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Multicenter Study
. 2025 Feb;32(2):e70084.
doi: 10.1111/ene.70084.

Disease Progression in Charcot-Marie-Tooth Disease Type 4B (CMT4B) Associated With Mutations in Myotubularin-Related Proteins 2 and 13

Alessandro Bertini  1 , Mary M Reilly  2 , Chiara Pisciotta  1 , Stefano C Previtali  3   4 , Yesim Parman  5 , Esra Battaloglu  6 , Matilde Laurà  2 , Julian Blake  2   7 , Sabrina Sacconi  8 , Shahram Attarian  9 , Tanya Stojkovic  10 , Mounia Bellatache  11 , Sonia Nouioua  11 , Meriem Tazir  11 , Arman Cakar  5 , Antonio Gambardella  12 , Paola Valentino  12 , Richard A Lewis  13 , Rita Horvath  14 , Alberto A Zambon  3   4 , Mario Sabatelli  15 , Marco Luigetti  16   17 , Stefano Tozza  18 , Fiore Manganelli  18 , David N Herrmann  19 , Steven S Scherer  20 , Nicole Kressin  21 , Kailee Ward  21 , Alessandra Bolino  3   22 , Michael E Shy  21 , Davide Pareyson  1 ; CMT4B Study Group; Inherited Neuropathy Consortium
Collaborators, Affiliations
Multicenter Study

Disease Progression in Charcot-Marie-Tooth Disease Type 4B (CMT4B) Associated With Mutations in Myotubularin-Related Proteins 2 and 13

Alessandro Bertini et al. Eur J Neurol. 2025 Feb.

Abstract

Background and aims: In 2019, we conducted a cross-sectional study, collecting information on 50 patients with CMT4B, an ultrarare CMT subtype, to better define the clinical phenotype. We now aimed at investigating disease progression in 26 patients with CMT4B1/CMT4B2, recruited from the previous study and among the Inherited Neuropathy Consortium.

Materials and methods: We retrospectively analysed disease progression in patients with CMT4B1/CMT4B2, collecting MRC scores from nine muscle pairs, Charcot-Marie-Tooth Examination Score (CMTES), and a minimal dataset of clinical information (walking difficulties, aids dependency, upper limb impairment, cranial nerves involvement) at baseline and follow-up visits. Thirteen centres from four continents were involved.

Results: Thirteen CMT4B1 and 13 CMT4B2 patients were followed up for 7.1 ± 4.9 and 7.9 ± 4.5 years, respectively. During follow-up, walking aid dependency increased: two CMT4B1 patients adopted AFOs (overall 11/12 at follow-up), and one started using wheelchair (6/12 at follow-up) at the age of 19; among CMT4B2 patients, two more required unilateral support in walking (4/11 at follow-up) by the age of 33 and 49 years, respectively. We found that disease progression, as measured by CMTES, was faster in CMT4B1 as compared to CMT4B2 patients (ΔCMTES/year 0.7 vs. 0.3, p = 0.037) but tended to slow down over time as burden of disease increased. At the end of follow-up, CMT4B1 was associated to higher disability.

Conclusions: This international collective effort enabled collection of relevant data for characterizing natural history and estimating disease progression of CMT4B1/CMT4B2 ultrarare diseases, aiming at improving their management and paving the way for designing future clinical trials.

Keywords: CMT4B; Charcot‐Marie‐Tooth disease; neuromuscular.

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Conflict of interest statement

M.L. received financial grants (honoraria and speaking) from Ackea, Alnylam, AstraZeneca, Sobi, and Pfizer, and travel grants from Ackea, Alnylam, Sobi, Pfizer, Kedrion, and Grifols. S.S.S. actively serves as a consultant to Applied Therapeutics, Novartis, and Toray Industries and has research support from the National Institutes of Health, Muscular Dystrophy Association, and the Charcot‐Marie‐Tooth Association, and Applied Therapeutics. D.P. acknowledges payments or reimbursement for consultancy and participation in Advisory Boards of Inflectis, Alnylam, Akcea, Arvinas, Augustine Tx, DTx, speaker honorarium from Alnylam, participation as local PI in clinical trials sponsored by Alnylam, Ionis, AT Therapeutics, Nido‐Biosciences. S.S. acknowledges payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Lupin, Fulcrum therapeutics, payment for expert testimony from Alexys, Ology, support for attending meetings and/or travel from Biogen, Sanofi, UCB, and Fulcrum therapeutics. A. Bertini., M.M.R., C.P., S.C.P., Y.P., E.B., M.L., J.B., S.A., T.S., M.B., S.N., M.T., A.G., P.V., R.A.L., R.H., A.A.Z., M.S., S.T., F.M., D.N.H., N.K., K.W., A. Bolino., and M.E.S. have no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Disease progression, assessed through CMTES (A, B) and MRC‐Total score (C, D) variation over follow‐up time in CMT4B1 (n = 11 and n = 12, respectively)* and CMT4B2 (n = 12 and n = 9, respectively)§ patients. bl = baseline; F‐up = follow‐up; hom = homozygous; yr. = year; yrs. = years; rs = Spearman rank correlation. *Data on CMTES progression missing for two patients with CMT4B1 and one with CMT4B2. §Data on MRC‐Total score variation missing for one patient with CMT4B1 and four with CMT4B2. (Box A–D) Age at baseline is reported on the right side of each box. Red arrow indicates the CMT4B1 patient carrying homozygous p.R628Pfs*18 mutation, exhibiting milder phenotype and negligible progression (ΔCMTES/year = 0; ΔMRC‐Total score/year = −0.5) over time.
See this image and copyright information in PMC

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