Mays Talib1, Mary J van Schooneveld2, Maria M van Genderen3, Jan Wijnholds1, Ralph J Florijn4, Jacoline B Ten Brink4, Nicoline E Schalij-Delfos1, Gislin Dagnelie5, Frans P M Cremers6, Ron Wolterbeek7, Marta Fiocco8, Alberta A Thiadens9, Carel B Hoyng10, Caroline C Klaver11, Arthur A Bergen12, Camiel J F Boon13. 1. Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands. 2. Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands. 3. Bartiméus, Diagnostic Centre for Complex Visual Disorders, Zeist, The Netherlands. 4. Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands. 5. Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland. 6. Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. 7. Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands. 8. Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands; Mathematical Institute, Leiden University, Leiden, The Netherlands. 9. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands. 10. Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands. 11. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. 12. Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands; The Netherlands Institute for Neuroscience (NIN-KNAW), Amsterdam, The Netherlands. 13. Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands; Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: c.j.f.boon@lumc.nl.
Abstract
PURPOSE: To describe the phenotype, long-term clinical course, clinical variability, and genotype of patients with CRB1-associated retinal dystrophies. DESIGN: Retrospective cohort study. PARTICIPANTS: Fifty-five patients with CRB1-associated retinal dystrophies from 16 families. METHODS: A medical record review of 55 patients for age at onset, medical history, initial symptoms, best-corrected visual acuity, ophthalmoscopy, fundus photography, full-field electroretinography (ffERG), Goldmann visual fields (VFs), and spectral-domain optical coherence tomography. MAIN OUTCOME MEASURES: Age at onset, visual acuity survival time, visual acuity decline rate, and electroretinography and imaging findings. RESULTS: A retinitis pigmentosa (RP) phenotype was present in 50 patients, 34 of whom were from a Dutch genetic isolate (GI), and 5 patients had a Leber congenital amaurosis phenotype. The mean follow-up time was 15.4 years (range, 0-55.5 years). For the RP patients, the median age at symptom onset was 4.0 years. In the RP group, median ages for reaching low vision, severe visual impairment, and blindness were 18, 32, and 44 years, respectively, with a visual acuity decline rate of 0.03 logarithm of the minimum angle of resolution per year. The presence of a truncating mutation did not alter the annual decline rate significantly (P = 0.75). Asymmetry in visual acuity was found in 31% of patients. The annual VF decline rate was 5% in patients from the genetic isolate, which was significantly faster than in non-GI patients (P < 0.05). Full-field electroretinography responses were extinguished in 50% of patients, were pathologically attenuated without a documented rod or cone predominance in 30% of patients, and showed a rod-cone dysfunction pattern in 20% of RP patients. Cystoid fluid collections in the macula were found in 50% of RP patients. CONCLUSIONS: Mutations in the CRB1 gene are associated with a spectrum of progressive retinal degeneration. Visual acuity survival analyses indicate that the optimal intervention window for subretinal gene therapy is within the first 2 to 3 decades of life.
PURPOSE: To describe the phenotype, long-term clinical course, clinical variability, and genotype of patients with CRB1-associated retinal dystrophies. DESIGN: Retrospective cohort study. PARTICIPANTS: Fifty-five patients with CRB1-associated retinal dystrophies from 16 families. METHODS: A medical record review of 55 patients for age at onset, medical history, initial symptoms, best-corrected visual acuity, ophthalmoscopy, fundus photography, full-field electroretinography (ffERG), Goldmann visual fields (VFs), and spectral-domain optical coherence tomography. MAIN OUTCOME MEASURES: Age at onset, visual acuity survival time, visual acuity decline rate, and electroretinography and imaging findings. RESULTS:A retinitis pigmentosa (RP) phenotype was present in 50 patients, 34 of whom were from a Dutch genetic isolate (GI), and 5 patients had a Leber congenital amaurosis phenotype. The mean follow-up time was 15.4 years (range, 0-55.5 years). For the RP patients, the median age at symptom onset was 4.0 years. In the RP group, median ages for reaching low vision, severe visual impairment, and blindness were 18, 32, and 44 years, respectively, with a visual acuity decline rate of 0.03 logarithm of the minimum angle of resolution per year. The presence of a truncating mutation did not alter the annual decline rate significantly (P = 0.75). Asymmetry in visual acuity was found in 31% of patients. The annual VF decline rate was 5% in patients from the genetic isolate, which was significantly faster than in non-GI patients (P < 0.05). Full-field electroretinography responses were extinguished in 50% of patients, were pathologically attenuated without a documented rod or cone predominance in 30% of patients, and showed a rod-cone dysfunction pattern in 20% of RP patients. Cystoid fluid collections in the macula were found in 50% of RP patients. CONCLUSIONS: Mutations in the CRB1 gene are associated with a spectrum of progressive retinal degeneration. Visual acuity survival analyses indicate that the optimal intervention window for subretinal gene therapy is within the first 2 to 3 decades of life.
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