• Alessandro Bertini, Luca Gentile, Tiziana Cavallaro, Stefano Tozza, Paola Saveri, Massimo Russo, Sara Massucco, Yuri Matteo Falzone, Emilia Bellone, Federica Taioli, Alessandro Geroldi, Giuseppe Occhipinti, Moreno Ferrarini, Eleonora Cavalca, Luca Crivellari, Paola Mandich, Francesca Balistreri, Stefania Magri, Franco Taroni, Stefano Carlo Previtali, Angelo Schenone, Marina Grandis, Fiore Manganelli, Gian Maria Fabrizi, Anna Mazzeo, Davide Pareyson, and Chiara Pisciotta.
• Unità di Malattie Neurologiche Rare, Dipartimento di Neuroscienze Cliniche, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
• J. Neurol. Neurosurg. Psychiatr. 2024 Jun 5.

BackgroundWe aimed to investigate the clinical features of a large cohort of patients with myelin protein zero (MPZ)-related neuropathy, focusing on the five main mutation clusters across Italy.MethodsWe retrospectively gathered a minimal data set of clinical information in a series of patients with these frequent mutations recruited among Italian Charcot-Marie-Tooth (CMT) registry centres, including disease onset/severity (CMTES-CMT Examination Score), motor/sensory symptoms and use of orthotics/aids.ResultsWe collected data from 186 patients: 60 had the p.Ser78Leu variant ('classical' CMT1B; from Eastern Sicily), 42 the p.Pro70Ser (CMT2I; mainly from Lombardy), 38 the p.Thr124Met (CMT2J; from Veneto), 25 the p.Ser44Phe (CMT2I; from Sardinia) and 21 the p.Asp104ThrfsX13 (mild CMT1B; from Apulia) mutation. Disease severity (CMTES) was higher (p<0.001) in late-onset axonal forms (p.Thr124Met=9.2±6.6; p.Ser44Phe=7.8±5.7; p.Pro70Ser=7.6±4.8) compared with p.Ser78Leu (6.1±3.5) patients. Disease progression (ΔCMTES/year) was faster in the p.Pro70Ser cohort (0.8±1.0), followed by p.Ser44Phe (0.7±0.4), p.Thr124Met (0.4±0.5) and p.Ser78Leu (0.2±0.4) patients. Disease severity (CMTES=1.2±1.5), progression (ΔCMTES/year=0.1±0.4) and motor involvement were almost negligible in p.Asp104ThrfsX13 patients, who, however, frequently (78%, p<0.001) complained of neuropathic pain. In the other four clusters, walking difficulties were reported by 69-85% of patients, while orthotic and walking aids use ranged between 40-62% and 16-28%, respectively.ConclusionsThis is the largest MPZ (and late-onset CMT2) cohort ever collected, reporting clinical features and disease progression of 186 patients from five different clusters across Italy. Our findings corroborate the importance of differentiating between 'classical' childhood-onset demyelinating, late-onset axonal and mild MPZ-related neuropathy, characterised by different pathomechanisms, in view of different therapeutic targets.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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