Cataract is a leading cause of visual impairment worldwide, and its prevalence is increasing with population aging. The majority are age-related cataracts (ARC), clinically classified into nuclear, cortical, and posterior subcapsular cataracts (PSC) by opacity location. Mechanisms of cataractogenesis remain incompletely understood. While cortical and nuclear cataracts are largely attributed to crystallin aggregation, such protein-centric mechanisms fail to explain the early onset and axial location of PSC. Morphologically, PSC resembles posterior capsule opacification (PCO), a secondary cataract driven by epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs), suggesting LEC-EMT may also contribute to PSC. Using clinically stratified human lens samples, we confirmed EMT marker expression across PSC subtypes. Transcriptomic profiling revealed that LECs, the lens's sole metabolically active cells, in age-related PSC (ARC-PSC), compared with age-related nuclear cataract (ANC) and clear lenses, exhibit elevated EMT signatures tightly linked to senescence-associated inflammatory signaling. Aqueous humor (AqH) profiling demonstrated a pro-inflammatory milieu across PSC subtypes, with IL-17A uniquely elevated in ARC-PSC, consistent with transcriptomic findings. Integrated analyses support a model in which senescence functions as an upstream driver, whereby senescent LECs release SASP factors, including IL-17A, that activate NF-κB signaling to amplify inflammation, reinforce senescence, and drive EMT. In vitro, senolysis and IL-17A blockade disrupted this loop, attenuating senescence- and EMT-associated phenotypes. Collectively, our study demonstrates that senescent LECs sustain an IL-17A-NF-κB circuit that drives EMT and accelerates ARC-PSC progression, positioning ARC-PSC as a unique human context to study senescence-induced epithelial remodeling in aging tissues.

We report the case of a 42-year-old Venezuelan woman with childhood-onset autosomal recessive retinitis pigmentosa type 90 (RP90), presenting an unusual and distinctive clinical phenotype characterized by macular pseudocoloboma, very early-onset acquired color vision disorder progressing to severe functional dyschromatopsia, and early-onset severe posterior subcapsular cataracts. Her affected brother exhibited a similar phenotype, while her parents and the other two siblings remained unaffected. Massive parallel sequencing identified two novel IDH3A variants: c.127G>T (chr15:78449926 G>T; no dbSNP entry) and c.419T>C (chr15:78454052T>C; no dbSNP entry), in compound heterozygosity and confirmed to be in trans location. Both missense variants, absent from population databases, were predicted to be deleterious by multiple in silico tools and are located in critical domains involved in enzymatic complex stability, catalytic activity and subunit interactions. This case reinforces the association between IDH3A mutations and RP90, corroborates key phenotypic features described in limited published reports-the presence of macular pseudocoloboma-and expands the mutational spectrum of the gene. Moreover, it highlights the role of mitochondrial metabolism in photoreceptor degeneration and proposes a link between them. Our findings underscore the need for functional studies to elucidate the pathogenic mechanisms underlying IDH3A-related retinopathies.

Loeys-Dietz syndrome (LDS) is a heritable connective tissue disorder with variable expressivity. It is a multisystemic condition mainly characterized by a propensity for arterial aneurysms and dissections, skeletal manifestations, hypertelorism, bifid uvula, craniosynostosis, and cutaneous features. While LDS has significant clinical overlap with other heritable connective tissue disorders such as Marfan syndrome, the ocular manifestations of LDS have not yet been well characterized. We describe an individual with a variant in SMAD3 with a predominantly ocular phenotype and only mild arterial manifestations. The proband presented with early-onset high myopia (-25 diopters, bilaterally) and bilateral posterior subcapsular cataracts. Ocular phenotype also included esotropia, retinal hemorrhage, glaucoma, bilateral posterior staphylomas, and keratoconjunctivitis sicca. Extensive vascular imaging identified a right internal carotid artery dissection and mild tortuosity of numerous arteries. A molecular gene panel for heritable connective tissue disorders identified a heterozygous SMAD3 c.221G > T; p.(Arg74Leu) variant, initially reported as a variant of uncertain significance and subsequently re-interpreted as likely pathogenic. Other missense variants at this residue have been reported as pathogenic for LDS. High-grade myopia, premature cataracts, and premature glaucoma are part of the phenotypic spectrum in LDS caused by SMAD3 variants. Inclusion of SMAD3 in molecular gene panels for early-onset high-grade myopia should be considered.

Goldmann-Favre syndrome (GFS) is a rare vitreoretinal degenerative disorder caused by mutations in the NR2E3 gene located on the short arm of chromosome 15. This condition, inherited in an autosomal recessive manner, was first described by Favre in two siblings, with Ricci later confirming its hereditary pattern. In GFS, rod photoreceptors are essentially replaced by S-cone photoreceptors. Enhanced S-Cone Syndrome (ESCS) and Goldmann-Favre syndrome are two distinct entities within the spectrum of retinal degenerative diseases, both caused by mutations in the NR2E3 gene. Despite sharing a common genetic basis, these conditions exhibit significantly different clinical phenotypes. ESCS is characterized by an excessive number of S-cones (blue-sensitive cones) with degeneration of rods and L-/M-cones, leading to increased sensitivity to blue light and early-onset night blindness. In contrast, GFS is considered a more severe form of ESCS, involving additional features such as retinal schisis, vitreous degeneration, and more pronounced visual impairment. GFS typically manifests in the first decade of life as night blindness (nyctalopia) and progressive visual acuity impairment. The clinical features include degenerative vitreous changes such as liquefaction, strands, and bands, along with macular and peripheral retinoschisis, posterior subcapsular cataract, atypical pigmentary dystrophy, and markedly abnormal or nondetectable electroretinograms (ERGs). Although peripheral retinoschisis is more common in GFS, central retinoschisis may also occur. Despite the consistent genetic basis, the phenotype of GFS can vary significantly among individuals. The differential diagnosis should consider diseases within the retinal degenerative spectrum, including retinitis pigmentosa, congenital retinoschisis, and secondary pigmentary retinopathy.

Recessive Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) mutations can cause early onset muscle-eye-brain disease but have also more recently been associated with non-syndromic Retinitis Pigmentosa. In this case series, we describe three sisters affected by non-syndromic autosomal recessive POMGNT1 retinopathy with a report of a new variant. The three patients received care at West Virginia University Eye Institute, including full ophthalmic examination with additional fundus imaging, optical coherence tomography (OCT), electroretinogram (ERG), and visual field testing. Diagnostic panel testing of 330 genes was also obtained. The proband was seen for cataract evaluation at age 42, and her fundus examination was suggestive of retinitis pigmentosa. Her oldest sister had been treated for acute anterior uveitis with retinal vasculitis. Another sister was diagnosed with multiple sclerosis (MS) and peripheral retinal degeneration. Posterior subcapsular cataracts were diagnosed between age 42 and 55 in all three sisters, each with constricted fields with preserved central vision. We identified one pathogenic POMGNT1 variant (c.751 + 1G > A) and one likely pathogenic variant (c.1010T > C p.Ile337Thr) in all three sisters. A thorough family history and examination of the siblings with genotyping might have led to an earlier diagnosis of retinal inherited disease and avoidance of immunomodulatory treatment in the oldest sibling.