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

Davide Pareyson, Tanya Stojkovic, Mary M. Reilly, Sarah Leonard-Louis, Matilde Laurà, Julian Blake, Yesim Parman, Esra Battaloglu, Meriem Tazir, Mounia Bellatache, Nathalie Bonello-Palot, Nicolas Lévy, Sabrina Sacconi, Raquel Guimarães-Costa, Sharham Attarian, Philippe Latour, Guilhem Solé, André Megarbane, Rita Horvath, Giulia Ricci & 22 others Byung Ok Choi, Angelo Schenone, Chiara Gemelli, Alessandro Geroldi, Mario Sabatelli, Marco Luigetti, Lucio Santoro, Fiore Manganelli, Aldo Quattrone, Paola Valentino, Tatsufumi Murakami, Steven S. Scherer, Lois Dankwa, Michael E. Shy, Chelsea J. Bacon, David N. Herrmann, Alberto Zambon, Irene Tramacere, Chiara Pisciotta, Stefania Magri, Stefano C. Previtali, Alessandra Bolino

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)55-67
Number of pages13
JournalAnnals of Neurology
Volume86
Issue number1
DOIs
Publication statusPublished - Jul 1 2019

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Multicenter Studies
Retrospective Studies
Mutation
Proteins
Neural Conduction
Biomedical Research
Tooth
Charcot-Marie-Tooth Disease
Type 4B1 Charcot-Marie-Tooth disease
myotubularin
Wheelchairs
Vocal Cords
Myelin Sheath
Glaucoma
Disease Progression
Regression Analysis
Phenotype
Muscles
Genes
Type 4B2 Charcot-Marie-Tooth disease

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs). / Pareyson, Davide; Stojkovic, Tanya; Reilly, Mary M.; Leonard-Louis, Sarah; Laurà, Matilde; Blake, Julian; Parman, Yesim; Battaloglu, Esra; Tazir, Meriem; Bellatache, Mounia; Bonello-Palot, Nathalie; Lévy, Nicolas; Sacconi, Sabrina; Guimarães-Costa, Raquel; Attarian, Sharham; Latour, Philippe; Solé, Guilhem; Megarbane, André; Horvath, Rita; Ricci, Giulia; Choi, Byung Ok; Schenone, Angelo; Gemelli, Chiara; Geroldi, Alessandro; Sabatelli, Mario; Luigetti, Marco; Santoro, Lucio; Manganelli, Fiore; Quattrone, Aldo; Valentino, Paola; Murakami, Tatsufumi; Scherer, Steven S.; Dankwa, Lois; Shy, Michael E.; Bacon, Chelsea J.; Herrmann, David N.; Zambon, Alberto; Tramacere, Irene; Pisciotta, Chiara; Magri, Stefania; Previtali, Stefano C.; Bolino, Alessandra.

In: Annals of Neurology, Vol. 86, No. 1, 01.07.2019, p. 55-67.

Research output: Contribution to journalArticle

Pareyson, D, Stojkovic, T, Reilly, MM, Leonard-Louis, S, Laurà, M, Blake, J, Parman, Y, Battaloglu, E, Tazir, M, Bellatache, M, Bonello-Palot, N, Lévy, N, Sacconi, S, Guimarães-Costa, R, Attarian, S, Latour, P, Solé, G, Megarbane, A, Horvath, R, Ricci, G, Choi, BO, Schenone, A, Gemelli, C, Geroldi, A, Sabatelli, M, Luigetti, M, Santoro, L, Manganelli, F, Quattrone, A, Valentino, P, Murakami, T, Scherer, SS, Dankwa, L, Shy, ME, Bacon, CJ, Herrmann, DN, Zambon, A, Tramacere, I, Pisciotta, C, Magri, S, Previtali, SC & Bolino, A 2019, '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, no. 1, pp. 55-67. https://doi.org/10.1002/ana.25500
Pareyson, Davide ; Stojkovic, Tanya ; Reilly, Mary M. ; Leonard-Louis, Sarah ; Laurà, Matilde ; Blake, Julian ; Parman, Yesim ; Battaloglu, Esra ; Tazir, Meriem ; Bellatache, Mounia ; Bonello-Palot, Nathalie ; Lévy, Nicolas ; Sacconi, Sabrina ; Guimarães-Costa, Raquel ; Attarian, Sharham ; Latour, Philippe ; Solé, Guilhem ; Megarbane, André ; Horvath, Rita ; Ricci, Giulia ; Choi, Byung Ok ; Schenone, Angelo ; Gemelli, Chiara ; Geroldi, Alessandro ; Sabatelli, Mario ; Luigetti, Marco ; Santoro, Lucio ; Manganelli, Fiore ; Quattrone, Aldo ; Valentino, Paola ; Murakami, Tatsufumi ; Scherer, Steven S. ; Dankwa, Lois ; Shy, Michael E. ; Bacon, Chelsea J. ; Herrmann, David N. ; Zambon, Alberto ; Tramacere, Irene ; Pisciotta, Chiara ; Magri, Stefania ; Previtali, Stefano C. ; Bolino, Alessandra. / A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs). In: Annals of Neurology. 2019 ; Vol. 86, No. 1. pp. 55-67.
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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.",
author = "Davide Pareyson and Tanya Stojkovic and Reilly, {Mary M.} and Sarah Leonard-Louis and Matilde Laur{\`a} and Julian Blake and Yesim Parman and Esra Battaloglu and Meriem Tazir and Mounia Bellatache and Nathalie Bonello-Palot and Nicolas L{\'e}vy and Sabrina Sacconi and Raquel Guimar{\~a}es-Costa and Sharham Attarian and Philippe Latour and Guilhem Sol{\'e} and Andr{\'e} Megarbane and Rita Horvath and Giulia Ricci and Choi, {Byung Ok} and Angelo Schenone and Chiara Gemelli and Alessandro Geroldi and Mario Sabatelli and Marco Luigetti and Lucio Santoro and Fiore Manganelli and Aldo Quattrone and Paola Valentino and Tatsufumi Murakami and Scherer, {Steven S.} and Lois Dankwa and Shy, {Michael E.} and Bacon, {Chelsea J.} and Herrmann, {David N.} and Alberto Zambon and Irene Tramacere and Chiara Pisciotta and Stefania Magri and Previtali, {Stefano C.} and Alessandra Bolino",
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T1 - A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs)

AU - Pareyson, Davide

AU - Stojkovic, Tanya

AU - Reilly, Mary M.

AU - Leonard-Louis, Sarah

AU - Laurà, Matilde

AU - Blake, Julian

AU - Parman, Yesim

AU - Battaloglu, Esra

AU - Tazir, Meriem

AU - Bellatache, Mounia

AU - Bonello-Palot, Nathalie

AU - Lévy, Nicolas

AU - Sacconi, Sabrina

AU - Guimarães-Costa, Raquel

AU - Attarian, Sharham

AU - Latour, Philippe

AU - Solé, Guilhem

AU - Megarbane, André

AU - Horvath, Rita

AU - Ricci, Giulia

AU - Choi, Byung Ok

AU - Schenone, Angelo

AU - Gemelli, Chiara

AU - Geroldi, Alessandro

AU - Sabatelli, Mario

AU - Luigetti, Marco

AU - Santoro, Lucio

AU - Manganelli, Fiore

AU - Quattrone, Aldo

AU - Valentino, Paola

AU - Murakami, Tatsufumi

AU - Scherer, Steven S.

AU - Dankwa, Lois

AU - Shy, Michael E.

AU - Bacon, Chelsea J.

AU - Herrmann, David N.

AU - Zambon, Alberto

AU - Tramacere, Irene

AU - Pisciotta, Chiara

AU - Magri, Stefania

AU - Previtali, Stefano C.

AU - Bolino, Alessandra

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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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