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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. 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

6. 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

7. 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

8. 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

9. <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

11. 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

12. 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

13. 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

14. 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

15. 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

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