Laurence H M Pierrache1,2,3,4, Babak Ghafaryasl2,5, Muhammad I Khan6,7, Susanne Yzer1, Maria M van Genderen8,9, José Schuil8, F Nienke Boonstra10,11, Jan W R Pott12, Jan Tjeerd H N de Faber1, Martha J H Tjon-Fo-Sang1, Koenraad A Vermeer2, Frans P M Cremers6,7, Caroline C W Klaver3,4,10, L Ingeborgh van den Born1,2. 1. The Rotterdam Eye Hospital, Rotterdam, the Netherlands. 2. Rotterdam Ophthalmic Institute, Rotterdam, the Netherlands. 3. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands. 4. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. 5. Department of Imaging Physics, Delft University of Technology, Delft, the Netherlands. 6. Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. 7. Department of Cognitive Neuroscience, Radboud University Medical Centre Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, the Netherlands. 8. Bartiméus Diagnostic Centre for Complex Visual Disorders, Zeist, the Netherlands. 9. Department of Ophthalmology, University Medical Centre Utrecht, Utrecht, the Netherlands. 10. Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands. 11. Royal Dutch Visio, National Foundation for the Visually Impaired and Blind, Huizen, the Netherlands; and. 12. Department of Ophthalmology, University Medical Center Groningen, Groningen, the Netherlands.
Abstract
PURPOSE: To study the disease course of RPE65-associated inherited retinal degenerations (IRDs) as a function of the genotype, define a critical age for blindness, and identify potential modifiers. METHODS: Forty-five patients with IRD from 33 families with biallelic RPE65 mutations, 28 stemming from a genetic isolate. We collected retrospective data from medical charts. Coexisting variants in 108 IRD-associated genes were identified with Molecular Inversion Probe analysis. RESULTS: Most patients were diagnosed within the first years of life. Daytime visual function ranged from near-normal to blindness in the first four decades and met WHO criteria for blindness for visual acuity and visual field in the fifth decade. p.(Thr368His) was the most common variant (54%). Intrafamilial variability and interfamilial variability in disease severity and progression were observed. Molecular Inversion Probe analysis confirmed all RPE65 variants and identified one additional variant in LRAT and one in EYS in two separate patients. CONCLUSION: All patients with RPE65-associated IRDs developed symptoms within the first year of life. Visual function in childhood and adolescence varied but deteriorated inevitably toward blindness after age 40. In this study, genotype was not predictive of clinical course. The variance in severity of disease could not be explained by double hits in other IRD genes.
PURPOSE: To study the disease course of RPE65-associated inherited retinal degenerations (IRDs) as a function of the genotype, define a critical age for blindness, and identify potential modifiers. METHODS: Forty-five patients with IRD from 33 families with biallelic RPE65 mutations, 28 stemming from a genetic isolate. We collected retrospective data from medical charts. Coexisting variants in 108 IRD-associated genes were identified with Molecular Inversion Probe analysis. RESULTS: Most patients were diagnosed within the first years of life. Daytime visual function ranged from near-normal to blindness in the first four decades and met WHO criteria for blindness for visual acuity and visual field in the fifth decade. p.(Thr368His) was the most common variant (54%). Intrafamilial variability and interfamilial variability in disease severity and progression were observed. Molecular Inversion Probe analysis confirmed all RPE65 variants and identified one additional variant in LRAT and one in EYS in two separate patients. CONCLUSION: All patients with RPE65-associated IRDs developed symptoms within the first year of life. Visual function in childhood and adolescence varied but deteriorated inevitably toward blindness after age 40. In this study, genotype was not predictive of clinical course. The variance in severity of disease could not be explained by double hits in other IRD genes.