Author: "Jean-Marie Cuisset" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Jean-Marie Cuisset"' showing total 163 results

Start Over Author "Jean-Marie Cuisset"

163 results on '"Jean-Marie Cuisset"'

1. Confirmatory validation of the french version of the Duchenne Muscular Dystrophy module of the pediatric quality of life inventory (PedsQLTM3.0DMDfv)

Author: Elisabeth Wallach, Virginie Ehlinger, Maelle Biotteau, Ulrike Walther-Louvier, Yann Péréon, Carole Vuillerot, Stephanie Fontaine, Pascal Sabouraud, Caroline Espil-Taris, Jean-Marie Cuisset, Vincent Laugel, Eloïse Baudou, Catherine Arnaud, and Claude Cances
Subjects: Neuromuscular disorder, Duchenne Muscular Dystrophy, Pediatric Quality of Life (PedsQL), Pediatrics, RJ1-570
Abstract: Abstract Duchenne Muscular Dystrophy (DMD) is a neuromuscular disease that inevitably leads to total loss of autonomy. The new therapeutic strategies aim to both improve survival and optimise quality of life. Evaluating quality of life is nevertheless a major challenge. No DMD-specific quality of life scale to exists in French. We therefore produced a French translation of the English Duchenne Muscular Dystrophy module of the Pediatric Quality of Life Inventory (PedsQLTMDMD) following international recommendations. The study objective was to carry out a confirmatory validation of the French version of the PedsQLTMDMD for paediatric patients with DMD, using French multicentre descriptive cross-sectional data. The sample consisted of 107 patients. Internal consistency was acceptable for proxy-assessments, with Cronbach's alpha coefficients above 0.70, except for the Treatment dimension. For self-assessments, internal consistency was acceptable only for the Daily Activities dimension. Our results showed poor metric qualities for the French version of the PedsQLTMDMD based on a sample of about 100 children, but these results remained consistent with those of the original validation. This confirms the interest of its use in clinical practice.
Published: 2023
Full Text: View/download PDF

2. Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study

Author: Frédérique Audic, Marta Gomez Garcia de la Banda, Delphine Bernoux, Paola Ramirez-Garcia, Julien Durigneux, Christine Barnerias, Arnaud Isapof, Jean-Marie Cuisset, Claude Cances, Christian Richelme, Carole Vuillerot, Vincent Laugel, Juliette Ropars, Cécilia Altuzarra, Caroline Espil-Taris, Ulrike Walther-Louvier, Pascal Sabouraud, Mondher Chouchane, Catherine Vanhulle, Valérie Trommsdorff, Anne Pervillé, Hervé Testard, Emmanuelle Lagrue, Catherine Sarret, Anne-Laude Avice, Pierre Beze-Beyrie, Vanessa Pauly, Susana Quijano-Roy, Brigitte Chabrol, and Isabelle Desguerre
Subjects: Spinal muscular atrophy type I, Spinal muscular atrophy type II, Nusinersen, Motor function measure, MFM, Medicine
Abstract: Abstract Background Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord. Nusinersen has been covered by public healthcare in France since May 2017. The aim of this article is to report results after 1 year of treatment with intrathecal nusinersen in children with SMA types 1 and 2 in France. Comparisons between treatment onset (T0) and after 1 year of treatment (Y1) were made in terms of motor function and need for nutritional and ventilatory support. Motor development milestone achievements were evaluated using the modified Hammersmith Infant Neurologic Examination–Part 2 (HINE-2) for patients under 2 years of age and Motor Function Measure (MFM) scores for patients over 2 years of age. Results Data on 204 SMA patients (type 1 or 2) were retrospectively collected from the 23 French centers for neuromuscular diseases. One hundred and twenty three patients had been treated for at least 1 year and were included, 34 of whom were classified as type 1 (10 as type 1a/b and 24 as type 1c) and 89 as type 2. Survival motor Neuron 2 (SMN2) copy numbers were available for all but 6 patients. Patients under 2 years of age (n = 30), had significantly higher HINE-2 scores at year 1 than at treatment onset but used more nutritional and ventilatory support. The 68 patients over 2 years of age evaluated with the Motor Function Measure test had significantly higher overall scores after 1 year, indicating that their motor function had improved. The scores were higher in the axial and proximal motor function (D2) and distal motor function (D3) parts of the MFM scale, but there was no significant difference for standing and transfer scores (D1). No child in either of the two groups achieved walking. Conclusion Nusinersen offers life-changing benefits for children with SMA, particularly those with more severe forms of the disorder. Caregiver assessments are positive. Nevertheless, patients remain severely disabled and still require intensive support care. This new treatment raises new ethical challenges.
Published: 2020
Full Text: View/download PDF

3. Myostatin: a Circulating Biomarker Correlating with Disease in Myotubular Myopathy Mice and Patients

Author: Catherine Koch, Suzie Buono, Alexia Menuet, Anne Robé, Sarah Djeddi, Christine Kretz, Raquel Gomez-Oca, Marion Depla, Arnaud Monseur, Leen Thielemans, Laurent Servais, Jocelyn Laporte, Belinda S. Cowling, Mélanie Annoussamy, Andreea Seferian, Jonathan Baets, Nicole Voermans, Antony Behin, U. Schara, Adele D’Amico, Arturo Hernandez, Capucine de Lattre, Jean-Michel Arnal, Michèle Mayer, Jean-Marie Cuisset, Carole Vuillerot, Stéphanie Fontaine, and Rémy Bellance
Subjects: centronuclear myopathies, myotubular myopathy, dynamin, antisense oligonucleotides, therapy, GDF8, Genetics, QH426-470, Cytology, QH573-671
Abstract: Myotubular myopathy, also called X-linked centronuclear myopathy (XL-CNM), is a severe congenital disease targeted for therapeutic trials. To date, biomarkers to monitor disease progression and therapy efficacy are lacking. The Mtm1−/y mouse is a faithful model for XL-CNM, due to myotubularin 1 (MTM1) loss-of-function mutations. Using both an unbiased approach (RNA sequencing [RNA-seq]) and a directed approach (qRT-PCR and protein level), we identified decreased Mstn levels in Mtm1−/y muscle, leading to low levels of myostatin in muscle and plasma. Myostatin (Mstn or growth differentiation factor 8 [Gdf8]) is a protein released by myocytes and inhibiting muscle growth and differentiation. Decreasing Dnm2 by genetic cross with Dnm2+/− mice or by antisense oligonucleotides blocked or postponed disease progression and resulted in an increase in circulating myostatin. In addition, plasma myostatin levels inversely correlated with disease severity and with Dnm2 mRNA levels in muscles. Altered Mstn levels were associated with a generalized disruption of the myostatin pathway. Importantly, in two different forms of CNMs we identified reduced circulating myostatin levels in plasma from patients. This provides evidence of a blood-based biomarker that may be used to monitor disease state in XL-CNM mice and patients and supports monitoring circulating myostatin during clinical trials for myotubular myopathy.
Published: 2020
Full Text: View/download PDF

4. Palliative Care in SMA Type 1: A Prospective Multicenter French Study Based on Parents' Reports

Author: Marie Hully, Christine Barnerias, Delphine Chabalier, Sophie Le Guen, Virginie Germa, Elodie Deladriere, Catherine Vanhulle, Jean-Marie Cuisset, Brigitte Chabrol, Claude Cances, Carole Vuillerot, Caroline Espil, Michele Mayer, Marie-Christine Nougues, Pascal Sabouraud, Jeremie Lefranc, Vincent Laugel, Francois Rivier, Ulrike Walther Louvier, Julien Durigneux, Sylvia Napuri, Catherine Sarret, Michel Renouil, Alice Masurel, Marcel-Louis Viallard, and Isabelle Desguerre
Subjects: SMA, palliative care, caregivers, ethics, standard of care, Pediatrics, RJ1-570
Abstract: Spinal muscular atrophy type 1 (SMA-1) is a severe neurodegenerative disorder, which in the absence of curative treatment, leads to death before 1 year of age in most cases. Caring for these short-lived and severely impaired infants requires palliative management. New drugs (nusinersen) have recently been developed that may modify SMA-1 natural history and thus raise ethical concerns about the appropriate level of care for patients. The national Hospital Clinical Research Program (PHRC) called “Assessment of clinical practices of palliative care in children with Spinal Muscular Atrophy Type 1 (SMA-1)” was a multicenter prospective study conducted in France between 2012 and 2016 to report palliative practices in SMA-1 in real life through prospective caregivers' reports about their infants' management. Thirty-nine patients were included in the prospective PHRC (17 centers). We also studied retrospective data regarding management of 43 other SMA-1 patients (18 centers) over the same period, including seven treated with nusinersen, in comparison with historical data from 222 patients previously published over two periods of 10 years (1989–2009). In the latest period studied, median age at diagnosis was 3 months [0.6–10.4]. Seventy-seven patients died at a median 6 months of age[1–27]: 32% at home and 8% in an intensive care unit. Eighty-five percent of patients received enteral nutrition, some through a gastrostomy (6%). Sixteen percent had a non-invasive ventilation (NIV). Seventy-seven percent received sedative treatment at the time of death. Over time, palliative management occurred more frequently at home with increased levels of technical supportive care (enteral nutrition, oxygenotherapy, and analgesic and sedative treatments). No statistical difference was found between the prospective and retrospective patients for the last period. However, significant differences were found between patients treated with nusinersen vs. those untreated. Our data confirm that palliative care is essential in management of SMA-1 patients and that parents are extensively involved in everyday patient care. Our data suggest that nusinersen treatment was accompanied by significantly more invasive supportive care, indicating that a re-examination of standard clinical practices should explicitly consider what treatment pathways are in infants' and caregivers' best interest. This study was registered on clinicaltrials.gov under the reference NCT01862042 (https://clinicaltrials.gov/ct2/show/study/NCT01862042?cond=SMA1&rank=8).
Published: 2020
Full Text: View/download PDF

5. Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients

Author: Pierre Meyer, Cécile Notarnicola, Albano C. Meli, Stefan Matecki, Gérald Hugon, Jérémy Salvador, Mirna Khalil, Léonard Féasson, Claude Cances, Jérôme Cottalorda, Isabelle Desguerre, Jean-Marie Cuisset, Pascal Sabouraud, Alain Lacampagne, Hugues Chevassus, François Rivier, and Gilles Carnac
Subjects: Duchenne muscular dystrophy, ryanodine receptor, myogenesis, endomysial fibrosis, human, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major role in DMD as well as intracellular calcium (Ca2+) mishandling. Ca2+ release from the sarcoplasmic reticulum is mostly mediated by the type 1 ryanodine receptor (RYR1) that is required for skeletal muscle differentiation in animals. The study objective was to determine whether altered RYR1-mediated Ca2+ release contributes to myogenic differentiation impairment in DMD patients. The comparison of primary cultured myoblasts from six boys with DMD and five healthy controls highlighted delayed myoblast differentiation in DMD. Silencing RYR1 expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca2+ concentration was increased, but RYR1-mediated Ca2+ release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca2+ concentration in DMD myotubes to control values and improved calstabin1 binding to the RYR1 complex. S107 also improved myogenic differentiation in DMD. Furthermore, intracellular Ca2+ concentration was correlated with endomysial fibrosis, which is the only myopathologic parameter associated with poor motor outcome in patients with DMD. This suggested a potential relationship between RYR1 dysfunction and motor impairment. Our study highlights RYR1-mediated Ca2+ leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD.
Published: 2021
Full Text: View/download PDF

6. ISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto α-dystroglycan

Author: Isabelle Gerin, Benoît Ury, Isabelle Breloy, Céline Bouchet-Seraphin, Jennifer Bolsée, Mathias Halbout, Julie Graff, Didier Vertommen, Giulio G. Muccioli, Nathalie Seta, Jean-Marie Cuisset, Ivana Dabaj, Susana Quijano-Roy, Ammi Grahn, Emile Van Schaftingen, and Guido T. Bommer
Subjects: Science
Abstract: Mutations in genes required for the glycosylation of α-dystroglycan lead to dystroglycanopathies. Here, the authors show that three of these enzymes (ISPD, FKTN and FKRP) work together to attach ribitol phosphate to α-dystroglycan.
Published: 2016
Full Text: View/download PDF

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

Author: Aurélie Chabanon, Andreea Mihaela Seferian, Aurore Daron, Yann Péréon, Claude Cances, Carole Vuillerot, Liesbeth De Waele, Jean-Marie Cuisset, Vincent Laugel, Ulrike Schara, Teresa Gidaro, Stéphanie Gilabert, Jean-Yves Hogrel, Pierre-Yves Baudin, Pierre Carlier, Emmanuel Fournier, Linda Pax Lowes, Nicole Hellbach, Timothy Seabrook, Elie Toledano, Mélanie Annoussamy, Laurent Servais, and NatHis-SMA study group
Subjects: Medicine, Science
Abstract: Spinal muscular atrophy (SMA) is a monogenic disorder caused by loss of function mutations in the survival motor neuron 1 gene, which results in a broad range of disease severity, from neonatal to adult onset. There is currently a concerted effort to define the natural history of the disease and develop outcome measures that accurately capture its complexity. As several therapeutic strategies are currently under investigation and both the FDA and EMA have recently approved the first medical treatment for SMA, there is a critical need to identify the right association of responsive outcome measures and biomarkers for individual patient follow-up. As an approved treatment becomes available, untreated patients will soon become rare, further intensifying the need for a rapid, prospective and longitudinal study of the natural history of SMA Type 2 and 3. Here we present the baseline assessments of 81 patients aged 2 to 30 years of which 19 are non-sitter SMA Type 2, 34 are sitter SMA Type 2, 9 non-ambulant SMA Type 3 and 19 ambulant SMA Type 3. Collecting these data at nine sites in France, Germany and Belgium established the feasibility of gathering consistent data from numerous and demanding assessments in a multicenter SMA study. Most assessments discriminated between the four groups well. This included the Motor Function Measure (MFM), pulmonary function testing, strength, electroneuromyography, muscle imaging and workspace volume. Additionally, all of the assessments showed good correlation with the MFM score. As the untreated patient population decreases, having reliable and valid multi-site data will be imperative for recruitment in clinical trials. The pending two-year study results will evaluate the sensitivity of the studied outcomes and biomarkers to disease progression. TRIAL REGISTRATION:ClinicalTrials.gov (NCT02391831).
Published: 2018
Full Text: View/download PDF

8. Muscle Activation during Gait in Children with Duchenne Muscular Dystrophy.

Author: Juliette Ropars, Mathieu Lempereur, Carole Vuillerot, Vincent Tiffreau, Sylviane Peudenier, Jean-Marie Cuisset, Yann Pereon, Fabien Leboeuf, Ludovic Delporte, Yannick Delpierre, Raphaël Gross, and Sylvain Brochard
Subjects: Medicine, Science
Abstract: The aim of this prospective study was to investigate changes in muscle activity during gait in children with Duchenne muscular Dystrophy (DMD). Dynamic surface electromyography recordings (EMGs) of 16 children with DMD and pathological gait were compared with those of 15 control children. The activity of the rectus femoris (RF), vastus lateralis (VL), medial hamstrings (HS), tibialis anterior (TA) and gastrocnemius soleus (GAS) muscles was recorded and analysed quantitatively and qualitatively. The overall muscle activity in the children with DMD was significantly different from that of the control group. Percentage activation amplitudes of RF, HS and TA were greater throughout the gait cycle in the children with DMD and the timing of GAS activity differed from the control children. Significantly greater muscle coactivation was found in the children with DMD. There were no significant differences between sides. Since the motor command is normal in DMD, the hyper-activity and co-contractions likely compensate for gait instability and muscle weakness, however may have negative consequences on the muscles and may increase the energy cost of gait. Simple rehabilitative strategies such as targeted physical therapies may improve stability and thus the pattern of muscle activity.
Published: 2016
Full Text: View/download PDF

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

Author: Andreea Mihaela Seferian, Amélie Moraux, Mélanie Annoussamy, Aurélie Canal, Valérie Decostre, Oumar Diebate, Anne-Gaëlle Le Moing, Teresa Gidaro, Nicolas Deconinck, Frauke Van Parys, Wendy Vereecke, Sylvia Wittevrongel, Michèle Mayer, Kim Maincent, Isabelle Desguerre, Christine Thémar-Noël, Jean-Marie Cuisset, Vincent Tiffreau, Severine Denis, Virginie Jousten, Susana Quijano-Roy, Thomas Voit, Jean-Yves Hogrel, and Laurent Servais
Subjects: Medicine, Science
Abstract: INTRODUCTION:Upper limb evaluation of patients with Duchenne Muscular Dystrophy is crucially important to evaluations of efficacy of new treatments in non-ambulant patients. In patients who have lost ambulation, there are few validated and informative outcome measures. In addition, longitudinal data demonstrating sensitivity to clinical evolution of outcome measures over short-term periods are lacking. PATIENTS AND METHODS:We report here the results of a one-year multicenter study using specifically designed tools to assess grip, pinch strength, and hand function in wheelchair-bound patients. Our study assessed 53 non-ambulant patients with Duchenne muscular dystrophy aged 17.1 ± 4.8 years (range: 9 - 28.1 years). The average Brooke functional score of these patients was 4.6 ± 1.1. The average forced vital capacity was 44.5% predicted and 19 patients used non-invasive ventilation. Patients were assessed at baseline, 6 months, and one year using the Motor Function Measure and innovative devices (namely the MyoSet composed of MyoGrip, MyoPinch, and MoviPlate). RESULTS:Our study confirmed preliminary data previously reported regarding feasibility of use and of reliability of the MyoSet and the correlation at baseline between distal strength and clinical outcomes such as FVC, Brooke score, age, and duration since loss of ambulation. A significant correlation was observed between the distal upper limb strength and clinical variables. The sensitive dynamometers (MyoGrip and MyoPinch) and MoviPlate captured a 12-month change in non-ambulant Duchenne muscular dystrophy patients of all ages. TRIAL REGISTRATION:ClinicalTrials.gov NCT00993161 NCT00993161.
Published: 2015
Full Text: View/download PDF

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

Author: Andreea Mihaela Seferian, Amélie Moraux, Aurélie Canal, Valérie Decostre, Oumar Diebate, Anne Gaëlle Le Moing, Teresa Gidaro, Nicolas Deconinck, Frauke Van Parys, Wendy Vereecke, Sylvia Wittevrongel, Mélanie Annoussamy, Michèle Mayer, Kim Maincent, Jean-Marie Cuisset, Vincent Tiffreau, Severine Denis, Virginie Jousten, Susana Quijano-Roy, Thomas Voit, Jean-Yves Hogrel, and Laurent Servais
Subjects: Medicine, Science
Abstract: Assessment of the upper limb strength in non-ambulant neuromuscular patients remains challenging. Although potential outcome measures have been reported, longitudinal data demonstrating sensitivity to clinical evolution in spinal muscular atrophy patients are critically lacking. Our study recruited 23 non-ambulant patients, 16 patients (males/females = 6/10; median age 15.4 years with a range from 10.7 to 31.1 years) with spinal muscular atrophy type II and 7 patients (males/females = 2/5; median age 19.9 years with a range from 8.3 to 29.9 years) with type III. The Brooke functional score was on median 3 with a range from 2 to 6. The average total vital capacity was 46%, and seven patients required non-invasive ventilation at night. Patients were assessed at baseline, 6 months, and 1 year using the Motor Function Measure and innovative devices MyoGrip, MyoPinch, and MoviPlate, which assess handgrip strength, key pinch strength, and hand/finger extension-flexion function, respectively. The study demonstrated the feasibility and reliability of these measures for all patients, and sensitivity to negative changes after the age of 14 years. The younger patients showed an increase of the distal force in the follow-up period. The distal force measurements and function were correlated to different functional scales. These data represent an important step in the process of validating these devices as potential outcome measures for future clinical trials.
Published: 2015
Full Text: View/download PDF

11. Lack of functional benefit with glutamine versus placebo in Duchenne muscular dystrophy: a randomized crossover trial.

Author: Elise Mok, Guy Letellier, Jean-Marie Cuisset, André Denjean, Frédéric Gottrand, Corinne Alberti, and Régis Hankard
Subjects: Medicine, Science
Abstract: Oral glutamine decreases whole body protein breakdown in Duchenne muscular dystrophy (DMD). We evaluated the functional benefit of 4 months oral glutamine in DMD.30 ambulant DMD boys were included in this double-blind, randomized crossover trial with 2 intervention periods: glutamine (0.5 g/kg/d) and placebo, 4 months each, separated by a 1-month wash-out, at 3 outpatient clinical investigation centers in France. Functional benefit was tested by comparing glutamine versus placebo on change in walking speed at 4 months. Secondary outcome measures were: 2-minute walk test, work, power, muscle mass (urinary creatinine), markers of myofibrillar protein breakdown (urinary 3-methyl-histidine/creatinine), serum creatine phospho-kinase, body composition (fat free mass, fat mass percentage), safety and oral nutrient intake. There was no improvement in the primary end point (walking speed) or in secondary measures of muscle function (2-minute walk test, work, power) in the glutamine group compared with placebo. However, subjects receiving glutamine or placebo showed no deterioration in functional measures over the course of the 9-month trial. No differences in muscle mass, markers of protein breakdown or serum creatine phosho-kinase were observed, except for a blunted increase in fat free mass in the glutamine group which led to a greater increase in fat mass percentage. Glutamine was safe and well-tolerated.This trial did not identify additional benefit of 4 months oral glutamine over placebo on muscle mass or function in ambulatory DMD boys. Although apparently safe, current data cannot support routine supplementation in this population as a whole, until further research proves otherwise.(ClinicalTrials.gov) NCT00296621.
Published: 2009
Full Text: View/download PDF

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

Author: A. Daron, James J. Dowling, Carole Vuillerot, Severine Denis, Bruno Boulanger, Rémi Bellance, Jean-Michel Arnal, Carina Wallgren-Pettersson, Kimberly Amburgey, Etsuko Tsuchiya, A. Hernandez, Jean-Marie Cuisset, Bradley P. Carlin, Enrico Bertini, Andrea Gangfuß, Barbara Andres, Arnaud Monseur, E. Gargaun, Dominique Duchene, Ruxandra Cardas, Virginie Latournerie, Ana Buj-Bello, Ulrike Schara, Basil T. Darras, H. Landy, V. Chê, Chris Freitag, Laurent Servais, S. Fontaine, Adele D'Amico, Jean-Yves Hogrel, Teresa Gidaro, Nacera Reguiba, Andreea Mihaela Seferian, L. Thielemans, Valérie Biancalana, Michèle Mayer, and Capucine de Lattre
Subjects: Statistics and Probability, medicine.medical_specialty, Clinical study design, Bayesian probability, Context (language use), Disease, Placebo, Biochemistry, Genetics and Molecular Biology (miscellaneous), Natural history, Physical medicine and rehabilitation, medicine, Biostatistics, Psychology, Type I and type II errors
Abstract: The small sample sizes inherent in rare and pediatric disease settings offer significant challenges for clinical trial design. In such settings, Bayesian adaptive trial methods can often pay dividends, allowing the sensible incorporation of auxiliary data and other relevant information to bolster that collected by the trial itself. Previous work has also included the use of one-arm trials augmented by the participants’ own natural history data, from which the future course of the disease in the absence of intervention can be predicted. Patient response can then be defined by the degree to which post-intervention observations are inconsistent with the predicted “natural” trajectory. While such trials offer obvious advantages in efficiency and ethical hazard (since they expose no new patients to a placebo, anathema to patients or their parents and caregivers), they can offer no protection against bias arising from the presence of any “placebo effect,” the tendency of patients to improve merely by being in the trial. In this paper, we investigate the impact of both static and transient placebo effects on one-arm responder studies of this type, as well as two-arm versions that incorporate a small concurrent placebo group but still borrow strength from the natural history data. We also propose more traditional Bayesian changepoint models that specify a parametric functional form for the patient’s post-intervention trajectory, which in turn allow quantification of the treatment benefit in terms of the model parameters, rather than semi-parametrically in terms of a response relative to some “null” model. We compare the operating characteristics of our designs in the context of an ongoing investigation of centronuclear myopathies (CNMs), a group of congenital neuromuscular diseases whose most common and severe form is X-linked, affecting approximately 1 in 50,000 newborn boys. Our results indicate our two-arm responder and changepoint methods can offer protection against placebo effects, improving power while protecting the trial’s Type I error rate. However, further research into innovative trial designs as well as ongoing dialog with regulatory authorities remain critically important in rare disease research.
Published: 2021

13. New insights into CC2D2A -related Joubert syndrome

Author: Madeleine Harion, Leila Qebibo, Audrey Riquet, Christelle Rougeot, Alexandra Afenjar, Catherine Garel, Malek Louha, Emmanuelle Lacaze, Frédérique Audic-Gérard, Magali Barth, Patrick Berquin, Dominique Bonneau, Frédéric Bourdain, Tiffany Busa, Estelle Colin, Jean-Marie Cuisset, Vincent Des Portes, Nathalie Dorison, Christine Francannet, Bénédicte Héron, Cécile Laroche, Marine Lebrun, Julia Métreau, Sylvie Odent, Laurent Pasquier, Yaumara Perdomo Trujillo, Laurine Perrin, Lucile Pinson, François Rivier, Sabine Sigaudy, Christel Thauvin-Robinet, Ulrike Walther Louvier, Olivier Labayle, Diana Rodriguez, Stéphanie Valence, Lydie Burglen, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105 (GRAMFC), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de référence Maladies Rares CLAD-Ouest [Rennes], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: phenotype, genotype, [SDV]Life Sciences [q-bio], cerebellar diseases, Genetics, nervous system malformations, Genetics (clinical), genetic testing
Abstract: PurposeIn this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes,CC2D2A.MethodsWe selected 53 patients with pathogenic variants onCC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature.ResultsDevelopmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype–phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype.ConclusionThis study contradicts previous literature stating an association betweenCC2D2A-related JS and ventriculomegaly. Our study implies thatCC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.
Published: 2022

14. Confirmatory Validation of the French Version of the Duchenne Muscular Dystrophy Module of the Pediatric Quality of Life Inventory (PedsQL TM3.0DMDvf)

Author: Elisabeth Wallach, Valerie Ehlinger, Maelle Biotteau, Ulrike Walther-Louvier, Yann Péréon, Carole Vuillerot, Stephanie Fontaine, Pascal Sabouraud, Caroline Espil-Taris, Jean-Marie Cuisset, Vincent Laugel, Eloïse Baudou, Catherine Arnaud, and Claude Cances
Abstract: Duchenne muscular dystrophy (DMD) is a neuromuscular disease that inevitably leads to total loss of autonomy. The new therapeutic strategies aim to both improve survival and optimize quality of life. Evaluating quality of life is nevertheless a major challenge. No DMD-specific quality of life scale to exists in French. We therefore produced a French translation of the English Duchenne muscular dystrophy module of the Pediatric Quality of Life Inventory (PedsQLTMDMD) following international recommendations. The study objective was to carry out a confirmatory validation of the French version of the PedsQLTMDMD for pediatric patients with DMD, using French multicenter descriptive cross-sectional data. The sample consisted of 107 patients. Internal consistency was acceptable for proxy-assessments, with Cronbach's alpha coefficients above 0.70, except for the Treatments dimension. For self-assessments, internal consistency was acceptable only for the Daily Activities dimension. Our results showed poor metric qualities for the French version of the PedsQLTMDMD based on a sample of about 100 children, but these results remained consistent with those of the original validation. This confirms the interest of its use in clinical practice.
Published: 2022

15. New insights into

Author: Madeleine, Harion, Leila, Qebibo, Audrey, Riquet, Christelle, Rougeot, Alexandra, Afenjar, Catherine, Garel, Malek, Louha, Emmanuelle, Lacaze, Frédérique, Audic-Gérard, Magali, Barth, Patrick, Berquin, Dominique, Bonneau, Frédéric, Bourdain, Tiffany, Busa, Estelle, Colin, Jean-Marie, Cuisset, Vincent, Des Portes, Nathalie, Dorison, Christine, Francannet, Bénédicte, Héron, Cécile, Laroche, Marine, Lebrun, Julia, Métreau, Sylvie, Odent, Laurent, Pasquier, Yaumara Perdomo, Trujillo, Laurine, Perrin, Lucile, Pinson, François, Rivier, Sabine, Sigaudy, Christel, Thauvin-Robinet, Ulrike Walther, Louvier, Olivier, Labayle, Diana, Rodriguez, Stéphanie, Valence, and Lydie, Burglen
Abstract: In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes,We selected 53 patients with pathogenic variants onDevelopmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype.This study contradicts previous literature stating an association between
Published: 2022

16. Skeletal Ryanodine Receptors Are Involved in Impaired Myogenic Differentiation in Duchenne Muscular Dystrophy Patients

Author: Jean-Marie Cuisset, Jérôme Cottalorda, Stefan Matecki, Gérald Hugon, Alain Lacampagne, Pierre Meyer, Cécile Notarnicola, Hugues Chevassus, Albano C. Meli, Pascal Sabouraud, François Rivier, Léonard Féasson, Mirna Khalil, Gilles Carnac, Jérémy Salvador, Claude Cances, Isabelle Desguerre, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Reims (CHU Reims), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Paris Cité (UPCité), Herrada, Anthony, Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), and Université de Paris (UP)
Subjects: Male, Duchenne muscular dystrophy, Muscle Fibers, Skeletal, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Muscle Development, Calcium in biology, Dystrophin, Myoblasts, 0302 clinical medicine, Myocyte, Biology (General), Child, Spectroscopy, Cells, Cultured, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Ryanodine receptor, Myogenesis, Cell Differentiation, General Medicine, musculoskeletal system, Computer Science Applications, Chemistry, Sarcoplasmic Reticulum, medicine.anatomical_structure, Child, Preschool, myogenesis, tissues, Intracellular, musculoskeletal diseases, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, QH301-705.5, Catalysis, Article, Inorganic Chemistry, Tacrolimus Binding Proteins, 03 medical and health sciences, ryanodine receptor, endomysial fibrosis, human, Internal medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine, Humans, Calcium Signaling, Physical and Theoretical Chemistry, Muscle, Skeletal, Molecular Biology, QD1-999, 030304 developmental biology, RYR1, business.industry, Organic Chemistry, Skeletal muscle, Ryanodine Receptor Calcium Release Channel, medicine.disease, Muscular Dystrophy, Duchenne, Endocrinology, Calcium, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major role in DMD as well as intracellular calcium (Ca2+) mishandling. Ca2+ release from the sarcoplasmic reticulum is mostly mediated by the type 1 ryanodine receptor (RYR1) that is required for skeletal muscle differentiation in animals. The study objective was to determine whether altered RYR1-mediated Ca2+ release contributes to myogenic differentiation impairment in DMD patients. The comparison of primary cultured myoblasts from six boys with DMD and five healthy controls highlighted delayed myoblast differentiation in DMD. Silencing RYR1 expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca2+ concentration was increased, but RYR1-mediated Ca2+ release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca2+ concentration in DMD myotubes to control values and improved calstabin1 binding to the RYR1 complex. S107 also improved myogenic differentiation in DMD. Furthermore, intracellular Ca2+ concentration was correlated with endomysial fibrosis, which is the only myopathologic parameter associated with poor motor outcome in patients with DMD. This suggested a potential relationship between RYR1 dysfunction and motor impairment. Our study highlights RYR1-mediated Ca2+ leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD.
Published: 2021

17. Giant axonal neuropathy: a multicenter retrospective study with genotypic spectrum expansion

Author: Patrick Aubourg, Jean-Marie Cuisset, Philippe Latour, Kouider Beladgham, Jimmy Perrot, Lucie Guyant-Marechal, Bruno Francou, Laurent Kremer, Naziha Baaloul, Alain Verloes, and Andoni Echaniz-Laguna
Subjects: Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Weakness, Pes cavus, Adolescent, Encephalopathy, Consanguinity, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Genetics, medicine, Humans, Child, Genetics (clinical), Retrospective Studies, Giant axonal neuropathy, business.industry, Gigaxonin, Brain, medicine.disease, Cytoskeletal Proteins, 030104 developmental biology, medicine.anatomical_structure, Giant Axonal Neuropathy, Child, Preschool, Peripheral nervous system, Mutation, Female, medicine.symptom, business, Polyneuropathy, 030217 neurology & neurosurgery
Abstract: Giant axonal neuropathy (GAN) is an autosomal recessive disease caused by mutations in the GAN gene encoding gigaxonin. Patients develop a progressive sensorimotor neuropathy affecting peripheral nervous system (PNS) and central nervous system (CNS). Methods: In this multicenter observational retrospective study, we recorded French patients with GAN mutations, and 10 patients were identified. Mean age of patients was 9.7 years (2-18), eight patients were female (80%), and all patients met infant developmental milestones and had a family history of consanguinity. Mean age at disease onset was 3.3 years (1-5), and progressive cerebellar ataxia and distal motor weakness were the initial symptoms in all cases. Proximal motor weakness and bulbar symptoms appeared at a mean age of 12 years (8-14), and patients used a wheelchair at a mean age of 16 years (14-18). One patient died at age 18 years from aspiration pneumonia. In all cases, nerve conduction studies showed a mixed demyelinating and axonal sensorimotor neuropathy and MRI showed brain and cerebellum white matter abnormalities. Polyneuropathy and encephalopathy both aggravated during the course of the disease. Patients also showed a variety of associated findings, including curly hair (100% of cases), pes cavus (80%), ophthalmic abnormalities (30%), and scoliosis (30%). Five new GAN mutations were found, including the first synonymous mutation and a large intragenic deletion. Our findings expand the genotypic spectrum of GAN mutations, with relevant implications for molecular analysis of this gene, and confirm that GAN is an age-related progressive neurodegenerative disease involving PNS and CNS.
Published: 2019

18. 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

19. The lncRNA 44s2 Study Applicability to the Design of 45-55 Exon Skipping Therapeutic Strategy for DMD

Author: Elena Gargaun, Sestina Falcone, Guilhem Solé, Julien Durigneux, Andoni Urtizberea, Jean Marie Cuisset, Sofia Benkhelifa-Ziyyat, Laura Julien, Anne Boland, Florian Sandron, Vincent Meyer, Jean François Deleuze, David Salgado, Jean-Pierre Desvignes, Christophe Béroud, Anatole Chessel, Alexia Blesius, Martin Krahn, Nicolas Levy, France Leturcq, France Pietri-Rouxel, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Reference des Maladies Neuromusculaires - Atlantique Occitanie Caraïbe (CRMN - AOC), 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), 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), Centre de référence des maladies rares neuromusculaires, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Laboratoire d'Optique et Biosciences (LOB), École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches Internationales Servier [Suresnes] (IRIS), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gestionnaire, HAL Sorbonne Université 5, Centre de recherche en myologie, Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU de Bordeaux Pellegrin [Bordeaux], Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de référence des maladies neuromusculaires Nord/Est/Ile-de-France [Paris], Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Université Paris-Saclay, Aix Marseille Université (AMU), Hôpital Cochin [AP-HP], Université Paris Descartes, Sorbonne Paris Cité, Paris, France, Centre de Recherche en Myologie, ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-10-LABX-0013,GENMED,Medical Genomics(2010), Centre de Reference des Maladies Neuromusculaires AOC, Partenaires INRAE, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École polytechnique (X)
Subjects: musculoskeletal diseases, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, lncRNA, medicine, long noncoding RNA, Muscular dystrophy, lcsh:QH301-705.5, 030304 developmental biology, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Myogenesis, medicine.disease, Non-coding RNA, ncRNA, Long non-coding RNA, Exon skipping, lcsh:Biology (General), Becker muscular dystrophy (BMD), Duchenne muscular dystrophy (DMD), Cancer research, biology.protein, Biomarker (medicine), Protein stabilization, Dystrophin, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; In skeletal muscle, long noncoding RNAs (lncRNAs) are involved in dystrophin protein stabilization but also in the regulation of myocytes proliferation and differentiation. Hence, they could represent promising therapeutic targets and/or biomarkers for Duchenne and Becker muscular dystrophy (DMD/BMD). DMD and BMD are X-linked myopathies characterized by a progressive muscular dystrophy with or without dilatative cardiomyopathy. Two-thirds of DMD gene mutations are represented by deletions, and 63% of patients carrying DMD deletions are eligible for 45 to 55 multi-exons skipping (MES), becoming BMD patients (BMDΔ45-55). We analyzed the genomic lncRNA presence in 38 BMDΔ45-55 patients and characterized the lncRNA localized in introns 44 and 55 of the DMD gene. We highlighted that all four lncRNA are differentially expressed during myogenesis in immortalized and primary human myoblasts. In addition, the lncRNA44s2 was pointed out as a possible accelerator of differentiation. Interestingly, lncRNA44s expression was associated with a favorable clinical phenotype. These findings suggest that lncRNA44s2 could be involved in muscle differentiation process and become a potential disease progression biomarker. Based on these results, we support MES45-55 therapy and propose that the design of the CRISPR/Cas9 MES45-55 assay consider the lncRNA sequences bordering the exonic 45 to 55 deletion.
Published: 2021
Full Text: View/download PDF

20. Gait characteristics in children with Duchenne Muscular Dystrophy during the last 2 years of free ambulation (Preprint)

Author: Juliette Ropars, Laetitia Houx, Sylvain Brochard, François Rousseau, Carole Vuillerot, Yann Pereon, Jean-Marie Cuisset, Stephanie Fontaine, Julien Durigneux, Vincent Tiffreau, Arnaud Delval, Raphael Gross, Fabien Leboeuf, Ludovic Delporte, Christelle Pons, and Mathieu Lempereur
Subjects: musculoskeletal diseases, human activities
Abstract: BACKGROUND Duchenne Muscular Dystrophy (DMD), the most common neuromuscular disease in children, is a severe, progressive disease that affects skeletal muscle. Abnormal gait patterns in children with DMD result from compensatory adaptations of their locomotor system to maintain free ambulation in response to the slow, progressive muscle weakness, contractures and osteoarticular changes caused by the disease. Identification of gait abnormalities can be challenging because current understanding of how gait patterns changes progressively in children with DMD is limited. 3D gait analysis could thus increase understanding about the effects of the disease on gait, guide treatments and help to predict key milestones, such as ambulation loss. This latter event is important because it is an endpoint for clinical trials and studies of DMD disease progression. OBJECTIVE The primary aim of this study was to analyze the gait characteristics of children with Duchenne Muscular Dystrophy (DMD) during their last 2 years of free ambulation. The secondary aim was to explore the capacity of gait variables to predict the time of loss of ambulation. METHODS The gait of eighteen children with DMD and fourteen age-matched control children was recorded using a 3D optoelectronic system. Statistical parametric mapping was used to compare kinematic and kinetic variables between groups. Multivariate regression was used to identify predictors of the time of ambulation loss among spatiotemporal, kinematic and kinetic variables. RESULTS Compared with the controls, anterior pelvic tilt was increased during the whole gait cycle, hip flexion was increased during the second part of stance phase and of the entire swing, knee flexion was increased during swing, dorsiflexion was reduced during stance, and plantar flexion occurred in swing in the DMD group. Maximal ground reaction force, ankle dorsiflexion moment at initial contact, knee power absorption and generation during loading response, and maximal power generation of the hip at the end of stance were all reduced. A combination of gait variables, mostly kinetic, predicted the duration before ambulation loss to be less than three months. CONCLUSIONS The gait of children with DMD who are close to losing ambulation is characterized by specific deviations. The time of ambulation loss was accurately predicted by 3D gait variables, particularly kinetic. Combined with data from the clinical examination, 3D gait analysis provides valuable information to guide physical therapy, including targeted muscle strengthening and stretching, to help patients maintain free ambulation as long as possible.
Published: 2021

21. Variable Presentation of Leber Hereditary Optic Neuropathy in Children of a Family Harboring a Rare m.13051GA mtDNA Mutation

Author: Vasily M. Smirnov, Philippe Debruyne, Jean-Marie Cuisset, Caroline Marks, Sabine Defoort-Dhellemmes, and Claire-Marie Dhaenens
Subjects: Genetics, Male, LEBER HEREDITARY OPTIC NEUROPATHY, Mitochondrial DNA, business.industry, DNA Mutational Analysis, Variable presentation, Optic Atrophy, Hereditary, Leber, DNA, Mitochondrial, Pedigree, Ophthalmology, Rare Diseases, Child, Preschool, Mutation (genetic algorithm), Mutation, Medicine, Humans, Female, Neurology (clinical), business
Published: 2020

22. Effects of nusinersen after one year of treatment in 123 children with SMA type 1 or 2: a French real-life observational study

Author: Brigitte Chabrol, Pierre Beze-Beyrie, Vincent Laugel, Carole Vuillerot, Anne-Laude Avice, Delphine Bernoux, Anne Perville, Cecilia Altuzarra, Christine Barnerias, Emmanuelle Lagrue, Paola Ramirez-Garcia, Catherine Sarret, Catherine Vanhulle, Jean-Marie Cuisset, Susana Quijano-Roy, Vanessa Pauly, Juliette Ropars, Caroline Espil-Taris, Frédérique Audic, Claude Cances, Julien Durigneux, Isabelle Desguerre, Arnaud Isapof, Hervé Testard, Mondher Chouchane, Marta Gomez Garcia de la Banda, Pascal Sabouraud, Valérie Trommsdorff, Ulrike Walther-Louvier, Christian Richelme, Institut Pascal (IP), and SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pediatrics, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Oligonucleotides, lcsh:Medicine, Spinal muscular atrophy type I, Spinal Muscular Atrophies of Childhood, Motor function measure, MFM, Muscular Atrophy, Spinal, 03 medical and health sciences, 0302 clinical medicine, Nusinersen, Humans, Medicine, Pharmacology (medical), 030212 general & internal medicine, Child, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Motor skill, Retrospective Studies, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Research, lcsh:R, Significant difference, Infant, General Medicine, Spinal muscular atrophy, Motor neuron, SMA, Spinal cord, medicine.disease, 3. Good health, Spinal muscular atrophy type II, medicine.anatomical_structure, Observational study, France, business, 030217 neurology & neurosurgery
Abstract: Background Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord. Nusinersen has been covered by public healthcare in France since May 2017. The aim of this article is to report results after 1 year of treatment with intrathecal nusinersen in children with SMA types 1 and 2 in France. Comparisons between treatment onset (T0) and after 1 year of treatment (Y1) were made in terms of motor function and need for nutritional and ventilatory support. Motor development milestone achievements were evaluated using the modified Hammersmith Infant Neurologic Examination–Part 2 (HINE-2) for patients under 2 years of age and Motor Function Measure (MFM) scores for patients over 2 years of age. Results Data on 204 SMA patients (type 1 or 2) were retrospectively collected from the 23 French centers for neuromuscular diseases. One hundred and twenty three patients had been treated for at least 1 year and were included, 34 of whom were classified as type 1 (10 as type 1a/b and 24 as type 1c) and 89 as type 2. Survival motor Neuron 2 (SMN2) copy numbers were available for all but 6 patients. Patients under 2 years of age (n = 30), had significantly higher HINE-2 scores at year 1 than at treatment onset but used more nutritional and ventilatory support. The 68 patients over 2 years of age evaluated with the Motor Function Measure test had significantly higher overall scores after 1 year, indicating that their motor function had improved. The scores were higher in the axial and proximal motor function (D2) and distal motor function (D3) parts of the MFM scale, but there was no significant difference for standing and transfer scores (D1). No child in either of the two groups achieved walking. Conclusion Nusinersen offers life-changing benefits for children with SMA, particularly those with more severe forms of the disorder. Caregiver assessments are positive. Nevertheless, patients remain severely disabled and still require intensive support care. This new treatment raises new ethical challenges.
Published: 2020

23. Expanding the phenotype of SCA19/22: Parkinsonism, cognitive impairment and epilepsy

Author: Jean-Christophe Cuvellier, Marie Delliaux, Kathy Dujardin, Delphine Dellacherie, Bernard Sablonnière, Isabelle Strubi-Vuillaume, David Devos, Luc Defebvre, Vincent Huin, Audrey Riquet, Marine Brion, Caroline Moreau, Jean-Marie Cuisset, HUIN, Vincent, 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, Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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), Service de Neurologie et Pathologies du Mouvement [CHU Lille], Service de neuropédiatrie [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), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Biologie Pathologie et Génétique, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut d'Immunologie [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Pôle de Biologie Pathologie Génétique [CHU Lille], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille
Subjects: Male, 0301 basic medicine, Pediatrics, Parkinson's disease, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Mesh:Adult, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SCCO]Cognitive science, Epilepsy, Mesh:Adolescent, 0302 clinical medicine, Medicine, Child, Neurogenetics, Mesh:Epilepsy/genetics, Mesh:Aged, Spinocerebellar Degenerations, Aged, 80 and over, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, Parkinsonism, Mesh:Spinocerebellar Degenerations/complications, Cognition, Middle Aged, Mesh:Cognitive Dysfunction/genetics, Pedigree, 3. Good health, Phenotype, Neurology, Spinocerebellar ataxia, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Adult, Mesh:Female, medicine.medical_specialty, Adolescent, Cognitive disorders, Mesh:Child, Mesh:Male, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, Parkinsonian Disorders, Mesh:Middle Aged, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Mesh:80 and over, Humans, Cognitive Dysfunction, Quantitative Biology - Genomics, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Aged, Genetic testing, Genomics (q-bio.GN), [SDV.GEN]Life Sciences [q-bio]/Genetics, Cerebellar ataxia, business.industry, Mesh:Pedigree, Mesh:Phenotype, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SCCO] Cognitive science, medicine.disease, Neuropsychiatric disorder, Mesh:Humans, 030104 developmental biology, KCND3 mutation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mesh:Parkinsonian Disorders/genetics, Parkinson''s disease, FOS: Biological sciences, Neurology (clinical), Geriatrics and Gerontology, business, Neuroscience, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: International audience; BACKGROUND: Spinocerebellar ataxia types 19 and 22 (SCA19/22) are rare conditions in which relatively isolated cerebellar involvement is frequently associated with cognitive impairment. Here, we report on new clinical features and provide details of the cognitive profile in two SCA19/22 families.METHODS: Two families displaying an autosomal-dominant form of cerebellar ataxia underwent clinical examinations and genetic testing.RESULTS: In addition to the classical clinical features of SCA, a wide spectrum of cognitive disorders (including visuospatial impairments) was observed. Eight patients had mild Parkinsonism, and five had epilepsy. Genetic testing showed that the KCND3 mutation (c.679_681delTTC, p.F227del) was present in both families.CONCLUSIONS: Our findings broaden the phenotypic spectrum of SCA19/22, and suggest that KCND3 should be included in the list of candidate genes for epilepsy, Parkinsonism and cognitive impairment.
Published: 2017

24. COLLAGEN RELATED MUSCLE DISEASES

Author: Y. Elaribi, K. Benistan, F. Jobic, Florence Demurger, Marie-Christine Nougues, Jean-Marie Cuisset, A. Afenjar, Arnaud Isapof, Sandra Whalen, Vincent Laugel, Corinne Metay, Valérie Jobic, Christine Barnerias, Ana Ferreiro, Isabelle Desguerre, A. Benezit, J. Davion, S. Quijano, Judith Melki, and P. Richard
Subjects: Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Genetics (clinical)
Published: 2021

25. Anti-HMGCR Antibody–Related Necrotizing Autoimmune Myopathy Mimicking Muscular Dystrophy

Author: Claude-Alain Maurage, Norma B. Romero, Vincent Tiffreau, Louis Vallée, Isabelle Nelson, Rabah Ben Yaou, Emmanuelle Jaillette, Céline Tard, Fabienne Jouen, Jean-Marie Cuisset, Gisèle Bonne, Sylvie Nguyen, Patrick Vermersch, 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), Laboratoire d'excellence Inflamex, Sorbonne Paris Cité, Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 (URePSSS), Université d'Artois (UA)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille, Département Anesthésie-Réanimation, Hôpital Roger Salengro, CHRU de Lille, Hôpital Roger Salengro, CHRU de Lille, Lille, France, Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], 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)-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), 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), Service de Neuropédiatrie, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de référence des maladies rares neuromusculaires, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Service de neuropédiatrie [CHU Lille]
Subjects: Pathology, medicine.medical_specialty, Delayed Diagnosis, Necrosis, [SDV]Life Sciences [q-bio], Inflammation, Autoimmune Diseases, Diagnosis, Differential, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Muscular Diseases, Fibrosis, Biopsy, medicine, Humans, Muscular dystrophy, Muscle, Skeletal, Autoantibodies, 030203 arthritis & rheumatology, Muscle biopsy, medicine.diagnostic_test, biology, business.industry, General Medicine, medicine.disease, Pediatrics, Perinatology and Child Health, Disease Progression, biology.protein, Immunohistochemistry, Female, Hydroxymethylglutaryl CoA Reductases, Creatine kinase, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Introduction Necrotizing autoimmune myopathies (NAMs) are acquired myopathies with myofibrillar necrosis and weak or absent inflammatory component, sometimes associated with anti-signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. Observation The patient, a girl now aged 20 years, was first assessed at the age of 5 years for abnormal gait revealing frank pelvic deficit. Creatine kinase (CK) levels were as high as 7,500 IU/L. Subsequent muscle biopsy showed some necrosis, fiber regeneration, and fibrosis consistent with muscular dystrophy (MD). Protein immunohistochemistry was normal. The disease course was progressive until wheelchair use at the age of 9 years. At 12 years of age, a second muscle biopsy found an advanced MD with some perivascular inflammatory mononuclear cells. All molecular analyses done through 14 years of follow-up were negative till anti-HMGCR antibodies were detected at a significant amount when she was 19 years old. Discussion NAMs begin at a pediatric age and may have a chronic course mimicking MDs. Muscular biopsy can be misleading with a predominantly dystrophic pattern without inflammation. Conclusion This observation should prompt the assessment of NAMs in all MDs, even pediatric, without molecular solutions.
Published: 2017

26. Intérêt des traitements pharmacologiques symptomatiques des maladies neuromusculaires de l’enfant

Author: Jean-Marie Cuisset, Alexandra Binoche, Sylvie Nguyen, Amélie Hamain, Stéphanie Coopman, and Louis Vallée
Abstract: Les traitements pharmacologiques symptomatiques representent un appoint utile dans la prise en charge des maladies neuromusculaires, qu’ils soient cibles sur un processus physiopathologique corolaire de la maladie (fibrose musculaire, oxydation), sur un symptome physique tel que la myotonie, la douleur, ou sur les troubles cognitifs lies a l’atteinte centrale associee (dystrophinopathies, dystrophie myotonique de Steinert). Ils permettent d’ameliorer l’esperance et la qualite de vie, en attendant les progres des therapies curatives emergentes.
Published: 2017

27. Risk of autoimmune diseases and human papilloma virus (HPV) vaccines: Six years of case-referent surveillance

Author: Lamiae Grimaldi-Bensouda, Michel Rossignol, Isabelle Koné-Paut, Alain Krivitzky, Christine Lebrun-Frenay, Johanna Clet, David Brassat, Caroline Papeix, Marc Nicolino, Pierre-Yves Benhamou, Olivier Fain, Nathalie Costedoat-Chalumeau, Marie-France Courcoux, Jean-François Viallard, Bertrand Godeau, Thomas Papo, Patrick Vermersch, Isabelle Bourgault-Villada, Gerard Breart, Lucien Abenhaim, Firas Abbas, Abdelhakim Abdelmoumni, Pascal Hilliquin, Elisabeth Requeda, Daniel Adoue, Christian Agard, Agathe Masseau, Nathalie Aladjidi, Helder Fernandes, Gwendal Lemasson, Yves Perel, Isabelle Raymond, Olivier Richer, Anne Vital, Emma Allain-Launay, Marie Bru, Caroline Thomas, Jean-Jacques Altman, Daniel Amsallem, Nazmiye Aras, Latifato Boukari, Marie Dubrel, Edouard Letellier, Nadine Lucidarme, Arsène Mekinian, Anne-Sophie Morin, Jérôme Stirnemann, Catherine Atlan, Dominique Audry, Jérôme Augustin, Redouane Bakir, Pablo Bartolucci, Xavier Chevalier, Constance Guillaud, Mehdi Khellaf, Nicolas Limal, Valentine Lousteau, Matthieu Mahevas, Gayane Méliksetyan, Marc Michel, Mathilde Roumier, Sophie Bayart, Fabrice Bonnet, Olivier Decaux, Amine Bekherraz, Benoit Brihaye, Roger Dachez, Eric Daugas, Gilles Hayem, Olivier Meyer, Elisa Pasqualoni, Karim Sacre, Florence Travert, Hélène Bellon, Jacques Beltrand, François Lefrere, Albane Simon, Olivier Benveniste, Francis Bolgert, Raphael De Paz, Sophie Demeret, Bruno Fautrel, Sophie Jacqueminet, Céline Louapre, Elizabeth Maillart, Nathalie Morel, Julie Rigabert, Philippe Bensaid, Claire Berger, Patrick Berquin, Anne-Gaëlle Le Moing, Stéphane Berroir, Gérard Besson, Célia Boutte, Olivier Casez, Bernard Bonnotte, Sylvain Audia, Cécile Bossu-Estour, Anne Bourgarit, Alain Dupuy, Homa Keshmandt, Bertrand Bourre, Aude Brac, Agnès Perrin, Corinne Pondarré, Sylvie Villar-Fimbel, Isabelle Bruckert, Anne Cosson, Nadine Magy-Bertrand, Guillaume Tisserand, William Camu, Bertrand Carlander, Raul Juntas Morales, Claude Cances, Marlene Pasquet, Maria Angela Castilla Lievre, Stephanie Chabroux, Mamoud Charif, Emmanuel Chatelus, Jean Sibilia, Jacqueline Chevrant-Breton, Sylvaine Clavel, Françoise Bille-Turc, Jacques Cohen, Marie France Courcoux, Guy Leverger, Laurent Machet, Jean-Marie Cuisset, Pascale Cony-Makhoul, Paul Darsy, Sandrine Favre, Pierrick Giraud, Laurence Leitenschenck, Irène Monteiro, Chafika Morati, Jérôme DeSeze, Monica Dinulescu, Taher Dhaoui, Florence Dommange-Romero, Elisabeth Drevard, Clémentine Dupuis, Marie-Laure Dumuis, Jean-Marc Durand, Samia Farad, Pierre Lecomte, Peggy Pierre, Fanny Fouyssac, Philippe Gaudin, Alain Gautier, Justine Gellen-Dautremer, Irène Jarrin, Pascal Richette, Emilie Georget, Pierre Gras, Thibault Moreau, Eric Giraud, Maya Hacini, Anne Mayer, Cécile Guillaumat, Séverine Guillaume, Corinne Guitton, Isabelle Kone-Paut, Céline Marsaud, Linda Rossi, Marie-Hélène Guyot, Patrick Hassler, Claude Heimfert, Olivier Heinzlef, Brigitte Hillion, Catherine Hocquelet, Helene Husson, Pierre Ichai, Eric Jeziorski, Chantal Job Deslandre, Véronique Le Guern, Kamen Kamenov, Véronique Kerlan, Philippe Lemoine, Laurent Misery, Brigitte Pan-Petesch, Pierre Labauge, Michel Rodier, Chadi Lacade, Berthe Razafimahefa, Karim Lachgar, Marie-Pierre Larmarau, Thierry Leblanc, Patrick Lefèbvre, Philippe Lejoyeux, Charles Leske, Kim Ly, Laurent Magy, Sylvie Mansuy, Richard Marechaud, Marie-Laure Martin Negrier, Guilhem Sole, Jean Maupetit, Françoise Mazingue, Stéphanie Mochon, Blidi Moktar, Donald Morcamp, Nathalie Morlet-Barla, Guillaume Nicolas, Vivien Pautot, Isabelle Pellier, Jean-Luc Verret, Olivier Outteryck, Beatrice Pallot-Prades, Jean Michel Paquet, Xavier Puechal, Annie Sortais, Jean Pelletier, Audrey Rico, Dominique Pez, Bruno Stankoff, Philippe Quittet, Claude Rémy, Eléna Roba, Hélène Rosario, Nathalie Roudaut, Emmanuel Sonnet, Michel Ruel, Samuel Sebban, Pauline Schaepelynck, Marie-Jeanne Simonin, Christophe Vial, Jean-Francois Viallard, Isabelle Ladedan, Thierry Zenone, LASER ANALYTICA, Paris (LA-SER), Centre d'enseignement Cnam Paris (CNAM Paris), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Service de Rhumatologie [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre de référence des maladies auto-inflammatoires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de médecine interne [Avicenne], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie [CHU Nice], Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), CHU Grenoble, Service de médecine interne [CHU Caen], Université de Caen Normandie (UNICAEN), 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 médecine interne et centre de référence des maladies rares [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], CHU Trousseau [APHP], Service de médecine interne et maladies infectieuses [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Saint-André, Service de médecine interne [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département Hospitalo-Universitaire Fibrosis, Inflammation, Remodeling in cardiovascular, respiratory and renal diseases (Paris), Lille Inflammation Research International Center - U 995 (LIRIC), 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 Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Claude Huriez [Lille], CHU Lille, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), 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), Hôpital Ambroise Paré [AP-HP], Equipe 1 : EPOPé - Épidémiologie Obstétricale, Périnatale et Pédiatrique (CRESS - U1153), Université Paris Descartes - Paris 5 (UPD5)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), DHU Risques Et Grossesse, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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 Toulouse [Toulouse], Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hôpital Avicenne, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Service d’oncologie hématologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-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)-Université Paris Diderot - Paris 7 (UPD7), Lille Inflammation Research International Center (LIRIC), Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Ambroise Paré, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-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)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [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), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), and Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, Risk, Pediatrics, medicine.medical_specialty, Adolescent, Immunology, HPV vaccines, Autoimmune Diseases, Autoimmune thyroiditis, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Autoimmune disease, Odds Ratio, medicine, Humans, Immunology and Allergy, Papillomavirus Vaccines, 030212 general & internal medicine, Family history, Young adult, Child, HPV vaccine, business.industry, Pharmacoepidemiology, Papillomavirus Infections, Odds ratio, medicine.disease, Thrombocytopenic purpura, Connective tissue disease, Confidence interval, 3. Good health, Population Surveillance, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Background Safety of HPV vaccines is still in question due to reports of autoimmune diseases (ADs) following HPV immunization. Objectives To assess the risk of ADs associated with HPV vaccination of female adolescents/young adults in France. Methods Systematic prospective case-referent study conducted to assess the risks associated with real-life use of HPV vaccines. Cases were female 11–25 years old with incident ADs [central demyelination/multiple sclerosis (CD/MS), connective tissue disease (CTD), Guillain-Barre syndrome (GBS), type-1 diabetes (T1D), autoimmune thyroiditis (AT), and idiopathic thrombocytopenic purpura (ITP)]. Cases were consecutively and prospectively identified at specialized centers across France (2008–2014) and individually matched by age and place of residence to referents recruited in general practice. Risk was computed using multivariate conditional logistic regression models adjusted for family history of ADs, living in France (north/south), co-medications and co-vaccinations. Results With a total of 478 definite cases matched to 1869 referents, all ADs combined were negatively associated to HPV vaccination with an adjusted odds ratio of 0.58 (95% confidence interval: 0.41–0.83). Similar results were obtained for CD/MS, AT, CT, and T1D, the last two not reaching statistical significance. No association was found for ITP and GBS. Sensitivity analyses combining definite and possible cases with secondary time window showed similar results. Conclusion Exposure to HPV vaccines was not associated with an increased risk of ADs within the time period studied. Results were robust to case definitions and time windows of exposure. Continued active surveillance is needed to confirm this finding for individual ADs.
Published: 2017

28. RecessiveMYPNmutations cause cap myopathy with occasional nemaline rods

Author: Jean-Marie Cuisset, Anne Boland, Edoardo Malfatti, Matteo Garibaldi, Jean-François Deleuze, Johann Böhm, Michel Fardeau, Jocelyn Laporte, Xavière Lornage, Norma B. Romero, Raphaël Schneider, Robert-Yves Carlier, Bruno Eymard, Valérie Biancalana, Chrystel Cheraud, and Julie D. Thompson
Subjects: 0301 basic medicine, Genetics, Messenger RNA, Mutation, Genetic heterogeneity, MYPN, Consanguinity, Biology, medicine.disease_cause, Sarcomere, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, medicine, Neurology (clinical), Cap myopathy, Exome, 030217 neurology & neurosurgery
Abstract: Congenital myopathies are phenotypically and genetically heterogeneous. We describe homozygous truncating mutations in MYPN in 2 unrelated families with a slowly progressive congenital cap myopathy. MYPN encodes the Z-line protein myopalladin implicated in sarcomere integrity. Functional experiments demonstrate that the mutations lead to mRNA defects and to a strong reduction in full-length protein expression. Myopalladin signals accumulate in the caps together with alpha-actinin. Dominant MYPN mutations were previously reported in cardiomyopathies. Our data uncover that mutations in MYPN cause either a cardiac or a congenital skeletal muscle disorder through different modes of inheritance. Ann Neurol 2017;81:467-473.
Published: 2017

29. Assessment of Procedural Pain in Children Using Analgesia Nociception Index

Author: Mathieu Jeanne, J Avez-Couturier, Louis Vallée, Jean-Marie Cuisset, Régis Logier, and Julien De Jonckheere
Subjects: Male, medicine.medical_specialty, Adolescent, Biopsy, Sedation, Pilot Projects, Pain, Procedural, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, 030225 pediatrics, Heart rate, medicine, Humans, Hypnotics and Sedatives, Single-Blind Method, Prospective Studies, Child, Prospective cohort study, Pain Measurement, Muscle biopsy, medicine.diagnostic_test, business.industry, Muscles, Age Factors, Infant, body regions, Procedural Pain, Anesthesiology and Pain Medicine, Nociception, Child, Preschool, Anesthesia, FLACC scale, Physical therapy, Female, Neurology (clinical), Analgesia, medicine.symptom, business
Abstract: The Analgesia Nociception Index (ANI), based on heart rate (HR) variability analysis, is known to decrease after a painful stimulus during surgery under general anesthesia in adults. It is measured continuously and noninvasively. We studied ANI response to procedural pain in a pediatric population and ANI measurement's feasibility in this context, across age. A prospective, noninterventional pilot study was performed. All children (between 6 mo and under 18 y) undergoing muscle biopsy conducted under analgesia and light sedation were included. Medical staff was blind to the ANI monitor. HR and ANI were recorded and analyzed during 2 periods: T1 before incision and T2 after incision. Pain was assessed by the FLACC scale at T2. We observed ANI and HR variations after incision. ANI, HR, and FLACC were compared between children younger or older than 6 years. Enrollment or technical issues were reported. A total of 26 children were included (median age, 6 y; ranging from 6 mo to 16 y; 16 male). ANI decreased from T1 to T2. HR, ANI, or FLACC values were not different in children younger or older than 6 years. No parents or children refused to take part in the study. No technical issues was reported. In this pilot study, ANI measurement seems relevant in pediatric procedural pain, across age. Further studies are needed to confirm these results.
Published: 2016

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

Author: A. Hernandez, Andrea Gangfuß, V. Chê, Adele D'Amico, Rémi Bellance, Laurent Servais, Capucine de Lattre, Basil T. Darras, E. Gargaun, James J. Dowling, Teresa Gidaro, C. Lilien, Ulrike Schara, A. Daron, Ana Buj-Bello, H. Landy, Jean-Marie Cuisset, Carole Vuillerot, Jean-Yves Hogrel, S. Fontaine, Jean-Michel Arnal, Valérie Biancalana, Michèle Mayer, M. Annoussamy, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Advanced BC.org, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Neuromuscular Physiology and Evaluation Laboratory, Service of Clinical Trials and Databases, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Adult, Male, Vital capacity, medicine.medical_specialty, Neuromuscular disease, Adolescent, [SDV]Life Sciences [q-bio], Population, Medizin, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Humans, Longitudinal Studies, Prospective Studies, education, Prospective cohort study, Child, education.field_of_study, business.industry, Exhalation, Infant, Middle Aged, medicine.disease, X-linked myotubular myopathy, 3. Good health, 030104 developmental biology, Phenotype, Child, Preschool, Breathing, Disease Progression, Neurology (clinical), business, 030217 neurology & neurosurgery, Natural history study, Follow-Up Studies, Myopathies, Structural, Congenital
Abstract: ObjectivesBecause X-linked myotubular myopathy (XLMTM) is a rare neuromuscular disease caused by mutations in the MTM1 gene with a large phenotypic heterogeneity, to ensure clinical trial readiness, it was mandatory to better quantify disease burden and determine best outcome measures.MethodsWe designed an international prospective and longitudinal natural history study in patients with XLMTM and assessed muscle strength and motor and respiratory functions over the first year of follow-up. The humoral immunity against adeno-associated virus serotype 8 was also monitored.ResultsForty-five male patients aged 3.5 months to 56.8 years were enrolled between May 2014 and May 2017. Thirteen patients had a mild phenotype (no ventilation support), 7 had an intermediate phenotype (ventilation support less than 12 hours a day), and 25 had a severe phenotype (ventilation support 12 or more hours a day). Most strength and motor function assessments could be performed even in very weak patients. Motor Function Measure 32 total score, grip and pinch strengths, and forced vital capacity, forced expiratory volume in the first second of exhalation, and peak cough flow measures discriminated the 3 groups of patients. Disease history revealed motor milestone loss in several patients. Longitudinal data on 37 patients showed that the Motor Function Measure 32 total score significantly decreased by 2%. Of the 38 patients evaluated, anti–adeno-associated virus type 8 neutralizing activity was detected in 26% with 2 patients having an inhibitory titer >1:10.ConclusionsOur data confirm that XLMTM is slowly progressive for male survivors regardless of their phenotype and provide outcome validation and natural history data that can support clinical development in this population.ClinicalTrials.gov identifierNCT02057705.
Published: 2019

31. A large multicenter study of pediatric myotonic dystrophy type 1 for evidence-based management

Author: Hubert Journel, Sylvie Ragot-Mandry, Delphine Héron, Brigitte Chabrol, S. Peudenier, Jean-Marie Cuisset, Guillaume Bassez, Pascal Sabouraud, Catherine Sarret, Claude Cances, Mélanie Fradin, Agnès Jacquin-Piques, Julie Perrier-Boeswillald, Isabelle Desguerre, Michèle Mayer, Susana Quijano-Roy, Arnaud Isapof, Vincent Laugel, Marie De Antonio, Frédérique Audic, Nathalie Bach, Emmanuelle Lagrue, C. Espil, Rémi Bellance, Catherine Vanhulle, Armelle Magot, Hervé Testard, Julien Durigneux, Yann Péréon, Cécile Laroche-Raynaud, Romain K. Gherardi, Christine Barnerias, Céline Dogan, Véronique Manel, François Rivier, Dalil Hamroun, Ulrike Walther-Louvier, Christian Richelme, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Département de Pédiatrie [CHU Toulouse], CHU Toulouse [Toulouse], Service de Neurologie Pédiatrique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de Référence des Maladies Héréditaires du Métabolisme, Service de neurométabolisme, Service de neuropédiatrie, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Groupe de recherche clinique 'déficience intellectuelle et autisme', Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Pontchaillou [Rennes], Hôpital de Hautepierre [Strasbourg], Laboratoire d'Explorations Fonctionnelles, Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Service de neurologie pédiatriques et maladies du dévéloppement, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Atlantic Gene Therapies, Service de Pédiatrie, Rééducation et Réanimation Neurorespiratoire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Service de pédiatrie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), American Memorial Hospital (Reims), Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), CHU Grenoble, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service d'histologie-Hôpital Henri Mondor, Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), AP-HP, Paris-CHU Necker - Enfants Malades [AP-HP], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service de neuropédiatrie [Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital Raymond Poincaré [Garches], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Pascal - Clermont Auvergne (IP), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), École Pratique des Hautes Études (EPHE), Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Foot Deformities, Male, Pediatrics, medicine.medical_specialty, Adolescent, Myotonic dystrophy, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Genotype-phenotype distinction, Cataracts, Severity of illness, medicine, Humans, Myotonic Dystrophy, Registries, Child, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Evidence-Based Medicine, Muscle Weakness, business.industry, Infant, Newborn, Evidence-based management, Infant, Cardiorespiratory fitness, Arrhythmias, Cardiac, Evidence-based medicine, medicine.disease, 3. Good health, 030104 developmental biology, Multicenter study, Child, Preschool, Cohort, Autism, Female, Neurology (clinical), France, business, Respiratory Insufficiency, Trinucleotide Repeat Expansion, 030217 neurology & neurosurgery
Abstract: ObjectiveTo genotypically and phenotypically characterize a large pediatric myotonic dystrophy type 1 (DM1) cohort to provide a solid frame of data for future evidence-based health management.MethodsAmong the 2,697 patients with genetically confirmed DM1 included in the French DM-Scope registry, children were enrolled between January 2010 and February 2016 from 24 centers. Comprehensive cross-sectional analysis of most relevant qualitative and quantitative variables was performed.ResultsWe studied 314 children (52% females, with 55% congenital, 31% infantile, 14% juvenile form). The age at inclusion was inversely correlated with the CTG repeat length. The paternal transmission rate was higher than expected, especially in the congenital form (13%). A continuum of highly prevalent neurodevelopmental alterations was observed, including cognitive slowing (83%), attention deficit (64%), written language (64%), and spoken language (63%) disorders. Five percent exhibited autism spectrum disorders. Overall, musculoskeletal impairment was mild. Despite low prevalence, cardiorespiratory impairment could be life-threatening, and frequently occurred early in the first decade (25.9%). Gastrointestinal symptoms (27%) and cataracts (7%) were more frequent than expected, while endocrine or metabolic disorders were scarce.ConclusionsThe pedDM-Scope study details the main genotype and phenotype characteristics of the 3 DM1 pediatric subgroups. It highlights striking profiles that could be useful in health care management (including transition into adulthood) and health policy planning.
Published: 2019

32. Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy

Author: Subhrajit Bhattacharya, Varun Kannan, Hirofumi Kusumoto, Yuehua Zhang, Gabrielle J. Kosobucki, An-Sofie Schoonjans, Annapurna Poduri, Sylvie Nguyen, Xinhua Bao, Elias Aizenman, Elisabeth Schuler, Dragan Marjanovic, Hongjie Yuan, Scott J. Myers, Christelle Moufawad El Achkar, Christina Fenger, Nina Dirkx, Gaetan Lesca, Yuwu Jiang, Stephen F. Traynelis, Jean-Marie Cuisset, Ye Wu, Wenshu XiangWei, Steffen Syrbe, Katherine L. Helbig, Anthony J. Schulien, Johannes R. Lemke, and Yuchen Xu
Subjects: 0301 basic medicine, Agonist, Adult, Male, medicine.drug_class, Protein subunit, Glutamic Acid, Neurotransmission, Polymorphism, Single Nucleotide, Receptors, N-Methyl-D-Aspartate, Synaptic Transmission, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Humans, Amino Acid Sequence, Receptor, Child, Neurons, Chemistry, Glutamate receptor, Original Articles, Cell biology, Rats, Transmembrane domain, 030104 developmental biology, HEK293 Cells, Gene Expression Regulation, Child, Preschool, NMDA receptor, Epilepsy, Generalized, Female, Neurology (clinical), Human medicine, 030217 neurology & neurosurgery, Ionotropic effect
Abstract: N-methyl D-aspartate receptors are ligand-gated ionotropic receptors mediating a slow, calcium-permeable component of excitatory synaptic transmission in the CNS. Variants in genes encoding NMDAR subunits have been associated with a spectrum of neurodevelopmental disorders. Here we report six novel GRIN2D variants and one previously-described disease-associated GRIN2D variant in two patients with developmental and epileptic encephalopathy. GRIN2D encodes for the GluN2D subunit protein; the GluN2D amino acids affected by the variants in this report are located in the pre-M1 helix, transmembrane domain M3, and the intracellular carboxyl terminal domain. Functional analysis in vitro reveals that all six variants decreased receptor surface expression, which may underline some shared clinical symptoms. In addition the GluN2D(Leu670Phe), (Ala675Thr) and (Ala678Asp) substitutions confer significantly enhanced agonist potency, and/or increased channel open probability, while the GluN2D(Ser573Phe), (Ser1271Phe) and (Arg1313Trp) substitutions result in a mild increase of agonist potency, reduced sensitivity to endogenous protons, and decreased channel open probability. The GluN2D(Ser573Phe), (Ala675Thr), and (Ala678Asp) substitutions significantly decrease current amplitude, consistent with reduced surface expression. The GluN2D(Leu670Phe) variant slows current response deactivation time course and increased charge transfer. GluN2D(Ala678Asp) transfection significantly decreased cell viability of rat cultured cortical neurons. In addition, we evaluated a set of FDA-approved NMDAR channel blockers to rescue functional changes of mutant receptors. This work suggests the complexity of the pathological mechanisms of GRIN2D-mediated developmental and epileptic encephalopathy, as well as the potential benefit of precision medicine.
Published: 2019

33. Deciphering the complexity of the 4q and 10q subtelomeres by molecular combing in healthy individuals and patients with facioscapulohumeral dystrophy

Author: Vincent Tiffreau, Albert David, Jon Andoni Urtizberea, Charlene Chaix, Emmanuelle Salort-Campana, Rafaëlle Bernard, Sabrina Sacconi, Karine Nguyen, André Mégarbané, Fabien Zagnoli, Natacha Broucqsault, Jérôme D. Robin, Shahram Attarian, Frédérique Magdinier, Jean-Marie Cuisset, Véronique Manel, Laurene Gerard, Bruno Eymard, Stéphane Roche, Catherine Vovan, Mélanie Fradin, Nicolas Lévy, Christine Barnerias, Rémi Bellance, 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), 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), Assistance Publique - Hôpitaux de Marseille (APHM), Unité de Génétique Médicale, Université Saint-Joseph de Beyrouth (USJ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], MLab, Dauphine Recherches en Management (DRM), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), 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), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Service epilepsie sommeil et explorations fonctionnelles neuropédiatriques (HFME), Hospices Civils de Lyon (HCL)-Université de Lyon, 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), Activité Physique, Muscle, Santé (EA4488), Université de Lille, Droit et Santé, Service de Neurologie [Brest], Hôpital d'Instruction des Armées 'Clermont-Tonnerre' (HIA), Maladies Neuromusculaires de l'Enfant, Hôpital Roger Salengro [Lille], Centre de référence des maladies neuromusculaires et de la SLA, Hôpital de la Timone [CHU - APHM] (TIMONE), Roche, Stephane, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Université Nice Sophia Antipolis (... - 2019) (UNS), and 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)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Genotype, Genetic counseling, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Locus (genetics), Biology, subtelomeres, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Homology (biology), 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene duplication, molecular combing, smchd1, Genetics, Humans, Genetic Predisposition to Disease, Genetics (clinical), Alleles, Genetic Association Studies, Chromosomes, Human, Pair 10, Haplotype, facio scapulo humeral dystrophy, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Dystrophy, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Telomere, Subtelomere, Muscular Dystrophy, Facioscapulohumeral, 3. Good health, Pedigree, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Chromosome Deletion, Chromosomes, Human, Pair 4, 030217 neurology & neurosurgery
Abstract: BackgroundSubtelomeres are variable regions between telomeres and chromosomal-specific regions. One of the most studied pathologies linked to subtelomeric imbalance is facioscapulohumeral dystrophy (FSHD). In most cases, this disease involves shortening of an array of D4Z4 macrosatellite elements at the 4q35 locus. The disease also segregates with a specific A-type haplotype containing a degenerated polyadenylation signal distal to the last repeat followed by a repetitive array of β-satellite elements. This classification applies to most patients with FSHD. A subset of patients called FSHD2 escapes this definition and carries a mutation in the SMCHD1 gene. We also recently described patients carrying a complex rearrangement consisting of a cis-duplication of the distal 4q35 locus identified by molecular combing.MethodsUsing this high-resolution technology, we further investigated the organisation of the 4q35 region linked to the disease and the 10q26 locus presenting with 98% of homology in controls and patients.ResultsOur analyses reveal a broad variability in size of the different elements composing these loci highlighting the complexity of these subtelomeres and the difficulty for genomic assembly. Out of the 1029 DNA samples analysed in our centre in the last 7 years, we also identified 54 cases clinically diagnosed with FSHD carrying complex genotypes. This includes mosaic patients, patients with deletions of the proximal 4q region and 23 cases with an atypical chromosome 10 pattern, infrequently found in the control population and never reported before.ConclusionOverall, this work underlines the complexity of these loci challenging the diagnosis and genetic counselling for this disease.
Published: 2018

34. LATE BREAKING NEWS E-POSTER PRESENTATION

Author: Francesco Tedesco, Jean-Marie Cuisset, Gisèle Bonne, Luca Pinton, S.M. Maffioletti, Shilpita Sarcar, Daniel Moore, Heather B. Steele-Stallard, Peter S. Zammit, and Tanel Ozdemir
Subjects: Presentation, History, Neurology, media_common.quotation_subject, Pediatrics, Perinatology and Child Health, Neurology (clinical), Genetics (clinical), Visual arts, media_common
Published: 2020

35. Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features

Author: Sophie Scheidecker, Françoise Devillard, Gaetan Lesca, Maryline Carneiro, Christèle Dubourg, Ganaëlle Remerand, Catherine Badens, Odile Boespflug-Tanguy, Nathalie Marle, Serge Romana, Nadia Bahi-Buisson, Jean-Paul Bonnefont, Hubert Journel, Bénédicte Duban-Bedu, Brigitte Gilbert-Dussardier, Mathilde Nizon, Nathalie Perreton, Sophie Julia, Cyril Goizet, Delphine Héron, Véronique Satre, Marguerite Miguet, Joris Andrieux, Pierre-Simon Jouk, Laurence Perrin, Renaud Touraine, Ghislaine Plessis, Dominique Martin-Coignard, Caroline Rooryck, Catherine Vincent-Delorme, Laurence Faivre, Salima El Chehadeh, Thierry Bienvenu, Jean-Luc Alessandri, Anne-Claude Tabet, Laurent Pasquier, Martine Raynaud, Réseau AChro-Puce, Marjolaine Willems, Bruno Leheup, Marianne Till, Jeanne Amiel, Jacqueline Vigneron, Nicole Philip, Valérie Kremer, Massimiliano Rossi, Boris Keren, Annick Toutain, Fabienne Prieur, Bertrand Isidor, Séverine Drunat, Marilyn Lackmy-Port-Lis, Albert David, Christel Thauvin-Robinet, Damien Sanlaville, Laetitia Lambert, Lydie Burglen, Klaus Dieterich, Catherine Sarret, Anne Moncla, Didier Lacombe, Fanny Laffargue, Kim Maincent, Marlène Rio, Clarisse Baumann, Mathilde Lefebvre, Sabine Sigaudy, Laurent Guibaud, Adeline Vigouroux, Valérie Malan, Patrick Callier, Chantal Missirian, Christophe Philippe, Christine Francannet, Anne-Laure Mosca-Boidron, Valérie Cormier-Daire, Cédric Le Caignec, Vincent des Portes, Charles Coutton, Alexandra Afenjar, Sandrine Chantot-Bastaraud, Julien Thevenon, Mylène Béri-Dexheimer, Hilde Van Esch, Bernard Echenne, Jean-Marie Cuisset, Jean-Michel Pedespan, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Service de Génétique Médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Clinique (CHU de Saint-Etienne), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service de Génétique Clinique [CHU Rennes] (Réseau de Génétique et Génomique Médicale), Hôpitaux Universitaires du Grand Ouest, Laboratoire de Génétique Moléculaire & Génomique [CHU Rennes], CHU Pontchaillou [Rennes], Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Image Guided Clinical Neurosciences and Connectomics (IGCNC), Université d'Auvergne - Clermont-Ferrand I (UdA), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire de Génétique Médicale (CHU de Nancy), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de neuro-pédiatrie (CHRU de Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Médicale, Hopital Jeanne de Flandre, Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), 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 génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Radiologie [Hôpital Femme Mère Enfant - HCL], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de génétique clinique [CHU Necker], Département de neurologie pédiatrique [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Service de génétique clinique [Debré], Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Maladies rares, génétique et métabolisme / Rare Diseases, Genetics and Metabolism, Institut National de la Santé et de la Recherche Médicale (INSERM)-École de sage femme - Groupe hospitalier Pellegrin - CHU de Bordeaux, Service de Génétique Médicale du CHU de Bordeaux, 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), Laboratoire de génétique chromosomique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Biologie Moléculaire (MARSEILLE - Biolo Moléculaire), Assistance Publique - Hôpitaux de Marseille (APHM), CIC 1407, Hospices Civils de Lyon (HCL), Service de neurologie pédiatrique [CHU de Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], GHICL-Hôpital Saint Vincent de Paul, Service de Neuropédiatrie [CHU Necker - Enfants Malades], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Laboratoire de génétique médicale et cytogénétique [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génétique Moléculaire [CHU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Service de Neurologie Pédiatrique [CHU Lyon], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre for Human Genetics, University Hospitals Leuven [Leuven], Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre de référence des déficiences intellectuelles de causes rares (Hospices Civils de Lyon), Hospices civils de Lyon (HCL), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Dynamiques Cellulaire et Tissulaire - Interdisciplinarité, Modélisation & Microscopie (TIMC-IMAG-DyCTiM2), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Groupement Hospitalier Lyon-Est (GHE), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-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)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, MECP2 duplication syndrome, MECP2gene, Scoliosis, MECP2duplication syndrome, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Gene duplication, Genetics, medicine, Spasticity, Genetics (clinical), X-linked, Vasomotor, business.industry, facial dysmorphism, medicine.disease, Gait, Hypotonia, 3. Good health, 030104 developmental biology, Xq28 duplication, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, medicine.symptom, business, 030217 neurology & neurosurgery, genetic counselling
Abstract: The Xq28 duplication involving theMECP2gene (MECP2duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitialMECP2duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype ofMECP2duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.
Published: 2018

36. Functional assessment of creatine transporter in control and X-linked SLC6A8-deficient fibroblasts

Author: Jean-Marie Cuisset, Isabelle Kim, Marie-Adélaïde Bout, Stéphanie Moortgat, David Cheillan, Marie Joncquel-Chevalier Curt, Monique Fontaine, Soumeya Bekri, Alexandre Moerman, Guillemette Huet, Joseph Vamecq, Gilles Morin, Centre de Génétique Humaine (Institut de Pathologie et de Génétique, Charleroi), Institut de Pathologie et de Génétique, Charleroi, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Service Maladies Héréditaires du Métabolisme, Centre de Biologie Est, Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, Male, Bioenergetics, diagnosis, guanidinoacetate, UPLC/tandem MS, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Biochemistry, Plasma Membrane Neurotransmitter Transport Proteins, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, tandem mass-spectrometry, Female carriers, Child, Incubation, metabolites, chemistry.chemical_classification, Genetics & Heredity, slc6a8 deficiency, D-3-creatine, SLC6A8 gene, Research & Experimental, Prognosis, urine, 3. Good health, Child, Preschool, RNA splicing, Medicine, Female, inborn-errors, medicine.medical_specialty, Adolescent, Nerve Tissue Proteins, Creatine, 03 medical and health sciences, Endocrinology & Metabolism, Guanidino, Internal medicine, Genetics, medicine, Humans, Molecular Biology, Gene, plasma, Brain Diseases, Metabolic, Inborn, Infant, Transporter, Fibroblasts, X-linked disorder, 030104 developmental biology, Enzyme, chemistry, Case-Control Studies, methyltransferase gamt deficiency, Mutation, mental-retardation, Mental Retardation, X-Linked, body-fluids, Creatine transporter, Male hemizygotes, 030217 neurology & neurosurgery, Fetal bovine serum, Follow-Up Studies
Abstract: International audience; Creatine transporter is currently the focus of renewed interest with emerging roles in brain neurotransmission and physiology, and the bioenergetics of cancer metastases. We here report on amendments of a standard creatine uptake assay which might help clinical chemistry laboratories to extend their current range of measurements of creatine and metabolites in body fluids to functional enzyme explorations. In this respect, short incubation times and the use of a stable-isotope-labeled substrate (D-3-creatine) preceded by a creatine wash-out step from cultured fibroblast cells by removal of fetal bovine serum (rich in creatine) from the incubation medium are recommended. Together, these measures decreased, by a first order of magnitude, creatine concentrations in the incubation medium at the start of creatine-uptake studies and allowed to functionally discriminate between 4 hemizygous male and 4 heterozygous female patients with X-linked SLC6A8 deficiency, and between this cohort of eight patients and controls. The functional assay corroborated genetic diagnosis of SLC6A8 deficiency. Gene anomalies in our small cohort included splicing site (c.912G \textgreater A [p.Ile260_Gln304del], c.778-2A \textgreater G and c.1495 + 2 T \textgreater G), substitution (c.407C \textgreater T) [p.Ala136Val] and deletion (c.635\₆36delAG [p.Glu212Valfs*84] and c.1324delC [p.Gln442Lysfs*21]) variants with reduced creatine transporter function validating their pathogenicity, including that of a previously unreported c.1324delC variant. The present assay adaptations provide an easy, reliable and discriminative manner for exploring creatine transporter activity and disease variations. It might apply to drug testing or other evaluations in the genetic and metabolic horizons covered by the emerging functions of creatine and its transporter, in a way, however, requiring and completed by additional studies on female patients and blood-brain barrier permeability properties of selected compounds. As a whole, the proposed assay of creatine transporter positively adds to currently existing measurements of this transporter activity, and determining on a large scale the extent of its exact suitability to detect female patients should condition in the future its transfer in clinical practice.
Published: 2018

37. Comment organiser la délibération collégiale pour limiter ou arrêter les traitements en pédiatrie ?

Author: Jean-Marie Cuisset, Robin Cremer, C. Minnaert, S. Joriot, Laurent Storme, S. Vandoolaeghe, A. Laffargue, D. Guimber, A. Matthews, K. Mention, Pierre Fayoux, D. Thomas, J. Le Cunff, and C. Lervat
Subjects: Withholding Treatment, Patient care team, Nursing, Clinical decision making, media_common.quotation_subject, Pediatrics, Perinatology and Child Health, MEDLINE, 16. Peace & justice, Deliberation, Psychology, 3. Good health, media_common
Abstract: In 2005, the French law on patients' rights at the end of life required that decisions to withdraw or withhold life-sustaining treatments be made and carried out by the physician in charge of the patient, after obtaining advice from an independent consulting colleague and the caregiving team. The purpose of this study was to identify theoretical and practical obstacles to this collaborative deliberation and to propose practical guidelines to organize it.
Published: 2015

38. Syndrome catatonique précoce et encéphalite à auto-anticorps antirécepteurs-NMDA : une mise au point

Author: C. Meurisse, Louis Vallée, A. Trauffler, J L Goeb, A. Parenti, Jean-Marie Cuisset, G Kechid, P.A. Geoffroy, L. Hagneré, Renaud Jardri, S. Joriot, P Delion, and H. Nasser
Subjects: Psychiatry and Mental health, Pediatrics, Perinatology and Child Health, Developmental and Educational Psychology
Abstract: Resume L’encephalite auto-immune a anticorps antirecepteurs au N-Methyl-D-Aspartate (NMDA) est une atteinte grave du systeme nerveux central, encore peu connue des cliniciens, pouvant etre a l’origine de symptomes psychiatriques frustres comportant des symptomes psychotiques ou catatoniques. Nous rapportons ici le cas d’une jeune fille de 15 ans, sans antecedent personnel notable, hospitalisee pour decompensation psychotique de debut brutal, rapidement compliquee d’une catatonie agitee puis stuporeuse, repondant insuffisamment au traitement par benzodiazepines. Le diagnostic d’encephalite a anticorps anti-RNMDA a pu etre confirme par le dosage des auto-anticorps dans le liquide cephalorachidien (LCR). L’evolution sera favorable sous corticoides et immunosuppresseurs. Nous proposons a l’issue de ce cas, une mise au point sur l’encephalite a auto-anticorps anti-RNMDA et sur l’hypothese d’un desequilibre de la balance excitation/inhibition a l’origine de la catatonie.
Published: 2015

39. New myotubular myopathy classification

Author: L. Servais, C. deLattre, V. Chê, Jean-Marie Cuisset, J.Y. Hogrel, A. Hernandez, E. Gargaun, Teresa Gidaro, Rémi Bellance, A. Daron, C. Lilien, S. Fontaine, M. Mayer, Ulrike Schara, H. Landy, Valérie Biancalana, Carole Vuillerot, Anna Buj-Bello, Alessandra D'Amico, M. Annoussamy, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, and Généthon
Subjects: 0303 health sciences, Pathology, medicine.medical_specialty, business.industry, Medizin, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 03 medical and health sciences, 0302 clinical medicine, Neurology, Pediatrics, Perinatology and Child Health, Medicine, Myotubular Myopathy, Neurology (clinical), business, 030217 neurology & neurosurgery, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2017

40. Further delineation of the

Author: Marguerite, Miguet, Laurence, Faivre, Jeanne, Amiel, Mathilde, Nizon, Renaud, Touraine, Fabienne, Prieur, Laurent, Pasquier, Mathilde, Lefebvre, Julien, Thevenon, Christèle, Dubourg, Sophie, Julia, Catherine, Sarret, Ganaëlle, Remerand, Christine, Francannet, Fanny, Laffargue, Odile, Boespflug-Tanguy, Albert, David, Bertrand, Isidor, Jacqueline, Vigneron, Bruno, Leheup, Laetitia, Lambert, Christophe, Philippe, Mylène, Béri-Dexheimer, Jean-Marie, Cuisset, Joris, Andrieux, Ghislaine, Plessis, Annick, Toutain, Laurent, Guibaud, Valérie, Cormier-Daire, Marlene, Rio, Jean-Paul, Bonnefont, Bernard, Echenne, Hubert, Journel, Lydie, Burglen, Sandrine, Chantot-Bastaraud, Thierry, Bienvenu, Clarisse, Baumann, Laurence, Perrin, Séverine, Drunat, Pierre-Simon, Jouk, Klaus, Dieterich, Françoise, Devillard, Didier, Lacombe, Nicole, Philip, Sabine, Sigaudy, Anne, Moncla, Chantal, Missirian, Catherine, Badens, Nathalie, Perreton, Christel, Thauvin-Robinet, Réseau, AChro-Puce, Jean-Michel, Pedespan, Caroline, Rooryck, Cyril, Goizet, Catherine, Vincent-Delorme, Bénédicte, Duban-Bedu, Nadia, Bahi-Buisson, Alexandra, Afenjar, Kim, Maincent, Delphine, Héron, Jean-Luc, Alessandri, Dominique, Martin-Coignard, Gaëtan, Lesca, Massimiliano, Rossi, Martine, Raynaud, Patrick, Callier, Anne-Laure, Mosca-Boidron, Nathalie, Marle, Charles, Coutton, Véronique, Satre, Cédric Le, Caignec, Valérie, Malan, Serge, Romana, Boris, Keren, Anne-Claude, Tabet, Valérie, Kremer, Sophie, Scheidecker, Adeline, Vigouroux, Marilyn, Lackmy-Port-Lis, Damien, Sanlaville, Marianne, Till, Maryline, Carneiro, Brigitte, Gilbert-Dussardier, Marjolaine, Willems, Hilde, Van Esch, Vincent Des, Portes, and Salima, El Chehadeh
Subjects: Adult, Male, Chromosomes, Human, X, Epilepsy, Adolescent, Methyl-CpG-Binding Protein 2, Developmental Disabilities, Hypertension, Pulmonary, Infant, Stereotypic Movement Disorder, Pedigree, Young Adult, Hyperopia, Phenotype, Child, Preschool, Intellectual Disability, Mental Retardation, X-Linked, Somatosensory Disorders, Exotropia, Humans, France, Child
Abstract: The Xq28 duplication involving the
Published: 2017

41. A fast method for high resolution oxymetry study of skeletal muscle mitochondrial respiratory chain complexes

Author: Raphael Favory, Marie Joncquel-Chevalier Curt, Anne-Frédérique Dessein, Jean-Marie Cuisset, Catherine Cimetta, Joseph Vamecq, Jean-Claude Vienne, Karine Mention-Mulliez, Claire Douillard, Monique Fontaine, Marie Dubois, Dries Dobbelaere, and Thibault Duburcq
Subjects: 0301 basic medicine, Swine, Biopsy, Cell Respiration, Muscle Fibers, Skeletal, Biophysics, Mitochondrion, Biochemistry, Permeability, Electron Transport, 03 medical and health sciences, Oxygen Consumption, Respiration, medicine, Animals, Muscle, Skeletal, Molecular Biology, Muscle biopsy, medicine.diagnostic_test, biology, Chemistry, Cytochrome c, Respiratory chain complex, Skeletal muscle, Cell Biology, Mitochondria, Muscle, 030104 developmental biology, Mitochondrial respiratory chain, medicine.anatomical_structure, Electron Transport Chain Complex Proteins, Mitochondrial Membranes, biology.protein, Female, Homogenization (biology)
Abstract: High resolution oxymetry study (HROS) of skeletal muscle usually requires 90–120 min preparative phase (dissection, permeabilization and washing). This work reports on the suitability of a rapid muscle preparation which by-passes this long preparation. For a few seconds only, muscle biopsy from pigs is submitted to gentle homogenization at 8000 rotations per minute using an ultra-dispersor apparatus. Subsequent HROS is performed using FCCP instead of ADP, compounds crossing and not plasma membrane, respectively. This simplified procedure compares favorably with classical (permeabilized fibers) HROS in terms of respiratory chain complex activities. Mitochondria from cells undergoing ultradispersion were functionally preserved as attested by relative inefficacy of added cytochrome C (not crossing intact mitochondrial outer membrane) to stimulate mitochondrial respiration. Responsiveness of respiration to ADP (in the absence of FCCP) suggested that these intact mitochondria were outside cells disrupted by ultradispersion or within cells permeated by this procedure.
Published: 2017

42. Recessive MYPN mutations cause cap myopathy with occasional nemaline rods

Author: Xavière, Lornage, Edoardo, Malfatti, Chrystel, Chéraud, Raphaël, Schneider, Valérie, Biancalana, Jean-Marie, Cuisset, Matteo, Garibaldi, Bruno, Eymard, Michel, Fardeau, Anne, Boland, Jean-François, Deleuze, Julie, Thompson, Robert-Yves, Carlier, Johann, Böhm, Norma B, Romero, and Jocelyn, Laporte
Subjects: Adult, Male, Muscle Proteins, Pedigree, Consanguinity, Neurology, Mutation, Humans, congenital myophthies, Exome, Female, dilated cardiomyophaty, Myopathies, Structural, Congenital
Abstract: Congenital myopathies are phenotypically and genetically heterogeneous. We describe homozygous truncating mutations in MYPN in 2 unrelated families with a slowly progressive congenital cap myopathy. MYPN encodes the Z-line protein myopalladin implicated in sarcomere integrity. Functional experiments demonstrate that the mutations lead to mRNA defects and to a strong reduction in full-length protein expression. Myopalladin signals accumulate in the caps together with alpha-actinin. Dominant MYPN mutations were previously reported in cardiomyopathies. Our data uncover that mutations in MYPN cause either a cardiac or a congenital skeletal muscle disorder through different modes of inheritance. Ann Neurol 2017;81:467-473.
Published: 2017

43. Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: a randomised, double-blind, placebo-controlled phase 2 trial

Author: Janbernd Kirschner, S. Fontaine-Carbonnel, Giuseppe Vita, Enrico Bertini, François Rivier, Nathalie Goemans, W. Ludo van der Pol, Mariacristina Scoto, Brigitte Chabrol, Carole Vuillerot, Helen Roper, Alessandra Govoni, Maggie C. Walter, Jeppe Buchbjerg, Anna Lusakowska, Ulrike Schara, Eugenio Mercuri, Jean Louis Abitbol, Thomas Blaettler, Nicolas Deconinck, Michela Guglieri, Eduardo Vianna, Claudio Bruno, Jean Marie Cuisset, Francesco Muntoni, Carol Reid, Eric Dessaud, Hanns Lochmüller, Giacomo P. Comi, Brigitte Estournet, Patricia Sanwald Ducray, Carole André, Francesca Magri, Bruno Scherrer, Leonard H. van den Berg, Paulo Fontoura, Ksenija Gorni, Wolfgang Müller-Felber, Michèle Mayer, and Schara, Ulrike (Beitragende*r)
Subjects: 0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Population, Medizin, Phases of clinical research, Spinal Muscular Atrophies of Childhood, Placebo, law.invention, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, Outcome Assessment (Health Care), 0302 clinical medicine, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Randomized controlled trial, Double-Blind Method, law, Outcome Assessment, Health Care, Clinical endpoint, medicine, Humans, Mobility Limitation, education, Adverse effect, Child, Preschool, Cholestenones, education.field_of_study, business.industry, Child, Preschool, Female, Neuroprotective Agents, Neurology (clinical), Clinical trial, 030104 developmental biology, chemistry, N/A, Olesoxime, business, 030217 neurology & neurosurgery
Abstract: Summary Background Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA. Methods This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3–25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in all patients who received one or more doses of the study drug. The trial is registered with ClinicalTrials.gov, number NCT01302600. Findings The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and −1·82 for placebo (treatment difference 2·00 points, 96% CI −0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment. Interpretation Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed. Funding AFM Telethon and Trophos SA.
Published: 2017

44. Characterization of pulmonary function in 10–18 year old patients with Duchenne muscular dystrophy

Author: Ulrike Schara, Diana Castro, T. Gidaro, S. Lutz, Ksenija Gorni, Janbernd Kirschner, Antonella Taglia, V. Doppler, F. Knipp, Christian Rummey, Jan J.G.M. Verschuuren, Thomas Meier, Gihan Tennekoon, J.J. Vílchez Padilla, E. Falcier, Luisa Politano, Craig M. McDonald, Chiara S. M. Straathof, S. Borell, S. Coopman, Matthew J. Will, Pierre-Yves Jeannet, Nathalie Goemans, Paolo Spagnolo, Jean-Marie Cuisset, Carsten G. Bönnemann, R.C. Richardson, G. Bernert, Thomas Sejersen, N. Muelas Gómez, Maria Grazia D'Angelo, Erika Brighina, Thomas Voit, S. Gandossini, Mika Leinonen, Susan T. Iannaccone, Oscar H. Mayer, Gunnar M. Buyse, Clemens Bloetzer, M. van den Hauwe, Susan D. Apkon, Richard S. Finkel, G. Buyse, P. D’Ambrosio, Erik K Henricson, Nanette C. Joyce, M. Hovmöller, Van den Hauwe, M, Meier, Thoma, Rummey, Christian, Leinonen, Mika, Spagnolo, Paolo, Mayer, Oscar H., Buyse, Gunnar M., Bernert, G., Knipp, F., Buyse, G. M., Goemans, N., Van den Hauwe, M., Voit, T., Doppler, V., Gidaro, T., Cuisset, J. -. M., Coopman, S., Schara, U., Lutz, S., Kirschner, J., Borell, S., Will, M., D'Angelo, M. G., Brighina, E., Gandossini, S., Gorni, K., Falcier, E., Politano, L., D'Ambrosio, P., Taglia, A., Verschuuren, J. J. G. M., Straathof, C. S. M., VÃlchez Padilla, J. J., Muelas GÃ³mez, N., Sejersen, T., Hovmã¶ller, M., Jeannet, P. -. Y., Bloetzer, C., Iannaccone, S., Castro, D., Tennekoon, G., Finkel, R., Bã¶nnemann, C., Mcdonald, C., Henricson, E., Joyce, N., Apkon, S., and Richardson, R. C.
Subjects: Duchenne muscular dystrophy, medicine.medical_specialty, Vital capacity, Adolescent, peak expiratory flow, Respiratory Tract Diseases, Medizin, Clinical Neurology, Pulmonary insufficiency, Placebo group, Pediatrics, Pulmonary function testing, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, forced vital capacity, Internal medicine, medicine, Humans, In patient, Genetics(clinical), Pediatrics, Perinatology, and Child Health, Longitudinal Studies, Muscular Dystrophy, Child, Genetics (clinical), Old patients, business.industry, pulmonary function, respiratory system, Perinatology and Child Health, medicine.disease, Duchenne, Cross-Sectional Studies, Muscular Dystrophy, Duchenne, Respiratory Function Tests, Pediatrics, Perinatology and Child Health, Neurology, Neurology (clinical), Surgery, respiratory tract diseases, 030228 respiratory system, Cardiology, business, 030217 neurology & neurosurgery, circulatory and respiratory physiology
Abstract: Pulmonary function loss in patients with Duchenne muscular dystrophy (DMD) is progressive and leads to pulmonary insufficiency. The purpose of this study in 10-18 year old patients with DMD is the assessment of the inter-correlation between pulmonary function tests (PFTs), their reliability and the association with the general disease stage measured by the Brooke score. Dynamic PFTs (peak expiratory flow [PEF], forced vital capacity [FVC], forced expiratory volume in one second [FEV1]) and maximum static airway pressures (MIP, MEP) were prospectively collected from 64 DMD patients enrolled in the DELOS trial (ClinicalTrials.gov, number NCT01027884). Baseline PEF percent predicted (PEF%p) was
Published: 2017

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

Author: Claude Cances, Jean-Marie Cuisset, Linda Lowes, Vincent Laugel, Laurent Servais, Teresa Gidaro, A. Chabanon, M. Annoussamy, Ulrike Schara, A. Daron, Omar Khwaja, Carole Vuillerot, Ricardo Hermosilla, J.Y. Hogrel, Andreea Mihaela Seferian, Nathalie Goemans, E. Gargaun, Yann Péréon, Pierre G. Carlier, and Christian Czech
Subjects: 0301 basic medicine, medicine.medical_specialty, Longitudinal data, business.industry, Medizin, Spinal muscular atrophy, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Physical medicine and rehabilitation, Neurology, Pediatrics, Perinatology and Child Health, Physical therapy, medicine, Neurology (clinical), business, 030217 neurology & neurosurgery, Genetics (clinical), Natural history study
Published: 2017

46. Amyotrophie spinale type 1 : enquête multicentrique des pratiques de soins et d’accompagnement palliatif sur deux périodes successives de 10ans

Author: Marcel-Louis Viallard, Stéphane Chabrier, M. Mayer, P. Beze-Beyrie, Cécile Laroche, C. Halbert, S. Sukno, Jean-Marie Cuisset, Carole Vuillerot, S. Quijano, A. Ledivenah, Christine Barnerias, S. Peudenier, Pascal Sabouraud, Claude Cances, Isabelle Desguerre, Brigitte Chabrol, and Brigitte Estournet
Subjects: Gynecology, medicine.medical_specialty, Oxygen inhalation therapy, Multicenter study, business.industry, Pediatrics, Perinatology and Child Health, medicine, Noninvasive ventilation, Exercise therapy, business
Abstract: Resume Etat actuel du probleme La place des soins palliatifs dans des pathologies neurodegeneratives de l’enfant a conduit la commission neuromusculaire de la Societe francaise de neuropediatrie a realiser une enquete a propos de l’amyotrophie spinale de type 1, pathologie genetique neuromusculaire le plus souvent lethale avant l’âge de 1 an. Materiel et methode Une enquete retrospective multicentrique aupres de neuropediatres integres dans des centres de reference des maladies neuromusculaires pediatriques a ete realisee sur deux periodes de 10 ans (1989–1998 et 1999–2009). Resultats La periode (1989–1998) avait inclus 12 centres avec 106 patients, la periode (1999–2009), 13 centres avec 116 enfants. La comparaison des donnees des deux periodes a revele une histoire naturelle de la maladie comparable : âge moyen d’apparition des premiers signes cliniques de 2,1 mois [0–5,5 mois], âge median au diagnostic de 4 mois [0–9 mois] versus (vs) 3 mois, âge median de deces de 7,5 mois [0–24 mois] vs 6 mois. Les modalites de soins avaient evolue avec des soins devenus plus actifs : kinesitherapie motrice (90 %), kinesitherapie respiratoire (93 %), les installations de confort (61 % vs 26 %), nutrition enterale par sonde gastrique (54 % vs 24 %). Les aides respiratoires au domicile etaient plus utilisees dans la seconde periode : aspiration nasopharyngee dans 64 % des cas (vs 41 %), oxygene dans 8 % et ventilation non invasive dans 7 %. Le delai moyen entre le diagnostic et le deces etait reste tres court : 4 mois vs 3 mois. Le deces avait eu lieu au domicile dans 23 % vs 17 % et dans un service de pediatrie pour 62 % vs 41 %. L’usage de traitements antalgiques et sedatifs au moment du deces etait rapporte dans 60 % des cas : morphiniques 40 % (vs 18 %), benzodiazepines 48 % (vs 29 %). Au moment du deces, le support respiratoire etait variable : oxygenotherapie (55 %), ventilation non invasive (9 %), ventilation mecanique assistee (2 %). Discussion et conclusion Ces resultats confirment une evolution de nos pratiques et le developpement des soins palliatifs chez l’enfant avec des positions differentes des standards de soins nord-americains et plus proches de la reflexion des equipes anglosaxonnes. Une etude prospective dans le cadre d’un Programme hospitalier de recherche clinique (PHRC) national 2011 a debute en juin 2012 impliquant les familles dans l’evaluation de ses soins.
Published: 2014

47. P.335Phenotypic and genomic characterization as predictors of DMD 45 to 55 multi-exon skipping therapy

Author: P. Laforêt, M. Guibaud, F. Leturcq, Bruno Eymard, G. Bassez, Karim Wahbi, M. Khran, Nicolas Lévy, A. Blesius, Jean-Marie Cuisset, R. Ben Yaou, Anne Boland, David Salgado, Guilhem Solé, M. Parent, Andoni Urtizberea, F. Pietri-Rouxel, M. Husson, Jean-François Deleuze, V. Tiffreau, and E. Gargaun
Subjects: Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Computational biology, Biology, Genetics (clinical), Exon skipping
Published: 2019

48. 21q21 deletion involving NCAM2: Report of 3 cases with neurodevelopmental disorders

Author: Florence Petit, Matthieu Decamp, Moira Blyth, Joris Andrieux, Ghislaine Plessis, Maria Pendlebury, and Jean-Marie Cuisset
Subjects: Male, Genetics, Chromosomes, Human, Pair 21, Developmental Disabilities, Neural Cell Adhesion Molecule L1, General Medicine, Biology, medicine.disease, Phenotype, Fasciculation, Child, Preschool, medicine, Humans, Autism, Female, Neural cell adhesion molecule, Chromosome Deletion, medicine.symptom, Child, Neural Cell Adhesion Molecules, Gene, Genetics (clinical), Genetic association, Comparative genomic hybridization
Abstract: Here we report three patients affected with neurodevelopmental disorders and harbouring 21q21 deletions involving NCAM2 gene. NCAM (Neural Cell Adhesion Molecule) proteins are involved in axonal migration, synaptic formation and plasticity. Poor axonal growth and fasciculation is observed in animal models deficient for NCAM2. Moreover, this gene has been proposed as a candidate for autism, based on genome-wide association studies. In this report, we provide a comprehensive molecular and phenotypical characterisation of three deletion cases giving additional clues for the involvement of NCAM2 in neurodevelopment.
Published: 2015

49. Intérêt de la biopsie musculaire chez l’enfant en 2012

Author: Louis Vallée, Jean-Marie Cuisset, N. Rouaix, Claude-Alain Maurage, A. Carpentier, G. Briand, and André Thevenon
Subjects: Pathology, medicine.medical_specialty, Muscle biopsy, medicine.diagnostic_test, business.industry, Metabolic myopathy, medicine.disease, Spinal muscular atrophies, Congenital myopathy, Mitochondrial respiratory chain, Neurology, Congenital muscular dystrophy, Medicine, Neurology (clinical), medicine.symptom, Muscular dystrophy, business, Myopathy
Abstract: Muscle biopsy is a mainstay diagnostic tool for investigating neuromuscular disorders in children. We report the yield of pediatric muscle biopsy in a population of 415 children by a retrospective study of 419 biopsies performed between 1/01/2000 and 31/12/2009 in a neuropediatric department, including mitochondrial respiratory chain analysis for 87 children. Two hundred and fifty-five biopsies were from boys (61%) 164 from girls (39%). Their mean age at biopsy was 6.5years; 155 (37%) biopsies were obtained before the child was 5years old. Final histopathological diagnoses were: congenital myopathy (n=193, including 15 structural congenital myopathies); progressive muscular dystrophy (n=75 [18%] including 57 dystrophinopathies); congenital muscular dystrophy (n=17, including six primary merosinopathies); dermatomyositis (n=11); spinal muscular atrophy (n=9, including six atypical spinal muscular atrophies); metabolic myopathy (n=32, including 19 mitochondrial myopathies); encephalomyopathy (n=53 [13%], including 27 with a mitochondrial respiratory chain defect). Pathological diagnosis remained undetermined in 16 cases. In 184 patients (44%), the muscle biopsy revealed specific histopathological anomalies (dystrophic process; specific ultrastructural abnormalities; perifascicular atrophy; neurogenic atrophy; metabolic anomalies) enabling a precise etiological diagnosis. For 85% of progressive muscular dystrophies, the biopsy resulted in a genetic diagnosis after identification of the protein defect. In 15% of the congenital myopathies, histopathological anomalies focused attention on one or several genes. Concerning dystrophinopathies, quantification of dystrophin deficiency on the biopsy specimen contributed to the definition of the clinical phenotype: Duchenne, or Becker. In children with a myopathy, muscle biopsy is often indispensable to establish the etiological diagnosis. Based on the results from this series, muscle biopsy can provide a precise orientation in 45% of patients, leading to a genetic hypothesis.
Published: 2013

50. The lung is involved in juvenile dermatomyositis

Author: Jean Marie Cuisset, Benoit Catteau, Antoine Deschildre, Caroline Thumerelle, Isabelle Tillie-Leblond, Guillaume Pouessel, C. Karila, Pierre Quartier, Muriel Le Bourgeois, and Véronique Nève
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Lung, business.industry, Interstitial lung disease, Aspiration pneumonia, medicine.disease, Surgery, Pulmonary function testing, medicine.anatomical_structure, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, Respiratory muscle, business, Prospective cohort study, Acute aspiration pneumonia, Juvenile dermatomyositis
Abstract: Background Juvenile dermatomyositis (JDM) is the main cause of chronic idiopathic inflammatory myopathy of autoimmune origin in children. The aim of this multicenter prospective study was to describe respiratory status and treatment of children followed for JDM. Methods and patients Clinical manifestations, pulmonary function tests (PFT), chest high-resolution computed tomography (HRCT) scan results, and treatments and their adverse effects were analyzed in children followed for JDM. Results Twenty-one patients (median age: 9.9 years; range: 20 months–18 years) were included. The median of disease duration at the time of the analysis was 3 years (range: 6 months–9 years 4 months). Overall 16 (76%) of 21 children presented with a respiratory involvement related to JDM including interstitial lung disease (n = 3) and/or respiratory muscle involvement (n = 7). Seven patients presented with other nonspecific manifestations. Three children had aspiration pneumonia. A chest HRCT was performed in 15 children, and abnormalities were observed in 12. PFT were performed in 20 of 21 patients. Seven showed functional abnormalities: restrictive ventilatory defect (n = 3) or obstructive ventilatory defect (n = 4). Six patients had abnormal respiratory muscle tests, including three with a restrictive ventilatory defect and one with an obstructive ventilatory defect. One other child with an acute aspiration pneumonia had a clearly muscle respiratory involvement but was too young to perform respiratory muscle tests and confirm this diagnosis. Treatment comprised systemic corticosteroid for all patients and adjuvant immunosuppressive therapy for 11. Adverse effects linked to treatment were reported in eight patients. Conclusion The frequency of lung involvement in children with JDM justifies systematic respiratory assessment with PFT including measures of respiratory muscle strength. We suggest that a chest HRCT scan is indicated in cases of respiratory symptoms and/or PFT abnormalities. Longitudinal studies are needed to assess pediatric characteristics, long-term outcomes, and responses to treatment taking into account the risk–benefit ratio. Pediatr Pulmonol. 2013; 48:1016–1025. © 2012 Wiley Periodicals, Inc.
Published: 2012

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

163 results on '"Jean-Marie Cuisset"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources