BACKGROUND:Gene variants in the unfolded protein response regulator activating transcription factor 6 (ATF6) are linked to achromatopsia (ACHM), an autosomal recessive cone dystrophy that impairs color vision and visual acuity. While most known variants appear in the transcriptional activator cytosolic region, the function and clinical impact of stress-sensing luminal domain variants remain poorly understood. METHODS:A patient with ACHM from a family carrying a new luminal domain ATF6 variant was clinically evaluated. Genetic testing was performed and compared to reference ATF6 sequence NM_007348.4. Deleterious ATF6 variants were analyzed using gnomAD allele frequencies, Combined Annotation Dependent Depletion (CADD) scores, multispecies sequence alignment, and spliceAI delta scores. RESULTS:An 18-year-old male from Taiwan presented with a homozygous missense exonic splice-region variant (c.1604G>A, p.Ser535Asn), bilateral foveal hypoplasia, disrupted inner outer photoreceptor segment layers, impaired color vision, and absent photopic but preserved scotopic responses. All known deleterious ATF6 variants had gnomAD frequencies below 0.0000627, and most were predicted to be deleterious by CADD. CONCLUSIONS:Clinical and genetic characterization of this new luminal ATF6 variant in an affected individual highlights the critical importance of the ATF6 stress-sensing luminal domain for normal visual function.

Purpose:Drusen are subretinal pigment epithelium extracellular matrix deposits. This study compared histomorphometric characteristics of age-related and atypical drusen found in an eye of a young woman with chronic retinal detachment (RD). Methods:We conducted a histomorphometric examination of drusen identified in 3 eyes: an eviscerated eye from a 35-year-old woman with chronic RD, and 2 specimens of 2 patients, aged 91 and 77 years, with typical age-related drusen. Sections of formalin-fixed tissue stained with hematoxylin and eosin (H&E), periodic acid-Schiff (PAS), Masson trichrome, luxol fast blue (LFB), and Von Kossa were evaluated using light microscopy. Drusen dimensions were quantified using Philips Digital Pathology Software. Results:Atypical drusen identified in the RD eye (n = 25) displayed spheroidal shape with peripherally radiating fibrils. There were foci of dystrophic calcification and localized chronic choroidal inflammation and within some drusen. Age-related drusen (n = 29) had a typical dome-shaped appearance. Atypical drusen had significantly larger (P < 0.001) average circumference (278 vs. 52 µm), diameter (96 vs. 20 µm), and area (0.006 vs. 0.00022 mm2) than age-related drusen, respectively. Both groups stained positively with PAS, negatively with LFB and Von Kossa, and blue on Masson Trichrome. Conclusions:Atypical drusen found in this RD case display significant differences in morphometric parameters compared to age-related drusen but similar histochemical staining patterns, suggesting a similar macromolecular composition. Further investigations are needed to inform drusen pathogenesis, morphology, and associations with sex, age, or long-standing RD. Translational Relevance:This case adds to the limited body of evidence on drusen in younger patients and suggests that atypical drusen may form in association with RD.

The Unfolded Protein Response (UPR) maintains endoplasmic reticulum (ER) homeostasis and is essential for retinal health. Activating Transcription Factor 6 (ATF6) controls a key UPR branch and upregulates genes that mitigate ER stress. Small molecule modulators of ATF6 have been characterized in cell culture models that increase or decrease the amount of the cleaved, transcriptional activator domain of ATF6 generated from the full-length precursor. However, the effects of these small molecule ATF6 modulators remain unclear in vivo, in part because of the lack of antibodies that robustly detect the cleaved, activated form of ATF6 in model organisms like mice. Here, we used targeted RNA sequencing (RNA-seq) to assess the transcriptional response to intraocular delivery of Ceapin-A7 (an ATF6 inhibitor) and AA147 (an ATF6 activator) in the mouse retina. Using this strategy, we demonstrate that Ceapin-A7 significantly suppressed ATF6 transcriptional targets, whereas AA147 induced ATF6-regulated genes in retinal tissue of the eye. We also show that neither small molecule ATF6 modulator caused retinal cell death, compromised vision, or triggered ER stress by histology, functional testing, and transcriptional analysis. These results identify a transcriptional strategy to sensitively detect and quantify Ceapin-A7 and AA147 modulation of ATF6 in vivo. These findings also identify nontoxic conditions for further in vivo evaluation of small molecule ATF6 modulators in mouse vision loss disease models linked to ER stress.

Nodular fasciitis is a benign, pseudoneoplastic condition often misdiagnosed as sarcoma due to its rapid growth, high cellularity, and mitotic activity. Herein is reported a case of a 7-year-old patient with a painless, enlarging nodule in the left superolateral orbit. Ultrasound revealed a 7.5 mm cystic mass, which was excised via an upper eyelid crease anterior orbitotomy. Histopathologic studies showed benign spindle cells, and molecular testing identified a UBC::USP6 fusion, confirming the diagnosis of nodular fasciitis. Nodular fasciitis is most common in the limbs, trunk, and head or neck region, with fewer than 1% of cases occurring in the orbit. Molecular testing is critical in differentiating this condition from malignancies. Complete surgical excision is the preferred treatment, with a low recurrence rate of 1% to 2%. This is the first reported pediatric case of orbital nodular fasciitis with a UBC::USP6 fusion mutation.

Purpose:The purpose of this study was to evaluate the relationship between serum and aqueous humor (AH) neurofilament light chain (NfL) and to determine whether serum NfL is elevated in patients undergoing ocular surgery who have glaucoma compared with those who do not. Methods:In this single-center, case-control study, we enrolled patients with various types and stages of glaucoma undergoing planned ophthalmic surgery as part of their routine care and compared them with patients without glaucoma undergoing phacoemulsification for age-related cataract. We recruited 110 patients with glaucoma and 113 patients without glaucoma and collected AH and blood from these participants. Levels of AH and serum NfL were quantified using the Single-Molecule Array (Simoa) NF-light assay (Quanterix). Clinical information was obtained by reviewing the medical records. Results:In a model controlling for age and body mass index (BMI), AH NfL was significantly elevated in patients with glaucoma compared with controls (P < 0.001). In contrast, after controlling for age, BMI, and Mini Mental Status Examination (MMSE) scores, serum NfL was not elevated in patients with glaucoma compared with controls (P = 0.81). Conclusions:Although our findings validate AH NfL as a marker of glaucomatous neurodegeneration, no such evidence was found for serum NfL. Translational Relevance:NfL levels in AH may be a molecular marker of retinal ganglion cell health in glaucoma; in contrast, serum NfL has limited utility for monitoring glaucomatous neurodegeneration.

To investigate histopathological conjunctival changes associated with topical netarsudil 0.02

The lacrimal fossa, located in the superolateral orbit, is a shallow depression in the orbital plate of the frontal bone. It primarily houses the orbital lobe of the lacrimal gland but also contains other tissues such as fat, blood vessels, and nerves. Lacrimal fossa lesions constitute a diverse spectrum of pathologies, originating from the frontal bone and adjacent soft tissues or from the resident lacrimal gland itself. We present a 42-year-old woman with slowly progressive right superolateral orbital swelling. Subsequent resection of a mass lesion demonstrated a solitary fibrous tumor (SFT) with a Demicco risk of two. We use SFT as a springboard to review the differential diagnosis of unilateral lesions of the lacrimal fossa and lacrimal gland. Nonglandular lesions of the lacrimal fossa primarily arise from its bony superstructure, neurovascular supply, and/or connective tissues. In contrast, lacrimal gland pathologies are like those of the salivary glands, being primarily neoplastic or infectious/inflammatory. Neoplastic lacrimal gland lesions can be of epithelial origin or nonepithelial origin, with lymphoma being the most common of the latter. While inflammatory lesions are often bilateral, unilateral involvement can occur. The clinical and imaging characteristics of multiple unilateral lacrimal fossa and lacrimal gland pathologies are explored herein.

Activating transcription factor 6 (ATF6) is a key regulator of the unfolded protein response (UPR) and is important for ER function and protein homeostasis in metazoan cells. Patients carrying loss-of-function ATF6 disease alleles develop the cone dysfunction disorder achromatopsia. The effect of loss of ATF6 function on other cell types, organs, and diseases in people remains unclear. Here, we report that progressive sensorineural hearing loss was a notable complaint in some patients carrying ATF6 disease alleles and that Atf6-/- mice also showed progressive auditory deficits affecting both sexes. In mice with hearing deficits, we found disorganized stereocilia on hair cells and focal loss of outer hair cells. Transcriptomics analysis of Atf6-/- cochleae revealed a marked induction of the UPR, especially through the protein kinase RNA-like endoplasmic reticulum kinase (PERK) arm. These findings identify ATF6 as an essential regulator of cochlear health and function. Furthermore, they support the idea that ATF6 inactivation in people causes progressive sensorineural hearing loss as part of a blindness-deafness genetic syndrome targeting hair cells and cone photoreceptors. Last, our genetic findings indicate that ER stress is an important pathomechanism underlying cochlear damage and hearing loss, with clinical implications for patient lifestyle modifications that minimize environmental and physiological sources of ER stress to the ear.

Pathological retinal neovascularization is a cause of vision loss in diseases including retinopathy of prematurity (ROP), wet age-related macular degeneration (AMD), and diabetic retinopathy. The Unfolded Protein Response (UPR) is an intracellular signal transduction mechanism that is activated by ER stress and upregulates many proteins, including angiogenesis factors like VEGF and HIF-1α. This suggests that UPR genes and pathways may drive retinal angiogenesis. Here, we tested the role of the UPR regulator Activating Transcription Factor 6 (ATF6) in pathological and developmental retinal angiogenesis. We induced pathological retinal neovascularization in Atf6−/− mice using the oxygen-induced retinopathy (OIR) model and found significantly preserved visual function, accompanied by decreased retinal neovascularization, endothelial cell proliferation, and UPR transcriptional program induction. When we chemically blocked ATF6 signaling by intraocular injection of the small molecule Ceapin-A7, we also saw suppressed retinal expression of UPR genes. Additionally, in postnatal day 7 Atf6−/− mice when the retinal vasculature is developing in response to physiologic intraocular hypoxia, there was a transient but significant defect in pruning and retinal blood vessel extension. Together, our results demonstrate ATF6’s causal role in developmental and pathological retinal angiogenesis and highlight its potential as a therapeutic target to preserve vision in retinal neovascularization diseases.

Neural retina leucine zipper (NRL) is essential for the development of rods. The Nrl knockout (Nrl−/−) mouse develops a cone-rich retina which facilitates investigations of cone biology. Previously, we identified the endoplasmic reticulum (ER) stress response gene ATF6 as a cause of cone dysfunction in people. Here, we investigated Atf6’s influence on mouse cones in the cone-dominant Nrl−/− mouse. We find that cone development appears unaffected, but the cone-dominant Nrl−/− retina is highly vulnerable to ER stress-induced damage.

ATF6 is a key regulator of the unfolded protein response (UPR) pathway that maintains cellular homeostasis during ER stress. In people, loss of ATF6 function causes cone dysfunction, manifesting as achromatopsia (ACHM). Previously, we generated ACHM retinal organoids (ROs) from patient induced pluripotent stem cells (iPSCs) carrying mutant ATF6 variants and gene-edited ATF6-knockout (KO) human embryonic stem cells (hESCs). ACHM and ATF6-KO ROs both showed severe stunting of cone inner and outer segments. RNA-Seq analysis of ACHM 290-day-old ROs showed downregulated cone gene expression and dysregulated mitochondria and ER stress gene expression. Here, we analyzed RNA-Seq analysis of 203-day-old ATF6-KO ROs. In younger ROs, we found dysregulation of genes involved in retinal and photoreceptor structural integrity, including CRB1, EGFLAM, and VTN. In addition, we found dysregulation of ATF6 and UPR-regulated transcriptional signatures. Dysregulation of retinal and photoreceptor structural integrity genes may underlie the observed stunting of cone inner/outer segments in ATF6-achromatopsia patients.

Purpose:To describe long term follow-up of two cases of corneally displaced conjunctival melanoma with multiple recurrences. Observations:Case 1 is a 49-year-old male with recurrent conjunctival melanoma and primary acquired melanosis treated over 13 years, who eventually presented with an elevated amelanotic corneal mass. Case 2 is a 61-year-old female with a similar history of recurrent conjunctival melanoma and primary acquired melanosis treated over 21 years, who presented with a subepithelial corneal opacity. Both patients were treated with a combination of topical chemotherapy, wide excision, map biopsy, cryotherapy, and local and systemic workup showing no evidence of metastasis. Conclusions and importance:Conjunctival melanoma has a high risk of recurrence and can present as amelanotic corneally displaced conjunctival melanoma, warranting thorough workup to detect potential subclinical spread of the disease.

Retinal detachment (RD) occurs when the neurosensory retina, the neurovascular tissue responsible for phototransduction, is separated from the underlying retinal pigment epithelium (RPE). Given the importance of the RPE for optimal retinal function, RD invariably leads to decreased vision. There are three main types of RD: rhegmatogenous, tractional and exudative (also termed serous) RD. In rhegmatogenous RD, one or more retinal breaks enable vitreous fluid to enter the subretinal space and separate the neurosensory retina from the RPE. In tractional RD, preretinal, intraretinal or subretinal membranes contract and exert tangential forces and elevate the retina from the underlying RPE. Finally, in exudative RD, an underlying inflammatory condition, vascular abnormality or the presence of a tumour causes exudative fluid to accumulate in the subretinal space, exceeding the osmotic pump function of the RPE. The surgical management of RD usually involves pars plana vitrectomy, scleral buckling or pneumatic retinopexy. The approach taken often depends on patient characteristics as well as on practitioner experience and clinical judgement. Advances in surgical technology and continued innovation have improved outcomes for many patients. However, even if retinal re-attachment is achieved, some patients still experience decreased vision or other visual symptoms, such as metamorphopsia, that diminish their quality of life. Continued research in the areas of neuroprotection and retinal biology as well as continued surgical innovation are necessary to enhance therapeutic options and outcomes for these patients. Retinal detachment describes the separation of the neurosensory retina from the underlying retinal pigment epithelium, leading to impaired vision or vision loss. This Primer discusses the epidemiology, pathophysiology, diagnosis and management of this disorder and highlights future research directions.

A 17-year-old boy presented with a painless, enlarging bulbar conjunctival lesion for 2 years. (A) Slit-lamp examination revealed a firm, pink papillomatous temporal lesion on the right eye measuring 7.01 × 1.09 mm. (B) The lesion was excised at the base, and histopathology showed spindle cells in dense fibrous substantia propria (scale bar = 500 μm). (C) Immunohistochemical staining of the spindle cells was diffusely positive for CD34 (scale bar = 50 μm), corresponding to a fibroblastic phenotype. (D) CD117 immunohistochemistry stained many mast cells (scale bar = 50 μm), a notable feature in ocular surface fibroma. Histopathology results are diagnostic of ocular surface fibroma of the conjunctiva. (Magnified version of Figure A-D is available online at www.aaojournal.org).

Purpose To report a rare case of a conjunctival blue nevus in a child Observations A 10-year-old girl underwent an excisional biopsy for an atypical growing melanocytic conjunctival lesion. The diagnosis of a conjunctival blue nevus was confirmed on histopathology. We describe the histopathology and the anterior segment optical coherence tomography features of a blue nevus in a 10-year-old child along with a review of literature. Conclusion and Importance Conjunctival blue nevus is rare and has rarely been reported in a child. Multimodal imaging may help document lesion progression. This condition should remain in the differential for a growing, pigmented conjunctival lesion.

Innovation in high angular resolution imaging is essential to identifying planet formation on solar-system scales (similar to 5-10 AU) in active star forming regions beyond 150 pc. The photonic lantern is a novel fiber-optic device that can be used to overcome the observational challenges associated with imaging such close-in protoplanets. Photonic lanterns spatially filter out modal noise with high throughput and low power loss, making them appealing for a wide variety of applications including wavefront-sensing, nulling, and spectro-astrometry. Spectro-astrometry, a technique that identifies wavelength-dependent centroid shifts in spectrally-dispersed datasets, could enable the resolution of circumstellar structures within the diffraction limit when conducted with photonic lanterns. Here, we present simulations of spectro-astrometric observations of embedded protoplanets using photonic lanterns. We generate mock, 6-port photonic lantern observations of young stars with gapped circumstellar disks containing accreting protoplanets with emission at the Paschen beta hydrogen line. The simulations assume a 10-m class telescope and realistic sources of both photon noise and residual adaptive optics errors. We demonstrate the detection of protoplanets with photonic lantern spectro-astrometry in the presence of circumstellar material by constraining planetary accretion characteristics such as planet separation, position angle, and stellar contrast, and we explore the biases introduced by the presence of the circumstellar material.

Topical therapies targeting Rho-associated protein kinase (ROCK) signalling, including netarsudil (Rhopressa®) and ripasudil (Glanatec®), have become widely adopted as part of standard clinical practice to lower intraocular pressure (IOP) in patients with ocular hypertension or glaucoma. Given the pleiotropic roles of ROCK signalling, ROCK inhibition has the potential to cause unintended ocular side effects beyond IOP lowering in other substructures of the eye, both beneficial and deleterious. Additional experience and observation of patients treated with this class of medications have uncovered both new side effects not reported in the initial clinical trials, as well as potential benefits that have inspired off-label uses and that have been the topic of numerous clinical studies, case series, case reports, and translational studies. Here, we performed a comprehensive systematic review and identified 170 studies describing ocular effects of ROCK inhibition. In addition to describing well-established ocular effects associated with inhibition of ROCK signalling, such as conjunctival hyperaemia, corneal verticillata, and reticular corneal epithelial oedema, we also highlight other effects, such as corneal haemorrhages, changes in corneal contour, anterior subcapsular opacities, contact dermatitis, punctal stenosis, and eyelid wound dehiscence, which have been described in case series and case reports. Finally, we evaluated studies describing potential novel applications of ROCK inhibition for treating disorders affecting the cornea, the retina, and the optic nerve, finding strong evidence in support of a beneficial effect of ROCK inhibitors on corneal oedema due to corneal endothelial cell dysfunction. The other potential applications require further research.