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

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.