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.

Center for Molecular Neurology VIB Antwerp Belgium Institute Born Bunge University of Antwerp Antwerpen Belgium Department of Neurology Antwerp University Hospital Antwerpen Belgium

CMT TRIAAL Milan Italy

Department of Child Neurology Charles University 2nd Medical School University Hospital Motol Prague Czech Republic

Department of Clinical Neurophysiology University Medical Center Göttingen Göttingen Germany

Department of Clinical Neurophysiology University Medical Center Göttingen Göttingen Germany Department of Neurogenetics Max Planck Institute of Experimental Medicine Göttingen Germany

Department of Clinical Neurosciences Unit of Neurological Rare Diseases of Adulthood IRCCS Foundation C Besta Neurological Institute Milan Italy

Department of Medical Statistics University Medical Center Göttingen Göttingen Germany

Department of Neurogenetics Max Planck Institute of Experimental Medicine Göttingen Germany

Department of Neurology Carver College of Medicine University of Iowa Iowa USA

Department of Neurology Ophthalmology and Genetics University of Genoa Genoa Italy

Department of Sleep Medicine and Neuromuscular Diseases University of Münster Münster Germany

Friedrich Baur Institut Department of Neurology Ludwig Maximilians University of Munich Munich Germany

Institute of Myology GH Pitié Salpêtrière Paris France

John Walton Muscular Dystrophy Research Centre Institute of Genetic Medicine Newcastle University UK

Service of Neurology University Hospital Marqués de Valdecilla Santander Spain

Unit of Neuroepidemiology IRCCS Foundation C Besta Neurological Institute Milan Italy

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$a Fledrich, Robert $u Department of Clinical Neurophysiology, University Medical Center Göttingen (UMG), Göttingen, Germany. Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

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$a Biomarkers predict outcome in Charcot-Marie-Tooth disease 1A / $c R. Fledrich, M. Mannil, A. Leha, C. Ehbrecht, A. Solari, AL. Pelayo-Negro, J. Berciano, B. Schlotter-Weigel, TJ. Schnizer, T. Prukop, N. Garcia-Angarita, D. Czesnik, J. Haberlová, R. Mazanec, W. Paulus, T. Beissbarth, MC. Walter, C. Triaal, JY. Hogrel, O. Dubourg, A. Schenone, J. Baets, P. De Jonghe, ME. Shy, R. Horvath, D. Pareyson, P. Seeman, P. Young, MW. Sereda,

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$a 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.

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$a Mannil, Manoj $u Department of Clinical Neurophysiology, University Medical Center Göttingen (UMG), Göttingen, Germany. Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

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$a Leha, Andreas $u Department of Medical Statistics, University Medical Center Göttingen (UMG), Göttingen, Germany.

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$a Berciano, José $u Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria, and "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain.

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$a De Jonghe, Peter $u Center for Molecular Neurology, VIB, Antwerp, Belgium. Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium. Department of Neurology, Antwerp University Hospital, Antwerpen, Belgium.

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$a Sereda, Michael W $u Department of Clinical Neurophysiology, University Medical Center Göttingen (UMG), Göttingen, Germany. Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

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