Xuan-Thanh-An Nguyen1, Mays Talib1, Mary J van Schooneveld2, Jan Wijnholds3, Maria M van Genderen4, Nicoline E Schalij-Delfos1, Caroline C W Klaver5, Herman E Talsma6, Marta Fiocco7, Ralph J Florijn8, Jacoline B Ten Brink8, Frans P M Cremers9, Magda A Meester-Smoor10, L Ingeborgh van den Born11, Carel B Hoyng12, Alberta A H J Thiadens10, Arthur A Bergen13, Camiel J F Boon14. 1. From the Department of Ophthalmology (X.-T.-A.N., M.T., J.W., N.E.S.-D., H.E.T., C.J.F.B.), Leiden University Medical Center, Leiden, the Netherlands. 2. Department of Ophthalmology (M.J.v.S., C.J.F.B.), Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, the Netherlands. 3. From the Department of Ophthalmology (X.-T.-A.N., M.T., J.W., N.E.S.-D., H.E.T., C.J.F.B.), Leiden University Medical Center, Leiden, the Netherlands; The Netherlands Institute for Neuroscience (NIN-KNAW) (J.W., A.A.B.), Amsterdam, the Netherlands. 4. Bartiméus Diagnostic Centre for Complex Visual Disorders (M.M.v.G., H.E.T.), Zeist, the Netherlands; Department of Ophthalmology (M.M.v.G.), University Medical Centre Utrecht, Utrecht, the Netherlands. 5. Department of Ophthalmology (C.C.W.K., M.A.M.-S., A.A.H.J.T.); Department of Epidemiology (C.C.W.K.), Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Ophthalmology (C.C.W.K., C.B.H.), Radboud University Medical Center, Nijmegen, the Netherlands; Institute for Molecular and Clinical Ophthalmology (C.C.W.K.), Basel, Switzerland. 6. From the Department of Ophthalmology (X.-T.-A.N., M.T., J.W., N.E.S.-D., H.E.T., C.J.F.B.), Leiden University Medical Center, Leiden, the Netherlands; Bartiméus Diagnostic Centre for Complex Visual Disorders (M.M.v.G., H.E.T.), Zeist, the Netherlands. 7. Mathematical Institute (M.F.), and Department of Biomedical Data Sciences (M.F.), Leiden University Medical Center, Leiden, the Netherlands. 8. Department of Clinical Genetics (R.J.F., J.B.t.B., A.A.B.), Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, the Netherlands. 9. Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour (F.P.M.C.), Radboud University Medical Center, Nijmegen, the Netherlands. 10. Department of Ophthalmology (C.C.W.K., M.A.M.-S., A.A.H.J.T.). 11. Rotterdam Eye Hospital (L.I.v.d.B.), Rotterdam, the Netherlands. 12. Department of Ophthalmology (C.C.W.K., C.B.H.), Radboud University Medical Center, Nijmegen, the Netherlands. 13. The Netherlands Institute for Neuroscience (NIN-KNAW) (J.W., A.A.B.), Amsterdam, the Netherlands; Department of Clinical Genetics (R.J.F., J.B.t.B., A.A.B.), Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, the Netherlands. 14. From the Department of Ophthalmology (X.-T.-A.N., M.T., J.W., N.E.S.-D., H.E.T., C.J.F.B.), Leiden University Medical Center, Leiden, the Netherlands; Department of Ophthalmology (M.J.v.S., C.J.F.B.), Amsterdam University Medical Center (UMC), Academic Medical Center, Amsterdam, the Netherlands. Electronic address: c.j.f.boon@lumc.nl.
Abstract
PURPOSE: To investigate the natural disease course of retinal dystrophies associated with crumbs cell polarity complex component 1 (CRB1) and identify clinical end points for future clinical trials. DESIGN: Single-center, prospective case series. METHODS: An investigator-initiated nationwide collaborative study that included 22 patients with CRB1-associated retinal dystrophies. Patients underwent ophthalmic assessment at baseline and 2 years after baseline. Clinical examination included best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study charts, Goldmann kinetic perimetry (V4e isopter seeing retinal areas), microperimetry, full-field electroretinography, full-field stimulus threshold (FST), fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. RESULTS: Based on genetic, clinical, and electrophysiological data, patients were diagnosed with retinitis pigmentosa (19 [86%]), cone-rod dystrophy (2 [9%]), or isolated macular dystrophy (1 [5%]). Analysis of the entire cohort at 2 years showed no significant changes in BCVA (P = .069) or V4e isopter seeing retinal areas (P = .616), although signs of clinical progression were present in individual patients. Macular sensitivity measured on microperimetry revealed a significant reduction at the 2-year follow-up (P < .001). FST responses were measurable in patients with nonrecordable electroretinograms. On average, FST responses remained stable during follow-up. CONCLUSION: In CRB1-associated retinal dystrophies, visual acuity and visual field measures remain relatively stable over the course of 2 years. Microperimetry showed a significant decrease in retinal sensitivity during follow-up and may be a more sensitive progression marker. Retinal sensitivity on microperimetry may serve as a functional clinical end point in future human treatment trials for CRB1-associated retinal dystrophies.
PURPOSE: To investigate the natural disease course of retinal dystrophies associated with crumbs cell polarity complex component 1 (CRB1) and identify clinical end points for future clinical trials. DESIGN: Single-center, prospective case series. METHODS: An investigator-initiated nationwide collaborative study that included 22 patients with CRB1-associated retinal dystrophies. Patients underwent ophthalmic assessment at baseline and 2 years after baseline. Clinical examination included best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study charts, Goldmann kinetic perimetry (V4e isopter seeing retinal areas), microperimetry, full-field electroretinography, full-field stimulus threshold (FST), fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. RESULTS: Based on genetic, clinical, and electrophysiological data, patients were diagnosed with retinitis pigmentosa (19 [86%]), cone-rod dystrophy (2 [9%]), or isolated macular dystrophy (1 [5%]). Analysis of the entire cohort at 2 years showed no significant changes in BCVA (P = .069) or V4e isopter seeing retinal areas (P = .616), although signs of clinical progression were present in individual patients. Macular sensitivity measured on microperimetry revealed a significant reduction at the 2-year follow-up (P < .001). FST responses were measurable in patients with nonrecordable electroretinograms. On average, FST responses remained stable during follow-up. CONCLUSION: In CRB1-associated retinal dystrophies, visual acuity and visual field measures remain relatively stable over the course of 2 years. Microperimetry showed a significant decrease in retinal sensitivity during follow-up and may be a more sensitive progression marker. Retinal sensitivity on microperimetry may serve as a functional clinical end point in future human treatment trials for CRB1-associated retinal dystrophies.