title: Progression of Late-Onset Stargardt Disease.
abstract: OBJECTIVE
  Identification of sensitive biomarkers is essential to determine potential effects of emerging therapeutic trials for Stargardt disease. This study aimed to describe the natural history of late-onset Stargardt, and demonstrates the accuracy of retinal pigment epithelium (RPE) atrophy progression as an outcome measure.
  
  
  METHODS
  We performed a retrospective cohort study collecting multicenter data from 47 patients (91 eyes) with late-onset Stargardt, defined by clinical phenotype, at least one ABCA4 mutation, and age at disease onset ≥ 45 years. We analyzed RPE atrophy progression on fundus autofluorescence and near-infrared reflectance imaging using semiautomated software and a linear mixed model. We performed sample size calculations to assess the power in a simulated 2-year interventional study and assessed visual endpoints using time-to-event analysis.
  
  
  RESULTS
  Over time, progression of RPE atrophy was observed (mean: 0.22 mm/year, 95% confidence interval [CI]: 0.19-0.27). By including only patients with bilateral RPE atrophy in a future trial, 32 patients are needed to reach a power of 83.9% (95% CI: 83.1-84.6), assuming a fixed therapeutic effect size of 30%. We found a median interval between disease onset and visual acuity decline to 20/32, 20/80, and 20/200 of 2.74 (95% CI: 0.54-4.41), 10.15 (95% CI: 6.13-11.38), and 11.38 (95% CI: 6.13-13.34) years, respectively.
  
  
  CONCLUSIONS
  We show that RPE atrophy represents a robust biomarker to monitor disease progression in future therapeutic trials. In contrast, the variability in terms of the course of visual acuity was high.
authors.affiliation: Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Stanley
authors.initials: S
authors.lastname: Lambertus
authors.affiliation: Department of Ophthalmology, University of Bonn, Bonn, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Lindner
authors.affiliation: Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Bax
authors.affiliation: Department of Ophthalmology, University of Bonn, Bonn, Germany.
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Mauschitz
authors.affiliation: Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nadal
authors.affiliation: Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmid
authors.affiliation: Department of Ophthalmology, University of Bonn, Bonn, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Schmitz-Valckenberg
authors.affiliation: Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands 4Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
authors.affiliation: Department of Ophthalmology, University of Bonn, Bonn, Germany.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Holz
authors.affiliation: Department for Health Evidence, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: van der Wilt
authors.affiliation: Department of Ophthalmology, University of Bonn, Bonn, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Fleckenstein
authors.affiliation: Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D018450:Disease Progression; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D008268:Macular Degeneration / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology*; D012189:Retrospective Studies; D000080362:Stargardt Disease; D013997:Time Factors; D041623:Tomography, Optical Coherence / Q000379:methods*; D014792:Visual Acuity
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D004247:DNA