Objective: To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene and to identify potential end points and optimal patient... Show moreObjective: To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene and to identify potential end points and optimal patient selection for future therapeutic trials.Design: International, multicenter, retrospective cohort study.Subjects: Eighty-two patients with GUCY2D-associated LCA or CORD from 54 families.Methods: Medical records were reviewed for medical history, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography, and retinal imaging (fundus photography, spectral -domain OCT [SD-OCT], fundus autofluorescence).Main Outcomes Measures: Age of onset, evolution of BCVA, genotype-phenotype correlations, anatomic characteristics on funduscopy, and multimodal imaging.Results: Fourteen patients with autosomal recessive LCA and 68 with autosomal dominant CORD were included. The median follow-up times were 5.2 years (interquartile range [IQR] 2.6-8.8 years) for LCA and 7.2 years (IQR 2.2-14.2 years) for CORD. Generally, LCA presented in the first year of life. The BCVA in patients with LCA ranged from no light perception to 1.00 logarithm of the minimum angle of resolution (logMAR) and remained relatively stable during follow-up. Imaging for LCA was limited but showed little to no structural degeneration. In patients with CORD, progressive vision loss started around the second decade of life. The BCVA declined annually by 0.022 logMAR (P < 0.001) with no difference between patients with the c.2513G>A and the c.2512C>T GUCY2D variants (P = 0.798). At the age of 40 years, the probability of being blind or severely visually impaired was 32%. The integrity of the ellipsoid zone (EZ) and that of the external limiting membrane (ELM) on SD-OCT correlated signifi-cantly with BCVA (Spearman r = 0.744, P = 0.001, and r = 0.712, P < 0.001, respectively) in those with CORD.Conclusions: Leber congenital amaurosis associated with GUCY2D caused severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting long pres-ervation of photoreceptors. Despite large variability, GUCY2D-associated CORD generally presented during adolescence, with a progressive loss of vision, and culminated in severe visual impairment during mid-to-late adulthood. The integrity of the ELM and EZ may be suitable structural end points for therapeutic studies of GUCY2D-associated CORD. Ophthalmology Retina 2022;6:711-722 (c) 2022 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). Show less
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... Show morePurpose: 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 rho = -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.(G1u72Lys)) (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. (C) 2021 by the American Academy of Ophthalmology. Show less
Talib, M.; Cauwenbergh, C. van; Zaeytijd, J. de; Wynsberghe, D. van; Baere, E. de; Boon, C.J.F.; Leroy, B.P. 2021
Aim To investigate the natural history in a Belgian cohort of CRB1-associated retinal dystrophies. Methods An in-depth retrospective study focusing on visual function and retinal structure. Results... Show moreAim To investigate the natural history in a Belgian cohort of CRB1-associated retinal dystrophies. Methods An in-depth retrospective study focusing on visual function and retinal structure. Results Forty patients from 35 families were included (ages: 2.5-80.1 years). In patients with a follow-up of >1 year (63%), the mean follow-up time was 12.0 years (range: 2.3-29.2 years). Based on the patient history, symptoms and/or electroretinography, 22 patients (55%) were diagnosed with retinitis pigmentosa (RP), 15 (38%) with Leber congenital amaurosis (LCA) and 3 (8%) with macular dystrophy (MD), the latter being associated with the p.(Ile167_Gly169del) mutation (in compound heterozygosity). MD later developed into a rod-cone dystrophy in one patient. Blindness at initial presentation was seen in the first decade of life in LCA, and in the fifth decade of life in RP. Eventually, 28 patients (70%) reached visual acuity-based blindness (<0.05). Visual field-based blindness (<10 degrees) was documented in 17/25 patients (68%). Five patients (13%) developed Coats-like exudative vasculopathy. Intermediate/posterior uveitis was found in three patients (8%). Cystoid maculopathy was common in RP (9/21; 43%) and MD (3/3; 100%). Macular involvement, varying from retinal pigment epithelium alterations to complete outer retinal atrophy, was observed in all patients. Conclusion Bi-allelic CRB1 mutations result in a range of progressive retinal disorders, most of which are generalised, with characteristically early macular involvement. Visual function and retinal structure analysis indicates a window for potential intervention with gene therapy before the fourth decade of life in RP and the first decade in LCA. Show less
Nguyen, X.T.A.; Talib, M.; Cauwenbergh, C. van; Schooneveld, M.J. van; Fiocco, M.; Wijnholds, J.; ... ; Boon, C.J.F. 2021
Purpose: To investigate the natural history of RHO-associated retinitis pigmentosa (RP). Methods: A multicenter, medical chart review of 100 patients with autosomal dominant RHO-associated RP.... Show morePurpose: To investigate the natural history of RHO-associated retinitis pigmentosa (RP). Methods: A multicenter, medical chart review of 100 patients with autosomal dominant RHO-associated RP. Results: Based on visual fields, time-to-event analysis revealed median ages of 52 and 79 years to reach low vision (central visual field <20 degrees) and blindness (central visual field <10 degrees), respectively. For the best-corrected visual acuity (BCVA), the median age to reach mild impairment (20/67 <= BCVA < 20/40) was 72 years, whereas this could not be computed for lower acuities. Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%), in terms of decline rates of the BCVA (P < 0.001) and V4e retinal seeing areas (P < 0.005). The foveal thickness of the photoreceptor-retinal pigment epithelium (PR + RPE) complex correlated significantly with BCVA (Spearman's rho = 0.733; P < 0.001). Conclusion: Based on central visual fields, the optimal window of intervention for RHO-associated RP is before the 5th decade of life. Significant differences in disease progression are present between generalized and sector RP phenotypes. Our findings suggest that the PR + RPE complex is a potential surrogate endpoint for the BCVA in future studies. Show less
Talib, M.; Schooneveld, M.J. van; Duuren, R.J.G. van; Cauwenbergh, C. van; Brink, J.B. ten; Baere, E. de; ... ; Boon, C.J.F. 2019
