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Purpose of Review: The purpose of this review was to provide a summary of currently available retinal imaging and visual function testing methods for assessing inherited retinal degenerations (IRDs), with the emphasis on the application of deep learning (DL) approaches to assist the determination of structural biomarkers for IRDs., Recent Findings: (clinical trials for IRDs; discover effective biomarkers as endpoints; DL applications in processing retinal images to detect disease-related structural changes)., Summary: Assessing photoreceptor loss is a direct way to evaluate IRDs. Outer retinal layer structures, including outer nuclear layer, ellipsoid zone, photoreceptor outer segment, RPE, are potential structural biomarkers for IRDs. More work may be needed on structure and function relationship., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To describe the outcomes from treatment of macular neovascularization in an eye affected by late-onset retinal degeneration., Methods: A 72-year-old female patient presented with a history of decreased vision since several years. The patient was previously diagnosed with age-related macular degeneration and treated with anti-vascular endothelial growth factors., Results: Clinical examination of the retina and ultra-widefield color fundus photographs showed extensive atrophy in both eyes. The left eye showed macular neovascularization on fluorescein angiography, subretinal fluid on optical coherence tomography, and correspondent hemorrhages on the color fundus photography. Aflibercept anti-vascular endothelial factor treatment was used to treat the macular neovascularization in the left eye., Conclusion: We report a case of genetically confirmed late-onset retinal degeneration (heterozygous pathogenic mutation p.Ser163Arg in one C1QTN5 allele) with advanced degeneration of the retina complicated by macular neovascularization, which responded well to treatment with a single aflibercept injection.

Purpose: To clarify the genetic and clinical features of Japanese patients with ABCA4-associated retinopathy., Design: Retrospective, multicenter cohort study., Methods: Patients with retinal degeneration and biallelic ABCA4 variants were recruited from 13 different hospitals. Whole exome sequencing analysis was used for genetic testing. Comprehensive ophthalmic examinations were performed on matched patients. The primary outcome measure was identifying multimodal retinal imaging findings associated with disease progression., Results: This study included 63 patients: 19 with missense/missense, 23 with missense/truncation, and 21 with truncation/truncation genotypes. In total, 62 variants were identified, including 29 novel variants. Six patients had a mild phenotype characterized by foveal-sparing or preserved foveal structure, including 4 with missense/missense and 2 with missense/truncation genotypes. The p.Arg212His variant was the most frequent in patients with mild phenotypes (4/12 alleles). Clinical findings showed a disease duration-dependent worsening of the phenotypic stage. Patients with the truncation/truncation genotype exhibited rapid retinal degeneration within a few years and definite fundus autofluorescence imaging patterns, including hyper autofluorescence at the macula and few or no flecks., Conclusions: Our results indicate that missense/missense or missense/truncation genotypes, including the p.Arg212His variant, are associated with a relatively mild phenotype. In contrast, the truncation/truncation genotype causes rapid and severe retinal degeneration in Japanese patients with ABCA4-associated retinopathy. These data are vital in predicting patient prognosis, guiding genetic counseling, and stratifying patients for future clinical trials., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pigmented paravenous chorioretinal atrophy (PPCRA) is an uncommon form of chorioretinal atrophy characterized by perivenous aggregations of pigment clumps associated with peripapillary and radial zones of retinal pigment epithelial atrophy that are distributed along the retinal veins. Most patients are asymptomatic, and evidence suggest that PPCRA is slowly progressing. Unless macular involvement is present, the majority of patients usually retain a normal visual function. Our ability to diagnose PPCRA has recently improved thanks to multimodal imaging, especially with the advent of ultra-widefield (UWF) imaging. Blood tests and functional and genetic testing can help with the correct differential diagnosis of pseudo-PPCRA or other disorders with similar characteristics. Although the cause of PPCRA is unknown, it is possible that it has a genetic basis. In this review we provide a summary of the multimodal imaging characteristics of PPCRA, and discuss its possible pathogenesis, based on the genes that have been associated with this disease.

Purpose: The purpose of this study was to evaluate self-reported functional vision (FV) and the impact of vision loss in patients with USH2A-associated retinal degeneration using a patient-reported outcome (PRO) measure, the Michigan Retinal Degeneration Questionnaire (MRDQ), to correlate MRDQ scores with well-established visual function measurements., Design: An observational cross-sectional study (n = 93) of participants who had Usher Syndrome Type 2 (USH2, n = 55) or autosomal recessive non-syndromic retinitis pigmentosa (ARRP; n = 38) associated with biallelic variants in the USH2A gene., Methods: The study protocol was approved by all ethics boards and informed consent was obtained from each participant. Participants completed the MRDQ at the 48-month study follow-up visit. Disease duration was self-reported by participants. One-way ANOVA was used to compare subgroups (clinical diagnosis, age, disease duration, and full-field stimulus threshold [FST] Blue-Red mediation) on mean scores per domain. Spearman correlation coefficients were used to assess associations between MRDQ domains and visual/retinal function assessments., Results: Of the study sample, 58% were female participants and the median disease duration was 13 years. MRDQ domains were sensitive to differences between subgroups of clinical diagnosis, age, disease duration, and FST Blue-Red mediation. MRDQ domains correlated with static perimetry, microperimetry, full-field stimulus testing, and best-corrected visual acuity (BCVA)., Conclusions: Self-reported FV measured by the MRDQ, when applied to USH2 and ARRP participants, had good distributional characteristics and correlated well with visual function tests. MRDQ adds a new dimension of understanding on vision-related functioning and establishes this PRO tool as an informative measure in evaluating USH2A outcomes.

Introduction: Diabetic retinopathy (DR) is both a microangiopathy and a neurodegenerative disease. However, the connections between both changes are not well known., Purpose: To characterise the longitudinal retinal ganglion cell layer + inner plexiform layer (GCL + IPL) changes and their association with microvascular changes in type-2 diabetes (T2D) patients with nonproliferative diabetic retinopathy (NPDR)., Methods: This two-year prospective study (CORDIS, NCT03696810) included 122 T2D individuals with NPDR identified as risk phenotypes B and C, which present a more rapid progression. Phenotype C was identified by decreased VD ≥ 2SD in healthy controls, and phenotype B, identified by subclinical macular oedema with only minimal vascular closure. The GCL + IPL thickness, vessel density, perfusion density and area of intercapillary spaces (AIS) were assessed by optical coherence tomography (OCT) and OCT angiography (OCTA). Linear mixed effects models were employed to evaluate the retinal GCL + IPL progression and its associations., Results: Regarding GCL + IPL thickness, T2D individuals presented on average 80.1 ± 7.49 μm, statistically significantly lower than the healthy control group, 82.5 ± 5.71 (p = 0.022), with only phenotype C differing significantly from controls (p = 0.006). GCL + IPL thickness steadily decreased during the two-year period in both risk phenotypes, with an annual decline rate of -0.372 μm/year (p < 0.001). Indeed, phenotype C showed a higher rate of progression (-0.459 μm/year, p < 0.001) when compared to phenotype B (-0.296 μm/year, p = 0.036). Eyes with ETDRS grade 20 showed GCL + IPL thickness values comparable to those of healthy control group (83.3 ± 5.80 and 82.7 ± 5.50 μm, respectively, p = 0.880), whereas there was a progressive decrease in GCL + IPL thickness in ETDRS grades 35 and 43-47 associated with the increase in severity of the retinopathy (-0.276 μm/year, p = 0.004; -0.585 μm/year, p = 0.013, respectively). Furthermore, the study showed statistically significant associations between the progressive thinning of GCL + IPL and the progressive increase in retinal capillary non-perfusion, with particular relevance for AIS (p < 0.001)., Conclusions: Our findings showed that, in eyes with NPDR and at risk for progression, retinal neurodegeneration occurs at different rates in different risk phenotypes, and it is associated with retinal microvascular non-perfusion., (© 2023 Association for Innovation and Biomedical Research on Light and Image. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: Hydroxychloroquine (HCQ) can cause irreversible damage to the retina, especially when taken over longer periods. The American Academy of Ophthalmology recommends a regimen for dosing, screening, and monitoring of patients treated with HCQ. We present an unusual case of a rapid development of severe HCQ-associated retinopathy already after 2 years after commencing HCQ treatment., Methods: Observational case report. Clinical examination, optical coherence tomography, fundus autofluorescence imaging, perimetry, and full-field and multifocal electroretinography were performed. Ancillary tests included neoplastic and paraneoplastic work-up, vitamin levels, and whole-exome sequencing, to rule out other potential causes of a panretinal degeneration., Results: We report on a 58-year-old woman with rheumatoid arthritis, treated initially with 200 mg HCQ daily for 1 year (daily dose 3.6 mg/kg), then 400 mg daily for 1 year (daily dose 7.2 mg/kg), and a cumulative dose of 216 g. Her medical history was otherwise unremarkable. No family history for inherited retinal conditions. She was referred due to a rapid and sudden progressive and severe concentric visual field constriction, 2 years after commencing HCQ treatment., Conclusion: This case of a rapid-onset, severe panretinal degeneration shortly after start of HCQ treatment suggests underlying mechanisms and risk factors for HCQ toxicity in addition to those previously reported and a potential need for supplementary screening tests to prevent HCQ toxicity. American Academy of Ophthalmology dosing guidelines of 5 mg/kg should be strictly adhered to in patients receiving HCQ therapy., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

The diagnosis of inherited retinal degeneration (IRD) is challenging owing to its phenotypic and genotypic complexity. Clinical information is important before a genetic diagnosis is made. Metabolomics studies the entire picture of bioproducts, which are determined using genetic codes and biological reactions. We demonstrated that the common diagnoses of IRD, including retinitis pigmentosa (RP), cone-rod dystrophy (CRD), Stargardt disease (STGD), and Bietti's crystalline dystrophy (BCD), could be differentiated based on their metabolite heatmaps. Hundreds of metabolites were identified in the volcano plot compared with that of the control group in every IRD except BCD, considered as potential diagnosing markers. The phenotypes of CRD and STGD overlapped but could be differentiated by their metabolomic features with the assistance of a machine learning model with 100% accuracy. Moreover, EYS-, USH2A-associated, and other RP, sharing considerable similar characteristics in clinical findings, could also be diagnosed using the machine learning model with 85.7% accuracy. Further study would be needed to validate the results in an external dataset. By incorporating mass spectrometry and machine learning, a metabolomics-based diagnostic workflow for the clinical and molecular diagnoses of IRD was proposed in our study., (© 2024. The Author(s).)

Purpose: To describe and evaluate a novel method to determine the validity of measurements made using cycle-by-cycle (CxC) recording techniques in patients with advanced retinal degenerations (RD) having low-amplitude flicker electroretinogram (ERG) responses., Methods: The method extends the original CxC recording algorithm introduced by Sieving et al., retaining the original recording setup and the preliminary analysis of raw data. Novel features include extended use of spectrum analysis, reduction of errors due to known sources, and a comprehensive statistical assessment using three different tests. The method was applied to ERG recordings from seven patients with RD and two patients with CNGB3 achromatopsia., Results: The method was implemented as a Windows application to processes raw data obtained from a commercial ERG system, and it features a computational toolkit for statistical assessment of ERG recordings with amplitudes as low as 1 µV, commonly found in advanced RD patients. When recorded using conditions specific for eliciting cone responses, none of the CNGB3 patients had a CxC validated response, indicating that no signal artifacts were present with our recording conditions. A comparison of the presented method with conventional 30 Hz ERG was performed. Bland-Altman plots indicated good agreement (mean difference, -0.045 µV; limits of agreement, 0.193 to -0.282 µV) between the resulting amplitudes. Within-session test-retest variability was 15%, comparing favorably to the variability of standard ERG amplitudes., Conclusions: This novel method extracts highly reliable clinical recordings of low-amplitude flicker ERGs and effectively detects artifactual responses. It has potential value both as a cone outcome variable and planning tool in clinical trials on natural history and treatment of advanced RDs.

Background: Inherited retinal disorders (IRDs) are a complex group of heritable diseases which are characterized by rod, cone, retinal pigment epithelium, or optic nerve dysfunction. Recently, mutations in CLN3 have also been associated with isolated IRDs. Herein, a case with heterozygous CLN3 variations that had not been previously linked to a CLN3 -isolated retinal degeneration ( CLN3 IRD) phenotype in a Hispanic female and its multimodal imaging findings across a 10-year follow-up are presented., Material and Methods: An observational, prospective, case report on a hispanic female with CLN3 IRD is presented. Patients underwent genetic testing and color fundus photography (CFC) and autofluorescence (FAF), fluorescein angiography (FA), Spectral domain optical coherence tomography (OCT) of the macular area, electroretinogram (ERG) and 30-2 visual field examination through automated perimetry., Results: A female, aged 24, affected by CLN3 IRD phenotype from c.944dup and c.1305C>G compound heterozygous variants, presented with bilateral hypopigmentary changes in the macular area of OU with that corresponded to hyporautofluorescent deposits in the macular area on FAF. An atrophic maculopathy was evident on structural OCT, and FA disclosed a symmetrical macular hyperflourescence with staining in the early and late stages in OU. Humphrey visual field testing showed a marked reduction of the central visual field in OU. Electrophysiological testing revealed an ERG with markedly decreased a and b waves in OU. In ten years follow up developed of bone spiculae in the midperipheral retina., Conclusions: We reported a patient with a novel CLN3 IRD severe phenotype associated with the variants c.944dup and c.1305C>G, which had previously only been associated with JCNL.

Background/aims: The purpose of this study was to investigate retinal structure in detail of subjects with autosomal-dominant (AD) and autosomal-recessive (AR) PROM1 -associated retinal degeneration ( PROM1 -RD), study design: institutional, cross-sectional study., Methods: Four eyes from four subjects (three with AD and one with AR) PROM1 -RD were investigated by ophthalmic examination including best-corrected visual acuity (BCVA) and multimodal retinal imaging: fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) and adaptive optics scanning light ophthalmoscopy. Quantitative assessment of atrophic lesions determined by FAF, thickness of individual retinal layers and cone photoreceptor quantification was performed., Results: BCVA ranged from 20/16 to 20/200. Initial pathological changes included the presence of hyperautofluorescent spots on FAF imaging, while later stages demonstrated discrete areas of atrophy. In all patients, thinning of the outer retinal layers on SD-OCT with varying degrees of atrophy could be detected depending on disease-causing variants and age. Cone density was quantified both in central and/or at different eccentricities from the fovea. Longitudinal assessments were possible in two patients., Conclusions: PROM1 -RD comprises a wide range of clinical phenotypes. Depending on the stage of disease, the cone mosaic in PROM1 -RD is relatively preserved and can potentially be targeted by cone-directed interventions., Competing Interests: Competing interests: SS serves as a consultant for Amgen, Apellis, Alnylam, Pfizer, Abbvie/Allergan, Roche/Genentech, Novartis, Regeneron, 4DMT, Oxurion, Gyroscope, Nanoscope, Heidelberg, Optos, and Centervue. He has received speaker fees from Heidelberg, Carl Zeiss Meditec, Nidek, Topcon, Optos, and Novartis. He has received research instruments from Heidelberg, Carl Zeiss Meditec, Nidek, Topcon, Optos and Centervue., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To evaluate olfaction in dogs with sudden acquired retinal degeneration syndrome (SARDS) compared with sighted dogs and blind dogs without SARDS as control groups., Animals Studied: Forty client-owned dogs., Procedure: Olfactory threshold testing was performed on three groups: SARDS, sighted, and blind/non-SARDS using eugenol as the test odorant. The olfactory threshold was determined when subjects indicated the detection of a specific eugenol concentration with behavioral responses. Olfactory threshold, age, body weight, and environmental room factors were evaluated., Results: Sixteen dogs with SARDS, 12 sighted dogs, and 12 blind/non-SARDS dogs demonstrated mean olfactory threshold pen numbers of 2.8 (SD = 1.4), 13.8 (SD = 1.4), and 13.4 (SD = 1.1), respectively, which correspond to actual mean concentrations of 0.017 g/mL, 1.7 × 10 -13  g/mL and 4.26 × 10 -13  g/mL, respectively. Dogs with SARDS had significantly poorer olfactory threshold scores compared with the two control groups (p < .001), with no difference between the control groups (p = .5). Age, weight, and room environment did not differ between the three groups., Conclusions: Dogs with SARDS have severely decreased olfaction capabilities compared with sighted dogs and blind/non-SARDS dogs. This finding supports the suspicion that SARDS is a systemic disease causing blindness, endocrinopathy, and hyposmia. Since the molecular pathways are similar in photoreceptors, olfactory receptors, and steroidogenesis with all using G-protein coupled receptors in the cell membrane, the cause of SARDS may exist at the G-protein associated interactions with intracellular cyclic nucleotides. Further investigations into G-protein coupled receptors pathway and canine olfactory receptor genes in SARDS patients may be valuable in revealing the cause of SARDS., (© 2023 The Authors. Veterinary Ophthalmology published by Wiley Periodicals LLC on behalf of American College of Veterinary Ophthalmologists.)

Purpose: To evaluate the progression of atrophy as determined by spectral-domain optical coherence tomography (SD-OCT) in patients with molecularly confirmed PROM1-associated retinal degeneration (RD) over a 24-month period., Design: International, multicenter, prospective case series., Methods: A total of 13 eyes (13 patients) affected with PROM1-associated RD were enrolled at 5 sites and SD-OCT images were obtained at baseline and after 24 months. Loss of mean thickness (MT) and intact area were estimated after semi-automated segmentation for the following individual retinal layers in the central subfield (CS), inner ring, and outer ring of the ETDRS grid: retinal pigment epithelium (RPE), outer segments (OS), inner segments (IS), outer nuclear layer (ONL), inner retina (IR), and total retina (TR)., Results: Statistically significant losses of thickness of RPE and TR were detected in the CS and inner ring and of ONL and IS in the outer ring (all P < .05); a statistically significant decrease in the intact area of RPE and IS was observed in the inner ring, and of ONL in the outer ring (all P < .05); the change in MT and the intact area of the other layers showed a trend of decline over an observational period of 24 months., Conclusions: Significant thickness losses could be detected in outer retinal layers by SD-OCT over a 24-month period in patients with PROM1-associated retinal degeneration. Loss of thickness and/or intact area of such layers may serve as potential endpoints for clinical trials that aim to slow down the disease progression of PROM1-associated retinal degeneration., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Retinitis pigmentosa (RP) is an inherited retinal disorder characterized by the degeneration of photoreceptors. Rho P23H/+ mice, which carry a Pro23His mutation in the RHODOPSIN (Rho) gene, are one of the most studied animal models for RP. However, except for the photoreceptors, other retinal neural cells have not been fully investigated in this model. Here, we record the temporal changes of the retina by optical coherence tomography (OCT) imaging of the Rho P23H/+ mice, from early to mid-phase of retinal degeneration. Based on thickness analysis, we identified a natural retinal thickness adaption in wild-type mice during early adulthood and observed morphological compensation of the inner retina layer to photoreceptor degeneration in the Rho P23H/+ mice, primarily on the inner nuclear layer (INL). Rho P23H/+ mice findings were further validated via: histology showing the negative correlation of INL and ONL thicknesses; as well as electroretinogram (ERG) showing an increased b-wave to a-wave ratio. These results unravel the sequential morphologic events in this model and suggest a better understanding of retinal degeneration of RP for future studies., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this study was to describe and diagnose the difficulty in a long-term follow-up (eleven years) patient with a very early presentation of late-onset retinal degeneration (L-ORD) and the significance of electrophysiological examinations and follow-up in assessing undiagnosed inherited retinal diseases., Methods: This is an observational case report of a 56-year-old woman, with scattered multiple yellow-white retinal dots firstly diagnosed as fundus albipunctatus. Ten years after presentation, a deterioration in rod and cone responses in ff-ERG was detected, which allowed us to discard the first diagnostic hypothesis and proceed with a genetic testing., Results: Ten years after presentation, she presented a clear progression of the abnormal photoreceptor response with a cone and rod involvement in ff-ERG, which was not compatible with the previous suspicion of fundus albipunctatus. Six months later, genetic testing results together with the typical progression of atrophic patchy lesions in multimodal imaging allowed a certain diagnosis of L-ORD, caused by an already reported pathogenic variant in the C1QTNF5 gene (c.563C > T; p. Pro188 Leu)., Conclusions: We demonstrate the importance of the ff-ERG examination and the follow-up (or ERG and imaging repetition) in the differential diagnosis of an incipient L-ORD, which can be easily misdiagnosed in the early stages, before the appearance of the characteristic chorioretinal atrophy seen with the progression of this rare disease., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Degenerative changes in the peripheral regions of the ocular fundus allow a closer look at both the role of collagen genes and their mutations in children with high myopia., Purpose: The study investigates the features of genetic mutations in children with high myopia combined with peripheral retinal degenerations., Material and Methods: Study group was formed from the database of genetic studies of the Scientific and Clinical Center OOO Oftalmic, which consists of 4362 patients referred for medical genetic counseling and molecular genetic testing from 2016 to 2021. Selection criteria were: male and female patients, aged 5-18 years old, who had the following clinical signs: high myopia (>6.00 D) and the presence of peripheral retinal degenerations (PRD). The study considered both isolated cases of ophthalmic pathology, as well as its syndromic forms. The final selection included 40 children. All patients had consulted with a geneticist. Whole-exome sequencing (WES), next generation sequencing (NGS), and single gene sequencing were conducted by taking 5 mL of peripheral venous blood and extracting deoxyribonucleic acid (DNA)., Results: In patients with isolated cases of ophthalmic pathology (peripheral retinal degenerations and high myopia) with a confirmed genetic diagnosis, mutations in the COL2A1 gene were detected in 77.4% of cases, and in the COL11A1 gene - in 22.6% of cases. In Stickler syndrome with a confirmed genetic diagnosis, mutations in the COL2A1 gene were detected in 33.3% of cases. In Marshall syndrome, the mutation in the COL11A1 gene was detected in 11.1% of cases. In children with Ehlers-Danlos, Knobloch type 1, Cohen, Marfan, Wagner syndromes mutations in the genes COL5A1 , COL18A1 , VPS13B , FBN1 , VCAN were detected in 55.6% of cases. In 33.3% of cases of Knobloch type 1, Cohen, Wagner syndromes the mutation is found in both copies of the gene (i.e., in both chromosomes), which leads to the development of peripheral retinal degenerations with high myopia., Conclusion: The results of the conducted molecular genetic testing expand our understanding of the mutation spectrum in the genes of children with both isolated cases of ophthalmic pathology, as well as syndromic pathology.

Introduction: Obtaining a genetic diagnosis via genetic testing (GT) is a fundamental step in determining the eligibility of a patient to be enrolled in emerging clinical trials and research studies. Besides, the knowledge of genetic outcome allows patients to plan for significant life choices. However, critical barriers exist to an equitable access to genetic services globally. The objective of this study was to explore patient experiences while seeking genomic services for inherited retinal degenerations (IRDs)., Methods: An online survey was designed based on a focus group conducted by Retina International and including people affected by IRDs and their families living in different regions around the world. The survey was then circulated to 43 Retina International member organisations globally via email newsletters and social networks. The survey involved questions in relation to the accessibility, affordability, and timeliness of genomic services for IRDs as well as patient perceived awareness of genomic services for IRDs among healthcare professionals., Results: A total of 410 respondents (IRD patients and caregivers) from over 30 countries across all continents responded to the survey. A considerable number of the patients had to go through a long and arduous journey to access GT and counselling services, wherein 40% had to visit more than 5 physicians, 27% had to visit more than 5 clinics, and 57% had to wait for more than 3 years before obtaining a genetic diagnosis. Furthermore, 46% of respondents reported not receiving genetic counselling prior to undergoing GT, and 39% reported not receiving genetic counselling after undergoing GT. Over 3/4th of the participants reported that they did not have to pay for their genomic services for IRDs. Thirty-seven percent of the respondents reported that their eye care professionals (ECPs) were either not aware of GT, remained neutral, or did not encourage them to undergo GT., Conclusion: Patients with IRDs do not have equitable access to best practice GT and counselling services. Greater awareness and training regarding IRDs and the benefits of GT and genetic counselling for patients and families are needed among ECPs. A best practice model on access to genomic services for IRDs is required., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Classify the appearance and quantify the growth rate of chorioretinal atrophy in patients who received voretigene neparvovec-rzyl (VN) for RPE65-mediated retinal degeneration., Design: Multicenter retrospective analysis., Subjects: Patients who underwent subretinal VN injection at 5 institutions and demonstrated posterior-pole chorioretinal atrophy., Methods: Ultrawidefield scanning laser ophthalmoscopy or color fundus photos were assessed before and after subretinal VN. Atrophy was defined as regions with ≥ 2 of the following: (1) partial or complete retinal pigment epithelial depigmentation; (2) round shape; (3) sharp margins; and (4) increased visibility of choroidal vessels. Atrophy was qualitatively classified into different subtypes. All atrophy was manually segmented. Linear mixed-effects models with random slopes and intercepts were fit using atrophy area and square root of atrophy area., Main Outcome Measures: Number of eyes with each atrophy pattern, and slopes of linear mixed-effects models., Results: Twenty-seven eyes from 14 patients across 5 centers developed chorioretinal atrophy after subretinal VN. A mean of 5.8 ± 2.7 images per eye obtained over 2.2 ± 0.8 years were reviewed, and atrophy was categorized into touchdown (14 eyes), nummular (15 eyes), and perifoveal (12 eyes) subtypes. Fifteen eyes demonstrated > 1 type of atrophy. Thirteen of 14 patients demonstrated bilateral atrophy. The slopes of the mixed-effects models of atrophy area and square root of atrophy area (estimate ± standard error) were 1.7 ± 1.3 mm 2 /year and 0.6 ± 0.2 mm/year for touchdown atrophy, 5.5 ± 1.3 mm 2 /year and 1.2 ± 0.2 mm/year for nummular atrophy, and 16.7 ± 1.8 mm 2 /year and 2.3 ± 0.2 mm/year for perifoveal atrophy. The slopes for each type of atrophy were significantly different in the square root of atrophy model, which best fit the data (P < 0.05)., Conclusions: Chorioretinal atrophy after subretinal VN for RPE65-mediated retinal degeneration developed according to a touchdown, nummular, and/or perifoveal pattern. Perifoveal atrophy grew the most rapidly, while touchdown atrophy grew the least rapidly. Understanding the causes of these findings, which are present in a minority of patients, merits further investigation., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to present our findings on the natural history of late-onset retinal degeneration (LORD) in patients with molecularly confirmed C1QTNF5 heterozygous pathogenic variants and assess suitability of retinal structure parameters for disease monitoring., Methods: Sixteen patients with C1QTNF5-LORD were retrospectively identified from Moorfields Eye Hospital, UK. Fundus autofluorescence (FAF), optical coherence tomography (OCT) scans, and best-corrected visual acuity (BCVA) were collected. Area of atrophy (AA) was manually drawn in FAF images. Ellipsoid zone (EZ) width and foveal retinal thickness of the whole retina and outer retina were extracted from OCT scans. Age-related changes were tested with linear-mixed models., Results: Patients had median age of 62.3 years (interquartile range [IQR] = 58.8-65.4 years) at baseline, and median follow-up of 5.1 years (IQR = 2.6-7.6 years). AA, EZ width, and retinal thickness parameters remained unchanged until age 50 years, but showed significant change with age thereafter (all P < 0.0001). AA and EZ width progressed rapidly (dynamic range normalized rates = 4.3-4.5%/year) from age 53.9 and 50.8 years (estimated inflection points), respectively. Retinal thickness parameters showed slower progression rates (range = 1.6-2.5%/year) from age 60 to 62.3. BCVA (median = 0.3 LogMAR, IQR = 0.0-1.0 at baseline) showed a rapid decline (3.3%) from age 70 years. Findings from patients with earlier disease showed FAF atrophy manifests in the temporal retina initially, and then progresses nasally., Conclusions: Patients with LORD remained asymptomatic until age 50 years, before suffering rapid outer retinal degeneration. EZ width and AA showed rapid progression and high interocular correlation, representing promising outcome metrics. Clinical measures also capturing the temporal retina may be preferable, enabling earlier detection and better disease monitoring., Translational Relevance: Area of atrophy in FAF images and OCT-measured EZ width represent promising outcome metrics for disease monitoring in patients with C1QTNF5-LORD.

Rationale: Cohen syndrome is a rare genetic disorder that can cause various symptoms, including ophthalmic manifestations that can significantly impact a patient's visual health and quality of life., Patient Concerns: We present the case of a 12-year-old boy diagnosed with Cohen syndrome who exhibited retinal degeneration and macular edema but could not express ophthalmic symptoms due to a developmental disability., Diagnoses: The patient was diagnosed with Cohen syndrome by a heterozygous mutation in the VPS13B gene by whole exome sequencing and referred to ophthalmology for an ophthalmic examination., Intervention: Ophthalmologic tests, including visual acuity, intraocular pressure, slit lamp examination, fundus photography, and optical coherence tomography, were performed., Outcomes: Visual acuity and intraocular pressure were not measured due to poor cooperation, and no abnormal findings were observed on the slit lamp examination. However, peripheral retinal degeneration was observed in the fundus examination, and cystoid macular edema was observed in both eyes on optical coherence tomography., Lessons: Regular ophthalmologic examination is important for patients with Cohen syndrome, especially those with developmental disabilities who may not be able to express their symptoms. Clinicians should be aware of the potential ophthalmologic manifestations of Cohen syndrome and the importance of timely diagnosis and management., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To describe the clinical, preliminary electroretinographic and optical coherence tomography features of a newly identified form of progressive retinal atrophy (PRA) in German Spitzes, and identify the causal gene mutation., Animals: Thirty-three client-owned German Spitz dogs were included., Procedures: All animals underwent a full ophthalmic examination, including vision testing. In addition, fundus photography, ERG, and OCT were performed. A DNA-marker-based association analysis was performed to screen potential candidate genes and the whole genomes of four animals were sequenced., Results: Initial fundus changes were pale papilla and mild vascular attenuation. Oscillatory nystagmus was noted in 14 of 16 clinically affected puppies. Vision was impaired under both scotopic and photopic conditions. Rod-mediated ERGs were unrecordable in all affected dogs tested, reduced cone-mediated responses were present in one animal at 3 months of age and unrecordable in the other affected animals tested. Multiple small retinal bullae were observed in three clinically affected animals (two with confirmed genetic diagnosis). OCT showed that despite loss of function, retinal structure was initially well-preserved, although a slight retinal thinning developed in older animals with the ventral retina being more severely affected. Pedigree analysis supported an autosomal recessive inheritance. A mutation was identified in GUCY2D, which segregated with the disease (NM&#95;001003207.1:c.1598&#95;1599insT; p.(Ser534GlufsTer20)). Human subjects with GUCY2D mutations typically show an initial disconnect between loss of function and loss of structure, a feature recapitulated in the affected dogs in this study., Conclusion: We identified early-onset PRA in the German Spitz associated with a frameshift mutation in GUCY2D., (© 2023 American College of Veterinary Ophthalmologists.)

Background/aims: Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a neurodegenerative, blinding lysosomal storage disorder. The purpose of the current study was to characterise the progression of CLN2-associated retinal degeneration in patients under intraventricular enzyme replacement therapy (ERT) with cerliponase alfa., Methods: We analysed visual function, retinal morphology and neuropaediatric data using preferential looking test (PLT), Weill Cornell Batten Scale (WCBS), optical coherence tomography (OCT) imaging and the Hamburg Motor-Language late-infantile neuronal ceroid lipofuscinosis (LINCL) Scale (M-L scale)., Results: Fifty-six eyes of 28 patients had baseline PLT, WCBS and OCT. 15 patients underwent serial examinations, resulting in a total of 132 OCT scans and WCBS results, 66 Hamburg M-L scores and 49 PLT results during a mean follow-up time of 18.2 months (range 5-40). A negative correlation (r=-0.69, p<0.001) was found between central retinal thickness (CRT) values and age at examination with a maximal annual decrease of 23 µm between 56 and 80 months of age. A significant correlation was observed between PLT results and the age at examination (r=0.46, p=0.001), the WCBS scores (r=0.62; p<0.001) and CRT values (r=-0.64; p<0.001). The M-L score correlated with the ocular measurements (CRT: r=0.58, p<0.001; WCBS r=-0.64, p<0.001; PLT score: r=-0.57, p<0.001)., Conclusion: Despite intraventricular ERT, retinal degeneration progressed in patients with CLN2 and was particularly pronounced between 56 and 80 months of age. Retina-directed therapies should therefore be initiated before or as early as possible during the phase of rapid retinal degeneration. PLT and WCBS were identified as valuable outcome measures to monitor disease progression., Trial Registration Number: NCT04613089., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Late-onset retinal degeneration (L-ORD) is a rare autosomal dominant retinal degeneration that presents in the sixth decade and leads to severe visual loss. The objective of this paper is to describe outer retinal corrugations as a diagnostic feature of L-ORD., Methods: This retrospective study reviewed consecutive patients diagnosed with L-ORD, confirmed through complete ophthalmic examination, multimodal imaging and genetic tests. Multimodal imaging investigations included spectral domain-optical coherence tomography (SD-OCT) and ultra-wide-field colour and autofluorescence fundus photographs., Results: A total of 13 eyes of 9 patients with L-ORD had outer retinal corrugations identified on OCT scans., Conclusion: Outer retinal corrugations may be a diagnostic finding for L-ORD. The detection of this sign may aid diagnosis and characterisation of this disease and help in the differential diagnosis with other acquired pathologies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: An 18-year old highly myopic woman presented with bilateral retinoschisis associated with a unilateral macular hole in the right eye and vitreomacular traction in the left eye., Methods: Genetic studies disclosed a heterozygous pathogenic variant in the KCNJ13 gene was identified (c.484C>T (p.Arg162Trp)), consistent with a diagnosis of snowflake vitreoretinal degeneration (SVD)., Results: While there were no corneal guttata, juvenile cataracts, or perivascular sheathing in this case, salient features of SVD included a fibrillar vitreous structure, crystalline retinopathy, and flattened optic nerves. The patient developed a FTMH in the left eye at 17 months follow up, followed by a rhegmatogenous retinal detachment (RRD) requiring 2 surgical repairs., Conclusion: This case expands on the spectrum of clinical features in SVD, including retinoschisis and FTMH. It also characterizes optical coherence tomography findings in this rare disease entity. We emphasize the importance of using panel-based genetic testing to clinically distinguish and further define atypical vitreoretinopathies.

Purpose: Late-onset retinal degeneration (L-ORD) is a rare retinal dystrophy with anterior segment (AS) abnormalities, including long anterior zonules (LAZ) and iris atrophy. This investigation evaluates AS changes in a L-ORD cohort., Methods: Prospective, longitudinal study including L-ORD individuals (Ser163Arg) with ocular exam and standard slit-lamp photographs between 2011 and 2022. AS images were merged and assessed for LAZ number and zonule-free zone (ZFZ) radius. Further clinical findings such as iris atrophy patterns were reported descriptively., Results: Twelve eyes of 6 patients (4 males, median age = 60.5 years) were included, showing a median of 160 (11-372) LAZs, mainly localized superiorly (39%) and inferiorly (24%). There was a high inter-ocular correlation (rs = 0.94, p < 0.01), no difference in LAZ count between eyes (p = 0.82), and an inverse relationship between LAZ and age (r =  - 0.82; p < 0.05). The ZFZ had median 2.1 mm (1.3-5.4), with no inter-ocular difference (p = 0.31). Iris transillumination defects occurred in 11/12 eyes, with 4 major patterns identified: pupillary ruff rarefaction (10/12), patchy atrophy (6/12), notched defects (6/12), and radial streaks (2/12). In a short-term follow-up of 5.9 years, 4 eyes showed a reduction in LAZ count to median 139.5 (67-169) (p = 0.50) and a concomitant increase in ZFZ measurement to median 2.2 (1.7-2.6) (p = 0.17)., Conclusion: This study confirms symmetric LAZs count and ZFZ in L-ORD, with ZFZ measurements smaller than in previous cohorts. A reduction in LAZs count and an increase in ZFZ with age were suggested longitudinally, yet findings need further evaluation as follow-up was limited to two cases., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/aims: Voretigene neparvovec (VN) is the first and only subretinal gene therapy approved by the Food and Drug Administration and European Medicines Agency. Real-world application has started in 2018 in patients with vision impairment due to biallelic retinal pigment epithelium ( RPE ) 65 mutation-associated inherited retinal degenerations. Herein, we evaluated the development of retinal atrophy within in a single-centre patient cohort treated with VN., Methods: 13 eyes of eight patients treated with VN were retrospectively analysed for areas of retinal atrophy over a period of 6-24 months following surgery. Ultrawide field images were used to measure the area of atrophy. Fundus autofluorescence imaging is presented as an instrument for early detection of signs of retinal atrophy in these patients., Results: Atrophic changes beyond the retinotomy site were observed in all eyes. Areas of atrophy developed within the area of detachment (bleb) in all eight patients and outside the bleb in three patients. Changes in autofluorescence preceded the development of retinal atrophy and were already evident 2 weeks after surgery in the majority of patients. The areas of atrophy increase with time and progression continued over year 1. Functional outcomes remained stable (VA, FST, visual field)., Conclusion: Subretinal injection of VN can lead to RPE atrophy with consequent photoreceptor loss in and outside of the bleb area. Fundus autofluorescence is an important tool to monitor atrophic changes in patients after gene therapy. Interestingly, while areas of atrophy also included central areas, the functional benefits of the treatment did not appear to be affected and remained stable., Competing Interests: Competing interests: DF is on the advisory board of and/or consulting and/or receiving honoraria/grant money/travel support from following companies: Adelphi Values, Advent France Biotechnology, Alphasights, Arctos Medical, Atheneum, Axiom Healthcare Strategies, Biogen, Cambridge Consultants, Decision Resources, Dialectica, Frontera Therapeutics, Janssen Research & Development, Navigant, Novartis, Roche, RegenxBio, Sirion, System Analytic, and STZeyetrial. He is director of Fischer Consulting Limited and holds a patent (50%) on a gene therapy product for X-linked Retinitis Pigmentosa. FW reports personal fees from Novartis, outside the submitted work. KS reports personal fees from Novartis, outside the submitted work. SK reports grants from Charlotte & Tistou Kerstan Foundation, during the conduct of the study; personal fees from Novartis, outside the submitted work. No other disclosures were reported., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: In this study, we described a large family presenting different manifestations of cone dystrophy at different ages associated with GUCY2D gene mutation., Method: Sixty-three individuals of a single kindred, including 23 affected with cone dystrophies, were recruited and received ocular examinations, including best corrected visual acuity, intraocular pressure, slit-lamp biomicroscopy, color fundus photograph (CFP), fundus autofluorescence, optical coherence tomography, fluorescence fundus angiography, color vision testing, full-field electroretinography, and electro-oculogram. Whole exome sequencing (WES) and Sanger sequencing were performed for underlying mutations associated with cone dystrophy., Result: There were 23 affected family members. Clinical analysis showed that the proband and other patients had impaired visual acuity ranging from 20/800 to 20/50 with impaired color vision. Fundus photograph showed retinal pigment epithelium (RPE) granular abnormalities with depressed macular reflex in young patients and macular or retinochoriodal atrophy in older patients. OCT examination confirmed the reduced outer retinal thickness or inner retinal thickness, absence of the ellipsoid zone (EZ) and retinal atrophy to varying degrees. Electroretinography revealed a reduced cone response combined with a relatively maintained rod response. WES and Sanger sequencing revealed a heterozygous variant c.2512C>T in the GUCY2D gene of the affected family members., Conclusions: We reported cone dystrophy in 23 affected individuals in a five-generation family and demonstrated different macular abnormalities in OCT scans and CFP at different ages. The multimodal ocular records in our study provide physicians and ophthalmologists with a better understanding of cone dystrophy associated with GUCY2D mutation., (© 2022. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Purpose: To describe cone structure changes using adaptive optics scanning laser ophthalmoscopy (AOSLO) in the Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A) study., Design: Multicenter, longitudinal natural history study., Methods: AOSLO images were acquired at 4 centers, twice at baseline and annually for 24 months in this natural history study. For each eye, at least 10 regions of interest (ROIs) with ≥50 contiguous cones were analyzed by masked, independent graders. Cone spacing Z-scores, standard deviations from the normal mean at the measured location, were compared between graders and tests at baseline. The association of cone spacing with clinical characteristics was assessed using linear mixed effects regression models weighted by image quality score. Annual rates of change were calculated based on differences between visits., Results: Fourteen eyes of 14 participants were imaged, with 192 ROIs selected at baseline. There was variability among graders, which was greater in images with lower image quality score (P < .001). Cone spacing was significantly correlated with eccentricity, quality score, and disease duration (P < .02). On average, the cone spacing Z-score increased 0.14 annually (about 9%, P < .001). We observed no significant differences in rate of change between disease type (Usher syndrome or retinitis pigmentosa), imaging site, or grader., Conclusions: Using current methods, the analysis of quantitative measures of cone structure showed some challenges, yet showed promise that AOSLO images can be used to characterize progressive change over 24 months. Additional multicenter studies using AOSLO are needed to advance cone mosaic metrics as sensitive outcome measures for clinical trials. NOTE: Publication of this article is sponsored by the American Ophthalmological Society., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To report a case of nonparaneoplastic autoimmune retinopathy with phenotypical features of pericentral retinal degeneration (PRD) who responded to IV immunoglobulin therapy., Methods: A case report. A 27-year-old man presented with recent subacute progressive nyctalopia and photopsia., Results: Dilated fundoscopy demonstrated confluent yellow-white patches along the main temporal vascular arcades with sparing of the central island in the posterior pole. Color vision, fundus autofluorescence, fluorescein angiography, static visual field, and electroretinographic studies were inconclusive for retinal degeneration. Subsequent genetic testing for known mutations was negative. Workup for paraneoplastic autoimmune retinopathy was negative. Antiretinal antibodies were positive. The patient was diagnosed with nonparaneoplastic autoimmune retinopathy and was treated with IV immunoglobulin, which resulted in objective and subjective improvement on electroretinography, visual field, and optical coherence tomography of the retina., Conclusion: Nonparaneoplastic autoimmune retinopathy may present in a patient with the clinical phenotype of PRD. It is essential to rule out nonparaneoplastic autoimmune retinopathy in patients with subacute changes in the natural course of pericentral retinal degeneration because treatment with IV immunoglobulin may be helpful.

Purpose: To describe the natural history, genetic landscape, and phenotypic spectrum of Eyes shut homolog (EYS)-associated retinal degeneration (EYS-RD)., Design: Retrospective, single-center cohort study complemented by a cross-sectional examination., Subjects: Patients with biallelic EYS variants were recruited at an inherited RD referral center in Portugal., Methods: Every patient underwent a cross-sectional examination comprising a comprehensive ophthalmic examination including best-corrected visual acuity (BCVA), dilated slit-lamp anterior segment, and fundus biomicroscopy; ultrawide-field color fundus photography and fundus autofluorescence imaging; and spectral domain-OCT. In the setting of a retinitis pigmentosa (RP) diagnosis, every patient was classified as typical or atypical RP according to imaging criteria. Baseline demographics, age at onset of symptoms, family history, history of consanguinity, symptoms, age at diagnosis, BCVA at baseline and throughout follow-up, and EYS variants were collected from each individual patient file., Main Outcome Measures: Clinical/demographic, genetic, multimodal imaging data, and BCVA variation were compared between typical and atypical RP. Additionally, BCVA variation during follow-up was used as an endpoint to describe EYS-RD natural history., Results: Fifty-eight patients (59% men; mean age 52 ± 14 years) from 48 White families of Portuguese ancestry were included. Twenty distinct EYS variants were identified, 8 of which are novel. In 32.8% of patients, onset of symptoms was in early adulthood (21-30 years). A clinical diagnosis of RP was established in 57 patients and cone-rod dystrophy in 1 patient. Regarding RP, 75.0% of the patients were graded as typical and 25.0% as atypical. Atypical EYS-RP commonly presents with inferior crescent-shaped macular atrophy with superior midperipheral sparing. In EYS-RD, a negative correlation was found between age and BCVA (r = -0.50; P < 0.001), with an average loss of 1.45 letters per year. When stratifying for RP phenotype, lower average loss of letters per year (P < 0.001), higher BCVA (P < 0.001), and larger ellipsoid zone widths (P < 0.001) were found in atypical RP., Conclusions: This study expands the genetic spectrum of EYS-RD by reporting 8 novel variants. A high frequency of atypical phenotypes was identified. These patients have better BCVA and larger ellipsoidal zone widths, thus presenting an overall better prognosis., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To report a case of nonparaneoplastic autoimmune retinopathy in a patient with a diagnosis of Lambert-Eaton myasthenic syndrome., Methods: Case report. Main outcome measures included findings on retinal examination and analysis of fundus autofluorescence, spectral-domain optical coherence tomography, and full-field electroretinogram. Vitamin A levels and results of antiretinal antibody testing and paraneoplastic workup are also presented., Results: A 47-year-old male presented with a 1-year history of bilateral vision loss and nyctalopia. Past medical history was significant for Lambert-Eaton myasthenic syndrome, confirmed by positive voltage-gated calcium channel antibodies, and thymectomy reported as thymic follicular hyperplasia. Optical coherence tomography showed bilateral diffuse outer retinal atrophy and ellipsoid zone loss. Fundus autofluorescence displayed a bull's pattern of hyperautofluorescence around each fovea. Full-field electroretinogram showed an extinguished rod response and a severely depressed cone response in each eye., Conclusion: We describe a case of nonparaneoplastic autoimmune retinopathy in a patient with Lambert-Eaton myasthenic syndrome. Multimodal retinal imaging and electroretinogram confirmed the presence of autoimmune retinopathy with severe rod-cone degeneration. The association of this myasthenic syndrome with AIR is novel.

Purpose: To describe the clinical phenotype and molecular diagnosis of a patient with atypical presentation of enhanced S-cone syndrome., Methods: This is a case report of a patient who underwent best-corrected visual acuity, slit-lamp exam, fundus examination, autofluorescence, optical coherence tomography, kinetic perimetry, and full-field electroretinography. Genetic testing was performed via next-generation sequencing., Results: A 33-year-old female patient presented with mild nyctalopia, but normal rod function measured by electroretinogram and foveoschisis on optical coherence tomography. She also presented a double hyperautofluorescent ring on autofluorescence. Genetic testing found a pathogenic variant c.925C>G (p.Arg309Gly) and a likely pathogenic variant c.299C>T (p.Arg77Trp) in NR2E3 gene., Conclusion: Enhanced S-cone syndrome may present without the pathognomonic findings of decreased rod function on electroretinogram, suggesting the importance of genetic testing in retinal diseases for diagnosis., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Background: Single-stranded DNA-binding protein 1 (SSBP1) plays an essential role in mitochondrial DNA (mtDNA) replication and maintenance, as well as development of retina. Here, we describe the clinical findings and genetic basis of a family with two members affected with bilateral optic atrophy., Materials and Methods: Clinical data were retrospectively collected from an electronic medical record system. Genetic results were obtained using exome sequencing (ES) and genome sequencing (GS)., Results: A 36-year-old man presented with low vision in both eyes since early childhood, with a best-corrected visual acuity of 20/500 in both eyes. He exhibited generalized optic atrophy and diffuse retinal nerve fiber layer thinning without retinal degeneration in both eyes. The family history was consistent with autosomal dominant traits. ES was performed; however, we did not identify any pathogenic variants in the known dominant optic atrophy genes. Subsequently, GS was performed, and it revealed a novel heterozygous c.364A>G p.(Lys122Glu) variant in SSBP1 . In silico prediction supported it as deleterious, while segregation analysis detected it in his affected mother and his unaffected sister. No foveopathy or retinal degeneration was observed in the patient's family members., Conclusions: We report a novel pathogenic heterozygous SSBP1 variant in a family with autosomal dominant optic atrophy and incomplete penetrance. Furthermore, we demonstrated that GS is advantageous over ES even for the discovery of coding variants, providing uniform coverage. Therefore, GS should be emphasized to improve the molecular diagnostic rate of inherited optic neuropathy.

Purpose: To evaluate disease progression using static perimetry (SP) in patients with USH2A-related retinal degeneration, including Usher syndrome type 2 (USH2) and nonsyndromic autosomal recessive retinitis pigmentosa., Design: Prospective, observational cohort study., Methods: A total of 102 patients with biallelic disease-causing sequence variants in USH2A with baseline best-corrected visual acuity (BCVA) letter score ≥54 were recruited from 16 clinical sites in Europe and North America. SP, BCVA, full-field stimulus thresholds, spectral domain optical coherence tomography macular scans, and fundus-guided mesopic microperimetry were performed at baseline and annually. The main outcome measures were total hill of vision (V TOT ), hill of vision in the central 30° (V 30 ), V TOT minus V 30 (V PERIPH ), and mean sensitivity., Results: The average decline (95% CI) was 2.05 (1.40, 2.70) decibel-steradian (dB-sr)/y for V TOT , 0.48 (0.32, 0.65) dB-sr/y for V 30 , 1.53 (0.97, 2.08) dB-sr/y for V PERIPH , and 0.55 (0.40, 0.71) dB/y for mean sensitivity. Average percentage decline per year was 8.3 (5.5, 11.1) for V TOT , 5.2 (3.0, 7.4) for V 30 , 16.0 (9.5, 22.0) for V PERIPH , and 5.1 (3.5, 6.7) for mean sensitivity. Changes from baseline to year 2 in all SP measures were highly correlated (r's ranging from 0.52 [V 30 vs V PERIPH ] to 0.98 [V TOT vs V PERIPH ])., Conclusions: Quantitative measures of SP declined significantly over 2 years in USH2A-related retinal degeneration. The annual percentage rate of change was greatest for V TOT and V PERIPH , whereas V 30 and mean sensitivity changed least, reflecting earlier and more severe peripheral degeneration compared with central loss., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To compare cone structure and function between RPGR- and USH2A-associated retinal degeneration., Design: Retrospective, observational, cross-sectional study., Methods: This multicenter study included 13 eyes (9 participants) with RPGR-related X-linked retinitis pigmentosa (RPGR), 15 eyes (10 participants) with USH2A-related Usher syndrome type 2 (USH2), 16 eyes (9 participants) with USH2A-related autosomal recessive retinitis pigmentosa (ARRP), and 7 normal eyes (6 participants). Structural measures included cone spacing and density from adaptive optics scanning laser ophthalmoscopy and photoreceptor inner segment (IS), outer segment (OS), and outer nuclear layer (ONL) thickness from optical coherence tomography (OCT) images. OCT angiography images were used to study choriocapillaris flow deficit percent (CCFD). Cone function was assessed by fundus-guided microperimetry. Measures were compared at designated regions using analysis of variance with pairwise comparisons among disease groups, adjusted for disease duration and eccentricity., Results: OCT segmentation revealed shorter OS and IS, with reduced ONL thickness in RPGR compared to normal (OS: P < .001, IS: P = .001, ONL: P = .005), USH2 (OS: P = .01, IS: P = .03, ONL: P = .03), or ARRP (OS: P = .001, ONL: P = .03). Increased cone spacing was observed in both RPGR (P = .03) and USH2 compared with normal (P = .048). The mean CCFD in RPGR was greater than in USH2 (P = .02). Microperimetry demonstrated below-normal regional sensitivity in RPGR (P = .004), USH2 (P = .02), and ARRP (P = .009), without significant intergroup differences., Conclusions: Outer retinal structure and choriocapillaris perfusion were more abnormal in RPGR- than USH2A-related retinal degenerations, whereas there were no significant differences in below-normal regional sensitivity between each rod-cone degeneration associated with variants in these 2 genes expressed at the photoreceptor-connecting cilium., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To review and describe in detail the clinical course, functional and anatomic characteristics of RP2-associated retinal degeneration., Design: Retrospective case series., Participants: Male participants with disease-causing variants in the RP2 gene., Methods: Review of all case notes and results of molecular genetic testing, retinal imaging (fundus autofluorescence [FAF] imaging, OCT), and electrophysiology assessment., Main Outcome Measures: Molecular genetic testing, clinical findings including best-corrected visual acuity (BCVA), qualitative and quantitative retinal imaging analysis, and electrophysiology parameters., Results: Fifty-four molecularly confirmed patients were identified from 38 pedigrees. Twenty-eight disease-causing variants were identified, with 20 not previously clinically characterized. Fifty-three patients (98.1%) presented with retinitis pigmentosa. The mean age of onset (range ± standard deviation [SD]) was 9.6 years (1-57 ± 9.2 years). Forty-four patients (91.7%) had childhood-onset disease, with mean age of onset of 7.6 years. The most common first symptom was night blindness (68.8%). Mean BCVA (range ± SD) was 0.91 logarithm of the minimum angle of resolution (logMAR) (0-2.7 ± 0.80) and 0.94 logMAR (0-2.7 ± 0.78) for right and left eyes, respectively. On the basis of the World Health Organization visual impairment criteria, 18 patients (34%) had low vision. The majority (17/22) showed electroretinogram (ERG) evidence of a rod-cone dystrophy. Pattern ERG P50 was undetectable in all but 2 patients. A range of FAF findings was observed, from normal to advanced atrophy. There were no statistically significant differences between right and left eyes for ellipsoid zone width (EZW) and outer nuclear layer (ONL) thickness. The mean annual rate of EZW loss was 219 μm/year, and the mean annual decrease in ONL thickness was 4.93 μm/year. No patient with childhood-onset disease had an identifiable ellipsoid zone (EZ) after the age of 26 years at baseline or follow-up. Four patients had adulthood-onset disease and a less severe phenotype., Conclusions: This study details the clinical phenotype of RP2 retinopathy in a large cohort. The majority presented with early-onset severe retinal degeneration, with early macular involvement and complete loss of the foveal photoreceptor layer by the third decade of life. Full-field ERGs revealed rod-cone dystrophy in the vast majority, but with generalized (peripheral) cone system involvement of widely varying severity in the first 2 decades of life., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To describe blindness, initially presenting as a unilateral condition and diagnosed as sudden acquired retinal degeneration syndrome (SARDS)., Animals Studied: One Dachshund and four Maltese dogs presented with unilateral blindness, for which the results of general ophthalmic examinations were insufficient to explain the blindness. All dogs were spayed females., Results: Intraocular pressures were normal, and the optical media of the eyes were clear. Fundus appearances of the initially blind eyes were within normal variations, with slightly attenuated retinal blood vessels in some cases when compared with the sighted contralateral eyes. Electroretinography (ERG) amplitudes of the affected eyes were flat and reduced in the contralateral-sighted eyes in four dogs. One dog underwent ERG after the blindness progressed bilaterally 8 days after initial presentation (despite topical steroid medication). Two dogs had no recheck visits, but phone call follow-ups reported bilateral blindness 3 months later in one dog. One dog received no medication and retained vision in the contralateral eye until the last follow-up (94 days later). One dog received systemic cyclosporine and steroid medications and maintained vision in the contralateral eye; however, regular ERG rechecks showed a trend of declining amplitude (448 days). In this dog, optical coherence tomography (OCT) showed different stages of disorganized retinal layers as well as different retinal thickness between the eyes., Conclusions: Despite normal-looking fundi, ERG and OCT revealed different degrees of retinal changes between both eyes in this study. Eyes with vision might develop progressive blindness after a substantial amount of time in these presumed SARDS cases., (© 2023 American College of Veterinary Ophthalmologists.)

To review disparities in the field of inherited retinal degenerations to establish foundations for future discussions oriented toward finding possible solutions. A narrative overview of the literature. Despite collective efforts towards democratization of genetic testing and investigation, genetic databases containing primarily European populations are heavily relied upon. Access to specialized care and other resources is also still not available to all. Recognizing and addressing disparities and inequities within the field of inherited retinal degenerations will improve our care of these patients and our knowledge of their conditions.

Background: Wagner vitreoretinopathy (WVR) is a rare autosomal dominant vitreoretinopathy caused by pathogenic variants in the VCAN gene. The aim of this study was to report a novel splicing variant in VCAN identified in a three-generation Chinese family initially diagnosed with familial exudative vitreoretinopathy and to describe the patients' clinical features., Methods: Four affected individuals from a three-generation family underwent detailed ophthalmic examinations, including best-corrected visual acuity by Snellen E chart, slit-lamp biomicroscopy, indirect ophthalmoscopy under pupil dilatation, ocular B-ultrasonography, optical coherence tomography scans, and fundus autofluorescence. Targeted next-generation sequencing was performed to identify variants of the disease-causing gene for the proband, followed by co-segregation analysis using Sanger-DNA sequencing. Reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out to verify the effects of a variant on VCAN pre-mRNA splicing in the lymphocytes from the patients., Results: We detected a novel heterozygous variant c.4004-4&#95;c.4004-3delinsCA of VCAN in all four affected individuals. RT-PCR revealed that the novel variant caused an abnormal splicing in exon 8 of the VCAN and imbalanced versican transcripts. All four patients presented vitreous syneresis and bilateral retinal detachment occurring at different ages. The patients also showed different extents of visual defects and diverse clinical manifestations, including cataract, iris-lens synechiae, inverted papillae, and ectopic foveas., Conclusions: Our results expand the mutation spectrum of VCAN and further confirm that the splicing sites for exon 8 are mutation hot spots. Patients with WVR may present high phenotype variation; therefore, molecular analysis is very important for precise diagnosis of patients with inherited vitreoretinopathy., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Introduction: An increasing number of gene-specific therapies are being developed for inherited retinal degenerations (IRDs). Identification of well-characterized patients is an emerging need. We conducted the second multinational survey among the www.evicr.net and ERN-EYE members to understand the management and treatment of IRDs in Europe and compared it to the 2019 survey., Methods: An electronic survey questionnaire was developed and sent to 124 clinical centers (25 countries) by June/July 2021. Statistical analysis was performed with Excel and R., Results: The overall response rate was 44% but varied among countries. Only 9% of responding centers do not see IRD patients (2019 survey 14%), 42% follow at least 200 patients per year, 18% follow 500-999, and 2% more than 1,000. Databases exist in 86% of the centers (local 86%; national web based 12%). IRD patients are referred to www.evicr.net and ERN-EYE centers mainly by general ophthalmologists, patient self-referral, or medical retina specialists. Most IRD patients are first seen as adults. Signs and symptoms depend on age of onset: in infancy, nystagmus; at older age, night blindness and reduced visual field; reduced visual acuity is described at any age. Comprehensive ophthalmic examination always includes visual acuity and almost always visual field multimodal retinal imaging, electrophysiology, color vision testing, and refraction. Identification of genotypes is successful in 72% of centers in 40-80% of cases (2019 survey 69% of centers). The time for confirmation of the genetic diagnosis varies from 2-4 weeks to 24 months (2019 survey &gt;4 weeks ≤10 years). Genetic testing is covered by public health service in 83%, private health insurance in 29%, research funds in 24%; 5% do not have access to genetic testing (2019 survey 15%). The most striking result is the high increase in the involvement of centers in natural history and gene therapy trials that more than doubled for the latter., Discussion: This second multinational survey on management of IRDs in Europe highlights persistent important differences in the number of IRD patients managed per center, comparable diagnostic work-up, and increasing genotyping in diagnostic laboratories. The important increase in involvement of centers in natural history and gene therapy trials reflects the rapidly evolving field of gene therapy development. The survey provides important follow-up data for researchers, clinicians, caregivers, patient advocate groups, pharmaceutical companies, and investors., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

The overlapping genetic and clinical spectrum in inherited retinal degeneration (IRD) creates challenges for accurate diagnoses. The goal of this work was to determine the genetic diagnosis and clinical features for patients diagnosed with an IRD. After signing informed consent, peripheral blood or saliva was collected from 64 patients diagnosed with an IRD. Genetic testing was performed on each patient in a Clinical Laboratory Improvement Amendments of 1988 (CLIA) certified laboratory. Mutations were verified with Sanger sequencing and segregation analysis when possible. Visual acuity was measured with a traditional Snellen chart and converted to a logarithm of minimal angle of resolution (logMAR). Fundus images of dilated eyes were acquired with the Optos ® camera (Dunfermline, UK). Horizontal line scans were obtained with spectral-domain optical coherence tomography (SDOCT; Spectralis, Heidelberg, Germany). Genetic testing combined with segregation analysis resolved molecular and clinical diagnoses for 75% of patients. Ten novel mutations were found and unique genotype phenotype associations were made for the genes RP2 and CEP83 . Collective knowledge is thereby expanded of the genetic basis and phenotypic correlation in IRD.

Background: Bietti crystalline dystrophy is primarily a retinal dystrophy caused by a CYP4V2 mutation and typically presents with crystalline retinal deposits in the posterior fundus., Case Presentation: We present the case of an otherwise healthy 39-year-old Iranian woman with no family history of ocular disease who suffered with progressive vision loss that had started 2 years prior to presentation. Ocular examination revealed blurry optic nerve head margin and diffuse retinal crystalline deposit in both eyes. Spectral domain optical coherence tomography images showed retinal crystals, located mostly in outer retinal layers, with some areas of outer retinal tubulation and attenuation of outer retinal layers. Crystalline deposits were better visualized on near-infrared images as hyperreflective spots. Fundus autofluorescence images showed hyperautofluorescence areas on optic nerve head consistent with optic nerve head drusen and large hypoautofluorescence areas in posterior retina consistent with retinal pigment epithelium atrophy. Cystinosis was ruled out by blood testing., Conclusion: Bietti crystalline dystrophy may be associated with optic nerve head drusen., (© 2022. The Author(s).)

Purpose: To report a case of pigmented paravenous retinochoroidal atrophy in a patient that was found to have an autosomal dominant pathogenic variant of the hexokinase 1 ( HK1 ) gene., Methods: A case report., Results: A 41-year-old White woman with a distant family history of retinitis pigmentosa presented with a 5-year history of bilateral blurry and decreased vision that led to eventual loss of ability to drive. Color funduscopic photographs revealed retinochoroidal atrophy, hyper-reflective spots within the retina, and a paravenous distribution of pigment bilaterally. Given the patient's familial ocular history and workup, she was diagnosed with inherited retinal degeneration with phenotype suggestive of pigmented paravenous retinochoroidal atrophy. Genetic testing revealed a single rare variant, c.2551 G>A in the HK1 gene., Discussion: This case describes a pathogenic variant in HK1 , a gene that has been associated with RP, but has not been previously reported in association with the pigmented paravenous retinochoroidal atrophy phenotype. This expands the phenotypes associated with HK1 pathogenic variant, p.Glu851Lys, and the genetic association of pigmented paravenous retinochoroidal atrophy to include HK1 . Although pigmented paravenous retinochoroidal atrophy has been previously reported to be associated with CRB1 gene, no previous relationship to the HK1 gene has been described.