title: Progression of Friedreich ataxia: quantitative characterization over 5 years.
abstract: Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder of adults and children. This study analyzed neurological outcomes and changes to identify predictors of progression and generate power calculations for clinical trials.
  
  
  
  Eight hundred and twelve subjects in a natural history study were evaluated annually across 12 sites using the Friedreich Ataxia Rating Scale (FARS), 9-Hole Peg Test, Timed 25-Foot Walk, visual acuity tests, self-reported surveys and disability scales. Cross-sectional outcomes were assessed from recent visits, and longitudinal changes were gaged over 5 years from baseline.
  
  
  
  Cross-sectional outcomes correlated with measures of disease severity. Age, genetic severity (guanine-adenine-adenine [GAA] repeat length), and testing site predicted performance. Serial progression was relatively linear using FARS and composite measures of performance, while individual performance outcomes were nonlinear over time. Age strongly predicted change from baseline until removing the effects of baseline FARS scores, when GAA becomes a more important factor. Progression is fastest in younger subjects and subjects with longer GAA repeats. Improved coefficients of variation show that progression results are more reproducible over longer assessment durations.
  
  
  
  While age predicted progression speed in simple analyses and may provide an effective way to stratify cohorts, separating the effects of age and genetic severity is difficult. Controlling for baseline severity, GAA is the major determinant of progression rate in FRDA. Clinical trials will benefit from enrollment of younger subjects, and sample size requirements will shrink with longer assessment periods. These findings should prove useful in devising gene therapy trials in the near future.
authors.affiliation: Departments of Pediatrics and Neurology The Children's Hospital of Philadelphia Philadelphia Pennsylvania.
authors.forename: Maya
authors.initials: M
authors.lastname: Patel
authors.affiliation: Departments of Pediatrics and Neurology The Children's Hospital of Philadelphia Philadelphia Pennsylvania.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Isaacs
authors.affiliation: Departments of Pediatrics and Neurology The Children's Hospital of Philadelphia Philadelphia Pennsylvania.
authors.forename: Lauren
authors.initials: L
authors.lastname: Seyer
authors.affiliation: Departments of Pediatrics and Neurology The Children's Hospital of Philadelphia Philadelphia Pennsylvania.
authors.forename: Karlla
authors.initials: K
authors.lastname: Brigatti
authors.affiliation: Departments of Pediatrics and Neurology The Children's Hospital of Philadelphia Philadelphia Pennsylvania.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gelbard
authors.affiliation: Departments of Pediatrics and Neurology The Children's Hospital of Philadelphia Philadelphia Pennsylvania.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Strawser
authors.affiliation: Departments of Pediatrics and Neurology The Children's Hospital of Philadelphia Philadelphia Pennsylvania.
authors.forename: Debbie
authors.initials: D
authors.lastname: Foerster
authors.affiliation: Departments of Pediatrics and Neurology The Children's Hospital of Philadelphia Philadelphia Pennsylvania.
authors.forename: Julianna
authors.initials: J
authors.lastname: Shinnick
authors.affiliation: Departments of Pediatrics and Neurology The Children's Hospital of Philadelphia Philadelphia Pennsylvania.
authors.forename: Kimberly
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authors.lastname: Schadt
authors.affiliation: Bruce Lefroy Centre Murdoch Childrens Research Institute Parkville Victoria Australia.
authors.forename: Eppie M
authors.initials: EM
authors.lastname: Yiu
authors.affiliation: Bruce Lefroy Centre Murdoch Childrens Research Institute Parkville Victoria Australia.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Delatycki
authors.affiliation: Department of Neurology David Geffen School of Medicine University of California Los Angeles Los Angeles California.
authors.forename: Susan
authors.initials: S
authors.lastname: Perlman
authors.affiliation: Department of Neurology Emory University Atlanta Georgia.
authors.forename: George R
authors.initials: GR
authors.lastname: Wilmot
authors.affiliation: Department of Neurology University of South Florida and the James A. Haley Veterans' Administration Tampa Florida.
authors.forename: Theresa
authors.initials: T
authors.lastname: Zesiewicz
authors.affiliation: Department of Neurology and Pediatrics University of Iowa Iowa City Iowa.
authors.forename: Katherine
authors.initials: K
authors.lastname: Mathews
authors.affiliation: Department of Neurology University of Chicago Chicago Illinois.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Gomez
authors.affiliation: Division of Clinical and Metabolic Genetics The Hospital for Sick Children University of Toronto Toronto Ontario Canada.
authors.forename: Grace
authors.initials: G
authors.lastname: Yoon
authors.affiliation: Department of Neurology University of Florida Gainesville Florida.
authors.forename: Sub H
authors.initials: SH
authors.lastname: Subramony
authors.affiliation: Center for Human Experimental Therapeutics University of Rochester Rochester New York.
authors.forename: Alicia
authors.initials: A
authors.lastname: Brocht
authors.affiliation: Departments of Pediatrics and Neurology The Children's Hospital of Philadelphia Philadelphia Pennsylvania.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Farmer
authors.affiliation: Departments of Pediatrics and Neurology The Children's Hospital of Philadelphia Philadelphia Pennsylvania; Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania.
authors.forename: David R
authors.initials: DR
authors.lastname: Lynch