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Mays Talib, Mary J. van Schooneveld, Caroline Van Cauwenbergh, Jan Wijnholds, Jacoline B. ten Brink, Ralph J. Florijn, Nicoline E. Schalij-Delfos, Gislin Dagnelie, Maria M. van Genderen, Elfride De Baere, Magda A. Meester-Smoor, Julie De Zaeytijd, Frans P. M. Cremers, L. Ingeborgh van den Born, Alberta A. Thiadens, Carel B. Hoyng, Caroline C. Klaver, Bart P. Leroy, Arthur A. Bergen, Camiel J. F. Boon; The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in the RPGR Gene. Invest. Ophthalmol. Vis. Sci. 2018;59(10):4123-4133. doi: 10.1167/iovs.17-23453.
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The purpose of this study was to investigate the phenotype and long-term clinical course of female carriers of RPGR mutations.
This was a retrospective cohort study of 125 heterozygous RPGR mutation carriers from 49 families.
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).
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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