1. A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs)
- Author
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Nathalie Bonello-Palot, Chiara Pisciotta, Mario Sabatelli, Rita Horvath, Stefano C. Previtali, Alessandro Geroldi, Esra Battaloglu, Julian Blake, André Mégarbané, Raquel Guimarães-Costa, Matilde Laura, Alberto A. Zambon, Angelo Schenone, Lucio Santoro, Sabrina Sacconi, Philippe Latour, Yesim Parman, Michael E. Shy, Chiara Gemelli, Irene Tramacere, Sarah Leonard-Louis, Mounia Bellatache, Nicolas Lévy, Steven S. Scherer, Byung Ok Choi, Aldo Quattrone, S. Attarian, Tatsufumi Murakami, Lois Dankwa, Paola Valentino, David N. Herrmann, Marco Luigetti, Mary M. Reilly, Stefania Magri, Fiore Manganelli, Davide Pareyson, Meriem Tazir, Chelsea Bacon, Guilhem Solé, Alessandra Bolino, Tanya Stojkovic, Giulia Ricci, Pareyson, D., Stojkovic, T., Reilly, M. M., Leonard-Louis, S., Laura, M., Blake, J., Parman, Y., Battaloglu, E., Tazir, M., Bellatache, M., Bonello-Palot, N., Levy, N., Sacconi, S., Guimaraes-Costa, R., Attarian, S., Latour, P., Sole, G., Megarbane, A., Horvath, R., Ricci, G., Choi, B. -O., Schenone, A., Gemelli, C., Geroldi, A., Sabatelli, M., Luigetti, M., Santoro, L., Manganelli, F., Quattrone, A., Valentino, P., Murakami, T., Scherer, S. S., Dankwa, L., Shy, M. E., Bacon, C. J., Herrmann, D. N., Zambon, A., Tramacere, I., Pisciotta, C., Magri, S., Previtali, S. C., Bolino, A., CHU Pitié-Salpêtrière [AP-HP], 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), Sorbonne Université (SU), Service de Neurologie, CHU Mustapha, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), 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), CHU Nice, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Filière Neuromusculaire (FILNEMUS), Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, Centre de référence des maladies rares neuromusculaires Aquitaine-Grand Sud Ouest, CHU Bordeaux [Bordeaux], Unité de génétique médicale, Université Saint-Joseph de Beyrouth (USJ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jérôme Lejeune, CHU Trousseau [APHP], University of Pisa - Università di Pisa, Department of Neuroscience, Ophtalmology and Genetics, Genova, Università cattolica del Sacro Cuore [Roma] (Unicatt), Department of Neuroscience, Catholic University, Roma, University of Naples Federico II, Institute of Bioimaging and Molecular Physiology [Germaneto], National Research Council [Italy] (CNR), Istituto di Ricerche Farmacologiche 'Mario Negri', 20156 Milan, Human Inherited Neuropathies Unit, San Raffaele Scientific Institute-INSPE-Institute for Experimental Neurology, Dulbecco Telethon Institute, San Raffaele Scientific Institute, Bonello-Palot, Nathalie [0000-0002-8657-1271], Previtali, Stefano C [0000-0003-2546-4357], Bolino, Alessandra [0000-0002-8980-4878], Apollo - University of Cambridge Repository, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), and University of Naples Federico II = Università degli studi di Napoli Federico II
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Cord ,Adolescent ,Myotubularin ,Glaucoma ,Disease ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Charcot-Marie-Tooth Disease ,Internal medicine ,medicine ,Humans ,Young adult ,Child ,Loss function ,Retrospective Studies ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,business.industry ,hereditary neuropathies ,Retrospective cohort study ,Middle Aged ,Protein Tyrosine Phosphatases, Non-Receptor ,medicine.disease ,Phenotype ,3. Good health ,Settore MED/26 - NEUROLOGIA ,030104 developmental biology ,Neurology ,Child, Preschool ,Mutation ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
International audience; Objective Charcot-Marie-Tooth (CMT) disease 4B1 and 4B2 (CMT4B1/B2) are characterized by recessive inheritance, early onset, severe course, slowed nerve conduction, and myelin outfoldings. CMT4B3 shows a more heterogeneous phenotype. All are associated with myotubularin-related protein (MTMR) mutations. We conducted a multicenter, retrospective study to better characterize CMT4B. Methods We collected clinical and genetic data from CMT4B subjects in 18 centers using a predefined minimal data set including Medical Research Council (MRC) scores of nine muscle pairs and CMT Neuropathy Score. Results There were 50 patients, 21 of whom never reported before, carrying 44 mutations, of which 21 were novel and six representing novel disease associations of known rare variants. CMT4B1 patients had significantly more-severe disease than CMT4B2, with earlier onset, more-frequent motor milestones delay, wheelchair use, and respiratory involvement as well as worse MRC scores and motor CMT Examination Score components despite younger age at examination. Vocal cord involvement was common in both subtypes, whereas glaucoma occurred in CMT4B2 only. Nerve conduction velocities were similarly slowed in both subtypes. Regression analyses showed that disease severity is significantly associated with age in CMT4B1. Slopes are steeper for CMT4B1, indicating faster disease progression. Almost none of the mutations in the MTMR2 and MTMR13 genes, responsible for CMT4B1 and B2, respectively, influence the correlation between disease severity and age, in agreement with the hypothesis of a complete loss of function of MTMR2/13 proteins for such mutations. Interpretation This is the largest CMT4B series ever reported, demonstrating that CMT4B1 is significantly more severe than CMT4B2, and allowing an estimate of prognosis. ANN NEUROL 2019
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- 2019