Background Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited neuropathy, a debilitating disease without known cure. Among patients with CMT1A, disease manifestation, progression and severity are strikingly variable, which poses major challenges for the development of new therapies. Hence, there is a strong need for sensitive outcome measures such as disease and progression biomarkers, which would add powerful tools to monitor therapeutic effects in CMT1A.
Methods We established a pan-European and American consortium comprising nine clinical centres including 311 patients with CMT1A in total. From all patients, the CMT neuropathy score and secondary outcome measures were obtained and a skin biopsy collected. In order to assess and validate disease severity and progression biomarkers, we performed qPCR on a set of 16 animal model-derived potential biomarkers in skin biopsy mRNA extracts.
Results In 266 patients with CMT1A, a cluster of eight cutaneous transcripts differentiates disease severity with a sensitivity and specificity of 90% and 76.1%, respectively. In an additional cohort of 45 patients with CMT1A, from whom a second skin biopsy was taken after 2–3 years, the cutaneous mRNA expression of GSTT2, CTSA, PPARG, CDA, ENPP1 and NRG1-Iis changing over time and correlates with disease progression.
Conclusions In summary, we provide evidence that cutaneous transcripts in patients with CMT1A serve as disease severity and progression biomarkers and, if implemented into clinical trials, they could markedly accelerate the development of a therapy for CMT1A.
- Charcot Marie Tooth disease 1A
- disease severity
- disease progression
- skin biopsy
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Contributors RF monitored data collection, supervised sample processing and qPCR analyses, drafted the statistical analysis plan, and wrote and revised the paper. He is guarantor. AL collected and curated all data, drafted the statistical analysis plan, analysed the data, and wrote and revised the paper. He is guarantor. MM implemented the biomarker trial and collected clinical data in Göttingen, Germany, and monitored collection of all clinical data. CE performed qPCR analyses. TB supervised statistical analyses. MM, AS, ALPN, JB, BSW, TJS, TP, NGA, DC, JH, RM, WP, MCW, CMT-TRIAAL, JYH, OD, AS, JB, PDJ, MES, RH, DP, PS, PY and MWS were involved in patient recruitment, patient assessment and skin biopsy sampling. MM, TJS, TP, DC, BSW, NGA, MCW, WP, PY and MWS implemented the study in Germany. AS, AS, DP and CMT-TRIAAL implemented the study in Italy. ALPN and JB implemented the study in Spain. JH, RM and PS implemented the study in the Czech Republic. JYH and OD implemented the study in France. JB and PDJ implemented the study in Belgium. RH implemented the study in the UK. MES implemented the study in the USA. MWS initiated, coordinated and supervised the biomarker study. He is guarantor.
Funding MWS was supported by the German Ministry of Education and Research (BMBF, CMT-BIO, FKZ: 01ES0812, CMT-NET, FKZ: 01GM1511C, CMT-NRG, ERA-NET ‘ERARE3’, FKZ: 01GM1605) and by the Association Francaise contre Les Myopathies (AFM, Nr: 15037). MWS holds a DFG Heisenberg Professorship (SE 1944/1-1). TP was supported by the European Leukodystrophie Society (ELA 2014-020I1 to MWS). JH and PS were supported by Ministry of Health of the Czech Republic grant AZV 16-30206A and DRO 00064203. JB and PDJ were supported by the Association Belge contre les Maladies Neuromusculaire (ABMM)-Aide à la Recherche ASBL and the EU FP7/2007-2013 under grant agreement number 2012-305121 (NEUROMICS). JB is also supported by a Senior Clinical Researcher mandate of the Research Fund-Flanders (FWO). DP and CMT-TRIAAL were supported by Telethon-UILDM (GUP04002, GUP05007) and AIFA (Italian Medicines Agency, FARM53APAH) grants in Italy.
Competing interests The authors declare no competing interests.
Patient consent Obtained.
Ethics approval All clinical centres involved obtained prior ethical approval of their local institutional review board and their respective regional ethics committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Collaborators The CMT-TRIAAL Group IRCCS Foundation, C. Besta Neurological Institute, Milan: C. Marchesi, E. Salsano, L. Nanetti, C. Marelli, V. Scaioli, C. Ciano, M. Rimoldi, G. Lauria, G. Ferrari, E. Rizzetto, F. Camozzi; Department of Neurology, Ophthalmology and Genetics, University of Genoa, Genoa: A. Schenone, E. Narciso, M. Grandis, M. Monti-Bragadin, L. Nobbio; Department of Neurological, Neuropsychological, Morphological and Motor Sciences, University of Verona, Verona: G.M. Fabrizi, T. Cavallaro, A. Casano, L. Bertolasi, I. Cabrini, K. Corrà, N. Rizzuto; Department of Neurological Sciences, Federico II University of Naples, Naples: L. Santoro, F. Manganelli, C. Pisciotta; Department of Neurology, “Salvatore Maugeri” Foundation, IRCCS, Telese Terme: M. Nolano; Department of Neurosciences, University of Messina, Messina: G. Vita, A. Mazzeo, R. Di Leo, G. Majorana, M. Russo;Magna Graecia University, Neurology Clinic, and Neuroimaging Research Unit, National Research Council, Catanzaro: A. Quattrone, P. Valentino, R. Nisticò, D. Pirritano, A. Lucisano, M. Canino; Institute of Neurology, Department of Neurosciences, Sacro Cuore Catholic University, and Don Gnocchi Foundation, Rome: L. Padua, C. Pazzaglia, G. Granata, M. Foschini.
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