Leo C Hahn1, Mary J van Schooneveld2, Nieneke L Wesseling1, Ralph J Florijn3, Jacoline B Ten Brink3, Birgit I Lissenberg-Witte4, Ine Strubbe5, Magda A Meester-Smoor6, Alberta A Thiadens6, Roselie M Diederen1, Caroline van Cauwenbergh7, Julie de Zaeytijd5, Sophie Walraedt5, Elfride de Baere7, Caroline C W Klaver8, Jeannette Ossewaarde-van Norel9, L Ingeborgh van den Born10, Carel B Hoyng11, Maria M van Genderen12, Paul A Sieving13, Bart P Leroy14, Arthur A Bergen15, Camiel J F Boon16. 1. Department of Ophthalmology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands. 2. Department of Ophthalmology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; Bartiméus, Diagnostic Center for Complex Visual Disorders, Zeist, The Netherlands. 3. Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands. 4. Department of Epidemiology and Biostatistics, Amsterdam University Medical Centers, Amsterdam, The Netherlands. 5. Department of Ophthalmology, University Hospital Ghent, Ghent University & Ghent University, Ghent, Belgium. 6. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands. 7. Department of Ophthalmology, University Hospital Ghent, Ghent University & Ghent University, Ghent, Belgium; Center for Medical Genetics Ghent, Ghent University Hospital & Ghent University, Ghent, Belgium. 8. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands; Institute of Molecular and Clinical Ophthalmology, University Hospital Basel, University of Basel, Basel, Switzerland. 9. Department of Ophthalmology, University Medical Center Utrecht, Utrecht, The Netherlands. 10. The Rotterdam Eye Hospital and the Rotterdam Ophthalmic Institute, Rotterdam, The Netherlands. 11. Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands. 12. Bartiméus, Diagnostic Center for Complex Visual Disorders, Zeist, The Netherlands; Department of Ophthalmology, University Medical Center Utrecht, Utrecht, The Netherlands. 13. Department of Ophthalmology, School of Medicine, University of California at Davis, Sacramento, California. 14. Department of Ophthalmology, University Hospital Ghent, Ghent University & Ghent University, Ghent, Belgium; Division of Ophthalmology & CCMT, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 15. Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; The Netherlands Institute for Neuroscience (NIN-KNAW), Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands. 16. Department of Ophthalmology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: Camiel.boon@amsterdamumc.nl.
Abstract
PURPOSE: To describe the natural course, phenotype, and genotype of patients with X-linked retinoschisis (XLRS). DESIGN: Retrospective cohort study. PARTICIPANTS: Three hundred forty patients with XLRS from 178 presumably unrelated families. METHODS: This multicenter, retrospective cohort study reviewed medical records of patients with XLRS for medical history, symptoms, visual acuity (VA), ophthalmoscopy, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain [SD] OCT, fundus autofluorescence). MAIN OUTCOME MEASURES: Age at onset, age at diagnosis, severity of visual impairment, annual visual decline, and electroretinography and imaging findings. RESULTS: Three hundred forty patients were included with a mean follow-up time of 13.2 years (range, 0.1-50.1 years). The median ages to reach mild visual impairment and low vision were 12 and 25 years, respectively. Severe visual impairment and blindness were observed predominantly in patients older than 40 years, with a predicted prevalence of 35% and 25%, respectively, at 60 years of age. The VA increased slightly during the first 2 decades of life and subsequently transitioned into an average annual decline of 0.44% (P < 0.001). No significant difference was found in decline of VA between variants that were predicted to be severe and mild (P = 0.239). The integrity of the ellipsoid zone (EZ) as well as the photoreceptor outer segment (PROS) length in the fovea on SD OCT correlated significantly with VA (Spearman's ρ = -0.759 [P < 0.001] and -0.592 [P = 0.012], respectively). Fifty-three different RS1 variants were found. The most common variants were the founder variant c.214G→A (p.(Glu72Lys)) (101 patients [38.7%]) and a deletion of exon 3 (38 patients [14.6%]). CONCLUSIONS: Large variabilities in phenotype and natural course of XLRS were seen in this study. In most patients, XLRS showed a slow deterioration starting in the second decade of life, suggesting an optimal window of opportunity for treatment within the first 3 decades of life. The integrity of EZ as well as the PROS length on SD OCT may be important in choosing optimal candidates for treatment and as potential structural end points in future therapeutic studies. No clear genotype-phenotype correlation was found.
PURPOSE: To describe the natural course, phenotype, and genotype of patients with X-linked retinoschisis (XLRS). DESIGN: Retrospective cohort study. PARTICIPANTS: Three hundred forty patients with XLRS from 178 presumably unrelated families. METHODS: This multicenter, retrospective cohort study reviewed medical records of patients with XLRS for medical history, symptoms, visual acuity (VA), ophthalmoscopy, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain [SD] OCT, fundus autofluorescence). MAIN OUTCOME MEASURES: Age at onset, age at diagnosis, severity of visual impairment, annual visual decline, and electroretinography and imaging findings. RESULTS: Three hundred forty patients were included with a mean follow-up time of 13.2 years (range, 0.1-50.1 years). The median ages to reach mild visual impairment and low vision were 12 and 25 years, respectively. Severe visual impairment and blindness were observed predominantly in patients older than 40 years, with a predicted prevalence of 35% and 25%, respectively, at 60 years of age. The VA increased slightly during the first 2 decades of life and subsequently transitioned into an average annual decline of 0.44% (P < 0.001). No significant difference was found in decline of VA between variants that were predicted to be severe and mild (P = 0.239). The integrity of the ellipsoid zone (EZ) as well as the photoreceptor outer segment (PROS) length in the fovea on SD OCT correlated significantly with VA (Spearman's ρ = -0.759 [P < 0.001] and -0.592 [P = 0.012], respectively). Fifty-three different RS1 variants were found. The most common variants were the founder variant c.214G→A (p.(Glu72Lys)) (101 patients [38.7%]) and a deletion of exon 3 (38 patients [14.6%]). CONCLUSIONS: Large variabilities in phenotype and natural course of XLRS were seen in this study. In most patients, XLRS showed a slow deterioration starting in the second decade of life, suggesting an optimal window of opportunity for treatment within the first 3 decades of life. The integrity of EZ as well as the PROS length on SD OCT may be important in choosing optimal candidates for treatment and as potential structural end points in future therapeutic studies. No clear genotype-phenotype correlation was found.