Emiko Kawasaki, Naoki Yamamoto, Hirohiko Ono, Tomoko Tsuda, Shigeki Ohashi, Yuka Fujisawa, Yumiko Yokota, Yuriko Nagane, Kameda Ayumi, Yuka Takematsu, Hiroyuki Naito, Kumiko Kuwada, Konrad Rejdak, Sebastian Szklener, Monika Kitowska, Kandyda Derkacz, Tomasz Berkowicz, Paulina Budzinska, Marek Halas, Leonid Zaslavskiy, Evgeniya Skornyakova, Sergey Kotov, Ekaterina Novikova, Olga Sidorova, Vitalii Goldobin, Tatiana Alekseeva, Patimat Isabekova, Nadezhda Malkova, Denis Korobko, Gordana Djordjevic, Aleksandar Stojanov, Stojan Peric, Dragana Lavrnic, Ivo Bozovic, Aleksa Palibrk, Carlos Casasnovas, Velina Nedkova-Hristova, Nuria Vidal Fernández, Elena Cortés Vicente, Luis Querol Gutiérrez, Maria Salvadó Figueras, Anna Canovas Segura, Raúl Juntas Morales, Daniel Sanchez Tejerina, Albert Saiz, Yolanda Blanco Morgado, Sara Llufriú Durán, María Sepúlveda Gázquez, Eugenia María Martínez Hernández, Gerardo Gutiérrez Gutiérrez, Paqui Iniesta, José Meca Lallana, Yuh-Cherng Guo, Hou-Chang Chiu, Jiann-Horng Yeh, Ya Hui Chen, Mei Fen Lee, Yi-Chung Lee, Kuan Lin Lai, Said Beydoun, Salma Akhter, Lucy Lam, Alisha Thomas, Michael Rivner, Brandy Quarles, Dale Lange, Shara Holzberg, Pantelis Pavlakis, Ashwathy Goutham, Henry Kaminski, Radwa Aly, Lisa Ashworth, Kathryn Bender, Karie Bond, Joanne Buckner, Sara Byerly, James Caress, Jessyca Clemons, Asha Farmer, Catherine Franklin, Summer Harris, Meredith Hiatt, Rachana Gandhi Mehta, Gina Miller, Lynn Smith, Rose Smith, Brian Strittmatter, Tahseen Mozaffar, Isela Hernandez, Kelsey Moulton, Chafic Karam, Pranali Ravikumar, Catherine Lomen-Hoerth, Laura Rosow, Hannah George, Viktoriya Irodenko, Carol Denny, Bart Hanson, Sara Klein, Jennifer Martinez-Thompson, Elie Naddaf, Denny Padgett, Eric Sorenson, Jane L Sultze, Delena Weis, Kourosh Rezania, Jason Thonhoff, Sheetal Shroff, Robert Pascuzzi, Angela Micheels, Cynthia Bodkin, Adam Comer, Gelasio Baras, Renee Wagner, Zabeen Mahuwala, Stephen Ryan, Kai Su, Khema Sharma, Andrew Brown, and Kore Liow
Subjects: Neurology (clinical)
Published: 2023

10. Hypertrophie musculaire : signe de bonne santé ou de maladie ?

Author: Aleksandra Nadaj-Pakleza
Abstract: In order to explain muscle hypertrophy in a patient complaining of muscular symptoms one must take into account the patient’s daily professional or leisure physical activity. If muscle hypertrophy cannot be attributed to active lifestyle, an underlying neuromuscular pathology should be suspected. The check-up includes a meticulous neurological examination (looking for myotonia, rippling, myoclonus, etc.), a CK level dosage, an electromyography (for myotonic discharges), and, if necessary, it should be completed by muscle biopsy and molecular examinations. Several diagnostic hypotheses should be considered. Most are related to a genetic defect leading to dysfunction of the excitation-contraction coupling in the muscle. The diagnosis of a myotonic syndrome is the most common but caveolinopathy 3, RYR1-related myopathy or Brody’s disease are also possible.
Published: 2022

11. Refining inflammatory myopathies incidence and characteristics: a quadruple source capture‐recapture survey using 2017 <scp>ACR</scp> / <scp>EULAR</scp> criteria

Author: Léa Debrut, Margherita Giannini, Delphine Klein, Lionel Spielmann, Philippe Mertz, Thierry Martin, Aleksandra Nadaj‐Pakleza, Sandrine Hirschi, Benoit Nespola, Béatrice Lannes, Joëlle Terzic, Olivier Hinschberger, Benjamin Dervieux, Dan Lipsker, Laurent Arnaud, Jacques‐Eric Gottenberg, Jean François Kleinmann, Bernard Geny, François Séverac, Michel Velten, Jean Sibilia, and Alain Meyer
Subjects: Rheumatology, Immunology, Immunology and Allergy
Published: 2023

12. <scp> SORD </scp> ‐related peripheral neuropathy in a French and Swiss cohort: Clinical features, genetic analyses, and sorbitol dosages

Author: Nicolas Pons, Gorka Fernández‐Eulate, Antoine Pegat, Marie Théaudin, Régis Guieu, Paolo Ripellino, Manon Devedjian, Patrick Mace, Marion Masingue, Sarah Léonard‐Louis, Philipe Petiot, Pauline Roche, Emilien Bernard, Françoise Bouhour, Jean‐Marc Good, Annie Verschueren, Aude‐Marie Grapperon, Emmanuelle Salort, Anaïs Grosset, Jean‐Baptiste Chanson, Aleksandra Nadaj‐Pakleza, Anne‐Laure Bédat‐Millet, Ariane Choumert, Anne Barnier, Ghassen Hamdi, Gaëtan Lesca, Fabienne Prieur, Arnaud Bruneel, Philippe Latour, Tanya Stojkovic, Shahram Attarian, and Nathalie Bonello‐Palot
Subjects: Neurology, Neurology (clinical)
Published: 2023

13. Intérêts et limites de l’électroneuromyographie chez les enfants : étude de 137 cas

Author: Yvan de Feraudy, Aleksandra Nadaj-Pakleza, Laugel Vincent, and Jean-Baptiste Chanson
Subjects: Neurology, Neurology (clinical)
Published: 2023

14. A rise in cases of nitrous oxide abuse: neurological complications and biological findings

Author: Cécile Reschwein, Laurent Kremer, Pauline Kalaaji, Stanislas Demuth, Ivana Schroder, Lucas Gauer, Thomas Bogdan, Jérôme De Seze, Paul Voulleminot, Maximilian Einsiedler, Aleksandra Nadaj-Pakleza, and Kévin Bigaut
Subjects: Vitamin, Pediatrics, medicine.medical_specialty, Neurology, Homocysteine, Vitamin B-12, Methylmalonic acid, Toxicology, chemistry.chemical_compound, medicine, Humans, Pandemics, Original Communication, Nitrous oxide, business.industry, SARS-CoV-2, Incidence (epidemiology), COVID-19, Vitamin B 12 Deficiency, medicine.disease, Substance abuse, Vitamin B 12, chemistry, Communicable Disease Control, Subacute Combined Degeneration, Neurology (clinical), business, Substance-related disorders
Abstract: Background The recent lockdown due to the COVID-19 pandemic has been linked to a higher incidence of psychiatric manifestations and substance abuse. The recreative use of nitrous oxide is more and more widespread and neurological complications are frequent. Methods We report clinical characteristics and biological findings of five consecutive patients presenting to our tertiary care center between April 2020 and February 2021 with various neurological symptoms occurring after recent nitrous oxide abuse. Results Our patients presented with subacute combined degeneration of the spinal cord (4/5 patients) or with acute inflammatory demyelinating polyneuropathy (1/5 patients). No patient had reduced vitamin B-12 titer, but all had elevated blood levels of homocysteine and methylmalonic acid. This reflects the functional deficit in vitamin B-12 that can be linked to nitrous oxide consumption. After vitamin B-12 supplementation, clinical signs regressed at least partially in all 5 patients. Conclusion We report an elevated incidence of neurological complications of nitrous oxide abuse occurring during the recent COVID-19 lockdown. Nitrous oxide abuse should be tracked down in patients presenting with compatible neurological symptoms and elevated homocysteinemia. Vitamin B-12 should be supplemented as soon as the diagnosis is made.
Published: 2021

15. Expanding the phenotypic variability of MORC2 gene mutations: From Charcot-Marie-Tooth disease to late-onset pure motor neuropathy

Author: Arnaud Jacquier, Shams Ribault, Michel Mendes, Nicolas Lacoste, Valérie Risson, Julien Carras, Philippe Latour, Aleksandra Nadaj‐Pakleza, Tanya Stojkovic, and Laurent Schaeffer
Subjects: Genetics, Genetics (clinical)
Abstract: MORC2 gene encodes a ubiquitously expressed nuclear protein involved in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous mutations in MORC2 gene have been associated with a spectrum of disorders affecting the peripheral nervous system such as Charcot-Marie-Tooth (CMT2Z), spinal muscular atrophy-like with or without cerebellar involvement, and a developmental syndrome associated with impaired growth, craniofacial dysmorphism and axonal neuropathy (DIGFAN syndrome). Such variability in clinical manifestations associated with the increasing number of variants of unknown significance detected by next-generation sequencing constitutes a serious diagnostic challenge. Here we report the characterization of an in vitro model to evaluate the pathogenicity of variants of unknown significance based on MORC2 overexpression in a neuroblastoma cell line SH-EP or cortical neurons. Likewise, we show that MORC2 mutants affect survival and trigger apoptosis over time in SH-EP cell line. Furthermore, overexpression in primary cortical neurons increases apoptotic cell death and decreases neurite outgrowth. Altogether, these approaches establish the pathogenicity of two new variants p.Gly444Arg and p.His446Gln in three patients from two families. These new mutations in MORC2 gene are associated with autosomal dominant CMT and with adult late onset proximal motor neuropathy, further increasing the spectrum of clinical manifestations associated with MORC2 mutations.
Published: 2022

16. Impact of Coronavirus Disease 2019 in a French Cohort of Myasthenia Gravis

Author: Diane Friedman, Djillali Annane, Guillemette Beaudonnet, Emmanuelle Salort-Campana, Bernard Clair, Jean-Baptiste Chanson, Frédérique Audic, Tiphaine Saulnier, Marco Spinazzi, Louis Carla, Gwendal Le Masson, Stéphane Mathis, Alexandra Foubert-Samier, Aleksandra Nadaj-Pakleza, Antoine Soulages, Shahram Attarian, Fanny Duval, Laurent Kremer, Tanya Stojkovic, Françoise Bouhour, Jean-Christophe Antoine, Pascal Cintas, Céline Tard, Sandrine Segovia-Kueny, Marie-Hélène Violleau, Guilhem Solé, Léa Kern, and Armelle Magot
Subjects: Adult, Male, medicine.medical_specialty, Referral, History, 21st Century, law.invention, Serology, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, law, Internal medicine, Myasthenia Gravis, medicine, Humans, 030212 general & internal medicine, Aged, Retrospective Studies, Aged, 80 and over, SARS-CoV-2, business.industry, COVID-19, Retrospective cohort study, Odds ratio, Middle Aged, medicine.disease, Intensive care unit, Myasthenia gravis, 3. Good health, Cohort, France, Neurology (clinical), business, 030217 neurology & neurosurgery, Cohort study
Abstract: ObjectiveTo describe the clinical characteristics and outcomes of coronavirus disease 2019 (COVID-19) among patients with myasthenia gravis (MG) and identify factors associated with COVID-19 severity in patients with MG.MethodsThe CO-MY-COVID registry was a multicenter, retrospective, observational cohort study conducted in neuromuscular referral centers and general hospitals of the FILNEMUS (Filière Neuromusculaire) network (between March 1, 2020, and June 8, 2020), including patients with MG with a confirmed or highly suspected diagnosis of COVID-19. COVID-19 was diagnosed based on a PCR test from a nasopharyngeal swab or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology, thoracic CT scan, or typical symptoms. The main outcome was COVID-19 severity based on location of treatment/management (home, hospitalized in a medical unit, or in an intensive care unit). We collected information on demographic variables, general history, and risk factors for severe COVID-19. Multivariate ordinal regression models were used to identify factors associated with severe COVID-19 outcomes.ResultsAmong 3,558 patients with MG registered in the French database for rare disorders, 34 (0.96%) had COVID-19. The mean age at COVID-19 onset was 55.0 ± 19.9 years (mean MG duration: 8.5 ± 8.5 years). By the end of the study period, 28 patients recovered from COVID-19, 1 remained affected, and 5 died. Only high Myasthenia Gravis Foundation of America (MGFA) class (≥IV) before COVID-19 was associated with severe COVID-19 (p = 0.004); factors that were not associated included sex, MG duration, and medium MGFA classes (≤IIIb). The type of MG treatment had no independent effect on COVID-19 severity.ConclusionsThis registry-based cohort study shows that COVID-19 had a limited effect on most patients, and immunosuppressive medications and corticosteroids used for MG management are not risk factors for poorer outcomes. However, the risk of severe COVID-19 is elevated in patients with high MGFA classes (odds ratio, 102.6 [4.4–2,371.9]). These results are important for establishing evidence-based guidelines for the management of patients with MG during the COVID-19 pandemic.
Published: 2021

17. New MORC2 gene mutations are associated with distinctive features: from axonal neuropathy to late adult-onset spinal muscular atrophy like phenotype

Author: Arnaud Jacquier, Shams Ribault, Michel Mendes, Nicolas Lacoste, Valérie Risson, Julien Carras, Philippe Latour, Aleksandra Nadaj-Pakleza, Tanya Stojkovic, and Laurent Schaeffer
Abstract: MORC2 gene encodes a ubiquitously expressed nuclear protein involved in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous mutations in MORC2 gene have been associated with a spectrum of disorders affecting the peripheral nervous system such as Charcot-Marie-Tooth (CMT2Z), spinal muscular atrophy-like (SMA-like) with or without cerebellar involvement, and a developmental syndrome associated with impaired growth, craniofacial dysmorphism and axonal neuropathy (DIGFAN syndrome). Such variability in clinical manifestations associated with the increasing number of variants of unknown significance detected by next-generation sequencing constitutes a serious diagnostic challenge. Here we report the characterization of an in vitro model to evaluate the pathogenicity of variants of unknown significance based on MORC2 overexpression in a neuroblastoma cell line SH-EP or in cortical neurons. Likewise, we show that MORC2 mutants affect survival and trigger apoptosis over time in SH-EP cell line. Furthermore, overexpression in primary cortical neurons increases apoptotic cell death and decreases neurite outgrowth. Altogether, these approaches establish the pathogenicity of two new variants p.G444R and p.H446Q in three patients from two families. These new mutations in MORC2 gene are associated with autosomal dominant CMT and with adult late onset SMA-like phenotype, further increasing the spectrum of clinical manifestations associated with MORC2 mutations.
Published: 2022

18. No effect of resveratrol on fatty acid oxidation or exercise capacity in patients with fatty acid oxidation disorders:A randomized clinical cross-over trial

Author: Jesper H. Storgaard, Nicoline Løkken, Karen L. Madsen, Nicol C. Voermans, Pascal Laforêt, Aleksandra Nadaj‐Pakleza, Céline Tard, Gerrit van Hall, John Vissing, and Mette C. Ørngreen
Subjects: Cross-Over Studies, Exercise Tolerance, Mitochondrial Diseases, Carnitine O-Palmitoyltransferase, fatty acid oxidation disorders, Acyl-CoA Dehydrogenase, Long-Chain, Fatty Acids, VLCAD, resveratrol, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Lipid Metabolism, Inborn Errors, metabolic myopathy, Muscular Diseases, Resveratrol, Genetics, Congenital Bone Marrow Failure Syndromes, Humans, Oxidation-Reduction, CPTII, Genetics (clinical), Metabolism, Inborn Errors
Abstract: Contains fulltext : 252095.pdf (Publisher’s version ) (Open Access) The objective was to investigate whether resveratrol (RSV) can improve exercise capacity in patients with fatty acid oxidation (FAO) disorders. The study was a randomized, double-blind, cross-over trial. Nine patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency or carnitine palmitoyl transferase (CPT) II deficiency were randomized to receive either 8 weeks of 1000 mg day(-1) RSV or placebo (P) followed by a 4-weeks wash-out period and subsequently 8 weeks of the opposite treatment. Primary outcome measures were heart rate and FAO as measured via stable isotope technique during constant workload exercise. Secondary outcome measures included fat and glucose metabolism; perceived exertion; as well as subjective measures of energy expenditure, fatigue, and daily function. Eight participants completed the trial. Heart rate did not differ at the end of exercise after treatment with RSV vs placebo (P = .063). Rate of oxidation of palmitate at end of exercise was not different with 1.5 ± 0.8 (RSV) vs 1.3 ± 0.6 (P) μmol kg(-1) min(-1) (P = .109). Secondary outcomes did not change except for increased plasma glycerol and decreased plasma glucose levels at the end of exercise after treatment with RSV vs placebo. A daily dose of 1000 mg resveratrol does not improve exercise capacity or FAO during exercise in patients with CPTII or VLCAD deficiencies.
Published: 2022

19. A multicenter cross-sectional French study of the impact of COVID-19 on neuromuscular diseases

Author: Vincent Laugel, Karim Wahbi, Lucie Isoline Pisella, Rabab Debs, Sarah Souvannanorath, Martial Mallaret, Thierry Kuntzer, Sylvain Nollet, Jean-Christophe Antoine, Maud Michaud, Rocío-Nur Villar-Quiles, Aude-Marie Grapperon, Sandrine Segovia-Kueny, Pascal Laforêt, Céline Tard, EL-Hadi Hammouda, Géraldine Merret, Kévin Bigaut, Juliette Svahn, Laurent Kremer, Armelle Magot, Jean-Baptiste Noury, Guillemette Beaudonnet, Louise Debergé, Aleksandra Nadaj-Pakleza, Diane Friedman, Yann Péréon, Emmanuelle Salort-Campana, Pascal Cintas, Sara Fernandes, David H. Adams, Annamaria Molon, Fanny Duval, Anthony Behin, Shahram Attarian, Frédérique Audic, Jean-Philippe Camdessanché, Isabelle Desguerre, Tanya Stojkovic, Françoise Bouhour, Marion Masingue, Guilhem Solé, Caroline Espil-Taris, Savine Vicart, Jean-Baptiste Chanson, Assistance Publique - Hôpitaux de Marseille (APHM), Groupe hospitalier Pellegrin, 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), CHU Lille, Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Strasbourg, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), Hôpital Bicêtre, Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Raymond Poincaré [AP-HP], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Henri Mondor [Créteil], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Lausanne University Hospital, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Necker - Enfants Malades [AP-HP], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Association française contre les myopathies (AFM-Téléthon), Admin, Oskar, Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Henri Mondor, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Thérapie des maladies du muscle strié, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hôpital Purpan [Toulouse], and CHU Toulouse [Toulouse]
Subjects: medicine.medical_specialty, Cross-sectional study, Population, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Health care, medicine, Humans, Pharmacology (medical), Risk factor, education, Myopathy, Pandemics, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, SARS-CoV-2, Research, COVID-19, General Medicine, medicine.disease, Prognosis, Myasthenia gravis, 3. Good health, Neuromuscular diseases, Cross-Sectional Studies, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cohort, Medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Background Due to their health condition, patients with neuromuscular diseases (NMD) are at greater risk of developing serious complications with COVID-19. The objective of this study was to analyze the prevalence of COVID-19 among NMD patients and the risk factors for its impact and severity during the first wave of the pandemic. Clinical data were collected from NMD-COVID-19 patients, between March 25, 2020 and May 11, 2020 in an anonymous survey carried out by expert physicians from the French Health Care Network Filnemus. Results Physicians reported 84 patients, including: 34 with myasthenia gravis, 27 with myopathy and 23 with neuropathy. COVID-19 had no effect on NMD for 48 (58%) patients and 48 (58%) patients developed low COVID-19 severity. COVID-19 caused the death of 9 (11%) NMD patients. Diabetic patients were at greater risk of dying. Patients with diabetes, hypertension or severe forms of NMD had a higher risk of developing a moderate or severe form of COVID-19. In our cohort, corticosteroids and other immunosuppressants were not significantly associated with higher COVID-19 severity for acquired NMD. Conclusion During this period, a small percentage of French NMD patients was affected by COVID-19 compared to the general French population and COVID-19 had a limited short-term effect on them. Diabetes, hypertension and a severe degree of NMD were identified as risk factors of unfavorable outcome following COVID-19. Conversely, in our cohort of patients with acquired NMD, corticosteroids or other immunosuppressants did not appear to be risk factors for more severe COVID-19.
Published: 2021

20. Motor and respiratory decline in patients with late onset Pompe disease after cessation of enzyme replacement therapy during COVID-19 pandemic

Author: Céline, Tard, Emmanuelle, Salort-Campana, Maud, Michaud, Marco, Spinazzi, Aleksandra, Nadaj Pakleza, Hélène, Durr, Françoise, Bouhour, Claire, Lefeuvre, Romain, Thomas, Azzeddine, Arrassi, Nadjib, Taouagh, Guilhem, Solé, and Tardieu, M
Subjects: Treatment Outcome, Neurology, Glycogen Storage Disease Type II, SARS-CoV-2, COVID-19, Humans, Enzyme Replacement Therapy, alpha-Glucosidases, Neurology (clinical), Pandemics
Abstract: Data on interruption of enzyme replacement therapy (ERT) are scarce in late onset Pompe disease. Due to the COVID-19 crisis, eight neuromuscular reference centers in France were obligated to stop the treatment for 31 patients.We collected the motor and respiratory data from our French registry, before COVID-19 and at treatment restart.In 2.2 months (mean), patients showed a significant deterioration of 37 m (mean) in the 6-min walk test and a loss of 210 ml (mean) of forced vital capacity, without ad integrum restoration after 3 months of ERT restart.This national study based on data from the French Pompe Registry shows that the interruption of ERT, even as short as a few months, worsens Pompe patients' motor and respiratory function.
Published: 2021

21. Diagnostic tardif de myopathie nécrosante associée aux anticorps anti-HMG-CoA réductase

Author: Hanna Landsberger, Béatrice Lannes, Alain Meyer, and Aleksandra Nadaj-Pakleza
Subjects: Neurology, Neurology (clinical)
Published: 2022

22. Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies

Author: Mélanie Fradin, Nicolas Sadoul, Xavier Waintraub, Didier Klug, Albert Hagège, Pascal Sabouraud, Arnaud Isapof, Julien Durigneux, Olivier Lascols, Pascal Laforêt, Armelle Magot, Ivana Dabaj, Eloi Marijon, Camille Vatier, Pascal Cintas, Emmanuelle Salort, Bénédicte Gaborit, Antoine Muchir, Xavier Ferrer, Pascale Richard, Corinne Metay, Stéphane Boulé, Sarah Leonard-Louis, Philippe Mabo, V. Tiffreau, Caroline Stalens, Jitendra K. Vohra, Stéphane Schaeffer, Khadija Chikhaoui, Eric Bieth, Sandra Mercier, Pierre Ambrosi, Aleksandra Nadaj-Pakleza, Michèle Mayer, Katja Zeppenfeld, Gisèle Bonne, Véronique Manel, Jean-Marc Davy, Guilhem Sole, Ghassan Moubarak, Nicolas Lamblin, Klaus Dieterich, Christophe Meune, Abdallah Fayssoil, Arnaud Lazarus, Philippe Maury, Karim Wahbi, Philippe Petiot, Isabelle Jéru, Annick Toutain, Corinne Vigouroux, Ana Ferreiro, Maud Michaud, H.M. Bécane, Bruno Eymard, Thomas D. Gossios, Marie-Christine Vantyghem, Saurabh Kumar, Estelle Gandjbakhch, Yann Péréon, T. Thompson, Marie-Christine Minot-Myhié, Anthony Behin, Frédéric Sacher, Philippe Charron, Nicolas Combes, Julien Praline, Dominique Babuty, Emmanuelle Lagrue, Usha B. Tedrow, Jean-Marc Sellal, Florence Petit, Perry M. Elliott, Frédéric Anselme, Philippe Chevalier, Frederic Taithe, Christine Barnerias, Vincent Laugel, Andoni Echaniz-Laguna, Raphaël P. Martins, Alexander F.A. Androulakis, Rabah Ben Yaou, Franck Boccara, Ulrike Walther-Louvier, Tanya Stojkovic, Françoise Bouhour, Annachiara De Sandre-Giovannoli, Susana Quijano-Roy, Françoise Chapon, Jean-Noël Trochu, Céline Tard, Anne Rollin, Jean-Marie Cuisset, Denis Duboc, Raphaël Porcher, Catherine Sarret, Jonathan M. Kalman, Florence Demurger, Damien Bonnet, Christine Francannet, Neal K. Lakdawala, Romain Eschalier, Fabien Labombarda, Kostantinos Savvatis, Raul Juntas Morales, Isabelle Desguerre, Nicolas Lévy, Anne-Claire Brehin, Service de Cardiologie [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 – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Rouen, Normandie Université (NU), St Bartholomew's Hospital (London), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Association française contre les myopathies (AFM-Téléthon), IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Service de Cardiologie B, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hôpital Ambroise Paré [AP-HP], William Harvey Research Institute, Barts and the London Medical School, Biostatistique et épidemiologie clinique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Filière Neuromusculaire (FILNEMUS), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université de Caen Normandie (UNICAEN), Laboratoire d'Informatique Scientifique et Industrielle (LISI), Université de Poitiers-Ecole Nationale Supérieure de Mécanique et d'Aérotechnique [Poitiers] (ISAE-ENSMA), Hôpital Raymond Poincaré [AP-HP], CHU Lille, Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Aix Marseille Université (AMU), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de cardiologie [CHU Pitié-Salpêtrière], 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 cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique Pasteur [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), The Royal Melbourne Hospital, Leiden University Medical Center (LUMC), Universiteit Leiden, Service de neurologie pédiatrique [CHU Necker], Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Hôpital Privé Le Bois Ramsay Santé [Lille], Service de génétique [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Roger Salengro [Lille], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire [Grenoble] (CHU), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Clermont-Ferrand, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Bordeaux], Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie cadiovasculaire et thoracique [Rouen], Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Service de cardiologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Trousseau [APHP], Département de neurologie [Montpellier], 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), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Strasbourg, Clinique Ambroise Paré [Centres Médico-Chirurgicaux Ambroise Pré, Pierre Cherest, Hartmann], Hôpital Cochin [AP-HP], Hospices Civils de Lyon (HCL), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Lorraine (UL), Service de neurologie [Angers], Université d'Angers (UA)-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 Nantes (CHU Nantes), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Laboratoire d'étude de la motricité humaine - EA 3608 (LEMH), Université de Lille, Droit et Santé, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montréal (UdeM), Laboratoire Génie des procédés papetiers (LGP2 ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), The Heart Hospital [London], University College of London [London] (UCL), This study was funded by grants from the AFM-Téléthon (French Alliance against Myopathies), which was not involved in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication. Some of this work was undertaken at University College London (United Kingdom) and St. Bartholomew’s Hospital (London, United Kingdom), which received a portion of funding from the United Kingdom Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme., Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [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), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], CHU Bordeaux [Bordeaux]-Université Bordeaux Segalen - Bordeaux 2, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de cardiologie et maladies vasculaires, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], CHU Pitié-Salpêtrière [APHP], 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) (APHP)-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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP]-Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-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) (APHP)-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), Centre de référence des maladies rares neuromusculaires Aquitaine-Grand Sud Ouest, CHU Bordeaux [Bordeaux], Laboratoire d'Informatique Scientifique et Industrielle (LISI / ENSMA), LISI-ENSMA, Service de Biochimie-Génétique [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Cardiologie A, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Endocrinologie et Métabolisme, Unité de Cardiologie et Soins Intensifs, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Centre de Référence M3C Malformations Cardiaques Congénitales Complexes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Hôpital neurologique, Centre Hospitalier Universitaire de Lille (CHU de Lille), Service Neurologie Pédiatrique, Service de Neuropédiatrie, INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Département de Neurologie, Hôpital Civil de Strasbourg, Groupe 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) (APHP)-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) (APHP)-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 National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, CHU - HÔTEL-DIEU Clermont-Ferrand, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Centre recherche en CardioVasculaire et Nutrition (C2VN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Clinique Ambroise Paré, CHU Cochin [AP-HP], Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hopital Neurologique-Hôpital Femme Mère Enfant, Department of Medicine, Columbia University [New York]-College of Physicians and Surgeons, Service de neurologie, Hospices Civils de Lyon (HCL)-Hôpital de la Croix-Rousse [CHU - HCL], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Hôpital de Rangueil, Institut Pascal - Clermont Auvergne (IP), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), laboratoire d'étude de la motricité humaine (LEMH EA3608), Université de Montréal - UdeM (CANADA), Laboratoire Génie des procédés papetiers (LGP2), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Myologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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), European Genomic Institute for Diabetes - FR 3508 (EGID), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Hôpital Purpan [Toulouse], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut de Myologie, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, Tachycardia, medicine.medical_specialty, implantable, Accurate estimation, Ventricular Tachyarrhythmias, Validation Studies as Topic, 030204 cardiovascular system & hematology, tachycardia, Sudden death, LMNA, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, death, Physiology (medical), Internal medicine, defibrillators, medicine, Humans, In patient, 030212 general & internal medicine, sudden, [SDV.GEN]Life Sciences [q-bio]/Genetics, Prediction score, business.industry, Defibrillators, Implantable, ventricular, Tachycardia, Ventricular, Cardiology, Female, medicine.symptom, Cardiomyopathies, Cardiology and Cardiovascular Medicine, business
Abstract: Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator–treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0–7.2] and 5.1 [2.0–9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711–0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642–0.959), and the calibration slope was 1.082 (95% CI, 0.643–1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03058185.
Published: 2019

23. Efficacy and safety of mexiletine in non-dystrophic myotonias: A randomised, double-blind, placebo-controlled, cross-over study

Author: Savine, Vicart, Jérôme, Franques, Françoise, Bouhour, Armelle, Magot, Yann, Péréon, Sabrina, Sacconi, Aleksandra, Nadaj-Pakleza, Anthony, Behin, Noël, Zahr, Marianne, Hézode, Emmanuel, Fournier, Christine, Payan, Lucette, Lacomblez, and Bertrand, Fontaine
Subjects: Adult, Male, Cross-Over Studies, Myotonia Congenita, Mexiletine, Middle Aged, Myotonia, Treatment Outcome, Double-Blind Method, Quality of Life, Humans, Female, Aged, Myotonic Disorders
Abstract: The MYOMEX study was a multicentre, randomised, double-blind, placebo-controlled, cross-over study aimed to compare the effects of mexiletine vs. placebo in patients with myotonia congenita (MC) and paramyotonia congenita (PC). The primary endpoint was the self-reported score of stiffness severity on a 100 mm visual analogic scale (VAS). Mexiletine treatment started at 200 mg/day and was up-titrated by 200 mg increment each three days to reach a maximum dose of 600 mg/day for total treatment duration of 18 days for each cross-over period. The modified intent-to-treat population included 25 patients (13 with MC and 12 with PC; mean age, 43.0 years; male, 68.0%). The median VAS score for mexiletine was 71.0 at baseline and decreased to 16.0 at the end of the treatment while the score did not change for placebo (81.0 at baseline vs. 78.0 at end of treatment). A mixed effects linear model analysis on ranked absolute changes showed a significant effect of treatment (p 0.001). The overall score of the Individualized Neuromuscular Quality of Life questionnaire (INQoL) was significantly improved (p 0.001). No clinically significant adverse events were reported. In conclusion, mexiletine improved stiffness and quality of life in patients with nondystrophic myotonia and was well tolerated.
Published: 2021

24. Biallelic RFC1-expansion in a French multicentric sporadic ataxia cohort

Author: Aleksandra Nadaj-Pakleza, Lucas Corti, Hélène Puccio, Mathieu Anheim, Jamel Chelly, Cecilia Marelli, Julien Tarabeux, Nicolas Dondaine, Nadège Diedhiou, Odile Gebus, Marilyne Almeras, Pauline Fahrer, Cécile Cauquil, Jean-Baptiste Chanson, Béatrice Lannes, Laura Robelin, Marie Claire Vincent, Mehdi Benkirane, Guillaume Taieb, Christine Tranchant, Gabrielle Rudolf, Matthieu Canuet, Andoni Echaniz-Laguna, Lise Larrieu, Solveig Montaut, and Benoit Lhermitte
Subjects: Vestibular areflexia, Pathology, medicine.medical_specialty, Cerebellum, Ataxia, Cerebellar ataxia, business.industry, Genetic heterogeneity, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Atrophy, medicine.anatomical_structure, Peripheral neuropathy, Neurology, medicine, 030212 general & internal medicine, Neurology (clinical), medicine.symptom, business, Trinucleotide repeat expansion, 030217 neurology & neurosurgery
Abstract: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the RFC1 gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C). 163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C. A pathogenic biallelic RFC1 AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two RFC1 AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found. Our study confirms the genetic heterogeneity of the CANVAS and that RFC1 repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.
Published: 2021

25. Comparison of Corticosteroid Tapering Regimens in Myasthenia Gravis: A Randomized Clinical Trial

Author: Diane Friedman, Tarek Sharshar, Bruno Eymard, Aleksandra Nadaj-Pakleza, Marco Spinazzi, Bernard Clair, Simone Birnbaum, Christine Tranchant, Raphaël Porcher, Antoine Gueguen, Lamiae Grimaldi, S. Demeret, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Hôpital Hôtel-Dieu [Paris], UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Strasbourg, CHU Rothschild [AP-HP], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Novartis Roche Teva Pharmaceutical Industries Ministère des Affaires Sociales et de la Santé, reported receiving nonfinancial support from Allergan and nonfinancial support from Merz outside the submitted work. Dr Gueguen reported receiving grants from French Ministry of Social Affairs and Health during the conduct of the study, has received honoraria and consulting fees from Novartis, Roche, Merck-Serono, Sanofi-Genzyme, Teva, and Mylan, and has received travel funding from Roche, Novartis, Sanofi-Genzyme. A close relative is an Ipsen employee. No other disclosures were reported., Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [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), Hôpital Rothschild [AP-HP], HAL UVSQ, Équipe, Institut Pasteur [Paris]-Université de Paris (UP), Université de Paris (UP), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Pediatrics, medicine.medical_specialty, medicine.drug_class, [SDV]Life Sciences [q-bio], Population, Azathioprine, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Prednisone, Interquartile range, law, medicine, 030212 general & internal medicine, 10. No inequality, education, Original Investigation, education.field_of_study, business.industry, 3. Good health, [SDV] Life Sciences [q-bio], Regimen, Relative risk, Corticosteroid, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract: International audience; Importance: The tapering of prednisone therapy in generalized myasthenia gravis (MG) presents a therapeutic dilemma; however, the recommended regimen has not yet been validated. Objective: To compare the efficacy of the standard slow-tapering regimen of prednisone therapy with a rapid-tapering regimen. Design: From June 1, 2009, to July 31, 2013, a multicenter, parallel, single-blind randomized trial was conducted to compare 2 regimens of prednisone tapering. Data analysis was conducted from February 18, 2019, to January 23, 2020. A total of 2291 adults with a confirmed diagnosis of moderate to severe generalized MG at 7 specialized centers in France were assessed for eligibility. Interventions: The slow-tapering arm included a gradual increase of the prednisone dose to 1.5 mg/kg every other day and a slow decrease once minimal manifestation status of MG was attained. The rapid-tapering arm consisted of immediate high-dose daily administration of prednisone, 0.75 mg/kg, followed by an earlier and rapid decrease once improved MG status was attained. Azathioprine, up to a maximum dose of 3 mg/kg/d, was prescribed for all participants. Main Outcomes and Measures: The primary outcome was attainment of minimal manifestation status of MG without prednisone at 12 months and without clinical relapse at 15 months. Intention-to-treat analysis was conducted. Results: Of the 2291 patients assessed, 2086 did not fulfill the inclusion criteria, 87 declined to participate, and 1 patient registered after trial closure. A total of 117 patients (58 in the slow-tapering arm and 59 in the rapid-tapering arm) were selected for inclusion by MG specialists and were randomized. The population included 62 men (53%); median age was 65 years (interquartile range, 35-69 years). The proportion of patients having met the primary outcome was higher in the rapid- vs slow-tapering arm (23 [39%] vs 5 [9%]), with a risk ratio of 3.61 (95% CI, 1.64-7.97; P
Published: 2021

26. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial

Author: Stella Mazurová, John W. Day, Mazen M. Dimachkie, Sónia Tizon, Anna Kostera-Pruszczyk, Tahseen Mozaffar, Joel Charrow, Chafic Karam, Ricardo Maré, Jean-Baptiste Noury, Dewi Guellec, Jorge Alonso-Pérez, Acary Souza Bulle Oliveira, Loren D M Pena, Tianyue Zhou, Sergey Illarioshkin, Nathan Thibault, Marcelo Rugiero, Can Ebru Bekircan-Kurt, Lauren Chase, Monica Sciacco, Mamatha Pasnoor, Jenny Billy, Mark Tarnopolsky, Fabien Zagnoli, Marie Wencel, Sevim Erdem-Ozdamar, Erin Hatcher, Madoka Mori, Céline Tard, Nicolas Mavroudakis, Emmanuelle Salort-Campana, Antonio Toscano, Shafeeq Ladha, Angela Genge, Ans T. van der Ploeg, Michela Guglieri, Judith Johnson, Fanny Duval, Loïc Danjoux, Christopher Hug, Robert D. Henderson, Robert Neel, Luca Solera, Aleksandra Nadaj-Pakleza, Silvia Boschi, Nizar Chahin, Maurizio Gualtiero Moggio, Peter Young, Priya S. Kishnani, Yin-Hsiu Chien, Alexandra Kautzky-Willer, Claire Questienne, Francoise Bouhour, Gabriela A Niizawa, Ekaterina Fedotova, Tiziana Enrica Mongini, Harmke A. van Kooten, Vera Malinova, Sina Helms, Shahram Attarian, Patrick Deegan, Guilhem Sole, Hamilton Cirne, Ludwig Gutmann, Kenneth I. Berger, Laura Carrera Garcia, N A M E van der Beek, Stephanie Dearmey, Suzara Souto Lopes, Anna Potulska-Chromik, Joao Lindolfo Borges, Yesim Parman, Michaela Riedl, Sergey A. Klyushnikov, Olivier Huynh-Ba, Gauthier Remiche, Paula R. Clemens, Andrea Swenson, Stephan Wenninger, Miriam Hufgard-Leitner, Eugen Mengel, Kristina An Haack, Eve Gandolfo, David Reyes-Leiva, Jean-Baptiste Davion, Chester Whitley, Young Chul Choi, Patricia Altemus, Maria Judit Molnar, Perry B. Shieh, Matthias Vorgerd, Julia B Hennermann, Cheryl Smith, Volker Straub, Lauren Noll, Pascal Laforet, Andres Nascimento Osorio, Clarisa Maxit, Anne-Catherine Aubé-Nathier, Ozlem Goker-Alpan, Olimpia Musumeci, Louisa Müller-Miny, Tarekegn Hiwot, Jacqui Langton, Christopher Nance, Daniel Natera-de Benito, Jeffrey Statland, Nicola Longo, Vivien Pautot, Zoltan Grosz, Thomas Stulnig, Matthias Boentert, Anne-Katrin Guettsches, Chong Yew Tan, Erik Ortega, Derralynn Hughes, Hacer Durmus Tekce, Mark Roberts, Lenka Linková, Amel Karaa, Hani Kushlaf, Anthony Behin, Margarida Ramos Lopes, Jordi Diaz-Manera, Alessia Pugliese, Paulo Victor Sgobbi Souza, Carrie Bailey, Jennifer B Avelar, Hirofumi Komaki, Frederic Taithe, Benedikt Schoser, Sabine Specht, Kathryn E Brown, Gerson Carvalho, and Pediatrics
Subjects: medicine.medical_specialty, Population, Walking, FEV1/FVC ratio, stomatognathic system, SDG 3 - Good Health and Well-being, Double-Blind Method, Internal medicine, Statistical significance, Child, Preschool, Enzyme Replacement Therapy, Humans, Treatment Outcome, Glycogen Storage Disease Type II, alpha-Glucosidases, medicine, Respiratory function, Adverse effect, education, Child, Preschool, Alglucosidase alfa, education.field_of_study, business.industry, Standard treatment, virus diseases, Enzyme replacement therapy, Neurology (clinical), business, medicine.drug
Abstract: Summary Background Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and accumulation of lysosomal glycogen. We assessed the safety and efficacy of avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy specifically designed for enhanced mannose-6-phosphate-receptor targeting and enzyme uptake aimed at increased glycogen clearance, compared with the current approved standard of care, alglucosidase alfa, in patients with late-onset Pompe disease. Methods We did a randomised, double-blind, phase 3 trial at 55 sites in 20 countries. We enrolled individuals (aged ≥3 years) with enzymatically confirmed late-onset Pompe disease who had never received treatment. We used a centralised treatment allocation system to randomly allocate participants to either avalglucosidase alfa or alglucosidase alfa. Participants and investigators were unaware of their treatment allocation. The primary outcome measure was change from baseline to week 49 in upright forced vital capacity percent (FVC%) predicted. We used a hierarchical fixed sequential testing strategy, whereby non-inferiority of avalglucosidase alfa compared with alglucosidase alfa was assessed first, with a non-inferiority margin of 1·1. If non-inferiority was seen, then superiority was tested with a 5% significance level. The key secondary objective was effect on functional endurance, measured by the 6-minute walk test (6MWT). Safety was assessed, including treatment-emergent adverse events and infusion-associated reactions. The modified intent-to-treat population was the primary analysis population for all efficacy analyses. The safety population was the analysis population for safety analyses. This trial is registered with ClinicalTrials.gov , NCT02782741 . We report results of the 49-week primary analysis period. Findings Between Nov 2, 2016, and March 29, 2019, 100 participants were randomly allocated avalglucosidase alfa (n=51) or alglucosidase alfa (n=49). Treatment with avalglucosidase alfa resulted in a least-squares mean improvement in upright FVC% predicted of 2·89% (SE 0·88) compared with 0·46% (0·93) with alglucosidase alfa at week 49 (difference 2·43% [95% CI −0·13 to 4·99]). Non-inferiority was shown because the lower bound of the 95% CI for the difference far exceeded the predefined non-inferiority margin but did not exclude 0 (p=0·0074). Superiority was not reached (p=0·063), so formal testing was stopped, as per the testing hierarchy. Improvements were also seen in the 6MWT with avalglucosidase alfa compared with alglucosidase alfa, with greater increases in distance covered (difference 30·01 m [95% CI 1·33 to 58·69]) and percent predicted (4·71% [0·25 to 9·17]). Treatment-emergent adverse events potentially related to treatment were reported in 23 (45%) of 51 participants in the avalglucosidase alfa group and in 24 (49%) of 49 in the alglucosidase alfa group, and infusion-associated reactions were reported in 13 (26%) participants in the avalglucosidase alfa group and 16 (33%) in the alglucosidase alfa group. Of the five trial withdrawals, all in the alglucosidase alfa group, four were due to adverse events, including two infusion-associated reactions. Serious treatment-emergent adverse events were reported in eight (16%) participants who received avalglucosidase alfa and in 12 (25%) who received alglucosidase alfa. One participant treated with alglucosidase alfa died because of acute myocardial infarction determined to be unrelated to treatment. Antidrug antibody responses were similar in both groups. High and persistent titres (≥12 800) and neutralising antibodies were more common with alglucosidase alfa (in 16 [33%] participants) than with avalglucosidase alfa (ten [20%]). Interpretation We consider that this study provides evidence of clinically meaningful improvement with avalglucosidase alfa therapy over alglucosidase alfa in respiratory function, ambulation, and functional endurance, with no new safety signals reported. An open-label extended-treatment period is ongoing to confirm the long-term safety and efficacy of avalglucosidase alfa, with the aim for this therapy to become the new standard treatment in late-onset Pompe disease. Funding Sanofi Genzyme.
Published: 2021

27. Biallelic RFC1-expansion in a French multicentric sporadic ataxia cohort

Author: Solveig, Montaut, Nadège, Diedhiou, Pauline, Fahrer, Cécilia, Marelli, Benoit, Lhermitte, Laura, Robelin, Marie Claire, Vincent, Lucas, Corti, Guillaume, Taieb, Odile, Gebus, Gabrielle, Rudolf, Julien, Tarabeux, Nicolas, Dondaine, Matthieu, Canuet, Marilyne, Almeras, Mehdi, Benkirane, Lise, Larrieu, Jean-Baptiste, Chanson, Aleksandra, Nadaj-Pakleza, Andoni, Echaniz-Laguna, Cécile, Cauquil, Béatrice, Lannes, Jamel, Chelly, Mathieu, Anheim, Hélène, Puccio, and Christine, Tranchant
Subjects: Cohort Studies, Cerebellar Ataxia, Humans, Ataxia, Replication Protein C, Spinocerebellar Degenerations
Abstract: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the RFC1 gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C).163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C.A pathogenic biallelic RFC1 AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two RFC1 AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found.Our study confirms the genetic heterogeneity of the CANVAS and that RFC1 repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.
Published: 2020

28. Respiratory decline in adult patients with Becker muscular dystrophy: A longitudinal study

Author: Bertien Buyse, Sofie Willaert, Dries Testelmans, Anne-Catherine Aubé-Nathier, Bram De Wel, Aleksandra Nadaj-Pakleza, and Kristl G. Claeys
Subjects: 0301 basic medicine, Spirometry, Adult, Male, medicine.medical_specialty, Vital capacity, Neuromuscular disease, Duchenne muscular dystrophy, spirometry, Vital Capacity, Natural history, Walking, Pulmonary function testing, Body Mass Index, BMI, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, BMD, Internal medicine, medicine, Humans, Respiratory function, Longitudinal Studies, Muscular dystrophy, Lung, Genetics (clinical), Aged, medicine.diagnostic_test, DMD-gene, business.industry, Respiration, Middle Aged, medicine.disease, FVC, Muscular Dystrophy, Duchenne, 030104 developmental biology, Neurology, Pediatrics, Perinatology and Child Health, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Becker muscular dystrophy (BMD) is a rare hereditary neuromuscular disease, caused by a genetic defect in the Duchenne Muscular Dystrophy (DMD) gene. We studied the natural history of respiratory function and its affecting factors in 23 adult BMD patients. These important data are needed for (future) clinical trials in BMD but are largely lacking. Patients had a median age of 51 years (28-78y) and median follow-up duration of 14 years (2-25y). We analysed 190 pulmonary function measurements with a median interval of one year (1-17y) and measured a 1.00% decline of Forced Vital Capacity percent predicted (FVC%pred) per year (p = 0.004). Loss of ambulation significantly increased the annual rate of FVC decline and was dependent of patient's body mass index (BMI; p = 0.015), with increases in BMI correlating with an even more rapid deterioration of FVC. A decline in Medical Research Council (MRC) sum score was significantly correlated with a decline in FVC (p = 0.003). We conclude that adult BMD patients experience a significant but mild respiratory decline. However, this decline is significantly more rapid and clinically relevant after loss of ambulation, which warrants a more vigilant follow-up of respiratory function in this subgroup. ispartof: NEUROMUSCULAR DISORDERS vol:31 issue:3 ispartof: location:England status: published
Published: 2020

29. Homozygous C-terminal loss-of-function NaV1.4 variant in a patient with congenital myasthenic syndrome

Author: Aleksandra Nadaj-Pakleza, Michael G. Hanna, Roope Männikkö, Emma Matthews, Emmanuel Fournier, Andoni Echaniz-Laguna, Valérie Biancalana, Hôpital Bicêtre, Petites Molécules de neuroprotection, neurorégénération et remyélinisation, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institute of Neurology [London], University College of London [London] (UCL), and univOAK, Archive ouverte
Subjects: [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Bioinformatics, channels, Neuromuscular junction, Article, Ophthalmoparesis, 03 medical and health sciences, 0302 clinical medicine, Ptosis, medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business.industry, Sodium channel, Muscle weakness, Skeletal muscle, Congenital myasthenic syndrome, medicine.disease, Congenital myopathy, myasthenia, Psychiatry and Mental health, medicine.anatomical_structure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Surgery, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), neuromuscular, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Congenital myasthenic syndromes (CMS) are a group of rare inherited disorders of neuromuscular transmission.1 Clinical presentations range from predominant ptosis, ophthalmoparesis, facial and bulbar weakness, and generalised muscle weakness to predominant limb girdle weakness with sparing of the eye and face muscles. Symptoms may appear during the neonatal period, late childhood, adolescence or even adulthood. Clinical presentation and response to treatment may be influenced by the underlying molecular mechanism. Mutations in more than 30 genes have been identified as causing CMS.1 The primary pathogenic mechanism is defective neuromuscular junction (NMJ) transmission but may include central nervous system and skeletal muscle involvement. Biallelic loss-of-function (LOF) genetic mutations in SCN4A encoding skeletal muscle sodium channel NaV1.4 are a rare cause of CMS.2–6 Heterozygous carriers are asymptomatic, demonstrating recessive inheritance. NaV1.4 conducts the depolarising current of the skeletal muscle action potential that when reduced results in attenuated action potentials and muscle force. Biallelic SCN4A LOF mutations can also be found in patients diagnosed with congenital myopathy6–8 and occasionally hypokalaemic periodic paralysis (hypoPP).9 10 A common pathogenic mechanism can account for the notion that patients diagnosed with SCN4A -associated CMS may present with additional features of myopathy5 or hypoPP.4 The mutant NaV1.4 channels within SCN4A LOF clinical spectra show distinct functional defects. Mutations associated with congenital myopathy show a range of alterations on NaV1.4 channel function but one allele is often null.6–8 Hitherto reported CMS-associated mutations enhance channel inactivation2–5 and typically affect fourth voltage sensing domain (VSD) of NaV1.4, the key VSD implicated in control of …
Published: 2020

30. Abundant electrical myotonia and left ventricular noncompaction: Unusual features of Danon disease due to a novel mutation in LAMP2 gene

Author: Franck Letournel, Aude Tassin, Paul Richard, Aleksandra Nadaj-Pakleza, Vivien Pautot, Philippe Codron, Damien Sternberg, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Pathology, medicine.medical_specialty, LAMP2, business.industry, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, medicine.disease, Myotonia, Phenotype, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Neurology, Mutation (genetic algorithm), medicine, Left ventricular noncompaction, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Danon disease, Neurology (clinical), business, Novel mutation, Gene, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery
Abstract: International audience
Published: 2019

31. Long term longitudinal study of muscle function in patients with glycogen storage disease type IIIa

Author: Abdallah Fayssoil, Bruno Eymard, Gwenn Ollivier, François Petit, Aurélie Canal, Aleksandra Nadaj-Pakleza, Karim Wahbi, Jean-Yves Hogrel, Anthony Behin, Pascal Laforêt, Valérie Decostre, Kahina Kachetel, Marie De Antonio, and Philippe Labrune
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Longitudinal study, Time Factors, Adolescent, Endocrinology, Diabetes and Metabolism, Metabolic myopathy, Glycogen storage disease type III, Biochemistry, Glycogen debranching enzyme, Glycogen Storage Disease Type III, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Muscular Diseases, Internal medicine, Genetics, medicine, Humans, Purdue Pegboard Test, Glycogen storage disease, Longitudinal Studies, Molecular Biology, Retrospective Studies, Hand Strength, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Clinical trial, Cross-Sectional Studies, Outcome and Process Assessment, Health Care, 030104 developmental biology, Physical therapy, Female, business, 030217 neurology & neurosurgery
Abstract: Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by mutations in the AGL gene coding for the glycogen debranching enzyme. Current therapy is based on dietary adaptations but new preclinical therapies are emerging. The identification of outcome measures which are sensitive to disease progression becomes critical to assess the efficacy of new treatments in upcoming clinical trials. In order to prepare future longitudinal studies or therapeutic trials with large cohorts, information about disease progression is required. In this study we present preliminary longitudinal data of Motor Function Measure (MFM), timed tests, Purdue pegboard test, and handgrip strength collected over 5 to 9years of follow-up in 13 patients with GSDIII aged between 13 and 56years old. Follow-up for nine of the 13 patients was up to 9years. Similarly to our previous cross-sectional retrospective study, handgrip strength significantly decreased with age in patients older than 37years. MFM scores started to decline after the age of 35. The Purdue pegboard score also significantly reduced with increasing age (from 13years of age) but with large inter-visit variations. The time to stand up from a chair or to climb 4 stairs increased dramatically in some but not all patients older than 30years old. In conclusion, this preliminary longitudinal study suggests that MFM and handgrip strength are the most sensitive muscle function outcome measures in GSDIII patients from the end of their third decade. Sensitive muscle outcome measures remain to be identified in younger GSDIII patients but is challenging as muscle symptoms remain discrete and often present as accumulated fatigue.
Published: 2017

32. Myasthénie auto-immune séronégative

Author: Oana Catar, Aleksandra Nadaj-Pakleza, and Anne-Catherine Aubé-Nathier
Subjects: 0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, business.industry, Medicine, General Medicine, Auto immune, business, Molecular biology, 030217 neurology & neurosurgery, General Biochemistry, Genetics and Molecular Biology
Abstract: La myasthenie est une maladie auto-immune avec, dans 80 % des cas, des anticorps diriges contre le recepteur de l’acetylcholine (anti-RACh) positifs et deux formes cliniques distinctes, oculaire et generalisee. Les formes seronegatives sont relativement rares et cliniquement heterogenes. Le diagnostic de la myasthenie seronegative reste souvent difficile, notamment pour les formes oculaires et est essentiellement base sur une symptomatologie fluctuante caracteristique. La decouverte des anticorps anti-RACh a faible affinite et des nouveaux anticorps comme les anti-MuSK (diriges contre le recepteur specifique de la tyrosine kinase), les anti-LRP4 (diriges contre la proteine 4 reliee au recepteur des lipoproteines de faible densite), les anti-agrine ou les anti-cortactine constitue un avancement considerable dans la comprehension de la physiopathologie de la myasthenie. Selon le profil serologique, il est possible de prevoir la gravite potentielle de la maladie, la reponse aux traitements et le risque de pathologie thymique associee.
Published: 2017

33. Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy

Author: Claire-Sophie Davoine, Michel Fardeau, Damien Sternberg, Emmanuel Fournier, Marie-Joséphine Fontenille, Arnaud Lacour, Norma B. Romero, Elodie De Bruyckere, D. Hantai, Julien Messéant, Geoffroy Vellieux, Sophie Nicole, Tanya Stojkovic, Sylvie Sukno, Françoise Bouhour, Jeanine Koenig, S. Bauche, E. Lacène, Pascal Laforêt, Lucie Wolf, Laure Strochlic, Guy Brochier, Bruno Eymard, Aleksandra Nadaj-Pakleza, Frédéric Chevessier, Véronique Manel, Nathalie Streichenberger, Bertrand Fontaine, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [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)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Universitätsklinikum Erlangen, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre National de la Recherche Scientifique (CNRS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut NeuroMyoGène (INMG), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Roger Salengro [Lille], Centre de référence des maladies rares neuromusculaires, Centre hospitalier de Béthune, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and HAL-UPMC, Gestionnaire
Subjects: Adult, 0301 basic medicine, medicine.medical_specialty, Weakness, Glycosylation, Neurology, Adolescent, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], Sarcoplasm, Neuromuscular Junction, 030105 genetics & heredity, Biology, Neuromuscular junction, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Prospective Studies, Muscle, Skeletal, Myopathy, Aged, Retrospective Studies, Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing), Myasthenic Syndromes, Congenital, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Middle Aged, Congenital myasthenic syndrome, medicine.disease, Transmembrane protein, 3. Good health, Endocrinology, medicine.anatomical_structure, Female, Synaptopathy, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, Follow-Up Studies, Myopathies, Structural, Congenital
Abstract: International audience; Mutations in GFPT1 (glutamine-fructose-6-phosphate transaminase 1), a gene encoding an enzyme involved in glycosylation of ubiquitous proteins, cause a limb-girdle congenital myasthenic syndrome (LG-CMS) with tubular aggregates (TAs) characterized predominantly by affection of the proximal skeletal muscles and presence of highly organized and remodeled sarcoplasmic tubules in patients’ muscle biopsies. We report here the first long-term clinical follow-up of 11 French individuals suffering from LG-CMS with TAs due to GFPT1 mutations, of which nine are new. Our retrospective clinical evaluation stresses an evolution toward a myopathic weakness that occurs concomitantly to ineffectiveness of usual CMS treatments. Analysis of neuromuscular biopsies from three unrelated individuals demonstrates that the maintenance of neuromuscular junctions (NMJs) is dramatically impaired with loss of post-synaptic junctional folds and evidence of denervation–reinnervation processes affecting the three main NMJ components. Moreover, molecular analyses of the human muscle biopsies confirm glycosylation defects of proteins with reduced O-glycosylation and show reduced sialylation of transmembrane proteins in extra-junctional area. Altogether, these results pave the way for understanding the etiology of this rare neuromuscular disorder that may be considered as a “tubular aggregates myopathy with synaptopathy”.
Published: 2017

34. La maladie de Steinert racontée par ceux qui la vivent…

Author: Anne-Chantal Hardy, Raphaële Chasserieau, Adeline Perrot, Aleksandra Nadaj Pakleza, Armelle Magot, Yann Péréon, and Didier Lecordier
Subjects: Psychology
Published: 2017

35. Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment

Author: Philippe Labrune, José C. Milisenda, Sarah Leonard-Louis, Thomas Krag, Benedikt Schoser, Louisa Jauze, Aleksandra Nadaj-Pakleza, Giuseppe Ronzitti, Claire Lefeuvre, Guy Brochier, Sabrina Sacconi, Ichizo Nishino, Federico Mingozzi, Carola Hedberg-Oldfors, Michio Inoue, Edoardo Malfatti, François Petit, Evelyne Goillot, Umut Cagin, Nathalie Streichenberger, Clémence Labasse, A. Madelaine, Julien Fabregue, John Vissing, Pascal Laforêt, Anders Oldfors, Norma B. Romero, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), AGROCAMPUS OUEST, 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), 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), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Nutrition, diabète et cerveau (NUDICE), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence Maladies Héréditaires du Métabolisme Hépatique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIBER de Enfermedades Raras (CIBERER), Centre de référence des maladies rares neuromusculaires, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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, Université de Bordeaux (UB), University of Copenhagen = Københavns Universitet (UCPH), ANR-17-CE18-0014,TRACeGSDIII,Optimisation translationnelle d'un vecteur AAV pour le traitement de GSDIII(2017), 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 d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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), Nutrition, diabète et cerveau, 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), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), and University of Copenhagen = Københavns Universitet (KU)
Subjects: Male, Pathology, Biopsy, [SDV]Life Sciences [q-bio], Sarcoplasm, Glycogen storage disease type III, lcsh:RC346-429, Glycogen Storage Disease Type III, Mice, chemistry.chemical_compound, 0302 clinical medicine, Metabolic myopathies, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, 0303 health sciences, Glycogen, medicine.diagnostic_test, Middle Aged, 3. Good health, medicine.anatomical_structure, Glycogenesis, Female, Adult, medicine.medical_specialty, Biology, Pathology and Forensic Medicine, Glycogen debranching enzyme, 03 medical and health sciences, Cellular and Molecular Neuroscience, Autophagy, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Humans, Glycogen storage disease III, Muscle, Skeletal, lcsh:Neurology. Diseases of the nervous system, Aged, 030304 developmental biology, Muscle biopsy, Research, Autophagic impairment, Skeletal muscle, Myopathology, medicine.disease, Disease Models, Animal, Muscle glycogenosis, chemistry, Vacuoles, Neurology (clinical), 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene. In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large non-membrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model. In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples. These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.
Published: 2019

36. [Seronegative myasthenia gravis]

Author: Oana, Catar, Anne-Catherine, Aubé-Nathier, and Aleksandra, Nadaj-Pakleza
Subjects: Diagnosis, Differential, Myasthenia Gravis, Humans, Receptor Protein-Tyrosine Kinases, Receptors, Cholinergic, Serologic Tests, LDL-Receptor Related Proteins, Autoantibodies
Published: 2017

37. Cognitive profile of patients with glycogen storage disease type III: a clinical description of seven cases

Author: François Petit, Valérie Hahn-Barma, Marcela Gargiulo, Ariane Herson, Philippe Labrune, Bruno Eymard, Aleksandra Nadaj-Pakleza, Pascal Laforêt, and Claire-Cécile Michon
Subjects: Adult, Male, medicine.medical_specialty, Pilot Projects, Neuropsychological Tests, Glycogen storage disease type III, Executive Function, Glycogen Storage Disease Type III, Young Adult, Cognition, Memory, Social cognition, Genetics, Humans, Medicine, Apathy, Episodic memory, Genetics (clinical), Language, business.industry, Neuropsychology, Middle Aged, Executive functions, medicine.disease, Physical therapy, Female, medicine.symptom, Cognition Disorders, business, Psychopathology, Clinical psychology
Abstract: Glycogen storage disease type III (GSDIII) is a rare autosomal recessive disorder due to glycogen debranching enzyme (GDE) deficiency. It results in a multisystemic disease with predominant hepatic and myopathic symptoms. While frequent social maladjustment has been observed in our clinical practice, cognitive and psychological disturbances have never been assessed. The aim of this pilot study was to examine and characterize the cognitive profile of patients with GSDIII. Seven patients (six women and one man, mean age: 38.7 ± 11.6 years) with GSDIII underwent a neuropsychological set of tests assessing global cognitive efficiency, executive functions, social cognition, apathy, and episodic memory. All patients presented previous psychopathological history. We observed attention fluctuations for each patient, and impaired global cognitive efficiency with deficiencies in executive functions in 5/7 patients. Emotional skills (social cognition) were impaired in five patients. Memory was mostly preserved. The impairment in social cognition (recognition of emotions and ability to attribute mental states to others) and executive functions observed could be a consequence of orbito-frontal dysfunction due to the abnormal glycogen metabolism characteristic of the underlying disease. These results are consistent with the hypothesis of a central nervous system involvement in patients with GSDIII, but need to be confirmed in future research. This could explain the social and economic difficulties, and the lack of compliance to the medical follow-up presented by these patients. It suggests that these disturbances need to be taken into account when planning the medical management of patients with GSDIII.
Published: 2014

38. Myoadenylate deaminase deficiency: a frequent cause of muscle pain A case detected by exercise testing

Author: Pascal Reynier, Lydie Lim, Aleksandra Nadaj-Pakleza, Gilles Simard, Antoine Bruneau, Cédric Le Maréchal, Franck Letournel, Chadi Homedan, Maeva Palayer, Laboratoire de Neurobiologie et Transgénèse (LNBT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Génétique moléculaire et génétique épidémiologique, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mitochondrie : Régulations et Pathologie, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre de reference des maladies neuromusculaires Nantes-Angers, CHU d'Angers et Nantes, Centre Hospitalier Universitaire d'Angers (CHU Angers), and PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)
Subjects: Exercise stress testing, Adult, Male, medicine.medical_specialty, Purine-Pyrimidine Metabolism, Inborn Errors, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, AMP Deaminase, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, Medicine, Humans, ComputingMilieux_MISCELLANEOUS, Gynecology, Exercise Tolerance, business.industry, [SDV.BA]Life Sciences [q-bio]/Animal biology, Homozygote, AMP deaminase, General Medicine, Myalgia, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, Mutation, Exercise Test, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery
Abstract: Le deficit en myoadenylate desaminase (MAD, MIM#615511) est la cause la plus frequente de myopathies metaboliques avec une prevalence estimee entre 1 et 2 % de la population generale. Nous rapportons le cas d’un homme de 39 ans souffrant depuis 4 ans de douleurs musculaires squelettiques invalidantes d’apparition progressive avec, comme seul signe biologique, une augmentation moderee de creatine kinase (CK). Ce cas clinique nous donne l’opportunite de faire le point sur cette pathologie frequente et meconnue, ainsi que sur l’interet des explorations metaboliques dynamiques realisees lors d’epreuves d’effort sur cyclo-ergometre. Cet examen clinicobiologique non invasif, a l’interface entre la physiologie et la biologie, nous a en effet permis d’identifier chez ce patient une absence totale d’elevation physiologique de l’ammoniemie lors de l’effort, evocatrice d’un deficit en MAD. Ce deficit enzymatique en MAD a par la suite ete confirme par histochimie et l’etude moleculaire qui a revele la presence du variant pathogene homozygote retrouve de maniere recurrente chez la majorite des patients dans le gene de l’adenosine monophosphate desaminase 1 (AMPD1).
Published: 2017

39. Sporadic late-onset nemaline myopathy: clinico-pathological characteristics and review of 76 cases

Author: Antje Bornemann, Lukas J. Schnitzler, Christian Hartmann, Peter De Jonghe, Jens Reimann, Peter Van den Bergh, Andreas Meisel, Jörg B. Schulz, Jens A. Petersen, Aleksandra Nadaj-Pakleza, Joachim Weis, Philip Van Damme, Kristl G. Claeys, Andreas Ferbert, Elisabeth J. Rushing, Tobias Schreckenbach, Thomas Tousseyn, Jean-Jacques Martin, Werner Stenzel, Dietmar Rudolf Thal, Susanne Petri, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, University of Zurich, and Claeys, Kristl G
Subjects: HIV-NM, 2716 Genetics (clinical), Weakness, Paraproteinemia, Pathology, medicine.medical_specialty, HIV-associated nemaline myopathy, lcsh:Medicine, 610 Medicine & health, Late onset, Review, Muscle disorder, Myopathies, Nemaline, SLONM, 03 medical and health sciences, 0302 clinical medicine, Nemaline myopathy, Atrophy, medicine, 2736 Pharmacology (medical), Animals, Humans, Pharmacology (medical), ddc:610, Age of Onset, Myopathy, Genetics (clinical), Immunosuppression Therapy, Muscle biopsy, medicine.diagnostic_test, business.industry, Muscles, lcsh:R, Monoclonal gammopathy, High-Throughput Nucleotide Sequencing, General Medicine, medicine.disease, 10040 Clinic for Neurology, 030220 oncology & carcinogenesis, NGS, Immunology, MGUS, Human medicine, medicine.symptom, business, 030217 neurology & neurosurgery, Stem Cell Transplantation
Abstract: Orphanet journal of rare diseases : OJRD 12(1), 86 (2017). doi:10.1186/s13023-017-0640-2, Published by BioMed Central, London
Published: 2017

40. Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy

Author: Emma Matthews, Edoardo Malfatti, Osorio Abath Neto, Sandra Donkervoort, Aleksandra Nadaj Pakleza, Bruno Eymard, Hernan Gonorazky, F Zorzato, Lucy Feng, Mai Thao Bui, Pinki Munot, Johann Böhm, Nicolas Dondaine, Guy Brochier, Anne Boland, Valérie Biancalana, Clémence Labasse, Ana Lia Taratuto, Susan Treves, Leigh Ramos-Platt, Emmanuelle Lacène, Xavière Lornage, Charlotte J. Sumner, Caroline Sewry, Vanessa Schartner, Julie D. Thompson, Jocelyn Laporte, Tyler Mark Pierson, Michel Fardeau, Irina Zaharieva, Susana Quijano-Roy, Rahul Phadke, Norma B. Romero, Diana Bharucha-Goebel, Maud Beuvin, Francesco Muntoni, Jean-François Deleuze, Carsten G. Bönnemann, Raphaël Schneider, Ivana Dabaj, 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), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Triad, Sequence Homology, Core myopathy, Muscle Cells/metabolism/pathology, Cohort Studies, 0302 clinical medicine, Child, Myotonia Congenita/diagnostic imaging/*genetics/*metabolism/pathology, Cells, Cultured, Congenital myopathy, Cultured, Ryanodine receptor, Malignant hyperthermia, Middle Aged, musculoskeletal system, Amino Acid, Myotubular myopathy, medicine.anatomical_structure, Phenotype, Muscle, Female, medicine.symptom, Muscle contraction, Adult, medicine.medical_specialty, Calcium/metabolism, Adolescent, Calcium Channels, L-Type, Myotonia Congenita, Cells, Biology, Skeletal/diagnostic imaging/metabolism/pathology, NO, Pathology and Forensic Medicine, Excitation–contraction coupling, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Hypokalemic periodic paralysis, Internal medicine, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Family, Calcium Channels/*genetics/*metabolism, Centronuclear myopathy, Muscle, Skeletal, RYR1, Muscle Cells, Sequence Homology, Amino Acid, DHPR, Skeletal muscle, medicine.disease, Excitation-contraction coupling, 030104 developmental biology, Endocrinology, Mutation, Calcium, Neurology (clinical), Calcium Channels, 030217 neurology & neurosurgery
Abstract: Muscle contraction upon nerve stimulation relies on excitation-contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of congenital myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.
Published: 2016

41. Autophagy impairment in muscle biopsies from debranching enzyme deficiency (GSDIII) patients: pinpointing novel therapeutic perspectives

Author: Sabrina Sacconi, Guy Brochier, Norma B. Romero, Anders Oldfors, Sarah Leonard-Louis, Nathalie Streichenberger, Bruno Eymard, Clémence Labasse, Aleksandra Nadaj-Pakleza, E. Goillot, E. Malfatti, Benedikt Schoser, P. Laforêt, A. Madelaine, and John Vissing
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Autophagy, Biology, Glycogen debranching enzyme, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, Pediatrics, Perinatology and Child Health, Cancer research, medicine, Neurology (clinical), 030217 neurology & neurosurgery, Genetics (clinical)
Published: 2017

42. Non Random Distribution of DMD Deletion Breakpoints and Implication of Double Strand Breaks Repair and Replication Error Repair Mechanisms

Author: Isabelle Marey, Rabah Ben Yaou, Nathalie Deburgrave, Aurélie Vasson, Juliette Nectoux, France Leturcq, Bruno Eymard, Pascal Laforet, Anthony Behin, Tanya Stojkovic, Michèle Mayer, Vincent Tiffreau, Isabelle Desguerre, François Constant Boyer, Aleksandra Nadaj-Pakleza, Xavier Ferrer, Karim Wahbi, Henri-Marc Becane, Mireille Claustres, Jamel Chelly, Mireille Cossee, Service de biochimie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [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 ), CHU Pitié-Salpêtrière [APHP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Trousseau [APHP], Activité Physique, Muscle, Santé ( EA4488 ), Université de Lille, Droit et Santé, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Service de neurologie pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Centre de Référence, Maladies Neuromusculaires Garches-Necker-Mondor-Hendaye (GNMH), Centre Hospitalier Universitaire de Reims ( CHU Reims ), Service de neurologie [Angers], Université d'Angers ( UA ) -CHU Angers, Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de Cardiologie [CHU Cochin], Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Service de biochimie et de génétique moléculaire [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Activité Physique, Muscle, Santé (EA4488), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Universitaire de Reims (CHU Reims), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: DNA Replication, Male, 0301 basic medicine, deletion breakpoints, DNA End-Joining Repair, DNA Copy Number Variations, DNA Repair, Biology, Origin of replication, Dystrophin, 03 medical and health sciences, Exon, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Humans, DNA Breaks, Double-Stranded, replication error repair mechanisms, Copy-number variation, Gene, Sequence Deletion, Genetics, Comparative Genomic Hybridization, Intron, Recombinational DNA Repair, Gene rearrangement, Introns, Double Strand Break Repair, Muscular Dystrophy, Duchenne, 030104 developmental biology, Neurology, double strand break repair, Neurology (clinical), [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, DMD gene, Comparative genomic hybridization
Abstract: BACKGROUND: Dystrophinopathies are mostly caused by copy number variations, especially deletions, in the dystrophin gene (DMD). Despite the large size of the gene, deletions do not occur randomly but mainly in two hot spots, the main one involving exons 45 to 55. The underlying mechanisms are complex and implicate two main mechanisms: Non-homologous end joining (NHEJ) and micro-homology mediated replication-dependent recombination (MMRDR). OBJECTIVE: Our goals were to assess the distribution of intronic breakpoints (BPs) in the genomic sequence of the main hot spot of deletions within DMD gene and to search for specific sequences at or near to BPs that might promote BP occurrence or be associated with DNA break repair. METHODS: Using comparative genomic hybridization microarray, 57 deletions within the intron 44 to 55 region were mapped. Moreover, 21 junction fragments were sequenced to search for specific sequences. RESULTS: Non-randomly distributed BPs were found in introns 44, 47, 48, 49 and 53 and 50% of BPs clustered within genomic regions of less than 700bp. Repeated elements (REs), known to promote gene rearrangement via several mechanisms, were present in the vicinity of 90% of clustered BPs and less frequently (72%) close to scattered BPs, illustrating the important role of such elements in the occurrence of DMD deletions. Palindromic and TTTAAA sequences, which also promote DNA instability, were identified at fragment junctions in 20% and 5% of cases, respectively. Micro-homologies (76%) and insertions or deletions of small sequences were frequently found at BP junctions. CONCLUSIONS: Our results illustrate, in a large series of patients, the important role of RE and other genomic features in DNA breaks, and the involvement of different mechanisms in DMD gene deletions: Mainly replication error repair mechanisms, but also NHEJ and potentially aberrant firing of replication origins. A combination of these mechanisms may also be possible.
Published: 2016

43. Cross-sectional retrospective study of muscle function in patients with glycogen storage disease type III

Author: Kahina Kachetel, Pascal Laforêt, Valérie Decostre, Philippe Labrune, Gwenn Ollivier, Aurélie Canal, Anthony Behin, Karim Wahbi, Bruno Eymard, Marie De Antonio, François Petit, Aleksandra Nadaj-Pakleza, Sylvain Leveugle, and Jean-Yves Hogrel
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Aging, Adolescent, Metabolic myopathy, Muscle Strength Dynamometer, Glycogen storage disease type III, Manual Muscle Testing, 03 medical and health sciences, Glycogen Storage Disease Type III, Young Adult, 0302 clinical medicine, medicine, Purdue Pegboard Test, Humans, In patient, Muscle, Skeletal, Genetics (clinical), Retrospective Studies, Muscle Weakness, Hand Strength, business.industry, Metabolic disorder, Retrospective cohort study, Middle Aged, medicine.disease, Clinical trial, 030104 developmental biology, Cross-Sectional Studies, Neurology, Pediatrics, Perinatology and Child Health, Physical therapy, Arm, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Glycogen storage disease type III is an inherited metabolic disorder characterized by liver and muscle impairment. This study aimed to identify promising muscle function measures for future studies on natural disease progression and therapeutic trials. The age-effect on the manual muscle testing (MMT), the hand-held dynamometry (HHD), the motor function measure (MFM) and the Purdue pegboard test was evaluated by regression analysis in a cross-sectional retrospective single site study. In patients aged between 13 and 56 years old, the Purdue pegboard test and dynamometry of key pinch and knee extension strength were age-sensitive with annual losses of 1.49, 1.10 and 0.70% of the predicted values (%pred), respectively. The MFM score and handgrip strength were also age-sensitive but only in patients older than 29 and 37 years old with annual losses of 1.42 and 1.84%pred, respectively. Muscle strength assessed by MMT and elbow extension measured by HHD demonstrated an annual loss of less than 0.50%pred and are thus unlikely to be promising outcome measures for future clinical trials. In conclusion, our results identified age-sensitive outcomes from retrospective data and may serve for future longitudinal studies in which an estimation of the minimal number of subjects is provided.
Published: 2016

44. Expanded phenotypic spectrum of the m.8344AG 'MERRF' mutation: data from the German mitoNET registry

Author: Aleksandra Nadaj-Pakleza, Kristl G. Claeys, Holger Prokisch, Jörg B. Schulz, Ronald R. Lautenschläger, Joachim Weis, Klaus A. Kuhn, Thomas Klopstock, Jochen Schäfer, Marcus Deschauer, Cornelia Kornblum, Judith Altmann, Robert Kopajtich, Sandra Jackson, Diana Lehmann, Ludger Schöls, Boriana Büchner, and Kathrin N. Karle
Subjects: 0301 basic medicine, Male, Pathology, RNA, Mitochondrial, Cohort Studies, Epilepsy, 0302 clinical medicine, epidemiology [MERRF Syndrome], Mitochondrial myopathy, Germany, Medicine, genetics [RNA], Registries, Age of Onset, genetics [MERRF Syndrome], Brain, Middle Aged, Heteroplasmy, Pedigree, Phenotype, Neurology, RNA, Transfer, Lys, Female, medicine.symptom, Adult, medicine.medical_specialty, Ataxia, Adolescent, Mitochondrial disease, genetics [RNA, Transfer, Lys], epidemiology [Germany], 03 medical and health sciences, Humans, ddc:610, diagnostic imaging [Brain], Aged, Cerebellar ataxia, business.industry, medicine.disease, MERRF Syndrome, 030104 developmental biology, drug therapy [MERRF Syndrome], physiopathology [MERRF Syndrome], Mutation, Myoclonic epilepsy, RNA, Neurology (clinical), business, Myoclonus, 030217 neurology & neurosurgery
Abstract: The m.8344A>G mutation in the MTTK gene, which encodes the mitochondrial transfer RNA for lysine, is traditionally associated with myoclonic epilepsy and ragged-red fibres (MERRF), a multisystemic mitochondrial disease that is characterised by myoclonus, seizures, cerebellar ataxia, and mitochondrial myopathy with ragged-red fibres. We studied the clinical and paraclinical phenotype of 34 patients with the m.8344A>G mutation, mainly derived from the nationwide mitoREGISTER, the multicentric registry of the German network for mitochondrial disorders (mitoNET). Mean age at symptom onset was 24.5 years ±10.9 (6-48 years) with adult onset in 75 % of the patients. In our cohort, the canonical features seizures, myoclonus, cerebellar ataxia and ragged-red fibres that are traditionally associated with MERRF, occurred in only 61, 59, 70, and 63 % of the patients, respectively. In contrast, other features such as hearing impairment were even more frequently present (72 %). Other common features in our cohort were migraine (52 %), psychiatric disorders (54 %), respiratory dysfunction (45 %), gastrointestinal symptoms (38 %), dysarthria (36 %), and dysphagia (35 %). Brain MRI revealed cerebral and/or cerebellar atrophy in 43 % of our patients. There was no correlation between the heteroplasmy level in blood and age at onset or clinical phenotype. Our findings further broaden the clinical spectrum of the m.8344A>G mutation, document the large clinical variability between carriers of the same mutation, even within families and indicate an overlap of the phenotype with other mitochondrial DNA-associated syndromes.
Published: 2015

45. Rola biopsji mięśnia szkieletowego w diagnostyce chorób nerwowo-mięśniowych

Author: Biruta Kierdaszuk, Aleksandra Nadaj-Pakleza, and Anna Kamińska
Subjects: Muscle tissue, Pathology, medicine.medical_specialty, Muscle biopsy, medicine.diagnostic_test, business.industry, medicine.disease, Oculopharyngeal muscular dystrophy, medicine.anatomical_structure, Mitochondrial myopathy, Biopsy, medicine, Surgery, Neurology (clinical), medicine.symptom, Inclusion body myositis, Muscular dystrophy, Myopathy, business
Abstract: Muscle biopsy is required to provide a definitive diagnosis in many neuromuscular disorders. Biopsy findings may indicate whether the pathological process is of neurogenic or myopathic origin. The muscle biopsy may give important information on the course of the disease (acute or chronic) and on the disease stage and progression. The interpretation of muscle biopsy, including histochemical and ultrastructural analysis, is a key factor in the diagnosis of muscular dystrophies, glycogenoses, inflammatory myopathies and congenital myopathies. An assessment of muscle biopsy on electron microscopy enables a definite diagnosis of oculopharyngeal muscular dystrophy, mitochondrial myopathy or inclusion body myositis. This paper presents an overview of general indications for muscle biopsy, biopsy procedures, as well as transportation and preparation of muscle tissue for final microscopic analysis. The interpretation of specific microscopic findings and a brief discussion on the clinical usefulness of muscle biopsy in the era of molecular diagnosis are also presented.
Published: 2010

46. Limb-girdle muscular dystrophy related to LAMA2 mutations: an unusual familial coincidence responsible for the phenotypic variability and diagnostic difficulties

Author: V. Guillet-Pichon, C. Beroud, Aleksandra Nadaj-Pakleza, F. Leturcq, and K. Claeys
Subjects: Neurology, business.industry, Pediatrics, Perinatology and Child Health, medicine, Neurology (clinical), Anatomy, medicine.disease, business, Phenotype, Genetics (clinical), Limb-girdle muscular dystrophy
Published: 2017

47. Permanent muscle weakness in M<scp>C</scp> Ardle disease

Author: Carlo M. Vincitorio, Marc Jeanpierre, Tanya Stojkovic, Pascal Laforêt, Carmen Navarro, Susana Teijeira, Aleksandra Nadaj-Pakleza, Elisabeth Dion, Irene Vietez, and Bruno Eymard
Subjects: medicine.medical_specialty, Weakness, Proximal muscle weakness, Muscle biopsy, medicine.diagnostic_test, Physiology, business.industry, Muscle weakness, Dystrophy, Surgery, Cellular and Molecular Neuroscience, Physiology (medical), Internal medicine, Myology, Biopsy, medicine, Neurology (clinical), medicine.symptom, business, Wasting
Abstract: McArdle disease is an autosomal recessive muscle glycogenosis. In the typical clinical presentation, only exercise-related symptoms are noted. Nevertheless, permanent weakness may occur, usually late in life. In this study we report on the clinical and genetic features of fixed muscle weakness in McArdle disease. Among the 80 McArdle patients being followed at the Institute of Myology of the Salpetriere Hospital, 9 patients have permanent weakness. The diagnosis of McArdle disease was confirmed by muscle biopsy and genetic investigations. Two patterns of muscle weakness and wasting were noted: (1) proximal and symmetric in 5 patients; and (2) asymmetric, mimicking facioscapulohumeral dystrophy (FSHD) in 4 patients. Computerized tomography scan showed fatty infiltration in the shoulder and pelvic girdle muscles. There was no clear correlation between genotype and the severity of muscle weakness. Proximal muscle weakness appeared after the age of 40 years and affected 11% of subjects in our series of 80 McArdle patients. Among patients over 40 years of age, 37.5% had muscle weakness.
Published: 2009

48. Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing

Author: Juliette Nectoux, Rafael de Cid, Sylvain Baulande, France Leturcq, Jon Andoni Urtizberea, Isabelle Penisson-Besnier, Aleksandra Nadaj-Pakleza, Carinne Roudaut, Audrey Criqui, Lucie Orhant, Delphine Peyroulan, Raba Ben Yaou, Isabelle Nelson, Anna Maria Cobo, Marie-Christine Arné-Bes, Emmanuelle Uro-Coste, Patrick Nitschke, Mireille Claustres, Gisèle Bonne, Nicolas Lévy, Jamel Chelly, Isabelle Richard, Mireille Cossée, Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génopole [Evry], Université d'Évry-Val-d'Essonne (UEVE), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Référence Maladies Neuromusculaires de l'Enfant et de l'Adulte, Nantes-Angers, Centre de Référence Maladies Neuromusculaires de l'Enfant et de l'Adulte, Service de neurologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Nowak, Cécile, and Centre de Recherche en Myologie
Subjects: Adult, Male, Screening techniques, Ubiquitin-Protein Ligases, ASTN2 Gene, DNA Mutational Analysis, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Article, Tripartite Motif Proteins, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Muscular dystrophy, Gene, Genetics (clinical), Loss function, 030304 developmental biology, Family Health, Comparative Genomic Hybridization, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Massive parallel sequencing, Base Sequence, Breakpoint, High-Throughput Nucleotide Sequencing, medicine.disease, Phenotype, Pedigree, Muscular Dystrophies, Limb-Girdle, Female, Gene Deletion, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathies (STM) and in Bardet-Biedl syndrome. Few cases have been described to date in LGMD2H/STM, but this gene is not systematically analysed because of the absence of specific signs and difficulties in protein analysis. By using high-throughput variants screening techniques, we identified variants in TRIM32 in two patients presenting nonspecific LGMD. We report the first case of total inactivation by homozygous deletion of the entire TRIM32 gene. Of interest, the deletion removes part of the ASTN2 gene, a large gene in which TRIM32 is nested. Despite the total TRIM32 gene inactivation, the patient does not present a more severe phenotype. However, he developed a mild progressive cognitive impairment that may be related to the loss of function of ASTN2 because association between ASTN2 heterozygous deletions and neurobehavioral disorders was previously reported. Regarding genomic characteristics at breakpoint of the deleted regions of TRIM32, we found a high density of repeated elements, suggesting a possible hotspot. These observations illustrate the importance of high-throughput technologies for identifying molecular defects in LGMD, confirm that total loss of function of TRIM32 is not associated with a specific phenotype and that TRIM32/ASTN2 inactivation could be associated with cognitive impairment.
Published: 2015

49. Muscle imaging in patients with tubular aggregate myopathy caused by mutations in STIM1

Author: Fabiana Fattori, Giorgio Tasca, Adele D'Amico, Enrico Bertini, Marc Vialle, Mauro Monforte, Aleksandra Nadaj-Pakleza, Enzo Ricci, and John Vissing
Subjects: Male, Pathology, MRI pattern, Thigh, medicine.disease_cause, Biceps, Congenital, Medicine, Child, Tomography, Genetics (clinical), Mutation, medicine.diagnostic_test, Subscapularis muscle, Skeletal, Anatomy, Middle Aged, musculoskeletal system, TAM, tubular aggregate myopathy, Magnetic Resonance Imaging, Muscle imaging, X-Ray Computed, Neoplasm Proteins, CT, computed tomography, Settore MED/26 - NEUROLOGIA, medicine.anatomical_structure, Neurology, Muscle, Myopathies, Female, medicine.symptom, Myopathies, Structural, Congenital, inorganic chemicals, Adult, medicine.medical_specialty, Adolescent, STIM1, Muscle MRI, Article, Structural, Humans, Stromal Interaction Molecule 1, Myopathy, Muscle, Skeletal, Aged, Muscle biopsy, business.industry, Genetic heterogeneity, Membrane Proteins, Magnetic resonance imaging, Tubular aggregate myopathy, Pediatrics, Perinatology and Child Health, Neurology (clinical), business, Tomography, X-Ray Computed
Abstract: Highlights • We characterized muscle imaging pattern in STIM1-related myopathy. • The subscapularis muscle was preferentially affected in the upper girdle. • Flexor hallucis longus was consistently affected in the lower limbs. • Muscle involvement is homogeneous and different from non-STIM1 patients., Tubular aggregate myopathy is a genetically heterogeneous disease characterized by tubular aggregates as the hallmark on muscle biopsy. Mutations in STIM1 have recently been identified as one genetic cause in a number of tubular aggregate myopathy cases. To characterize the pattern of muscle involvement in this disease, upper and lower girdles and lower limbs were imaged in five patients with mutations in STIM1, and the scans were compared with two patients with tubular aggregate myopathy not caused by mutations in STIM1. A common pattern of involvement was found in STIM1-mutated patients, although with variable extent and severity of lesions. In the upper girdle, the subscapularis muscle was invariably affected. In the lower limbs, all the patients showed a consistent involvement of the flexor hallucis longus, which is very rarely affected in other muscle diseases, and a diffuse involvement of thigh and posterior leg with sparing of gracilis, tibialis anterior and, to a lesser extent, short head of biceps femoris. Mutations in STIM1 are associated with a homogeneous involvement on imaging despite variable clinical features. Muscle imaging can be useful in identifying STIM1-mutated patients especially among other forms of tubular aggregate myopathy.
Published: 2015

50. Low penetrance in facioscapulohumeral muscular dystrophy type 1 with large pathological D4Z4 alleles: a cross-sectional multicenter study

Author: Françoise Bouhour, Sabrina Sacconi, Christine Tranchant, Jean Pouget, Nicolas Lévy, Elisabeth Ollagnon, Emmanuelle Salort-Campana, Shahram Attarian, Guilhem Solé, M. Arne-Bes, Thierry Kuntzer, Marc Bartoli, Karine Nguyen, Julien Niederhauser, Elisabeth Jouve, Rafaëlle Bernard, Estelle Charles, Claude Desnuelle, Frédérique Magdinier, Aleksandra Nadaj-Pakleza, Christophe Vial, Xavier Ferrer, Andoni Echaniz-Laguna, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies neuromusculaires et de la SLA, Hôpital de la Timone [CHU - APHM] (TIMONE), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de référence des maladies rares neuromusculaires Aquitaine-Grand Sud Ouest, CHU Bordeaux [Bordeaux], 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 Vaudois [Lausanne] (CHUV), Centre investigation clinique - Unité de pharmacologie clinique et d'évaluations thérapeutiques (CIC-UPCET), Assistance Publique - Hôpitaux de Marseille (APHM), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital neurologique, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Hôpital de Hautepierre [Strasbourg], Pôle Tête-Cou-CETD, Les Hôpitaux Universitaires de Strasbourg (HUS), Neurologie et Explorations Fonctionnelles du Système Nerveux [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Bartoli, Marc, Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, and CHU Toulouse [Toulouse]
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Cross-sectional study, Genetic counseling, Penetrance, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Epigenesis, Genetic, Young Adult, Facioscapulohumeral muscular dystrophy, Internal medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Genetics(clinical), Pharmacology (medical), Medical history, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Allele, Genetics (clinical), Alleles, Genetic testing, Aged, Medicine(all), Genetics, D4Z4, medicine.diagnostic_test, Research, Microfilament Proteins, Nuclear Proteins, RNA-Binding Proteins, General Medicine, Middle Aged, medicine.disease, Muscular Dystrophy, Facioscapulohumeral, 3. Good health, FSHD1, Cross-Sectional Studies, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Female, Age of onset
Abstract: International audience; Background: Facioscapulohumeral muscular dystrophy type 1(FSHD1) is an autosomal dominant disorder associated with the contraction of D4Z4 less than 11 repeat units (RUs) on chromosome 4q35. Penetrance in the range of the largest alleles is poorly known. Our objective was to study the penetrance of FSHD1 in patients carrying alleles ranging between 6 to 10 RUs and to evaluate the influence of sex, age, and several environmental factors on clinical expression of the disease. Methods: A cross-sectional multicenter study was conducted in six French and one Swiss neuromuscular centers. 65 FSHD1 affected patients carrying a 4qA allele of 6-10 RUs were identified as index cases (IC) and their 119 at-risk relatives were included. The age of onset was recorded for IC only. Medical history, neurological examination and manual muscle testing were performed for each subject. Genetic testing determined the allele size (number of RUs) and the 4qA/4qB allelic variant. The clinical status of relatives was established blindly to their genetic testing results. The main outcome was the penetrance defined as the ratio between the number of clinically affected carriers and the total number of carriers. Results: Among the relatives, 59 carried the D4Z4 contraction. At the clinical level, 34 relatives carriers were clinically affected and 25 unaffected. Therefore, the calculated penetrance was 57% in the range of 6-10 RUs. Penetrance was estimated at 62% in the range of 6-8 RUs, and at 47% in the range of 9-10 RUs. Moreover, penetrance was lower in women than men. There was no effect of drugs, anesthesia, surgery or traumatisms on the penetrance. Conclusions: Penetrance of FSHD1 is low for largest alleles in the range of 9-10 RUs, and lower in women than men. This is of crucial importance for genetic counseling and clinical management of patients and families.
Published: 2015

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