Mays Talib1, Mary J van Schooneveld2, Caroline Van Cauwenbergh3,4, Jan Wijnholds1, Jacoline B Ten Brink5, Ralph J Florijn5, Nicoline E Schalij-Delfos1, Gislin Dagnelie6, Maria M van Genderen7, Elfride De Baere4, Magda A Meester-Smoor8, Julie De Zaeytijd3, Frans P M Cremers9, L Ingeborgh van den Born10, Alberta A Thiadens8, Carel B Hoyng11, Caroline C Klaver8,11,12, Bart P Leroy3,4,13, Arthur A Bergen5,14, Camiel J F Boon1,2. 1. Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands. 2. Department of Ophthalmology, Amsterdam UMC, University of Amsterdam, The Netherlands. 3. Department of Ophthalmology, Ghent University and Ghent University Hospital, Ghent, Belgium. 4. Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium. 5. Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, The Netherlands. 6. Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, United States. 7. Bartiméus, Diagnostic Centre for Complex Visual Disorders, Zeist, The Netherlands. 8. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands. 9. Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. 10. Rotterdam Eye Hospital, Rotterdam, The Netherlands. 11. Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands. 12. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. 13. Ophthalmic Genetics & Visual Electrophysiology, Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States. 14. The Netherlands Institute for Neuroscience (NIN-KNAW), Amsterdam, The Netherlands.
Abstract
Purpose: The purpose of this study was to investigate the phenotype and long-term clinical course of female carriers of RPGR mutations. Methods: This was a retrospective cohort study of 125 heterozygous RPGR mutation carriers from 49 families. Results: Eighty-three heterozygotes were from retinitis pigmentosa (RP) pedigrees, 37 were from cone-/cone-rod dystrophy (COD/CORD) pedigrees, and 5 heterozygotes were from pedigrees with mixed RP/CORD or unknown diagnosis. Mutations were located in exon 1-14 and in ORF15 in 42 of 125 (34%) and 83 of 125 (66%) subjects, respectively. The mean age at the first examination was 34.4 years (range, 2.1 to 86.0 years). The median follow-up time in heterozygotes with longitudinal data (n = 62) was 12.2 years (range, 1.1 to 52.2 years). Retinal pigmentary changes were present in 73 (58%) individuals. Visual symptoms were reported in 51 (40%) cases. Subjects with both symptoms and pigmentary fundus changes were older than the other heterozygotes (P = 0.01) and had thinner foveal outer retinas (P = 0.006). Complete expression of the RP or CORD phenotype was observed in 29 (23%) heterozygotes, although usually in milder forms than in affected male relatives. Best-corrected visual acuity (BCVA) was <20/40 and <20/400 in at least one eye in 45 of 116 (39%) and 11 of 116 (9%) heterozygotes, respectively. Myopia was observed in 74 of 101 (73%) subjects and was associated with lower BCVA (P = 0.006). Increasing age was associated with lower BCVA (P = 0.002) and decreasing visual field size (P = 0.012; I4e isopter). Conclusions: RPGR mutations lead to a phenotypic spectrum in female carriers, with myopia as a significantly aggravating factor. Complete disease expression is observed in some individuals, who may benefit from future (gene) therapeutic options.
Purpose: The purpose of this study was to investigate the phenotype and long-term clinical course of female carriers of RPGR mutations. Methods: This was a retrospective cohort study of 125 heterozygous RPGR mutation carriers from 49 families. Results: Eighty-three heterozygotes were from retinitis pigmentosa (RP) pedigrees, 37 were from cone-/cone-rod dystrophy (COD/CORD) pedigrees, and 5 heterozygotes were from pedigrees with mixed RP/CORD or unknown diagnosis. Mutations were located in exon 1-14 and in ORF15 in 42 of 125 (34%) and 83 of 125 (66%) subjects, respectively. The mean age at the first examination was 34.4 years (range, 2.1 to 86.0 years). The median follow-up time in heterozygotes with longitudinal data (n = 62) was 12.2 years (range, 1.1 to 52.2 years). Retinal pigmentary changes were present in 73 (58%) individuals. Visual symptoms were reported in 51 (40%) cases. Subjects with both symptoms and pigmentary fundus changes were older than the other heterozygotes (P = 0.01) and had thinner foveal outer retinas (P = 0.006). Complete expression of the RP or CORD phenotype was observed in 29 (23%) heterozygotes, although usually in milder forms than in affected male relatives. Best-corrected visual acuity (BCVA) was <20/40 and <20/400 in at least one eye in 45 of 116 (39%) and 11 of 116 (9%) heterozygotes, respectively. Myopia was observed in 74 of 101 (73%) subjects and was associated with lower BCVA (P = 0.006). Increasing age was associated with lower BCVA (P = 0.002) and decreasing visual field size (P = 0.012; I4e isopter). Conclusions: RPGR mutations lead to a phenotypic spectrum in female carriers, with myopia as a significantly aggravating factor. Complete disease expression is observed in some individuals, who may benefit from future (gene) therapeutic options.
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