title: Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa.
abstract: OBJECTIVE
  USH2A mutations are an important cause of retinitis pigmentosa (RP) with or without congenital sensorineural hearing impairment. We studied genotype-phenotype correlations and compared visual prognosis in Usher syndrome type IIa and nonsyndromic RP.
  
  
  METHODS
  Clinic-based, longitudinal, multicenter study.
  
  
  METHODS
  Consecutive patients with Usher syndrome type IIa (n = 152) and nonsyndromic RP (n = 73) resulting from USH2A mutations from ophthalmogenetic clinics in the Netherlands and Belgium.
  
  
  METHODS
  Data on clinical characteristics, visual acuity, visual field measurements, retinal imaging, and electrophysiologic features were extracted from medical charts over a mean follow-up of 9 years. Cumulative lifetime risks of low vision and blindness were estimated using Kaplan-Meier survival analysis.
  
  
  METHODS
  Low vision and blindness.
  
  
  RESULTS
  Participant groups had similar distributions of gender (48% vs. 45% males in Usher syndrome type IIa vs. nonsydromic RP; P = 0.8), ethnicity (97% vs. 99% European; P = 0.3), and median follow-up time (6.5 years vs. 3 years; P = 0.3). Usher syndrome type IIa patients demonstrated symptoms at a younger age (median age, 15 years vs. 25 years; P < 0.001), were diagnosed earlier (median age, 26 years vs. 36.5 years; P < 0.001), and became visually impaired 13 years earlier (median age, 41 years vs. 54 years; P < 0.001) based on VF and 18 years earlier based on VA (median age, 54 years vs. 72 years; P < 0.001) than nonsyndromic RP patients. The presence of 2 truncating mutations in USH2A was associated mostly with the syndromic phenotype, whereas other combinations were present in both groups. We found novel variants in Usher syndrome type IIa (25%) and nonsyndromic RP (19%): 29 missense mutations, 10 indels, 14 nonsense mutations, 9 frameshift mutations, and 5 splice-site mutations.
  
  
  CONCLUSIONS
  Most patients with USH2A-associated RP have severe visual impairment by age 50. However, those with Usher syndrome type IIa have an earlier decline of visual function and a higher cumulative risk of visual impairment than those without nonsyndromic RP. Complete loss of function of the USH2A protein predisposes to Usher syndrome type IIa, but remnant protein function can lead to RP with or without hearing loss.
authors.affiliation: The Rotterdam Eye Hospital, Rotterdam, The Netherlands; Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Rotterdam Ophthalmic Institute, Rotterdam, The Netherlands.
authors.forename: Laurence H M
authors.initials: LH
authors.lastname: Pierrache
authors.affiliation: Department of Otorhinolaryngology, Head, and Neck Surgery, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Bas P
authors.initials: BP
authors.lastname: Hartel
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Erwin
authors.initials: E
authors.lastname: van Wijk
authors.affiliation: The Rotterdam Eye Hospital, Rotterdam, The Netherlands; Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Magda A
authors.initials: MA
authors.lastname: Meester-Smoor
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Elfride
authors.initials: E
authors.lastname: de Baere
authors.affiliation: Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: de Zaeytijd
authors.affiliation: Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands; Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: van Schooneveld
authors.affiliation: Department of Otorhinolaryngology, Head, and Neck Surgery, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Cor W R J
authors.initials: CW
authors.lastname: Cremers
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Gislin
authors.initials: G
authors.lastname: Dagnelie
authors.affiliation: Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands; The Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Bergen
authors.affiliation: Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.affiliation: Department of Otorhinolaryngology, Head, and Neck Surgery, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ronald J E
authors.initials: RJ
authors.lastname: Pennings
authors.affiliation: The Rotterdam Eye Hospital, Rotterdam, The Netherlands; Rotterdam Ophthalmic Institute, Rotterdam, The Netherlands.
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.affiliation: Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: c.c.w.klaver@erasmusmc.nl.
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001766:Blindness / Q000503:physiopathology; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000503:physiopathology; D052245:Usher Syndromes / Q000235:genetics* / Q000503:physiopathology; D015354:Vision, Low / Q000503:physiopathology; D014792:Visual Acuity / Q000502:physiology*; D014794:Visual Fields / Q000502:physiology
chemical_list: D016326:Extracellular Matrix Proteins; C112735:USH2A protein, human