This study evaluates primary and secondary clinical outcome measures in Charcot-Marie-Tooth disease type 1A (CMT1A) with regard to their contribution towards discrimination of disease severity. The nine components of the composite Charcot-Marie-Tooth disease Neuropathy Score and six additional secondary clinical outcome measures were assessed in 479 adult patients with genetically proven CMT1A and 126 healthy controls. Using hierarchical clustering, we identified four significant clusters of patients according to clinical severity. We then tested the impact of each of the CMTNS components and of the secondary clinical parameters with regard to their power to differentiate these four clusters. The CMTNS components ulnar sensory nerve action potential (SNAP), pin sensibility, vibration and strength of arms did not increase the discriminant value of the remaining five CMTNS components (Ulnar compound motor action potential [CMAP], leg motor symptoms, arm motor symptoms, leg strength and sensory symptoms). However, three of the six additional clinical outcome measures - the 10m-timed walking test (T10MW), 9 hole-peg test (9HPT), and foot dorsal flexion dynamometry - further improved discrimination between severely and mildly affected patients. From these findings, we identified three different composite measures as score hypotheses and compared their discriminant power with that of the CMTNS. A composite of eight components CMAP, Motor symptoms legs, Motor symptoms arms, Strength of Legs, Sensory symptoms), displayed the strongest power to discriminate between the clusters. As a conclusion, five items from the CMTNS and three secondary clinical outcome measures improve the clinical assessment of patients with CMT1A significantly and are beneficial for upcoming clinical and therapeutic trials.

Catholic University Department of Neurosciences and Don Gnocchi Foundation Rome Italy

Charles University Prague 2nd Medical School and University Hospital Motol Prague Czech Republic

Clinic of Central and Peripheral Degenerative Neuropathies Unit Department of Clinical Neurosciences IRCCS Foundation C Besta Neurological Institute Milan Italy

Department of Biochemistry University of Zurich Zurich Switzerland

Department of Clinical Neurophysiology University Medical Center Göttingen Göttingen Germany

Department of Medical Statistics University Medical Center Göttingen Göttingen Germany

Department of Neurological Neuropsychological Morphological and Motor Sciences University of Verona Verona Italy

Department of Neurological Sciences Naples Italy

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

Department of Neurology Ophthalmology and Genetics University of Genoa and IRRCS San Martino IST Genoa Italy

Department of Neurosciences University of Messina and Clinical Centre NEMO SUD Fondazione Aurora Onlus Messina Italy

Department of Neurosciences University of Parma Parma Italy

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

Friedrich Baur Institute Department of Neurology Ludwig Maximilians Universität Munich Germany

Magna Graecia University Neurology Clinic and Neuroimaging Research Unit National Research Council Catanzaro Italy

Medizinisch Genetisches Zentrum Munich Germany

MRC Centre for Neuromuscular Diseases UCL Institute of Neurology National Hospital for Neurology Queen Square London WC1N 3BG UK

Research Group Molecular and Translational Neurology Department of Neurogenetics Max Planck Institute of Experimental Medicine Göttingen Germany

Service of Neurology University Hospital Marqués de Valdecilla UC and CIBERNED Santander Spain

Unit of Neuroepidemiology IRCCS Foundation C Besta Neurological Institute Milan Italy

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$a Selected items from the Charcot-Marie-Tooth (CMT) Neuropathy Score and secondary clinical outcome measures serve as sensitive clinical markers of disease severity in CMT1A patients / $c M. Mannil, A. Solari, A. Leha, AL. Pelayo-Negro, J. Berciano, B. Schlotter-Weigel, MC. Walter, B. Rautenstrauss, TJ. Schnizer, A. Schenone, P. Seeman, C. Kadian, O. Schreiber, NG. Angarita, GM. Fabrizi, F. Gemignani, L. Padua, L. Santoro, A. Quattrone, G. Vita, D. Calabrese, . , P. Young, M. Laurà, J. Haberlová, R. Mazanec, W. Paulus, T. Beissbarth, ME. Shy, MM. Reilly, D. Pareyson, MW. Sereda,

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$a This study evaluates primary and secondary clinical outcome measures in Charcot-Marie-Tooth disease type 1A (CMT1A) with regard to their contribution towards discrimination of disease severity. The nine components of the composite Charcot-Marie-Tooth disease Neuropathy Score and six additional secondary clinical outcome measures were assessed in 479 adult patients with genetically proven CMT1A and 126 healthy controls. Using hierarchical clustering, we identified four significant clusters of patients according to clinical severity. We then tested the impact of each of the CMTNS components and of the secondary clinical parameters with regard to their power to differentiate these four clusters. The CMTNS components ulnar sensory nerve action potential (SNAP), pin sensibility, vibration and strength of arms did not increase the discriminant value of the remaining five CMTNS components (Ulnar compound motor action potential [CMAP], leg motor symptoms, arm motor symptoms, leg strength and sensory symptoms). However, three of the six additional clinical outcome measures - the 10m-timed walking test (T10MW), 9 hole-peg test (9HPT), and foot dorsal flexion dynamometry - further improved discrimination between severely and mildly affected patients. From these findings, we identified three different composite measures as score hypotheses and compared their discriminant power with that of the CMTNS. A composite of eight components CMAP, Motor symptoms legs, Motor symptoms arms, Strength of Legs, Sensory symptoms), displayed the strongest power to discriminate between the clusters. As a conclusion, five items from the CMTNS and three secondary clinical outcome measures improve the clinical assessment of patients with CMT1A significantly and are beneficial for upcoming clinical and therapeutic trials.

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