This study describes the clinical, genetic, and histopathological features in patients with RPGR-associated retinal dystrophies. Nine male patients from eight unrelated families underwent a comprehensive ophthalmic examination. Additionally, the histopathology of the right eye from a patient with an end-stage cone-rod-dystrophy (CRD)/sector retinitis pigmentosa (RP) phenotype was examined. All RPGR mutations causing a CRD phenotype were situated in exon ORF15. The mean best-corrected visual acuity (BCVA, decimals) was 0.58 (standard deviation (SD)): 0.34; range: 0.05–1.13); and the mean spherical refractive error was −4.1 D (SD: 2.11; range: −1.38 to −8.19). Hyperautofluorescent rings were observed in six patients. Full-field electroretinography responses were absent in all patients. The visual field defects ranged from peripheral constriction to central islands. The mean macular sensitivity on microperimetry was 11.6 dB (SD: 7.8; range: 1.6–24.4) and correlated significantly with BCVA (r = 0.907; p = 0.001). A histological examination of the donor eye showed disruption of retinal topology and stratification, with a more severe loss found in the peripheral regions. Reactive gliosis was seen in the inner layers of all regions. Our study demonstrates the highly variable phenotype found in RPGR-associated retinal dystrophies. Therapies should be applied at the earliest signs of photoreceptor degeneration, prior to the remodeling of the inner retina.

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: 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°) 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.

Purpose: To investigate the retinal structure and function in patients with CRB1‐associated retinal dystrophies (RD) and to explore potential clinical endpoints.Methods: In this prospective cross‐sectional study, 22 patients with genetically confirmed CRB1‐RD (aged 6–74 years), and who had a decimal best‐corrected visual acuity (BCVA) ≥ 0.05 at the last visit, were studied clinically with ETDRS BCVA, corneal topography, spectral‐domain optical coherence tomography (SD‐OCT), fundus autofluorescence, Goldmann visual field (VF), microperimetry, full‐field electroretinography (ERG) and full‐field stimulus testing (FST). Ten patients were from a genetic isolate (GI).Results: Patients had retinitis pigmentosa (n = 19; GI and non‐GI), cone‐rod dystrophy (n = 2; GI) or macular dystrophy (n = 1; non‐GI). Median age at first symptom onset was 3 years (range 0.8–49). Median decimal BCVA in the better and worse‐seeing eye was 0.18 (range 0.05–0.83) and 0.08 (range light perception‐0.72), respectively. Spectral‐domain optical coherence tomography (SD‐OCT) showed cystoid maculopathy in 8 subjects; inner retinal thickening (n = 20), a well‐preserved (para)foveal outer retina (n = 7) or severe (para)foveal outer retinal atrophy (n = 14). All retinal layers were discernible in 13/21 patients (62%), with mild to moderate laminar disorganization in the others. Nanophthalmos was observed in 8 patients (36%). Full‐field stimulus testing (FST) provided a subjective outcome measure for retinal sensitivity in eyes with (nearly) extinguished ERG amplitudes.Conclusions: Despite the generally severe course of CRB1‐RDs, symptom onset and central visual function are variable, even at advanced ages. Phenotypes may vary within the same family. Imaging and functional studies in a prospective longitudinal setting should clarify which endpoints may be most appropriate in a clinical trial.

Purpose: We developed and phenotyped a pigmented knockout rat model for lecithin retinol acyltransferase (LRAT) using CRISPR/Cas9. The introduced mutation (c.12delA) is based on a patient group harboring a homologous homozygous frameshift mutation in the LRAT gene (c.12delC), causing a dysfunctional visual (retinoid) cycle. Methods: The introduced mutation was confirmed by DNA and RNA sequencing. The expression of Lrat was determined on both the RNA and protein level in wildtype and knockout animals using RT-PCR and immunohistochemistry. The retinal structure and function, as well as the visual behavior of the Lrat^−/− and control rats, were characterized using scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), electroretinography (ERG) and vision-based behavioral assays. Results: Wildtype animals had high Lrat mRNA expression in multiple tissues, including the eye and liver. In contrast, hardly any expression was detected in Lrat^−/− animals. LRAT protein was abundantly present in wildtype animals and absent in Lrat^−/− animals. Lrat^−/− animals showed progressively reduced ERG potentials compared to wildtype controls from two weeks of age onwards. Vison-based behavioral assays confirmed reduced vision. Structural abnormalities, such as overall retinal thinning, were observed in Lrat^−/− animals. The retinal thickness in knockout rats was decreased to roughly 80% by four months of age. No functional or structural differences were observed between wildtype and heterozygote animals. Conclusions: Our Lrat^−/− rat is a new animal model for retinal dystrophy, especially for the LRAT-subtype of early-onset retinal dystrophies. This model has advantages over the existing mouse models and the RCS rat strain and can be used for translational studies of retinal dystrophies.

The development of a macular hole is relatively common in retinal dystrophies eligible for gene therapy such as choroideremia. However, the subretinal delivery of gene therapy requires an uninterrupted retina to allow dispersion of the viral vector. A macular hole may thus hinder effective gene therapy. Little is known about the outcome of macular hole surgery and its possible beneficial and/or adverse effects on retinal function in patients with choroideremia. We describe a case of a unilateral full-thickness macular hole (FTMH) in a 45year-old choroideremia patient (c.1349_1349+2dup mutation in CHM gene) and its management. Pars plana vitrectomy with internal limiting membrane (ILM) peeling and 20% SF₆ gas tamponade was performed, and subsequent FTMH closure was confirmed at 4 weeks, 3 months and 5 months postoperatively. No postoperative adverse events occurred, and fixation stability improved on microperimetry from respectively 11% and 44% of fixation points located within a 1° and 2° radius, preoperatively, to 94% and 100% postoperatively. This case underlines that pars plana vitrectomy with ILM peeling and gas tamponade can successfully close a FTMH in choroideremia patients, with subsequent structural and functional improvement. Macular hole closure may be important for patients to be eligible for future submacular gene therapy.

Purpose: To assess the longitudinal vision‐related quality of life among patients with CRB1‐associated inherited retinal dystrophies.Methods: In this longitudinal questionnaire study, the National Eye Institute Visual Function Questionnaire (39 items, NEI VFQ‐39) was applied at baseline, two‐year follow‐up, and 4‐year follow‐up in patients with pathogenic CRB1 variants. [Correction added on 20 November 2023, after first online publication: The preceding sentence has been updated in this version.] Classical test theory was performed to obtain subdomain scores and in particular ‘near activities’ and ‘total composite’ scores. The Rasch analysis based on previous calibrations of the NEI VFQ‐25 was applied to create visual functioning and socio‐emotional subscales.Results: In total, 22 patients with a CRB1‐associated retinal dystrophy were included, […] with a median age of 25.0 years (interquartile range: 13–31 years) at baseline and mean follow‐up of 4.0 ± 0.3 years. [Correction added on 20 November 2023, after first online publication: The preceding sentence has been updated in this version.] A significant decline at 4 years was observed for ‘near activities’ (51.0 ± 23.8 vs 35.4 ± 14.7, p = 0.004) and ‘total composite’ (63.0 ± 13.1 vs 52.0 ± 12.1, p = 0.001) subdomain scores. For the Rasch‐scaled scores, the ‘visual functioning’ scale significantly decreased after 2 years (−0.89 logits; p = 0.012), but not at 4‐year follow‐up (+0.01 logits; p = 0.975). [Correction added on 20 November 2023, after first online publication: In the preceding sentence, “…after 4 years…” has been corrected to “…after 2 years…” in this version.] The ‘socio‐emotional’ scale also showed a significant decline after 2 years (−0.78 logits, p = 0.033) and 4 years (−0.83 logits, p = 0.021).Conclusion: In the absence of an intervention, a decline in vision‐related quality of life is present in patients with pathogenic CRB1 variants at 4‐year follow‐up. Patient‐reported outcome measures should be included in future clinical trials, as they can be a potential indicator of disease progression and treatment efficacy.