title: Biological and clinical characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) cohort: a cross-sectional analysis of baseline data.
abstract: BACKGROUND
  Friedreich's ataxia is a rare autosomal recessive neurodegenerative disorder. Here we report cross-sectional baseline data to establish the biological and clinical characteristics for a prospective, international, European Friedreich's ataxia database registry.
  
  
  METHODS
  Within the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) framework, we assessed a cohort of patients with genetically confirmed Friedreich's ataxia. The primary outcome measure was the Scale for the Assessment and Rating of Ataxia (SARA) and secondary outcome measures were the Inventory of Non-Ataxia Signs (INAS), the performance-based coordination test Spinocerebellar Ataxia Functional Index (SCAFI), the neurocognitive phonemic verbal fluency test, and two quality-of-life measures: the activities of daily living (ADL) part of the Friedreich's Ataxia Rating Scale and EQ-5D. The Friedreich's ataxia cohort was subdivided into three groups: early disease onset (≤14 years), intermediate onset (15-24 years), and late onset (≥25 years), which were compared for clinical characteristics and outcome measures. We used linear regression analysis to estimate the annual decline of clinical outcome measures based on disease duration. This study is registered with ClinicalTrials.gov, number NCT02069509.
  
  
  RESULTS
  We enrolled 592 patients with genetically confirmed Friedreich's ataxia between Sept 15, 2010, and April 30, 2013, at 11 sites in seven European countries. Age of disease onset was inversely correlated with the number of GAA repeats in the frataxin (FXN) gene: every 100 GAA repeats on the smaller repeat allele was associated with a 2·3 year (SE 0·2) earlier onset. Regression analyses showed significant estimated annual worsening of SARA (regression coefficient 0·86 points [SE 0·05], INAS (0·14 points [0·01]), SCAFI Z scores (-0·09 [0·01]), verbal fluency (-0·34 words [0·07]), and ADL (0·64 points [0·04]) during the first 25 years of disease; the regression slope for health-related quality-of-life state from EQ-5D was not significant (-0·33 points [0·18]). For SARA, the predicted annual rate of worsening was significantly higher in early-onset patients (n=354; 1·04 points [0·13]) and intermediate-onset patients (n=137; 1·17 points [0·22]) than in late-onset patients (n=100; 0·56 points [0·10]).
  
  
  CONCLUSIONS
  The results of this cross-sectional baseline analysis of the EFACTS cohort suggest that earlier disease onset is associated with larger numbers of GAA repeats and more rapid disease progression. The differential estimated progression of ataxia symptoms related to age of onset have implications for the design of clinical trials in Friedreich's ataxia, for which SARA might be the most suitable measure to monitor disease progression.
  
  
  BACKGROUND
  European Commission.
authors.affiliation: Department of Neurology, University Hospital Rheinisch-Westfälische Technische Hochschule [RWTH], Aachen, Aachen, Germany; Centre for Rare Diseases, University Hospital Rheinisch-Westfälische Technische Hochschule [RWTH], Aachen, Aachen, Germany; JARA-Translational Brain Medicine, Jülich and Aachen, Germany; Institute of Neuroscience and Medicine 4, Research Centre Jülich, Jülich, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Reetz
authors.affiliation: Department of Neurology, University Hospital Rheinisch-Westfälische Technische Hochschule [RWTH], Aachen, Aachen, Germany; JARA-Translational Brain Medicine, Jülich and Aachen, Germany; Institute of Neuroscience and Medicine 4, Research Centre Jülich, Jülich, Germany.
authors.forename: Imis
authors.initials: I
authors.lastname: Dogan
authors.affiliation: Department of Neurology, University Hospital Rheinisch-Westfälische Technische Hochschule [RWTH], Aachen, Aachen, Germany; JARA-Translational Brain Medicine, Jülich and Aachen, Germany.
authors.forename: Ana S
authors.initials: AS
authors.lastname: Costa
authors.affiliation: Department of Neurology, University Hospital Rheinisch-Westfälische Technische Hochschule [RWTH], Aachen, Aachen, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Dafotakis
authors.affiliation: Department of Neurology, University Hospital Rheinisch-Westfälische Technische Hochschule [RWTH], Aachen, Aachen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Fedosov
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Giunti
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Parkinson
authors.affiliation: Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Mariotti
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Panzeri
authors.affiliation: Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Nanetti
authors.affiliation: Reference Unit of Hereditary Ataxias and Paraplegias, Department of Neurology, Instituto de Investigación Sanitaria, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Arpa
authors.affiliation: Reference Unit of Hereditary Ataxias and Paraplegias, Department of Neurology, Instituto de Investigación Sanitaria, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Sanz-Gallego
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Department of Genetics, Pitié-Salpêtrière Hospital, Paris, France; Institut du Cerveau et de la Moelle épinière; Institut National de la Santé et de la Recherche Médicale U1127; Centre National de la Recherche Scientifique Unité mixte recherché 7225; Université Pierre et Marie Curie Paris VI Unité mixte recherché S975, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Department of Genetics, Pitié-Salpêtrière Hospital, Paris, France; Institut du Cerveau et de la Moelle épinière; Institut National de la Santé et de la Recherche Médicale U1127; Centre National de la Recherche Scientifique Unité mixte recherché 7225; Université Pierre et Marie Curie Paris VI Unité mixte recherché S975, Paris, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Charles
authors.affiliation: Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Boesch
authors.affiliation: Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Nachbauer
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, University of Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, University of Munich, Munich, Germany.
authors.forename: Ivan
authors.initials: I
authors.lastname: Karin
authors.affiliation: Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Chantal
authors.initials: C
authors.lastname: Depondt
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Jennifer Müller
authors.initials: JM
authors.lastname: vom Hagen
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: Department of Neurology, University Hospital of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Ilaria A
authors.initials: IA
authors.lastname: Giordano
authors.affiliation: Department of Neurology, University Hospital of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.affiliation: Department of Neurology, Philipps University of Marburg, Marburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Bürk
authors.affiliation: Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pandolfo
authors.affiliation: Department of Neurology, University Hospital Rheinisch-Westfälische Technische Hochschule [RWTH], Aachen, Aachen, Germany; Centre for Rare Diseases, University Hospital Rheinisch-Westfälische Technische Hochschule [RWTH], Aachen, Aachen, Germany; Clinical Trial Centre, University Hospital Rheinisch-Westfälische Technische Hochschule [RWTH], Aachen, Aachen, Germany; JARA-Translational Brain Medicine, Jülich and Aachen, Germany. Electronic address: jschulz@ukaachen.de.
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
mesh_terms: D000203:Activities of Daily Living; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D016208:Databases, Factual; D005060:Europe / Q000453:epidemiology; D005260:Female; D005621:Friedreich Ataxia / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D057170:Translational Research, Biomedical / Q000379:methods; D018911:Trinucleotide Repeats / Q000235:genetics; D055815:Young Adult