Journal article
A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs)
Annals of Neurology, Vol.86(1), pp.55-67
2019
DOI: 10.1002/ana.25500
PMID: 31070812
Abstract
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
Details
- Title: Subtitle
- A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs)
- Creators
- Davide PareysonTanya Stojkovic - CHU Pitié-Salpêtrière [AP-HP]Mary M ReillySarah Leonard-Louis - Institut de MyologieMatilde LauraJulian BlakeYesim ParmanEsra BattalogluMeriem Tazir - Service de NeurologieMounia BellatacheNathalie Bonello-Palot - Marseille medical genetics - Centre de génétique médicale de MarseilleNicolas Levy - Marseille medical genetics - Centre de génétique médicale de MarseilleSabrina Sacconi - CHU NiceRaquel Guimaraes-Costa - Institut de MyologieShahram Attarian - Marseille medical genetics - Centre de génétique médicale de MarseillePhilippe Latour - Centre de Biologie et Pathologie EstGuilhem Sole - Centre de référence des maladies rares neuromusculaires Aquitaine-Grand Sud OuestAndré Mégarbané - Unité de génétique médicaleRita Horvath - CHU Trousseau [APHP]Giulia Ricci - University of Pisa - Università di PisaByung-Ok ChoiAngelo Schenone - Department of Neuroscience, Ophtalmology and Genetics, GenovaChiara GemelliAlessandro GeroldiMario Sabatelli - Università Cattolica del Sacro Cuore [Roma]Marco Luigetti - Department of Neuroscience, Catholic University, RomaLucio Santoro - University of Naples Federico IIFiore ManganelliAldo Quattrone - Institute of Bioimaging and Molecular Physiology [Germaneto]Paola ValentinoTatsufumi MurakamiSteven S SchererLois DankwaMichael E ShyChelsea J BaconDavid N HerrmannAlberto ZambonIrene Tramacere - Istituto di Ricerche Farmacologiche “Mario Negri”, 20156 MilanChiara PisciottaStefania MagriStefano C PrevitaliAlessandra Bolino - Human Inherited Neuropathies Unit
- Resource Type
- Journal article
- Publication Details
- Annals of Neurology, Vol.86(1), pp.55-67
- DOI
- 10.1002/ana.25500
- PMID
- 31070812
- NLM abbreviation
- Ann Neurol
- ISSN
- 0364-5134
- eISSN
- 1531-8249
- Grant note
- DOI: 10.13039/100002108, name: Friedreich's Ataxia Research Alliance, award: 1R01DK115687‐01A1; DOI: 10.13039/501100000265, name: Medical Research Council, award: MR/N025431/1; DOI: 10.13039/501100003725, name: National Research Foundation of Korea, award: NRF‐2017R1A2B2004699; DOI: 10.13039/100002721, name: Charcot-Marie-Tooth Association; DOI: 10.13039/501100000781, name: European Research Council, award: 309548; DOI: 10.13039/100005202, name: Muscular Dystrophy Association, award: MDA510281, MDA574294; DOI: 10.13039/501100002426, name: Telethon Foundation, award: GGP15012A; DOI: 10.13039/501100003196, name: Ministry of Health, Italy, award: GR‐2016‐02363337, RF‐2011‐02347127, RF‐2016‐02361246; DOI: 10.13039/100004440, name: Wellcome Trust, award: 201064/Z/16/Z
- Language
- English
- Date published
- 2019
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984070293302771
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