A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs)

Davide Pareyson , Tanya Stojkovic (1, 2) , Mary M. Reilly , Sarah Leonard-Louis (2, 1, 3) , Matilde Laura , Julian Blake , Yesim Parman , Esra Battaloglu , Meriem Tazir (4) , Mounia Bellatache , Nathalie Bonello-Palot (5, 6) , Nicolas Levy (5, 6) , Sabrina Sacconi (7) , Raquel Guimaraes-Costa (8) , Shahram Attarian (5, 9) , Philippe Latour (10) , Guilhem Sole (11) , André Mégarbané (12, 13, 5) , Rita Horvath (14) , Giulia Ricci (15) , Byung-Ok Choi , Angelo Schenone (16) , Chiara Gemelli , Alessandro Geroldi , Mario Sabatelli (17) , Marco Luigetti (18) , Lucio Santoro (19) , Fiore Manganelli , Aldo Quattrone (20) , Paola Valentino , Tatsufumi Murakami , Steven S. Scherer , Lois Dankwa , Michael E. Shy , Chelsea J. Bacon , David N. Herrmann , Alberto Zambon , Irene Tramacere (21) , Chiara Pisciotta , Stefania Magri , Stefano C. Previtali , Alessandra Bolino (22, 23)

1 CHU Pitié-Salpêtrière [AP-HP]
2 Institut de Myologie
3 SU - Sorbonne Université
4 Service de Neurologie
5 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
6 Département de génétique médicale [Hôpital de la Timone - APHM]
7 CHU Nice
8 Institut de Myologie
9 FILNEMUS - Filière Neuromusculaire
10 CBPE - Centre de Biologie et Pathologie Est
11 Centre de référence des maladies rares neuromusculaires Aquitaine-Grand Sud Ouest
12 Unité de génétique médicale
13 Institut Jérôme Lejeune
14 CHU Trousseau [APHP]
15 University of Pisa - Università di Pisa
16 Department of Neuroscience, Ophtalmology and Genetics, Genova
17 Unicatt - Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma]
18 Department of Neuroscience, Catholic University, Roma
19 University of Naples Federico II = Università degli studi di Napoli Federico II
20 Institute of Bioimaging and Molecular Physiology [Germaneto]
21 Istituto di Ricerche Farmacologiche “Mario Negri”, 20156 Milan
22 Human Inherited Neuropathies Unit
23 Dulbecco Telethon Institute

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

Domaines: Génétique

Davide Pareyson, Tanya Stojkovic, Mary M. Reilly, Sarah Leonard-Louis, Matilde Laura, et al.. A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs). Annals of Neurology, 2019, 86 (1), pp.55-67. ⟨10.1002/ana.25500⟩. ⟨hal-02461442⟩