title: 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.
abstract: 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.
authors.affiliation: Research Group "Molecular and Translational Neurology", Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Manoj
authors.initials: M
authors.lastname: Mannil
authors.affiliation: Unit of Neuroepidemiology, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Solari
authors.affiliation: Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Leha
authors.affiliation: Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", UC and CIBERNED, Santander, Spain.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Pelayo-Negro
authors.affiliation: Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", UC and CIBERNED, Santander, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Berciano
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Schlotter-Weigel
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Maggie C
authors.initials: MC
authors.lastname: Walter
authors.affiliation: Medizinisch Genetisches Zentrum, Munich, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Rautenstrauss
authors.affiliation: Research Group "Molecular and Translational Neurology", Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Tuuli J
authors.initials: TJ
authors.lastname: Schnizer
authors.affiliation: Department of Neurology, Ophthalmology and Genetics, University of Genoa, and IRRCS San Martino-IST, Genoa, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Schenone
authors.affiliation: Charles University in Prague, 2nd Medical School and University Hospital Motol, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Seeman
authors.affiliation: Department of Biochemistry, University of Zurich, Zurich, Switzerland.
authors.forename: Chandini
authors.initials: C
authors.lastname: Kadian
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Olivia
authors.initials: O
authors.lastname: Schreiber
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Natalia G
authors.initials: NG
authors.lastname: Angarita
authors.affiliation: Department of Neurological, Neuropsychological, Morphological and Motor Sciences, University of Verona, Verona, Italy.
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Fabrizi
authors.affiliation: Department of Neurosciences, University of Parma, Parma, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Gemignani
authors.affiliation: Catholic University, Department of Neurosciences and Don Gnocchi Foundation, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Padua
authors.affiliation: Department of Neurological Sciences, Naples, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Santoro
authors.affiliation: Magna Graecia University, Neurology Clinic, and Neuroimaging Research Unit, National Research Council, Catanzaro, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Quattrone
authors.affiliation: Department of Neurosciences, University of Messina, and Clinical Centre NEMO SUD, Fondazione Aurora Onlus, Messina, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Vita
authors.affiliation: Clinic of Central and Peripheral Degenerative Neuropathies Unit, Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Calabrese
authors.affiliation: Department of Sleep Medicine and Neuromuscular Disorders, University of Münster, Münster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Young
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, National Hospital for Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Matilde
authors.initials: M
authors.lastname: Laurà
authors.affiliation: Charles University in Prague, 2nd Medical School and University Hospital Motol, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Haberlová
authors.affiliation: Charles University in Prague, 2nd Medical School and University Hospital Motol, Prague, Czech Republic.
authors.forename: Radim
authors.initials: R
authors.lastname: Mazanec
authors.affiliation: Department of Clinical Neurophysiology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Paulus
authors.affiliation: Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Beissbarth
authors.affiliation: Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Shy
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, National Hospital for Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.affiliation: Clinic of Central and Peripheral Degenerative Neuropathies Unit, Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute, Milan, Italy. Electronic address: davide.pareyson@istituto-besta.it.
authors.forename: Davide
authors.initials: D
authors.lastname: Pareyson
authors.affiliation: Department of Clinical Neurophysiology, University Medical Center Göttingen, Göttingen, Germany; Research Group "Molecular and Translational Neurology", Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany. Electronic address: sereda@em.mpg.de.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sereda
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000975:Antioxidants / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000627:therapeutic use*; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000628:therapy; D016000:Cluster Analysis; D015331:Cohort Studies; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D053580:Muscle Strength; D017063:Outcome Assessment, Health Care; D010147:Pain Measurement; D011597:Psychomotor Performance / Q000502:physiology; D012720:Severity of Illness Index; D016138:Walking; D055815:Young Adult
chemical_list: D000975:Antioxidants; D001205:Ascorbic Acid
keywords: CMT1A; CMTNS; Charcot-Marie-Tooth; HMSN; Score generation; Secondary clinical outcome measures