Gyrate atrophy is a rare autosomal recessive chorioretinal dystrophy caused by ornithine aminotransferase deficiency, resulting in toxic accumulation of plasma ornithine and progressive retinal degeneration. We describe a 20-year-old male, born to consanguineous parents, who presented with progressive diminution of vision, nyctalopia, and peripheral visual field loss. Fundus examination revealed sharply demarcated, scalloped areas of midperipheral chorioretinal atrophy with relative macular sparing. Optical coherence tomography demonstrated cystoid macular edema, whereas plasma ornithine levels were markedly elevated. The patient was treated with dietary protein restriction and pyridoxine supplementation, with biochemical improvement and stabilization of visual function. Early recognition, metabolic monitoring, and evaluation of pyridoxine responsiveness may delay visual deterioration and improve visual prognosis in gyrate atrophy.

The optic nerve develops from the neuroectodermal optic stalk, which undergoes coordinated morphogenesis and gives rise to optic nerve astrocytes that support retinal ganglion cell axons. Here, we define the progression of astrocyte formation from the optic stalk and identify stage-specific functions of the SWI/SNF scaffolding subunits Smarcc1 and Smarcc2. Both factors are co-expressed in retinal pigment epithelium (RPE) and optic stalk progenitors, with Smarcc2 persisting in differentiated RPE and astrocytes. Conditional deletion using Dct-Cre revealed compensatory activity in pigmented lineages, whereas Smarcc1 loss uniquely disrupted optic nerve head morphogenesis, resulting in glial lamina collapse, retinal ganglion cell degeneration and progressive visual decline. Spatial transcriptomics and functional assays show that Smarcc1 enables dorsal optic stalk progenitors to transition from a pigmented, RPE-like state to astrocyte progenitors by repressing pigment gene programs and permitting Pax2 and Sox2 activity. After specification, Smarcc1 is also required for glial lamina assembly and astrocyte migration into the inner retina. These findings demonstrate that Smarcc1-dependent chromatin remodeling coordinates astrocyte specification with optic nerve head morphogenesis to maintain long-term retinal function.

Federated learning (FL) is increasingly relevant to ophthalmology because retinal photographs, optical coherence tomography (OCT), OCT angiography, visual fields, and linked clinical records are clinically valuable but difficult to pool across institutions. In this narrative review, we synthesize ophthalmology-focused FL literature across diabetic retinopathy (DR), glaucoma, age-related macular degeneration (AMD), pediatric retinal disease, multi-disease retinal diagnostics, and emerging ophthalmic platforms. Current evidence suggests that FL can support collaborative AI development without centralizing raw patient data, and selected studies show performance close to centralized training under controlled retrospective or multicenter experimental conditions. For example, multicenter glaucoma detection from volumetric OCT achieved an AUC of 0.92 with FL compared with 0.94 for centralized training. However, FL is privacy-enhancing rather than privacy-complete, and most ophthalmic FL systems have not yet undergone prospective clinical validation. Model updates may remain vulnerable to gradient inversion, membership inference, poisoning, site-level bias, and latent identity or attribute leakage. For eye-care networks, the main value of FL is therefore not simply algorithmic performance but a governance model for privacy-conscious collaboration. Prospective validation, interoperability, explainability, workflow integration, privacy auditing, and clear responsibility for monitoring are needed before FL-enabled ophthalmic AI can be deployed routinely.

Background/Objectives: Patient-reported outcomes (PROs) provide information on subjective visual function that is not fully captured by conventional clinical measures. This exploratory cross-sectional study evaluated item-level responses to an original 11-item questionnaire and their association with vision-related quality of life across ophthalmic diseases. Methods: A total of 262 participants, including patients with glaucoma, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, cataract, and individuals with long-standing severe visual impairment, completed the questionnaire and the National Eye Institute Visual Function Questionnaire-25 (VFQ-25). Associations with age, disease category, and better-eye visual acuity were examined using correlation analyses, multivariable regression, and ordinal logistic models. Results: Perceived change in vision after treatment or disease management (A6) showed the most consistent item-level associations. A6 remained associated with age after adjustment for disease category and visual acuity (β = -0.030, p < 0.001), whereas visual acuity was not associated with questionnaire domains. A6 was negatively correlated with the VFQ-25 composite score (r = -0.693, p < 0.001) and remained associated with this score in multivariable analysis (β = -0.230, p < 0.001). Conclusions: Item-level PRO responses varied across clinical backgrounds and were not adequately explained by visual acuity alone. These findings suggest that patient-perceived visual change after treatment or disease management may provide complementary information on vision-related quality of life. Further studies using validated instruments and disease-specific severity measures are needed.

Background/Objectives: Punctate hyperfluorescence (PH) on indocyanine green angiography (ICGA) is frequently observed in pachychoroid disease. However, the spatial relationship between PH lesions and vortex vein abnormalities remains unclear. This study quantified PH distribution in fellow eyes of patients with unilateral neovascular age-related macular degeneration (nAMD) and examined its association with vortex vein asymmetry and watershed-zone status. Methods: This retrospective observational study included 58 fellow eyes with PH from patients with unilateral nAMD. PH lesions were quantified on late-phase ICGA images using ImageJ software. Vortex vein distribution was classified as symmetric, superior-dominant, or inferior-dominant. Eyes were also classified by the presence of a horizontal watershed zone. PH distribution was compared by vortex vein morphology. Results: A watershed zone was absent in 14 eyes (24.1%). Vortex vein distribution was asymmetric in 27 eyes (46.6%), including 17 (29.3%) superior-dominant and 10 (17.2%) inferior-dominant. Overall, 3401 PH lesions were detected. Eyes without a watershed zone had significantly more PH lesions than those with a watershed zone (p = 0.002). The proportion of superior-region PH lesions differed significantly by vertical vortex vein predominance, with preferential distribution on the dominant side (p < 0.001). Although PH distribution did not differ significantly among the four quadrants overall, 30 eyes (51.7%) had >50% of PH lesions clustered in a single quadrant. Conclusions: PH lesions were preferentially distributed on the dominant side of vortex vein asymmetry, and eyes without a watershed zone had more PH lesions. These findings indicate that PH distribution and lesion burden are associated with vortex vein morphology and watershed-zone status and may reflect underlying alterations in choroidal venous drainage.

Ocular diseases are a significant public health problem worldwide and represent one of the leading causes of disability. The prevalence of visual impairment is steadily increasing, largely driven by the ageing population. Oxidative stress, chronic inflammation and neurodegenerative processes underlie the pathogenesis of many eye diseases, including age-related macular degeneration (AMD), diabetic retinopathy, glaucoma, and cataracts, contributing to progressive vision loss and functional impairment. Carotenoids such as lutein, zeaxanthin, meso-zeaxanthin, β-carotene, lycopene, and astaxanthin exhibit multidirectional biological effects, including antioxidant, anti-inflammatory, and neuroprotective properties. These compounds are selectively accumulated in the tissues of the eye, especially in the retina and macula, where they neutralise reactive oxygen species, modulate inflammatory pathways, stabilise mitochondrial function and support the survival and function of retinal ganglion cells and photoreceptors. The aim of our review was to provide a comprehensive review of current data regarding the mechanisms of action of carotenoids and their potential clinical significance in the prevention and treatment of retinal, optic nerve, lens, and eye surface diseases, including dry eye syndrome and Meibomian gland dysfunction. We identified results of available experimental and clinical research and outlined that an adequate supply of carotenoids in the diet or in the form of supplementation may support the protection of eye structures against oxidative and inflammatory damage, improve visual performance and potentially slow disease progression. However, high-quality prospective clinical trials are necessary to conclusively assess their therapeutic efficacy and establish evidence-based recommendations for clinical practice.

Retinal neurodegenerative diseases, such as age-related macular degeneration, diabetic retinopathy, glaucoma, and inherited retinal dystrophies, are major causes of irreversible vision loss worldwide. Although they originate from different causes, these disorders increasingly appear to share a network of cellular stress pathways, including impaired mitochondrial function, oxidative stress, endoplasmic reticulum proteostasis collapse, chronic neuroinflammation, epigenetic dysregulation, and activation of regulated cell death pathways. The interactions among these processes create an integrated stress network that gradually disrupts retinal homeostasis and promotes neuronal degeneration, which explains the failure of therapies targeting single molecular pathways. Nutraceutical compounds found in food are gaining interest as potential agents to support retinal health because many exhibit pleiotropic biological activities that influence mitochondrial function, inflammatory signaling, antioxidant defenses, and transcriptional regulation. Herein, we consolidate knowledge of the molecular mechanisms underlying retinal neurodegeneration and how major classes of nutraceuticals (polyphenols, carotenoids, omega-3 fatty acids, and metabolic modulators) may interact with these pathways. We also discuss key translational challenges in developing therapies, including poor bioavailability and differences between human phenotypes and model systems. Additionally, we highlight emerging concepts such as microbiome-dependent metabolism of nutraceuticals, personalized nutrition strategies, and advanced ocular drug-delivery technologies. Collectively, these findings support a systems-level framework in which selected nutraceuticals may influence multiple nodes of retinal stress biology, although clinical validation remains limited.

Age-related macular degeneration (AMD), characterized by pathologic choroidal neovascularization (CNV), is a leading cause of vision loss in the elderly. Vascular endothelial growth factor A (VEGFa) antagonists can prevent acute vision loss, but high treatment burden and loss of efficacy with chronic therapy highlight the need to explore alternative mechanisms. Recently, microRNA-34a (miR-34a) has emerged as a key regulator in aging and age-related diseases, but its role in neovascular AMD is unclear. In an injury-induced murine CNV model, we found miR-34a promoted pathological angiogenesis, without altering expression of Vegfa or its receptor Kdr, the canonical regulators of CNV. Mechanistically, miR-34a directly targets and inhibits the transcription factor KLF2, thereby upregulating the proangiogenic factors CXCR4 and CXCL12. Finally, we show miR-34a exacerbates CNV in aged mice and is expressed in CNV lesions excised from wet AMD patients. These findings establish a causal link between the age-related miR-34a and neovascularization in AMD.

Pathological choroidal neovascularization underlies vision loss in neovascular age-related macular degeneration (nAMD), yet the molecular regulators coordinating vascular and immune components remain incompletely defined. Here, we investigated the role of the endolysosomal cation channel, two-pore channel 2 (TPC2) in choroidal angiogenesis. Loss of TPC2 in mice markedly reduced ex vivo choroidal sprouting, while pharmacological activation enhanced vascular growth. Mechanistically, Tpc2-deficiency led to downregulation of multiple microglia-derived pro-angiogenic factors and impaired the ability of the microglial secretome to stimulate neovascularization. In choroidal vascular cells, TPC2 loss attenuated NF-κB/MAPK signaling pathways. Tpc2-deficiency is also associated with lysosomal secretion of cathepsins, especially CTSD, resulting in decreased extracellular proteolytic activity and impaired paracrine regulation of angiogenesis. Extending these findings to human cells, TPC2 knockout in iPSC-derived endothelial cells impaired migration, tube formation, and CTSD activity in the secretome, mirroring the murine phenotype. Together, these results establish TPC2 as one of the regulators of lysosome-mediated choroidal angiogenesis, highlighting its potential as a therapeutic target in nAMD.

Prostaglandin analogs, including travoprost, are widely used to lower intraocular pressure in primary open-angle glaucoma. While generally safe, rare posterior segment changes have been reported. Retinal pigment epithelial detachment (RPED) associated with travoprost is uncommon and poorly documented. We report three patients who developed serous RPED shortly after initiating topical travoprost, none of whom had preexisting macular disease. Optical coherence tomography (OCT) confirmed the detachments, and complete anatomical and visual recovery occurred following discontinuation of travoprost and initiation of alternative glaucoma therapy. A clear temporal relationship was observed between drug initiation and RPED onset. The absence of clinical or OCT features suggestive of alternative diagnoses-such as central serous chorioretinopathy, age-related macular degeneration, or pachychoroid spectrum disorders-combined with consistent reversibility, suggests a possible association between travoprost and RPED. These findings emphasize the importance of early recognition and timely intervention, as RPED appears fully reversible when identified promptly, preventing potential persistent visual impairment.

Loss-of-function mutations in the ABCA4 gene cause Stargardt disease (STGD1), the most common inherited macular dystrophy leading to progressive central vision loss. Here, we generated hiPSC-derived retinal organoids harboring a premature stop codon in exon-24 of ABCA4 to evaluate the impact of this mutation on mRNA and protein levels in a human model. Immunofluorescence analysis revealed the absence of ABCA4 protein in the mutant photoreceptor outer segment discs, while single-cell RNA sequencing detected no major transcriptional alterations in rods and cones. Unexpectedly, differential gene expression and pathway enrichment analyses of Müller glial cells (MGCs) and astrocytes highlighted disruption of neuronal development, microenvironment of glial cells, intercellular communication, and programmed cell death pathways. These findings suggest that ABCA4 deficiency in photoreceptor discs may trigger early stress-associated transcriptomic responses in retinal glial cells prior to overt photoreceptor degeneration, potentially contributing to Stargardt disease pathogenesis. Human induced pluripotent stem cells (hiPSCs) were engineered to generate ABCA4-mutant cell lines, later differentiated into retinal organoids as a model of Stargardt disease. The organoids showed loss of ABCA4 from the outer segment discs of rod and cone photoreceptors, while the mutant Müller glial cells and astrocytes exhibited transcriptional changes in pathways involved in neuronal development, microenvironment, and programmed cell death. Created in https://BioRender.com.