Background We 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. Methods We 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. Results We 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 (Delta CMTES/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 (Delta CMTES/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. Conclusions This 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.
Phenotypic spectrum of myelin protein zero-related neuropathies: a large cohort study from five mutation clusters across Italy
Cavallaro, Tiziana;Taioli, Federica;Ferrarini, Moreno;Fabrizi, Gian Maria;
2025-01-01
Abstract
Background We 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. Methods We 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. Results We 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 (Delta CMTES/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 (Delta CMTES/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. Conclusions This 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.
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