학술논문
Phenotypic spectrum of myelin protein zero-related neuropathies: a large cohort study from five mutation clusters across Italy.
Document Type
Academic Journal
Author
Bertini A; Unità di Malattie Neurologiche Rare, Dipartimento di Neuroscienze Cliniche, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.; Gentile L; Unità di Neurologia e Malattie Neuromuscolari, Dipartimento di Medicina Clinica e Sperimentale, Università di Messina, Messina, Italy.; Cavallaro T; Dipartimento di Neuroscienze, Biomedicina e Movimento, Università di Verona, Verona, Italy.; Tozza S; Dipartimento di Neuroscienze, Scienze Riproduttive ed Odontostomatologiche, Università Federico II di Napoli, Naples, Italy.; Saveri P; Unità di Malattie Neurologiche Rare, Dipartimento di Neuroscienze Cliniche, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.; Russo M; Unità di Neurologia e Malattie Neuromuscolari, Dipartimento di Medicina Clinica e Sperimentale, Università di Messina, Messina, Italy.; Massucco S; Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze materno-infantili, Università di Genova, Genoa, Italy.; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.; Falzone YM; INSPE and Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.; Bellone E; Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze materno-infantili, Università di Genova, Genoa, Italy.; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.; Taioli F; Dipartimento di Neuroscienze, Biomedicina e Movimento, Università di Verona, Verona, Italy.; Geroldi A; Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze materno-infantili, Università di Genova, Genoa, Italy.; Occhipinti G; Unità di Neurologia e Malattie Neuromuscolari, Dipartimento di Medicina Clinica e Sperimentale, Università di Messina, Messina, Italy.; Ferrarini M; Dipartimento di Neuroscienze, Biomedicina e Movimento, Università di Verona, Verona, Italy.; Cavalca E; Unità di Malattie Neurologiche Rare, Dipartimento di Neuroscienze Cliniche, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.; Crivellari L; Unità di Malattie Neurologiche Rare, Dipartimento di Neuroscienze Cliniche, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.; Mandich P; Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze materno-infantili, Università di Genova, Genoa, Italy.; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.; Balistreri F; Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.; Magri S; Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.; Taroni F; Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.; Previtali SC; INSPE and Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.; Schenone A; Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze materno-infantili, Università di Genova, Genoa, Italy.; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.; Grandis M; Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze materno-infantili, Università di Genova, Genoa, Italy.; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.; Manganelli F; Dipartimento di Neuroscienze, Scienze Riproduttive ed Odontostomatologiche, Università Federico II di Napoli, Naples, Italy.; Fabrizi GM; Dipartimento di Neuroscienze, Biomedicina e Movimento, Università di Verona, Verona, Italy.; Mazzeo A; Unità di Neurologia e Malattie Neuromuscolari, Dipartimento di Medicina Clinica e Sperimentale, Università di Messina, Messina, Italy.; Pareyson D; Unità di Malattie Neurologiche Rare, Dipartimento di Neuroscienze Cliniche, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.; Pisciotta C; Unità di Malattie Neurologiche Rare, Dipartimento di Neuroscienze Cliniche, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy chiara.pisciotta@istituto-besta.it.
Source
Publisher: BMJ Publishing Group Country of Publication: England NLM ID: 2985191R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1468-330X (Electronic) Linking ISSN: 00223050 NLM ISO Abbreviation: J Neurol Neurosurg Psychiatry Subsets: MEDLINE
Subject
Language
English
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 (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.
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.
Competing Interests: Competing interests: GMF acknowledges donations from Pfizer to support research activities of his Research Unit, financial support from Akcea, Kedrion, Pfizer for participation in national and international meetings and from Akcea, Alnylam and Pharnext for participation in Advisory Boards; MG acknowledges donations from Sanofi Genzyme to support research activities of her Research Unit, financial support from Alnylam and Sanofi Genzyme for participation in national and international Meetings, participation in Advisory Board of Pfizer, speaker honorarium from Sanofi Genzyme; AM acknowledges financial support from Pfizer, Alnylam and Akcea for participation in national and international meetings, participation in Advisory Board of Pfizer, Alnylam and Akcea; DP acknowledges participation in Advisory Board of Inflectis, Alnylam, Akcea, Arvinas, Augustine Tx, DTx; ST is supported by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) - A multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022). AB, LG, TC, PS, MR, SM, YMF, EM, FT, AG, GO, MF, EC, LC, PM, FB, SM, FT, SCP, AS, FM, CP report no disclosure.
(© 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.)
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 (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.
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.
Competing Interests: Competing interests: GMF acknowledges donations from Pfizer to support research activities of his Research Unit, financial support from Akcea, Kedrion, Pfizer for participation in national and international meetings and from Akcea, Alnylam and Pharnext for participation in Advisory Boards; MG acknowledges donations from Sanofi Genzyme to support research activities of her Research Unit, financial support from Alnylam and Sanofi Genzyme for participation in national and international Meetings, participation in Advisory Board of Pfizer, speaker honorarium from Sanofi Genzyme; AM acknowledges financial support from Pfizer, Alnylam and Akcea for participation in national and international meetings, participation in Advisory Board of Pfizer, Alnylam and Akcea; DP acknowledges participation in Advisory Board of Inflectis, Alnylam, Akcea, Arvinas, Augustine Tx, DTx; ST is supported by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) - A multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022). AB, LG, TC, PS, MR, SM, YMF, EM, FT, AG, GO, MF, EC, LC, PM, FB, SM, FT, SCP, AS, FM, CP report no disclosure.
(© 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.)