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Mays Talib, Mary J van Schooneveld, Jan Wijnholds, Nicoline Schalij-Delfos, Ralph J. Florijn, Ingeborgh Van Den Born, Frans P Cremers, Alberta A H J Thiadens, Carel C B Hoyng, Caroline Klaver, Arthur Bergen, Camiel J F Boon; RPGR-associated retinal dystrophies: a longitudinal study. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2012. doi: https://doi.org/.
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Variants in the RPGR gene account for the majority of X-linked retinal dystrophies. As RPGR gene therapy is being developed, a thorough understanding of the phenotypic spectrum and natural history of RPGR-associated retinal dystrophies is important. We performed a retrospective, observational clinical study to describe the clinical course of these patients.
Medical records of 71 male patients with RPGR-associated retinal dystrophies, from 37 families, were reviewed for age at onset, best corrected visual acuity (BCVA), retinal imaging, full-field electroretinography, and Goldmann visual fields (GVF). GVF areas were digitized to seeing retinal areas (mm2). The decline rate of the seeing retinal area was determined with mixed model analysis.
Presence of a pathogenic RPGR variant was molecularly confirmed in 68 patients (96%), while 3 patients were first degree relatives of patients with a confirmed RPGR mutation. We found 31 distinct variants; 10 in exon 1-14 (21 patients, 30%) and 21 in exon ORF15 (50 patients, 70%). The median follow-up time was 11.3 years (range 0-57.1). Forty-nine patients had a retinitis pigmentosa (RP) phenotype (69%), and 15 (21%) and 7 (10%) patients had a cone-rod dystrophy or cone dystrophy, respectively. ORF15 mutations were found in higher proportions (p<0.05) in patients with predominantly cone disease (20/22, 91%) than in RP patients (30/49, 61%). The mean age at symptom onset was 4.9 years (±4.8; range 0-14) for RP patients and 25.9 years (±21.7; range 0-65) for patients with predominantly cone disease. The mean ages for reaching low vision (BCVA<0.3) and blindness (BCVA<0.05) were 46.7 (SE 3.6) and 67.5 (SE 4.7) years for RP patients, and 61.9 (SE 5.0) and 73.3 (SE 6.2) years for patients with predominantly cone disease, respectively. The survival distributions for BCVA did not differ between patients with ORF15 or exon 1-14 mutations. Symmetry in BCVA was found in 86% of patients. RP patients had a faster decline in seeing retinal area than patients with predominantly cone disease (p<0.001), with a yearly decline of 7%.
Based on the BCVA survival, the intervention window for future gene therapy is broader in patients with primary cone disease than in RP patients, but does not differ between patients with ORF15 or exon 1-14 mutations. Patients with primary cone involvement had a more favourable course of GVF decline than RP patients.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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