Rod Function Research Articles

Exploring Scotopic Microperimetry as an Outcome Measure in Choroideremia.

Choroideremia is an X-linked outer retinal degeneration. Early symptoms include nyctalopia and progressive visual field loss, but visual acuity is preserved until late disease stages. Dark-adapted two-color fundus-controlled perimetry (also known as scotopic microperimetry) has been developed to enable spatial assessment of rod and cone photoreceptor function. This study explores the use of scotopic microperimetry in patients with choroideremia. Twenty patients with choroideremia and 21 age-matched healthy controls completed visual acuity and scotopic microperimetry testing, which used the Scotopic Macular Integrity Assessment (S-MAIA) microperimeter. A subset of participants completed repeat scotopic testing to enable Bland-Altman repeatability analyses. Test reliability was assessed using fixation stability, fixation losses, and assessment of the rod-free zones. Pointwise sensitivity, mean sensitivity, and volume sensitivity indices were analyzed. False positive responses were the main source of poor test reliability, indicated by stimuli responses in the physiological blind spot and lack of rod-free mapping. Scotopic cyan and red sensitivities were significantly reduced in choroideremia participants (n = 17) compared to healthy controls (n = 16) (P < 0.01, Mann-Whitney U test). Scotopic cyan sensitivity was statistically lower than scotopic red sensitivity in both healthy controls and choroideremia (P < 0.01, Wilcoxon signed rank test). Interpretation of scotopic cyan-red differences should be used with caution due to high test-retest variability. Scotopic microperimetry could be a useful outcome measure in patients with early choroideremia. Careful selection of test grid design and sensitivity indices is required. Scotopic microperimetry may be a useful outcome measure in clinical trials for patients with early stage choroideremia.

Maf-family bZIP transcription factor NRL interacts with RNA-binding proteins and R-loops in retinal photoreceptors.

RNA-binding proteins (RBPs) perform diverse functions including the regulation of chromatin dynamics and the coupling of transcription with RNA processing. However, our understanding of their actions in mammalian neurons remains limited. Using affinity purification, yeast-two-hybrid and proximity ligation assays, we identified interactions of multiple RBPs with NRL, a Maf-family bZIP transcription factor critical for retinal rod photoreceptor development and function. In addition to splicing, many NRL-interacting RBPs are associated with R-loops, which form during transcription and increase during photoreceptor maturation. Focusing on DHX9 RNA helicase, we demonstrate that its expression is modulated by NRL and that the NRL-DHX9 interaction is positively influenced by R-loops. ssDRIP-Seq analysis reveals both stranded and unstranded R-loops at distinct genomic elements, characterized by active and inactive epigenetic signatures and enriched at neuronal genes. NRL binds to both types of R-loops, suggesting an epigenetically independent function. Our findings suggest additional functions of NRL during transcription and highlight complex interactions among transcription factors, RBPs, and R-loops in regulating photoreceptor gene expression in the mammalian retina.

Age-dependencies of the electroretinogram in healthy subjects.

The purpose of this study was to evaluate the age-dependency of amplitudes and implicit times in the electroretinograms (ERGs) of healthy individuals and provide clinicians and researchers with a reference for a variety of stimulus paradigms. Full-field electroretinography was conducted on 73 healthy participants aged 14-73 using an extended ISCEV standard protocol that included an additional 9Hz flicker stimulus for assessing rod function and special paradigms for isolated On-Off and S-cone responses. Correlation coefficients and best-fit regression models for each parameter's age-dependency were calculated. Dark-adapted ERGs, in particular, displayed notable age-related alterations. The attenuation and delay of the b-wave with higher age were most significant in the dark-adapted, rod-driven 0.001cds/m2 flash ERG. The age-dependent reduction of the a-wave amplitude was strongest in the standard dark-adapted 3cds/m2 flash condition. Cone-driven, light-adapted responses to either flash or flicker stimuli displayed comparatively small alterations at higher age. S-cone function tended to diminish at an early age, but the effect was not significant in the whole population. The results suggest that rod and cone function decline at different rates with age, with rods being generally more affected by aging. Nonetheless, response amplitudes displayed a wide variability across the whole sample.

Reticular Pseudodrusen: Impact of Their Presence and Extent on Local Rod Function in Age-Related Macular Degeneration

To understand the spatial relationship between local rod-mediated visual function and reticular pseudodrusen (RPD) in eyes with large drusen. Retrospective cross-sectional study. One eye with large drusen (>125 μm) each from 91 individuals with intermediate age-related macular degeneration, with and without RPD. All participants underwent dark adaptation testing using a dark-adapted chromatic perimeter, where visual sensitivities were measured over 30 minutes of dark adaptation after photobleach. The rod intercept time (RIT; a measure of dynamic rod function) and pointwise sensitivity difference (PWSD; a relative measure of rod- compared with cone-mediated function) was determined at multiple retinal locations, and their association with the overall (central 20°× 20° region) and local (2° diameter region centered on the location tested) extent of RPD and drusen (quantified using multimodal imaging) was examined. Association between overall and local extent of RPD and drusen with RIT and PWSD at each retinal location tested. In a multivariable analysis, delayed RIT was associated with an increasing overall (P < 0.001), but not local (P= 0.884), extent of RPD. In contrast, the increasing local (P < 0.001), but not overall (P= 0.475), extent of drusen was associated with delayed RIT. Furthermore, only an increasing overall extent of RPD (P < 0.001) was associated with reduced PWSD (or worse rod compared with cone function), but not the local extent of RPD and drusen, or overall extent of drusen (P ≥ 0.344). Local rod-mediated function was associated with the overall, rather than local, extent of RPD in eyes with large drusen, suggesting that there may be widespread pathologic changes in eyes with RPD that account for this. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Dominant role for pigment epithelial CRALBP in supplying visual chromophore to photoreceptors

Cellular retinaldehyde-binding protein (CRALBP) supports production of 11-cis-retinaldehyde and its delivery to photoreceptors. It is found in the retinal pigment epithelium (RPE) and Müller glia (MG), but the relative functional importance of these two cellular pools is debated. Here, we report RPE- and MG-specific CRALBP knockout (KO) mice and examine their photoreceptor and visual cycle function. Bulk visual chromophore regeneration in RPE-KO mice is 15-fold slower than in controls, accounting for their delayed rod dark adaptation and protection against retinal phototoxicity, whereas MG-KO mice have normal bulk visual chromophore regeneration and retinal light damage susceptibility. Cone pigment regeneration is significantly impaired in RPE-KO mice but mildly affected in MG-KO mice, disclosing an unexpectedly strong reliance of cone photoreceptors on the RPE-based visual cycle. These data reveal a dominant role for RPE-CRALBP in supporting rod and cone function and highlight the importance of RPE cell targeting for CRALBP gene therapies.

Two-photon autofluorescence lifetime assay of rabbit photoreceptors and retinal pigment epithelium during light-dark visual cycles in rabbit retina

Two-photon excited fluorescence (TPEF) is a powerful technique that enables the examination of intrinsic retinal fluorophores involved in cellular metabolism and the visual cycle. Although previous intensity-based TPEF studies in non-human primates have successfully imaged several classes of retinal cells and elucidated aspects of both rod and cone photoreceptor function, fluorescence lifetime imaging (FLIM) of the retinal cells under light-dark visual cycle has yet to be fully exploited. Here we demonstrate a FLIM assay of photoreceptors and retinal pigment epithelium (RPE) that reveals key insights into retinal physiology and adaptation. We found that photoreceptor fluorescence lifetimes increase and decrease in sync with light and dark exposure, respectively. This is likely due to changes in all-trans-retinol and all-trans-retinal levels in the outer segments, mediated by phototransduction and visual cycle activity. During light exposure, RPE fluorescence lifetime was observed to increase steadily over time, as a result of all-trans-retinol accumulation during the visual cycle and decreasing metabolism caused by the lack of normal perfusion of the sample. Our system can measure the fluorescence lifetime of intrinsic retinal fluorophores on a cellular scale, revealing differences in lifetime between retinal cell classes under different conditions of light and dark exposure.

Scotopic and Photopic Conventional Visual Acuity and Hyperacuity - Binocular Summation.

The purpose of this study was to determine and compare binocular summation (BiS) of conventional visual acuity (cVA) versus hyperacuity (hVA) for photopic and scotopic luminance conditions as a potential biomarker to assess the outcome of interventions on binocular function. Sixteen young adults (age range [years] = 21-31; 8 women; cVA logMAR < 0.0) participated in this study. The Freiburg Visual Acuity Test (FrACT) was used for VA testing and retested on another day. Both cVA and hVA were determined for dark grey optotypes on light grey background. Participants underwent 40minutes of dark adaptation prior to scotopic VA testing. Binocular and monocular VA testing was performed. The eye with better VA over the 2 days of testing was selected, the BiS was quantified (binocular VA - better monocular VA) and repeated measures ANOVAs were performed. Binocular VA exceeded monocular VA for all luminance conditions, VA-types, and sessions. We report BiS estimates for photopic and scotopic cVA and hVA, (logMAR BiS ± SEM [decimal BiS]): photopic = -0.01 ± 0.01 [1.03] and -0.06 ± 0.03 [1.15]; and scotopic = -0.05 ± 0.01 [1.12] and -0.11 ± 0.04 [1.28], respectively). Improvement for binocular vision estimates ranged from 0.01 to 0.11 logMAR. A repeated-measures ANOVA (RM ANOVA) did not reveal significant effects of LUMINANCE or VA TYPE on BiS, albeit a trend for strongest BiS for scotopic hVA (15% vs. 28%, photopic versus scotopic, respectively) and weakest for photopic cVA (3% vs. 12%, photopic versus scotopic conditions, respectively). Our results indicate that BiS of VA is relevant to scotopic and photopic hVA and cVA. It appears therefore a plausible candidate biomarker to assess the outcome of retinal therapies restoring rod or cone function on binocular vision. Binocular summation of visual acuity might serve as a clinical biomarker to monitor therapy outcome on binocular rod and cone-mediated vision.

ATXN7-Related Cone-Rod Dystrophy

Reliable biomarkers with diagnostic and prognostic values are needed for upcoming gene therapy trials for spinocerebellar ataxias. To identify ophthalmological biomarkers in a sample of spinocerebellar ataxia type 7 (SCA7) carriers. This article presents baseline data from a cross-sectional natural history study conducted in Paris, France, reference centers for rare diseases from May 2020 to April 2021. Data were analyzed from September to December 2022. Fifteen adult ATXN7 pathogenic expansion carriers (9 with preataxia and 6 with ataxia) were included, all with a Scale for the Assessment and Rating of Ataxia (SARA) score of 15 of 40 or lower. Patients were recruited at the Paris Brain Institute, and all contacted patients accepted to participate in the study. Three visits (baseline, 6 months, and 12 months) were planned, including neurological examination (SARA and Composite Cerebellar Functional Severity Score), ophthalmological examination (best-corrected visual acuity, microperimetry, full-field electroretinogram, optical coherence tomography, and fundus autofluorescence imaging), and neurofilament light chain (NfL) measurements. Here we report the baseline ophthalmic data from the cohort and determine whether there is a correlation between disease scores and ophthalmic results. Among the 15 included SCA7 carriers (median [range] age, 38 [18-60] years; 8 women and 7 men), 12 displayed cone or cone-rod dystrophy, with the number of CAG repeats correlating with disease severity (ρ, 0.73, 95% CI, 0.34 to 0.90; P < .001). Two patients with cone-rod dystrophy exhibited higher repeat numbers and greater ataxia scores (median [range] SARA score, 9 [7-15]) compared to those with only cone dystrophy (median [range] SARA score, 2 [0-5]). A correlation emerged for outer nuclear layer thickness with SARA score (ρ, -0.88; 95% CI, -0.96 to -0.59; P < .001) and NfL levels (ρ, -0.87; 95% CI, -0.86 to 0.96; P < .001). Moreover, ataxia severity was correlated with visual acuity (ρ: 0.89; 95% CI, 0.68 to 0.96; P < .001) and retinal sensitivity (ρ, -0.88; 95% CI, -0.96 to 0.59; P < .001). In this cross-sectional study, retinal abnormalities were found at preataxic stages of the disease. Most of the carriers presented with cone dystrophy and preserved rod function. The outer nuclear layer thickness correlated with SARA score and plasma NfL levels suggesting nuclear layer thickness to be a biomarker of disease severity. These findings contribute to understanding the dynamics of SCA7-related retinal dystrophy and may help lay the groundwork for future therapeutic intervention monitoring and clinical trials. ClinicalTrials.gov Identifier: NCT04288128.

The dose-response relationship of subretinal gene therapy with rAAV2tYF-CB-hRS1 in a mouse model of X-linked retinoschisis.

X-linked retinoschisis (XLRS), due to loss-of-function mutations in the retinoschisin (RS1) gene, is characterized by a modest to severe decrease in visual acuity. Clinical trials for XLRS utilizing intravitreal (IVT) gene therapy showed ocular inflammation. We conducted a subretinal dose-response preclinical study using rAAV2tYF-CB-hRS1 utilizing the Rs1 knockout (Rs1-KO) mouse to investigate short- and long-term retinal rescue after subretinal gene delivery. Rs1-KO mice were subretinally injected with 2 μL of rAAV2tYF-CB-hRS1 vector with 8E9 viral genomes (vg)/eye, 8E8 vg/eye, 8E7 vg/eye, or sham injection, and compared to untreated eyes. Reconstitution of human RS1 protein was detected using western blotting. Analysis of retinal function by electroretinography (ERG) and structural analysis by optical coherence tomography (OCT) were performed at 1, 2, 3, 5, 7, and 12 months post injection (MPI). Immunohistochemistry (IHC) was performed to evaluate cone rescue on the cellular level. Functional vision was evaluated using a visually guided swim assay (VGSA). Western blotting analysis showed human RS1 protein expression in a dose-dependent manner. Quantification of western blotting showed that the RS1 protein expression in mice treated with the 8E8 vg dose was near the wild-type (WT) expression levels. ERG demonstrated dose-dependent effects: At 1 MPI the 8E8 vg dose treated eyes had higher light-adapted (LA) ERG amplitudes in 3.0 flash and 5 Hz flicker compared to untreated (p < 0.0001) and sham-treated eyes (p < 0.0001) which persisted until the 12 MPI endpoint, consistent with improved cone function. ERG b-wave amplitudes were higher in response to dark-adapted (DA) 0.01 dim flash and 3.0 standard combined response (SCR) compared to sham-treated (p < 0.01) and untreated eyes (p < 0.001) which persisted until 3 MPI, suggesting short-term improvement of the rod photoreceptors. All injections, including sham-treated, resulted in a cyst severity score of 1 (no cavities), with significant reductions compared to untreated eyes up to 3 MPI (p < 0.05). The high and low dose groups showed inconsistent ERG improvements, despite reduced cyst severity, emphasizing the dose-dependent nature of gene augmentation's efficacy and the tenuous connection between cyst reduction and ERG improvement. IHC data showed a significant cone rescue in eyes treated with the 8E8 vg dose compared to sham-treated and untreated eyes. VGSA showed better functional vision in 8E8 vg dose treated mice. Eyes treated with the highest dose showed occasional localized degeneration in the outer nuclear layer. Our data suggest that a dose of 8E8 vg/eye subretinally improves retinal function and structure in the Rs1-KO mouse. It improves cone function, rod function, and reduces cyst severity. Sham treatment resolves schisis cysts, but 8E8 vg/eye is needed for optimal retinal electrical function rescue. These findings offer a promising path for clinical translation to human trials.

Update on the range of visual electrophysiology tests and heir application with clinical examples

The International Society for clinical electrophysiology of vision (ISCEV) publishes open‐access standards and guidelines for routine electrophysiological tests of the visual system in order to optimize diagnostic value, to promote consistency and to allow meaningful inter‐laboratory comparisons. The ISCEV also publishes extended protocols with the aim of promoting convergence of methods that are not yet standardized, for tests that are widely used but often performed as an addition to the minimum ISCEV standard procedures (see www.ISCEV.org for all publications).This talk will outline the main ISCEV standard methods including the full‐field electroretinogram (ERG), pattern ERG (PERG) and multifocal ERG (mfERG). Several extended full‐field ERG protocols will also be highlighted, including the dark‐adapted (DA) red flash ERG, photopic On–Off ERG and S‐cone ERG. The use of these methods in the clinic will be illustrated in cases of inherited and acquired retinal disorders, to show how the extended protocols complement standard techniques, to aid diagnosis and patient management and to probe and detail retinal function phenotypes.The Standard full‐field ERG is recorded under dark‐adapted (DA) and light‐adapted (LA) conditions and provides a measure of generalized rod and cone system function at the level of the outer and inner retina, with minimal contribution from the macula. The mfERG assesses cone system function across the posterior pole and the PERG assesses macular and macular retinal ganglion cell function.The DA red flash ERG is an extended protocol that provides a measure of generalized dark‐adapted retinal function, with the advantage of having both a cone system x‐wave and a rod system b‐wave within the same waveform. This enables the relative involvement of rod and cone systems to be assessed simultaneously and can help determine the origins of severely attenuated standard DA strong flash ERGs. The DA red flash ERG is also useful for assessing cone system function in photophobic patients, and in patients with variable ability to comply with longer ERG protocols. The photopic On–Off ERG is a response to an extended light stimulus (duration 150 or 200 ms) and is used to assess generalized cone system function of both the On and Off retinal pathways, useful when there is a locus of dysfunction that is post‐phototransduction or post‐receptoral, when On and Off retinal systems may be similarly, selectively or specifically affected e.g., in different forms of congenital stationary night blindness (CSNB) or in forms of toxic retinopathy. The S‐cone ERG (short‐wavelength or “blue” flash ERG) is used to probe the function of the S‐cone retinal pathway, and can aid diagnosis and characterization in a variety of retinal dystrophies and disorders e.g., distinguishing between achromatopsia and S‐cone monochromacy.

Clinical, phenotypic and genetic characteristics of macula‐sparing stargardt disease

Aims/Purpose: Fundus flavimaculatus and Stargardt's disease are monogenic but heterogeneous disease entities leading to loss of central vision in adolescence, caused by more than 490 mutations in the ABCA4 gene. We herein report the clinical, phenotypic and genetic characteristics of adult onset fovea sparing Stargardt's disease.Methods: Two Caucasian males in their 40s presenting with complaints of paracentral scotomata underwent complete ophthalmic exam, visual field testing, optical coherence tomography (OCT), fundus autofluorescence (FAF), fluorescein angiography (FA), electroretinography (ERG) and genetic testing.Results: Visual acuity was 20/20 in both patients with normal IOP. Anterior segments were unremarkable. Posterior segment examination revealed pigment mottling in the macula with ring‐shaped perifoveal chorioretinal atrophy and numerous white deposits in the mid‐periphery. Visual fields confirmed the paracentral ring scotomata. OCT demonstrated concentric perifoveal loss of outer retinal layers with foveal sparing simulating oedema. Extensive hyperautofluorescence in the area of chorioretinal atrophy was revealed by FAF. Full‐field ERG confirmed incomplete loss of cone bioelectrical activity with preserved morphology of the foveal peak and normal rod function. Genetic testing discovered several pathogenic mutations in both patients with shared ABCA4 c.5603A&gt;T, p.(Asn1868Ile), a risk factor mutation. None of the mutations of our patients were previously reported in foveal sparing Stargardt's disease.Conclusions: The variant ABCA4 c.5603A&gt;T, p.(Asn1868Ile) might be associated with foveal sparing Stargardt's disease. Further population studies are need to confirm this association.

Transient Receptor Potential channels (TRP) in GtoPdb v.2023.3

Transient Receptor Potential channels (TRP) in GtoPdb v.2023.3

Cone-driven strong flash electroretinograms in healthy adults: Prevalence of negative waveforms

PurposeBoth rod and cone-driven signals contribute to the electroretinogram (ERG) elicited by a standard strong flash in the dark. Negative ERGs usually reflect inner retinal dysfunction. However, in diseases where rod photoreceptor function is selectively lost, a negative waveform might represent the response of the dark-adapted cone system. To investigate the dark-adapted cone-driven waveform in healthy individuals, we delivered flashes on a dim blue background, designed to saturate the rods, but minimally adapt the cones.MethodsERGs were recorded, using conductive fibre electrodes, in adults from the TwinsUK cohort. Responses to 13 cd m−2 s white xenon flashes (similar to the standard DA 10 flash), delivered on a blue background, were analysed. Photopic and scotopic strengths of the background were 1.3 and 30 cd m−2, respectively; through a dilated pupil, this is expected to largely saturate the rods, but adapt the cones much less than the standard ISCEV background. ResultsMean (SD) participant age was 62.5 (11.3) years (93% female). ERGs from 203 right and 204 left eyes were included, with mean (SD) b/a ratios of 1.22 (0.28) and 1.18 (0.28), respectively (medians, 1.19 and 1.17). Proportions with negative waveforms were 23 and 26%, respectively. Right and left eye b/a ratios were strongly correlated (correlation coefficient 0.74, p < 0.0001). We found no significant correlation of b/a ratio with age.ConclusionsOver 20% of eyes showed b/a ratios less than 1, consistent with the notion that dark-adapted cone-driven responses to standard bright flashes can have negative waveforms. The majority had ratios greater than 1. Thus, whilst selective loss of rod function can yield a negative waveform (with reduced a-wave) in some, our findings also suggest that loss of rod function can occur without necessarily yielding a negative ERG. One potential limitation is possible mild cone system adaptation by the background.

Paraoxonase 2 Deficiency Causes Mitochondrial Dysfunction in Retinal Pigment Epithelial Cells and Retinal Degeneration in Mice.

Although AMD is a complex disease, oxidative stress is a crucial contributor to its development, especially in view of the higher oxygen demand of the retina. Paraoxonase 2 (PON2) is a ubiquitously and constitutively expressed antioxidant protein that is found intracellularly associated with mitochondrial membranes and modulates mitochondrial ROS production and function. The contribution of PON2 to AMD has not been studied to date. In this study, we examined the role of PON2 in AMD utilizing both in vitro and in vivo models of AMD with emphasis on mitochondrial function. Mitochondrial localization and regulation of PON2 following oxidative stress were determined in human primary cultured retinal pigment epithelium (hRPE) cells. PON2 was knocked down in RPE cells using siRNA and mitochondrial bioenergetics were measured. To investigate the function of PON2 in the retina, WT and PON2-deficient mice were administered NaIO3 (20 mg/kg) intravenously; fundus imaging, optical coherence tomography (OCT), electroretinography (ERG) were conducted; and retinal thickness and cell death were measured and quantified. In hRPE, mitochondrial localization of PON2 increased markedly with stress. Moreover, a time-dependent regulation of PON2 was observed following oxidative stress, with an initial significant increase in expression followed by a significant decrease. Mitochondrial bioenergetic parameters (basal respiration, ATP production, spare respiratory capacity, and maximal respiration) showed a significant decrease with oxidative stress, which was further exacerbated in the absence of PON2. NaIO3 treatment caused significant retinal degeneration, retinal thinning, and reduced rod and cone function in PON2-deficient mice when compared to WT mice. The apoptotic cells and active caspase 3 significantly increased in PON2-deficient mice treated with NaIO3, when compared to WT mice. Our investigation demonstrates that deficiency of PON2 results in RPE mitochondrial dysfunction and a decline in retinal function. These findings imply that PON2 may have a beneficial role in retinal pathophysiology and is worthy of further investigation.

Choriocapillaris Impairment Is Associated With Delayed Rod-Mediated Dark Adaptation in Age-Related Macular Degeneration.

Progress toward treatment and prevention of age-related macular degeneration (AMD) requires imaging end points that relate to vision. We investigated choriocapillaris flow signal deficits (FD%) and visual function in eyes of individuals aged ≥60 years, with and without AMD. One eye of each participant in the baseline visit of the Alabama Study on Early Age-Related Macular Degeneration 2 (ALSTAR2; NCT04112667) was studied. AMD presence and severity was determined using the Age-Related Eye Disease Study (AREDS) grading system. FD% was quantified using macular spectral domain optical coherence tomography angiography (OCTA) scans. Vision tests included rod-mediated dark adaptation (RMDA), best-corrected visual acuity, and contrast sensitivity (photopic and mesopic), and microperimetric light sensitivity (scotopic, mesopic, and photopic). Presence of subretinal drusenoid deposits (SDD) was determined using multimodal imaging. In 410 study eyes of 410 participants (mean [SD] age = 71.7 years [5.9]), FD% was higher in early AMD (mean [SD] = 54.0% [5.5], N = 122) and intermediate AMD (59.8% [7.4], N = 92), compared to normal (52.1% [5.3], N = 196) eyes. Among visual functions evaluated, RMDA showed the strongest association with FD% (r = 0.35, P < 0.0001), followed by contrast sensitivity (r = -0.22, P < 0.0001). Eyes with SDD had worse FD% (58.3% [7.4], N = 87), compared to eyes without SDD (53.4% [6.0], N = 323, P = < 0.0001). Choriocapillaris FD% were associated with AMD severity and with impaired vision, especially RMDA. Reduced metabolic transport and exchange across the choriocapillaris-Bruch's membrane retinal pigment epithelium (RPE) complex, a causal factor for high-risk soft drusen formation, also may impair photoreceptor sustenance from the circulation. This includes retinoid resupply, essential to dynamic rod function.

Rod and Cone Function Measured Objectively by Chromatic Pupil Campimetry Show a Different Preservation Between Distinct Genotypes in Retinitis Pigmentosa.

Verifying whether specific genotypes causing retinitis pigmentosa (RP) show differences in the preservation of rod and cone function measured by chromatic pupil campimetry (CPC). Sixty-three RP eyes (37 male, 14-58 years) were measured using CPC with specific photopic and scotopic protocols, and the relative maximal constriction amplitudes and latencies to constriction onset were analyzed per genotype (RP due to variants in EYS, n = 14; PDE6A, n = 10; RPE65, n = 15; USH2A, n = 10; and RPGR, n = 14). Correlation analyses between the pupillary responses were performed with age, full-field stimulus threshold (FST), and optical coherence tomography (OCT) for cones and rods, respectively, to the genotype. Pupillary responses were most severely reduced in RPE65-RP. Patients with disease-associated variants in EYS and USH2A were accompanied with better-preserved rod function compared with the other subgroups, reaching statistical significance between EYS and RPE65. Cone function was statistically significantly correlated with age in USH2A-RP with an annual decline of 2.4%. Correlations of pupillary responses were found with FST but barely with the ellipsoid zone area in OCT. Latency was significantly more prolonged in RPE65-RP compared with the other genotypes for cones. Rod and cone function measured objectively by CPC showed a different preservation between genotypes in RP. However, heterogeneity inside the same genotype was present. CPC data correlated with FST, but structural OCT parameters seem to be limited indicators for photoreceptor function in RP. Prolonged time dynamics for cones in RPE65 mutations suggest an impact on cone processing and might provide additional information in the evaluation of therapy effects.

Transient Receptor Potential channels (TRP) in GtoPdb v.2023.2

Transient Receptor Potential channels (TRP) in GtoPdb v.2023.2

FDXR-associated disease in a Chinese cohort: Unraveling expanded ocular phenotypes and genetic spectrum

FDXRassociated disease is characterized by optic atrophy, acoustic neuropathy, and developmental delays. This study evaluated the ocular phenotypes and genetic features of patients with biallelic FDXR variants. Five individuals from unrelated non-consanguineous Chinese families with biallelic FDXR variants were identified using whole exome sequencing, Sanger sequencing, and co-segregation validation. In addition to optic atrophy and diverse extraocular manifestations, all patients presented with retinal dystrophy, and electroretinogram showed severely impaired cone and rod functions in their first decades. Three of the five patients showed attenuated retinal vessels that appeared as white lines on the fundus, and fundus fluorescein angiography (FFA) further revealed vascular abnormalities including delayed filling, completely occluded retinal vasculature, and severe retinal vascular nonperfusion of the peripheral retina. Five novel FDXR variants were identified: c.383C > T (p.A128V), c.963delG (p.R322fs*7), c.1052_1053delTC (p.L351Pfs*12), c.394-11T > G and c.1002+1G > A. Retinal dystrophy with attenuated retinal vessels appearing as white lines was observed in this cohort, and the FFA images revealed that retinal vascular occlusion could be a distinct clinical characteristic of FDXR-associated disease. Probands with FDXR revealed severe early onset ophthalmic features with rapid-progression, indicating the importance of early diagnosis and treatment. Moreover, this is the first study to report FFA manifestations in an FDXR cohort, expanding the FDXR-associated ocular disease phenotype and genetic spectrum.

Potential blindness from nutritional xerophthalmia in autistic patients

Vitamin A is vital to retinal rod function and epithelial cell differentiation. Although uncommon in the developed world, vitamin A deficiency (VAD) secondary to poor diets or gastrointestinal disease has been reported and can lead to xerophthalmia, which is characterized by night blindness and a spectrum of ocular surface changes. Patients with autism spectrum disorder have been shown to have restrictive diets secondary to sensory issues leading to rejection of foods except for those of certain color or texture. We present a case series of 6 pediatric patients with autism who developed varying degrees of xerophthalmia due to VAD, which resulted from restrictive eating. All patients presented with a history of eye irritation that was not relieved by antibiotic or allergy eye drops. Further questioning revealed they had restrictive diets consisting of only or mostly white and tan foods, and serum vitamin A testing confirmed severe VAD. Most stages of xerophthalmia were completely reversed with vitamin A supplementation, but in 2 patients more advanced xerophthalmia resulted in irreversible blindness and ocular damage. Both pediatricians and pediatric eye care providers must be vigilant for VAD as an etiology of eye irritation, photophobia, or new-onset visual impairment in autistic children. A review of the child's diet must be implemented as a standard part of routine history taken in this vulnerable population. Early identification and vitamin A supplementation can prevent irreversible ocular compromise and vision loss.

Cone dystrophy associated with autoimmune polyglandular syndrome type 1

To report the association of autoimmune polyglandular syndrome type 1 (APS1) with cone dystrophy in a large Saudi family. This is a Retrospective chart review and prospective genetic testing and ophthalmic examination of a large multiplex consanguineous family. Genetic testing was performed on 14 family members, seven of whom had detailed ophthalmic examinations. Medical history, ocular history and evaluation, visual field testing, full-field electroretinogram (ERG), and Whole Exome Sequencing (WES) results were analyzed. Three family members were homozygous for c.205_208dupCAGG;p.(Asp70Alafs*148) in AIRE and homozygous for c.481-1G>A in PDE6C. One additional family member was homozygous for only the AIRE variant and another additional family member was homozygous for only the PDE6C variant. All patients with homozygosity for the PDE6C variant had cone dystrophy, and all patients with homozygosity for the AIRE variant had APS1. In addition, two of the family members who were homozygous for the PDE6C and AIRE variants had reduced rod function on ERG. We report the co-inheritance for APS1 and PDE6C-related cone dystrophy, an unusual example of two seemingly independent recessive conditions coinciding within a family. Dual molecular diagnosis must be taken into account by ophthalmologists facing unusual constellations of findings, especially in consanguineous families.