Rod Function Research Articles

Scotopic thresholds on dark-adapted chromatic perimetry in healthy aging and age-related macular degeneration

To evaluate the effect of aging, intra- and intersession repeatability and regional scotopic sensitivities in healthy and age-related macular degeneration (AMD) eyes. Intra- and intersession agreement and effect of age was measured in healthy individuals. The mean sensitivity (MS) and pointwise retinal sensitivities (PWS) within the central 24° with 505 nm (cyan) and 625 nm (red) stimuli were evaluated in 50 individuals (11 healthy and 39 AMD eyes). The overall intra- and intersession had excellent reliability (intraclass correlation coefficient, ICC > 0.90) and tests were highly correlated (Spearman rs = 0.75–0.86). Eyes with subretinal drusenoid deposit (SDD) had reduced PWS centrally, particularly at inferior and nasal retinal locations compared with controls and intermediate AMD (iAMD) without SDD. There was no difference in MS or PWS at any retinal location between iAMD without SDD and healthy individuals nor between iAMD with SDD and non-foveal atrophic AMD groups. Eyes with SDD have reduced rod function compared to iAMD without SDD and healthy eyes, but similar to eyes with non-foveal atrophy. Our results highlight rod dysfunction is not directly correlated with drusen load and SDD location.

Correlations Between Dark-Adapted Rod Threshold Elevations and ERG Response Deficits in Duchenne Muscular Dystrophy.

PurposeThe purpose of this study was to characterize changes in the full-field flash electroretinogram (ERG) in association with psychophysical dark-adapted visual thresholds in patients with genetically characterized Duchenne muscular dystrophy (DMD) either lacking Dp427 (Up 30) or at least Dp260 in addition to Dp427 (Down 30).MethodsTwenty-one patients with DMD and 27 age-similar controls participated in this study. Dark-adapted (0.01, 3.0, and 10 cd.s/m² flashes) and light-adapted (3.0 cd.s/m² flash) ERGs were recorded following International Society for Clinical Electrophysiology of Vision (ISCEV) standard protocols. Visual detection thresholds to 625-nm (cone function) and 527-nm (rod function) light-emitting diode (LED) flashes (2 degree diameter) were measured during a dark adaptation period after a 1-minute exposure to a bleaching light (3000 cd/m²). Initially, 8 minutes of interleaved 625-nm and 527-nm thresholds were measured. After an additional 5 minutes of dark-adaptation, a second set of threshold measurements to 527-nm stimuli was performed during the subsequent 6 minutes.ResultsDark-adapted b-wave amplitude was significantly reduced to all strengths of flash and a-wave in response to the strong flash stimulus was delayed (15.6 vs. 14.7 ms, P < 0.05) in patients with Down 30 compared with controls. Dark-adapted cone thresholds did not differ among the groups (−2.0, −1.8, and −1.7 log cd/m² for Down 30, Up 30, and controls, respectively, P = 0.21). In contrast, dark-adapted rod thresholds were elevated (F(2,36) = 8.537, P = 0.001) in patients with Down 30 (mean = −3.2 ± 1.1 log cd/m²) relative to controls (mean = −4.2 ± 0.3 log cd/m²). Dark-adapted b-wave amplitudes were correlated with dark-adapted rod sensitivity in patients with DMD (Spearman Rho = 0.943, P = 0.005). The changes were much smaller or absent in patients with intact Dp260.ConclusionsDp260 is particularly required for normal rod-system function in dark adaptation.

Long-term follow-up of a patient with JAG1-associated retinopathy

To report the long-term structural and functional changes in the posterior segments of an adult with an unusual retinal dystrophy caused by a novel mutation in JAG1. A 33-year-old female underwent comprehensive ophthalmic examination, including best corrected visual acuity (BCVA) measurement, dilated fundus imaging (wide-angle fundus colour and short wavelength autofluorescence imaging), macular and peripheral spectral-domain optical coherence tomography (SD-OCT) and electroretinography (ERG) at baseline and 10years later at the age of 43. The patient also underwent systemic review with detailed cardiac, brain and renal investigations. During follow-up, genetic analysis using whole-exome sequencing was performed on the patient and her parents to identify disease-causing variants. The patient's main complaint was of a recent onset of bilateral photophobia and blurred vision in the left eye. On examination, the most striking retinal finding was of bilateral well-demarcated, anterior circumferential chorioretinal atrophy with scattered pigment clumping from the mid periphery to the ora. In addition, she had posterior pole RPE hypopigmentation, peripapillary chorioretinal atrophy, left macular choroidal folds and retinal vasculature tortuosity with atypical branching. Her retinal electrophysiology was consistent with a cone rod photoreceptor dystrophy and left macular dysfunction. Ten years later, her BCVA, the anterior circumferential chorioretinal atrophy and her visual field constriction all remained stable. Her retinal electrophysiology demonstrated deterioration of left rod function, while cone dysfunction remained stable. Macular function deteriorated in both eyes. During follow-up, she was also noted to have progressive aortic root dilatation, posterior embryotoxon and an x ray diagnosis of butterfly vertebrae. Whole-exome sequencing revealed a novel c.2412C > A p.(Tyr804Ter) truncating mutation in JAG1 that was predicted to be pathogenic and suggested a diagnosis of Alagille syndrome. This is the first report of the long-term detailed follow-up of a patient with Alagille syndrome whose most striking ophthalmic finding was bilateral well-demarcated, anterior circumferential chorioretinal atrophy. During follow-up, this finding remained stable, suggesting that this may be developmental in origin. This is in contrast with the progressive deterioration in the posterior pole retinal and macular function.

ERG assessment of altered retinal function in canine models of retinitis pigmentosa and monitoring of response to translatable gene augmentation therapy.

To analyze ERG responses from two dog models of retinitis pigmentosa, one due to a PDE6A mutation and the other a CNGB1 mutation, both to assess the effect of these mutations on retinal function and the ability of gene augmentation therapy to restore normal function. Scotopic and photopic ERGs from young affected and normal control dogs and affected dogs following AAV-mediated gene augmentation therapy were analyzed. Parameters reflecting rod and cone function were collected by modeling the descending slope of the a-wave to measure receptor response and sensitivity. Rod-driven responses were further assessed by Naka-Rushton fitting of the first limb of the scotopic b-wave luminance-response plot. PDE6A-/- dogs showed a dramatic decrease in rod-driven responses with very reduced rod maximal responses and sensitivity. There was a minor reduction in the amplitude of maximal cone responses. In contrast, CNGB1-/- dogs had some residual rod responses with reduced amplitude and sensitivity and normal cone responses. Following gene augmentation therapy, rod parameters were substantially improved in both models with restoration of sensitivity parameters log S and log K and a large increase in log Rmax in keeping with rescue of normal rod phototransduction in the treated retinal regions. Modeling of rod and cone a-waves and the luminance-response function of the scotopic b-wave characterized the loss of rod photoreceptor function in two dog models of retinitis pigmentosa and showed the effectiveness of gene augmentation therapy in restoring normal functional parameters.

Interspecies Correlations between Human and Mouse NR2E3-Associated Recessive Disease.

NR2E3-associated recessive disease in humans is historically defined by congenital night blinding retinopathy, characterized by an initial increase in short-wavelength (S)-cone sensitivity and progressive loss of rod and cone function. The retinal degeneration 7 (rd7) murine model, harboring a recessive mutation in the mouse ortholog of NR2E3, has been a well-studied disease model and recently evaluated as a therapeutic model for NR2E3-associated retinal degenerations. This study aims to draw parallels between human and mouse NR2E3-related disease through examination of spectral domain optical coherence tomography (SD-OCT) imaging between different stage of human disease and its murine counterpart. We propose that SD-OCT is a useful non-invasive diagnostic tool to compare human clinical dystrophy presentation with that of the rd7 mouse and make inference that may be of therapeutically relevance. Additionally, a longitudinal assessment of rd7 disease progression, utilizing available clinical data from our patients as well as extensive retrospective analysis of visual acuity data from published cases of human NR2E3-related disease, was curated to identify further valuable correlates between human and mouse Nr2e3 disease. Results of this study validate the slow progression of NR2E3-associated disease in humans and the rd7 mice and identify SD-OCT characteristics in patients at or near the vascular arcades that correlate well with the whorls and rosettes that are seen also in the rd7 mouse and point to imaging features that appear to be associated with better preserved S-cone mediated retinal function. The correlation of histological findings between rd7 mice and human imaging provides a solid foundation for diagnostic use of pathophysiological and prognostic information to further define characteristics and a relevant timeline for therapeutic intervention in the field of NR2E3-associated retinopathies.

Spatial and temporal resolution of the photoreceptors rescue dynamics after treatment with voretigene neparvovec

BackgroundVoretigene neparvovec is a gene therapeutic agent for treatment of retinal dystrophies caused by bi-allelic RPE65 mutations. In this study, we report on a novel and objective evaluation of a...

An update on the rod microglia variant in experimental and clinical brain injury and disease

Contemporary microglia morphologies include ramified, activated and amoeboid, with the morphology of microglia considered highly coupled to the cellular function. Rod microglia are an additional activated microglia variant observed in the ageing, injured and diseased brain. Rod microglia were reported frequently in the early 1900s by neuropathologists in post-mortem cases of general paresis, Alzheimer’s disease and encephalitis, and then remained largely ignored for almost 100 years. Recent reports have renewed interest in rod microglia, most notably after experimental traumatic brain injury. Rod microglia are formed by the narrowing of the soma and retraction of planar processes, which results in the appearance of an elongated, rod-shaped cell. Rod microglia are most commonly observed in the cortex, aligned perpendicular to the dural surface and adjacent to neuronal processes; in the hippocampus, they are aligned perpendicular to hippocampal layers. Furthermore, rod microglia form trains with one another, apical end to basal end. By replicating the process of sketching microscopic observation, rod microglia are re-defined by circumnutation around the long axis. In this update, we summarize the rod microglia variant in clinical and experimental literature and advocate for investigation into mechanisms of rod microglia origin and function.

Current Management of Patients with RPE65 Mutation-Associated Inherited Retinal Degenerations in Europe: Results of a Multinational Survey by the European Vision Institute Clinical Research Network

Purpose: The first ocular gene augmentation therapy, voretigene neparvovec (VN) (Luxturna®), has been approved for clinical use in an increasing number of countries (FDA USA 2017, EMA Europe 2018, MoHAP United Arab Emirates 2019, SFDA Saudi Arabia 2019, Swiss Medic Switzerland 2020, TGA Australia 2020, BFR Brazil 2020). Among the EVICR.net clinical centers, we conducted the first multinational survey to understand distribution, diagnostic work-up, and management of inherited retinal degeneration (IRD) cases in Europe with a special focus on RPE65 mutation-associated IRDs. Methods: An electronic survey questionnaire including 35 questions specifically addressing RPE65 mutation-associated IRDs was developed and sent to the 101 EVICR.net clinical centers. Results: The overall response rate was 49%. Forty-two centers see IRD patients, and 22/42 follow patients with confirmed biallelic RPE65 mutations. Fifteen of the 22 centers (68%) and 3/22 (14%) follow 1–5 and 6–10 patients with homozygous RPE65 mutations, respectively. Additionally, 15/22 (68%) and 3/22 (14%) follow 1–5 and >20 patients with compound heterozygous RPE65 mutations, respectively. Fifty-nine percent of mutations were ACMG Class 4 and 5 (at least 1 allele), 82.8% reported previously and 17.2% novel. Referral diagnoses (the mean per center) were Leber congenital amaurosis (38.2%), early-onset severe retinal degeneration (16.8%), rod-cone-dystrophy/retinitis pigmentosa (RP) (28.1%), and unclassified visual impairment (17.0%). Twenty-five percent of the centers changed the referral diagnosis in >47.5% of cases; 32% follow a specific referral process for RPE65 mutation-associated IRD patients. Annual follow-up visits are done in 55% of the centers and biannual visits in 23%. In 32%, other centers also follow the patients. Kinetic perimetry is done in 82%, static perimetry in 45%, and microperimetry in 18% of the centers. Full-field light stimulus threshold testing with blue and red stimuli to quantify the rod and cone function is used in 6/22 centers (27%). A mobility course is available in one center (5%). Conclusion: This first multinational survey on management of patients with RPE65 mutation-associated IRDs in Europe shows that about half of the responding EVICR.net centers have such patients under care. There is heterogeneity in diagnoses and management practices. At the start of clinical practice experience with VN, these data provide a useful baseline and highlight the need for consensus/guidelines to inform standard of care in this new era of gene therapy.

Loss of endocytosis-associated RabGEF1 causes aberrant morphogenesis and altered autophagy in photoreceptors leading to retinal degeneration.

Rab-GTPases and associated effectors mediate cargo transport through the endomembrane system of eukaryotic cells, regulating key processes such as membrane turnover, signal transduction, protein recycling and degradation. Using developmental transcriptome data, we identified Rabgef1 (encoding the protein RabGEF1 or Rabex-5) as the only gene associated with Rab GTPases that exhibited strong concordance with retinal photoreceptor differentiation. Loss of Rabgef1 in mice (Rabgef1-/-) resulted in defects specifically of photoreceptor morphology and almost complete loss of both rod and cone function as early as eye opening; however, aberrant outer segment formation could only partly account for visual function deficits. RabGEF1 protein in retinal photoreceptors interacts with Rabaptin-5, and RabGEF1 absence leads to reduction of early endosomes consistent with studies in other mammalian cells and tissues. Electron microscopy analyses reveal abnormal accumulation of macromolecular aggregates in autophagosome-like vacuoles and enhanced immunostaining for LC3A/B and p62 in Rabgef1-/- photoreceptors, consistent with compromised autophagy. Transcriptome analysis of the developing Rabgef1-/- retina reveals altered expression of 2469 genes related to multiple pathways including phototransduction, mitochondria, oxidative stress and endocytosis, suggesting an early trajectory of photoreceptor cell death. Our results implicate an essential role of the RabGEF1-modulated endocytic and autophagic pathways in photoreceptor differentiation and homeostasis. We propose that RabGEF1 and associated components are potential candidates for syndromic traits that include a retinopathy phenotype.

Optimal timing for activation of sigma 1 receptor in the Pde6brd10/J (rd10) mouse model of retinitis pigmentosa

Sigma 1 Receptor (Sig1R), a pluripotent modulator of cell survival, is a promising target for treatment of retinal degenerative diseases. Previously, we reported that administration of the high-affinity, high-specificity Sig1R ligand (+)-pentazocine, ((+)-PTZ) beginning at post-natal day 14 (P14) and continuing every other day improves visual acuity and delays loss of photoreceptor cells (PRCs) in the Pde6βrd10/J (rd10) mouse model of retinitis pigmentosa. Whether administration of (+)-PTZ, at time points concomitant with (P18) or following (P21, P24) onset of PRC death, would prove neuroprotective was investigated in this study. Rd10 mice were administered (+)-PTZ intraperitoneally [0.5 mg/kg], starting at either P14, P18, P21 or P24. Injections continued every other day through P42. Visual acuity was assessed using the optokinetic tracking response (OKR). Rd10 mice treated with (+)-PTZ beginning at P14 retained visual acuity for the duration of the study (~0.33 c/d at P21, ~0.38 c/d at P28, ~0.32 c/d at P35, ~0.32 c/d at P42), whereas mice injected beginning at P18, P21, P24 showed a decline in acuity when tested at P35 and P42. Their acuity was only slightly better than rd10-non-treated mice. Electrophysiologic function was assessed using scotopic and photopic electroretinography (ERG) to assess rod and cone function, respectively. Photopic a- and b-wave amplitudes were significantly greater in rd10 mice treated with (+)-PTZ beginning at P14 compared with non-treated mice and those in the later-onset (+)-PTZ injection groups. Retinal architecture was visualized in living mice using spectral domain-optical coherence tomography (SD-OCT) allowing measurement of the total retinal thickness, the inner retina and the outer retina (the area most affected in rd10 mice). The outer retina measured ~35 μm in rd10 mice treated with (+)-PTZ beginning at P14, which was significantly greater than mice in the later-onset (+)-PTZ injection groups (~25 μm) and non-treated rd10 mice (~25 μm). Following the visual function studies performed in the living mice, eyes were harvested at P42 for histologic analysis. While the inner retina was largely intact in all (+)-PTZ-injection groups, there was a marked reduction in the outer retina of non-treated rd10 mice (e.g. in the outer nuclear layer there were ~10 PRCs/100 μm retinal length). The rd10 mice treated with (+)-PTZ beginning at P14 had ~20 PRCs/100 μm retinal length, whereas the mice in groups beginning P18, P21 and P24 had ~16 PRCs/100 μm retinal length. In conclusion, the data indicate that delaying (+)-PTZ injection past the onset of PRC death in rd10 mice – even by a few days – can negatively impact the long-term preservation of retinal function. Our findings suggest that optimizing the administration of Sig1R ligands is critical for retinal neuroprotection.

The Michigan Vision-Related Anxiety Questionnaire: A Psychosocial Outcomes Measure for Inherited Retinal Degenerations

We sought to construct and validate a patient-reported outcome measure for screening and monitoring vision-related anxiety in patients with inherited retinal degenerations. Item-response theory and graded response modeling to quantitatively validate questionnaire items generated from qualitative interviews and patient feedback. Patients at the Kellogg Eye Center (University of Michigan, Ann Arbor, Michigan, USA) with a clinical diagnosis of an inherited retinal degeneration (n= 128) participated in an interviewer-administered questionnaire. The questionnaire consisted of 166 items, 26 of which pertained to concepts of "worry" and "anxiety." The subset of vision-related anxiety questions was analyzed by a graded response model using the Cai Metropolis-Hastings Robbins-Monro algorithm in the R software mirt package. Item reduction was performed based on item fit, item information, and item discriminability. To assess test-retest variability, 25 participants completed the questionnaire a second time 4 to 16days later. The final questionnaire consisted of 14 items divided into 2 unidimensional domains: rod function anxiety and cone function anxiety. The questionnaire exhibited convergent validity with the Patient Health Questionnaire for symptoms of depression and anxiety. This vision-related anxiety questionnaire has high marginal reliability (0.81 for rod-function anxiety, 0.83 for cone-function anxiety) and exhibits minimal test-retest variability (ρ= 0.81 [0.64-0.91] for rod-function anxiety and ρ= 0.83 [0.68-0.92] for cone-function anxiety). The Michigan Vision-Related Anxiety Questionnaire is a psychometrically validated 14-item patient-reported outcome measure to be used as a psychosocial screening and monitoring tool for patients with inherited retinal degenerations. It can be used in therapeutic clinical trials for measuring the benefit of an investigational therapy on a patient's vision-related anxiety.

Clinical and genetic analysis of the ABCA4 gene associated retinal dystrophy in a large Chinese cohort

ABCA4 gene associated retinal dystrophies (ABCA4-RD) are a group of inherited eye diseases caused by ABCA4 gene mutations, including Stargardt disease, cone-rod dystrophy and retinitis pigmentosa. With the development of next-generation sequencing (NGS), numerous clinical and genetic studies on ABCA4-RD have been performed, and the genotype and phenotype spectra have been elucidated. However, most of the studies focused on the Caucasian population and limited studies of large Chinese ABCA4-RD cohorts were reported. In this study, we summarized the phenotypic and genotypic characteristics of 129 Chinese patients with ABCA4-RD. We found a mutation spectrum of Chinese patients which is considerably different from that of the Caucasian population and identified 35 novel ABCA4 mutations. We also reported some rare and special cases, such as, pedigrees with patients in two generations, patients diagnosed with cone-rod dystrophy or retinitis pigmentosa, patients with subretinal fibrosis and patients with preserved foveal structure. At the same time, we focused on the correlation between the genotypes and phenotypes. By the comprehensive analysis of multiple clinical examinations and the application of multiple regression analysis, we proved that patients with two “null” variants had a younger onset age and reached legal blindness earlier than patients with two “none-null” variants. Patients with one or more "none-null" variants tended to have better visual acuity and presented with milder fundus autofluorescence changes and more preserved rod functions on the full-field electroretinography than patients with two “null” variants. Furthermore, most patients with the p.(Phe2188Ser) variant shared a mild phenotype with a low fundus autofluorescence signal limited to the fovea and with normal full-field electroretinography responses. Our findings expand the variant spectrum of the ABCA4 gene and enhance the knowledge of Chinese patients with ABCA4-RD.

GUCY2D mutations in retinal guanylyl cyclase 1 provide biochemical reasons for dominant cone–rod dystrophy but not for stationary night blindness

Mutations in the GUCY2D gene coding for the dimeric human retinal membrane guanylyl cyclase (RetGC) isozyme RetGC1 cause various forms of blindness, ranging from rod dysfunction to rod and cone degeneration. We tested how the mutations causing recessive congenital stationary night blindness (CSNB), recessive Leber's congenital amaurosis (LCA1), and dominant cone–rod dystrophy-6 (CORD6) affected RetGC1 activity and regulation by RetGC-activating proteins (GCAPs) and retinal degeneration-3 protein (RD3). CSNB mutations R666W, R761W, and L911F, as well as LCA1 mutations R768W and G982VfsX39, disabled RetGC1 activation by human GCAP1, -2, and -3. The R666W and R761W substitutions compromised binding of GCAP1 with RetGC1 in HEK293 cells. In contrast, G982VfsX39 and L911F RetGC1 retained the ability to bind GCAP1 in cyto but failed to effectively bind RD3. R768W RetGC1 did not bind either GCAP1 or RD3. The co-expression of GUCY2D allelic combinations linked to CSNB did not restore RetGC1 activity in vitro. The CORD6 mutation R838S in the RetGC1 dimerization domain strongly dominated the Ca2+ sensitivity of cyclase regulation by GCAP1 in RetGC1 heterodimer produced by co-expression of WT and the R838S subunits. It required higher Ca2+ concentrations to decelerate GCAP-activated RetGC1 heterodimer—6-fold higher than WT and 2-fold higher than the Ser838-harboring homodimer. The heterodimer was also more resistant than homodimers to inhibition by RD3. The observed biochemical changes can explain the dominant CORD6 blindness and recessive LCA1 blindness, both of which affect rods and cones, but they cannot explain the selective loss of rod function in recessive CSNB.

Loss of Class III Phosphoinositide 3-Kinase Vps34 Results in Cone Degeneration.

Simple SummaryCone photoreceptors are the class of neurons in the retina that support daylight and color vision. In humans and rodents, the cone photoreceptors constitute a small percentage of total retinal photoreceptors; in some retinal diseases, these cells malfunction over time and cease to work, and eventually die. Class III phosphoinositide 3-kinase, also known as vacuole protein sorting 34 (Vps34), generates phosphoinositide 3-phosphate (PI(3)P), a lipid molecule that transmits information inside of the cell. PI(3)P plays an essential role in removing injured cells, a process called autophagy, which maintains a healthy environment, as well as in protein trafficking inside of the cell. Furthermore, PI(3)P can act as a bridging molecule for proteins to bind to each other. We eliminated the class III phosphoinositide 3-kinase in mouse cones, which resulted in the loss of visual function and death of cone cells. Our studies suggest that PI(3)P generated by class III phosphoinositide 3-kinase is essential for cone photoreceptor function and survival.The major pathway for the production of the low-abundance membrane lipid phosphatidylinositol 3-phosphate (PI(3)P) synthesis is catalyzed by class III phosphoinositide 3-kinase (PI3K) Vps34. The absence of Vps34 was previously found to disrupt autophagy and other membrane-trafficking pathways in some sensory neurons, but the roles of phosphatidylinositol 3-phosphate and Vps34 in cone photoreceptor cells have not previously been explored. We found that the deletion of Vps34 in neighboring rods in mouse retina did not disrupt cone function up to 8 weeks after birth, despite diminished rod function. Immunoblotting and lipid analysis of cones isolated from the cone-dominant retinas of the neural retina leucine zipper gene knockout mice revealed that both PI(3)P and Vps34 protein are present in mouse cones. To determine whether Vps34 and PI(3)P are important for cone function, we conditionally deleted Vps34 in cone photoreceptor cells of the mouse retina. Overall retinal morphology and rod function appeared to be unaffected. However, the loss of Vps34 in cones resulted in the loss of structure and function. There was a substantial reduction throughout the retina in the number of cones staining for M-opsin, S-opsin, cone arrestin, and peanut agglutinin, revealing degeneration of cones. These studies indicate that class III PI3K, and presumably PI(3)P, play essential roles in cone photoreceptor cell function and survival.

DISRUPTION OF THE OUTER SEGMENTS OF THE PHOTORECEPTORS ON OPTICAL COHERENCE TOMOGRAPHY AS A FEATURE OF VITAMIN A DEFICIENCY.

To describe the optical coherence tomography features of vitamin A deficiency. Case series includes three male patients aged 50 to 66 years with vitamin A deficiency and visual symptoms ranging from 2 to 8 months. Examination included optical coherence tomography (OCT), fundus autofluorescence imaging, full-field electroretinography6 and laboratory work-up. Patient 1 had inoperable pancreatic neuroendocrine tumor and presented with worsening nyctalopia. The electroretinography showed absent rod function 2 months after the onset of symptoms, followed by a decrease of the cone function eight months after the onset. Optical coherence tomography showed poorly distinguishable outer segments of the photoreceptors with the disappearance of the interdigitation zone. At that time, vitamin A deficiency along with several other deficiencies was confirmed. After the initiation of parenteral nutrition, a substantial improvement of the patient's overall well-being was noted and the OCT showed normalization of the retinal structure. Two other patients were diagnosed with vitamin A deficiency based on similar OCT features. Disruption of the outer segments of the photoreceptors and the disappearance of the interdigitation zone on OCT may be helpful in recognition of vitamin A deficiency. Early detection and malnutrition evaluation are especially important in patients with a history of gastrointestinal disorders who may have several other underlying deficiencies. Treatment with either enteral or parenteral nutrition not only leads to resolution of visual symptoms but vastly improves their general condition and quality of life.

Clinical and Genetic Findings in CTNNA1-Associated Macular Pattern Dystrophy

Clinical and Genetic Findings in CTNNA1-Associated Macular Pattern Dystrophy

Mesopic and Scotopic Light Sensitivity and Its Microstructural Correlates in Pseudoxanthoma Elasticum

Correlates for Bruch membrane alterations are needed for interventional trials targeting the Bruch membrane in pseudoxanthoma elasticum (PXE). To quantify mesopic and scotopic light sensitivity and identify its microstructural correlates associated with a diseased Bruch membrane in patients with PXE. A prospective, single-center, cross-sectional case-control study was conducted at a tertiary referral center from January 31, 2018, to February 20, 2020. Twenty-two eyes of 22 patients with PXE and 40 eyes of 40 healthy individuals were included. Data analysis was completed March 15, 2020. Mesopic and dark-adapted 2-color fundus-controlled perimetry (microperimetry) and multimodal retinal imaging including spectral-domain optical coherence tomography (SD-OCT) and OCT angiography were performed. Perimetry thresholds were analyzed using mixed models, and structure-function correlation with SD-OCT data was performed using machine learning. Observed dark-adapted cyan sensitivity loss as measure of rod photoreceptor dysfunction, as well as mean absolute error between predicted and observed retinal sensitivity to assess the accuracy of structure-function correlation. Of the 22 patients with PXE included in this study, 15 were women (68%); median age was 56.5 years (interquartile range, 50.4-61.2). These patients exhibited mesopic (estimate, 5.13 dB; 95% CI, 2.89-7.38 dB), dark-adapted cyan (estimate, 9.08 dB; 95% CI, 6.34-11.82 dB), and dark-adapted red (estimate, 7.05 dB; 95% CI, 4.83-9.27 dB) sensitivity losses. This sensitivity loss was also evident in 9 eyes with nonneovascular PXE (mesopic: estimate, 3.21 dB; 95% CI, 1.28-5.14 dB; dark-adapted cyan: 5.93 dB; 95% CI, 3.59-8.27 dB; and dark-adapted red testing: 4.84 dB; 95% CI, 2.88-6.80 dB), showing a distinct centrifugal pattern of sensitivity loss with preserved function toward the periphery. Retinal function could be predicted from microstructure with high accuracy (mean absolute errors, of 4.91 dB for mesopic, 5.44 dB for dark-adapted cyan, and 4.99 dB for dark-adapted red). The machine learning-based analysis highlighted an association of a thinned inner retina and putative separation of the pigment-epithelium-photoreceptor complex with sensitivity loss. In this study, among 22 patients with PXE, those with and without choroidal neovascularization exhibited reductions of retinal sensitivity being most pronounced in dark-adapted cyan testing. This finding suggests that pathologic characteristics of this Bruch membrane disease may be dominated by rod photoreceptor degeneration and/or dysfunction. A putative pigment-epithelium-photoreceptor separation may further impair rod function, while inner retinal abnormalities appear to be correlated with overall dysfunction.

This issue of ACTA, printed and electronic

This issue of ACTA, printed and electronic

Threshold versus intensity functions in two-colour automated perimetry.

Two-colour computerised perimetry is a technique developed for assessing cone- and rod-function at fixed background luminances in retinal disease. However, the state of adaptation during testing is unknown but crucial in the interpretation of results. We therefore aimed to determine the adaptational state of rod- and cone-mechanisms in two-colour perimetry. Sensitivity to 480nm (blue) and 640nm (red) Goldmann size V targets was determined for 10 normal subjects aged 16 to 46years at 17 locations in the central 60 degrees of the visual field under scotopic conditions and then from -1.5 log cd m-2 to 2 log cd m-2 (white background) in 0.5 log unit steps. Data were fitted with threshold versus intensity (tvi) functions of the form logT=logT0 + log ((A+A0 )/A0 )n . No clear rod-cone break was observed for 640nm stimuli. For 480nm stimuli, transition from rod-detection to cone-detection occurred at mesopic illumination levels, where rod adaptation approached Weber behaviour. Cone detection mechanisms did not display Weber-like adaptation until the background luminance approached 1 log cd.m-2 . Diseases resulting in a "filter effect" - including disorders of the photoreceptors - are therefore predicted to affect sensitivity when rod function is probed with short-wavelength targets under scotopic conditions, but less so under mesopic conditions. Filter effects are similarly anticipated to affect cone function measured using long-wavelength targets under mesopic conditions (e.g., during microperimetry), but less so under photopic conditions. Asymmetries in adaptation in automated two-colour perimetry are predicted to artefactually favour the detection of losses in rod sensitivity under scotopic conditions and cones under mesopic conditions.

Metabolic Features of Mouse and Human Retinas: Rods versus Cones, Macula versus Periphery, Retina versus RPE.

SummaryPhotoreceptors, especially cones, which are enriched in the human macula, have high energy demands, making them vulnerable to metabolic stress. Metabolic dysfunction of photoreceptors and their supporting retinal pigment epithelium (RPE) is an important underlying cause of degenerative retinal diseases. However, how cones and the macula support their exorbitant metabolic demand and communicate with RPE is unclear. By profiling metabolite uptake and release and analyzing metabolic genes, we have found cone-rich retinas and human macula share specific metabolic features with upregulated pathways in pyruvate metabolism, mitochondrial TCA cycle, and lipid synthesis. Human neural retina and RPE have distinct but complementary metabolic features. Retinal metabolism centers on NADH production and neurotransmitter biosynthesis. The retina needs aspartate to sustain its aerobic glycolysis and mitochondrial metabolism. RPE metabolism is directed toward NADPH production and biosynthesis of acetyl-rich metabolites, serine, and others. RPE consumes multiple nutrients, including proline, to produce metabolites for the retina.