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Novel clinical findings in autosomal recessive NR2E3-related retinal dystrophy
摘要： Purpose To evaluate the clinical phenotype of autosomal recessive NR2E3-related retinal dystrophy. Methods We retrospectively studied 11 patients carrying out at least 2 NR2E3 mutations; they had undergone comprehensive ophthalmological examination, fundus photography, optical coherence tomography, electrophysiological testing, and visual field at the Regional Reference Center for Hereditary Retinal Degenerations of the Eye Clinic in Florence. Results Five females and six males with a diagnosis of NR2E3-related retinal dystrophy were included in the study. All patients complained of nyctalopia. Visual acuity ranged from 0.00 logMAR to hand motion. Two patients presented bull’s eye maculopathy, and one of these was characterized by a triple hyper-autofluorescent ring at the fundus autofluorescence examination. Three patients showed small yellowish dots and spots at the mid-periphery. One patient was characterized by widespread subretinal drusenoid deposits (SDD) at the posterior pole. Four patients showed vitreous abnormalities. Optical coherence tomography (OCT) examinations detected variable degrees of abnormal retinal lamination and schitic changes. Seven patients were compound heterozygous and four were homozygous for mutations in NR2E3. Conclusions Our study confirmed high variable phenotype in autosomal recessive NR2E3-related retinal dystrophy. Bull’s eye maculopathy, subretinal drusenoid deposits, and foveal hypoplasia represent novel clinical findings in NR2E3-related retinal dystrophy. Macular involvement was detectable in all the patients, and the abnormal foveal avascular zone (FAZ) supports the role of NR2E3 in retinal development.
关键词： Retinal dystrophy,Foveal hypoplasia,Retinitis pigmentosa,Subretinal drusenoid deposits,Autosomal recessive disease,Goldmann-Favre,NR2E3
更新于2025-09-23 15:23:52
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Early Onset Ultrastructural and Functional Defects in RPE and Photoreceptors of a Stargardt-Like Macular Dystrophy (STGD3) Transgenic Mouse Model
摘要： PURPOSE. We investigated the interplay between photoreceptors expressing mutant ELOVL4 (responsible for Stargardt-like disease, STGD3) and RPE in the initial stages of retinal degeneration. METHODS. Using electron microscopy and electroretinogram (ERG), we assessed RPE and photoreceptor ultrastructure and function in transgenic ELOVL4 (TG1-2 line; TG) and wild-type (WT) littermates. Experiments were done at P30, 1 month before photoreceptor loss in TG and at P90, a time point with approximately 30% rod loss. To further elucidate the mechanism underlying our ultrastructural and functional results, we undertook Western blotting and immunohistochemistry of key proteins involved in phagocytosis of outer segments by RPE cells. RESULTS. Firstly, we showed that in TG mouse photoreceptors, endogenous ELOVL4 protein is not mislocalized in the presence of the mutated ELOVL4 protein. Secondly, we found evidence of RPE toxicity at P30, preceding any photoreceptor loss. Pathology in RPE cells was exacerbated at P90. Furthermore, higher proportions of phagosomes remained at the apical side of RPE cells. Subretinal lysosomal deposits were immunopositive for phagocytic proteins. Ultrastructural analysis of photoreceptor (rod) outer segments showed disrupted surface morphology consisting of disc spacing irregularities. Finally, rods and RPE exhibited signs of dysfunction as measured by the ERG a-wave leading edge (P30) and c-wave (P90), respectively. CONCLUSIONS. The presence of human mutant ELOVL4 in transgenic mouse photoreceptors leads to early outer segment disc pathology and RPE cytotoxicity. Defective processing of these abnormal discs by RPE cells ultimately may be responsible for outer segment truncation, photoreceptor death, and vision loss.
关键词： mouse,outer segment,Stargardt-like dystrophy,photoreceptor,STGD3,phagocytosis,ELOVL4,RPE
更新于2025-09-23 15:23:52
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Contrast sensitivity deficits in patients with mutation-proven inherited retinal degenerations
摘要： Background: Patients with retinal diseases frequently complain of poor visual function even when visual acuity is relatively unaffected. This clinical finding has been attributed to deficits in contrast sensitivity (CS). The purpose of our study was to evaluate the CS in patients with clinical and genetic diagnosis of inherited retinal degeneration (IRD) and relatively preserved visual acuity. Methods: Seventeen patients (30 eyes) with IRD and visual acuity of 20/40 or better, and 18 controls (18 eyes) without any ocular condition underwent slit lamp examination, visual acuity testing via standard Snellen chart testing, CS testing via the Quick Contrast Sensitivity Function (QCSF), and Spectral Domain Optical Coherence Tomography (SD-OCT). CS were measured at 1.0, 1.5, 3.0, 6.0, 12.0, and 18.0 cycles per degree (cpd). T tests with general estimated equations were used to compare CS between groups. Wald chi square followed by pairwise comparisons was used to compare CS between multiple groups. Results: We included 12 patients with rod-cone dystrophy (RCD), 3 patients with Stargardt disease (STGD) and 2 patients with Best disease. Patients with IRD had significantly worse CS than controls (p < 0.001) in all spatial frequencies. Patients with STGD had more marked deficits in CS than patients with Best disease (p < 0.001) and RCD (p < 0.001) despite having similar visual acuities. Conclusion: Patients with IRD, especially patients with STGD with relatively preserved visual acuity have marked deficits in CS when measured across a range of spatial frequencies. We recommend that clinical trials for STGD incorporate CS measured over a range of spatial frequencies as a secondary clinical endpoint for monitoring visual function. CS may provide an explanation for complaints of visual dysfunction when visual acuity is not significantly altered.
关键词： Best disease,Contrast sensitivity,Retinal dystrophy,Retinitis Pigmentosa,Stargardt disease
更新于2025-09-23 15:23:52
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Biomicroscopia confocal en 4 pacientes con distrofia corneal policromática
摘要： Introduction: Polychromatic corneal dystrophy is an unusual pre-descemet dystrophy, about which there are very few publications. The findings are presented in a case series of four patients with polychromatic corneal dystrophy, using a slit lamp, specular biomicroscopy, and confocal microcospy. Clinical cases: Four women, between 36 and 72 year-old, with the diagnosis of polychromatic corneal dystrophy in routine reviews. None reported visual symptoms or ocular history of interest. Anterior biomicroscopy showed multiple and small multicoloured brilliant opacities in the posterior area of the corneal stroma, with normal epithelium and anterior stroma. The opacities were bilateral and distributed throughout the entire cornea. Direct family members were examined, but none of them showed opacities. In the specular biomicroscopy, a normal endothelium, with pre-descemet hypere?ective particles, was observed. With confocal microscopy, there were no abnormalities in epithelium, Bowman layer, or sub-basal nervous plexus. In two cases, the anterior stroma showed hyper-re?ective keratocytes and with small hypere?ective particles among them. In the middle stroma, hyper-re?ective keratocytes were seen in the four cases, two of them showed tiny hypere?ective particles, and in the other two there were abnormal keratocytes with prominent cytoplasmic processes. Posterior stroma in the four cases showed a lot of hypere?ective keratocytes and hypere?ective particles of different sizes. These particles prevented examining the endothelium. Conclusions: Polychromatic corneal dystrophy has typical signs that allow it to be diagnosed and characterised. Although the biomicroscopy image only seems to show alterations in the posterior stroma, confocal microscopy shows that the dystrophy affects the entire corneal stroma.
关键词： Pre-Descemet dystrophy,Polychromatic dystrophy,Confocal biomicroscopy
更新于2025-09-23 15:22:29
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Comparison of ultrasonic pachymetry and Fourier-domain optical coherence tomography for measurement of corneal thickness in dogs with and without corneal disease
摘要： Several ultrasonic and Fourier-domain optical coherence tomography (FD-OCT) pachymeters are used to measure corneal thickness in canine patients and research subjects. This study assessed the reliability of and consistency between two ultrasonic pachymetry (USP) devices, Pachette 3 and Accupach VI, as well as automated and manual measurements obtained using FD-OCT in dogs with and without corneal disease. Corneal thickness measurements were compiled from 108 dogs and analyzed using mixed effects linear regression, with Bonferonni adjustments for post-hoc comparisons, to determine the effects of age, weight and disease state. Data are presented as predicted mean ± standard error. Canine corneal disease can result in marked increases in thickness that frequently exceed the upper limits of measurement of some pachymetry devices developed for human use. In this study, the corneas of dogs with endothelial disease or injury frequently exceeded the upper limits of quantitation of 999 and 800 μm, respectively. Using values <800 μm for the Accupach VI and automated FD-OCT pachymeters, respectively. Of the two devices where measurements >1000 μm were obtained, manual FD-OCT demonstrated less variability than the Pachette 3. Corneal thickness increased linearly with age and weight with an increase of 6.9 ± 0.8 μm/year and 1.6 ± 0.38 μm/kg body weight (P < 0.005 and P = 0.038, respectively).
关键词： Corneal thickness,Corneal endothelial dystrophy,Optical coherence tomography,Ultrasonic pachymetry,Canine
更新于2025-09-23 15:21:21
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Complement inhibition as a therapeutic strategy in retinal disorders
摘要： Introduction: Dry age-related macular degeneration (AMD) and Stargardt Macular Dystrophy (STGD1) result in vision loss, due to progressive atrophy of the macula and lack of effective treatments. Numerous studies have implicated complement-associated inflammation as a contributor to both diseases. Areas covered: The complement factor D inhibitor, lampalizumab, failed to halt geographic atrophy (GA) progression in phase 3 studies. The complement factor 3 (C3) inhibitor, APL-2, has shown potential to reduce GA growth in a phase 2 trial, supporting advancement to phase 3 trials. The intravenous complement factor 5 (C5) inhibitor, eculizumab, failed to halt GA progression in a phase 2 study. Another C5 inhibitor, avacincaptad pegol, is delivered by intravitreal injection, and will be studied for safety and preliminary signs of efficacy for AMD and STGD1 patients in phase 2 trials. LFG316 (C5 inhibitor) and CLG561 (properdin inhibitor) failed to halt GA progression in phase 2 studies. A phase 1 trial is evaluating the effects of combining LFG316 and CL561. Complement inhibition by gene therapy will be explored in the phase 1 trial of HMR59 in AMD patients. Expert opinion: While complement inhibition has not yet demonstrated ability to halt GA progression in a phase 3 trial, further study is warranted.
关键词： Age-related macular degeneration,Stargardt Macular Dystrophy,geographic atrophy,LFG316,CL561,avacincaptad pegol,eculizumab,complement,APL-2,lampalizumab
更新于2025-09-19 17:15:36
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Three-Year Outcome Comparison Between Femtosecond Laser-Assisted and Manual Descemet Membrane Endothelial Keratoplasty
摘要： To evaluate 3-year outcomes of femtosecond laser-assisted Descemet membrane endothelial keratoplasty (F-DMEK) compared with manual Descemet membrane endothelial keratoplasty (M-DMEK) in patients with Fuchs endothelial corneal dystrophy (FECD). A retrospective, interventional study, including eyes with FECD and cataract that underwent either F-DMEK or M-DMEK combined with cataract extraction at either the Toronto Western Hospital or Kensington Eye Institute, and that had at least 18 months’ follow-up was conducted. Exclusion criteria: complicated anterior segments, previous vitrectomy, previous keratoplasty, corneal opacity, or any other visually signi?cant ocular comorbidity. Included were 16 eyes of 15 patients in the F-DMEK group (average follow-up 33.0 6 9.0 months) and 45 eyes of 40 patients in the M-DMEK group (average follow-up 32.0 6 7.0 months). There were no issues with the creation of femtosecond descemetorhexis (in the F-DMEK group)—all descemetorhexis cuts were complete. Best spectacle-corrected visual acuity improvement did not differ signi?cantly between the groups at 1, 2, and 3 years (P = 0.849, P = 0.465 and P = 0.936, respectively). Rates of signi?cant detachment in F-DMEK and M-DMEK were 1 of 16 eyes (6.25%) and 16 of 45 eyes (35.6%) (P = 0.027). Rebubbling rates were 1 of 16 eyes (6.25%) and 15 of 45 eyes (33.3%) (P = 0.047). Cell-loss rates following F-DMEK and M-DMEK were 26.8% and 36.5% at 1 year (P = 0.042), 30.5% and 42.3% at 2 years (P = 0.008), 37% and 47.5% at 3 years (P = 0.057), respectively. Graft failure rate was 0% in F-DMEK and 8.9% in M-DMEK (all were primary failures; P = 0.565). F-DMEK showed good ef?cacy with reduced detachment, rebubble, and cell-loss rates, compared with M-DMEK.
关键词： long-term,IEK,Fuchs dystrophy,femtosecond laser,descemetorhexis,Descemet membrane endothelial keratoplasty,DMEK
更新于2025-09-11 14:15:04
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Quantitative Fundus Autofluorescence and Optical Coherence Tomography in <i>PRPH2/RDS</i> - and <i>ABCA4</i> -Associated Disease Exhibiting Phenotypic Overlap
摘要： PURPOSE. To assess whether quantitative fundus autofluorescence (qAF), a measure of RPE lipofuscin, and spectral-domain optical coherence tomography (SD-OCT) can aid in the differentiation of patients with fundus features that could either be related to ABCA4 mutations or be part of the phenotypic spectrum of pattern dystrophies. METHODS. Autofluorescence images (308, 488-nm excitation) from 39 patients (67 eyes) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference and were quantified as previously described. In addition, horizontal SD-OCT images through the fovea were obtained. Patients were screened for ABCA4 and PRPH2/RDS mutations. RESULTS. ABCA4 mutations were identified in 19 patients (mean age, 37 ± 12 years) and PRPH2/RDS mutations in 8 patients (mean age, 48 ± 13 years); no known ABCA4 or PRPH2/RDS mutations were found in 12 patients (mean age, 48 ± 9 years). Differentiation of the groups using phenotypic SD-OCT and AF features (e.g., peripapillary sparing, foveal sparing) was not reliable. However, patients with ABCA4 mutations could be discriminated reasonably well from other patients when qAF values were corrected for age and race. In general, ABCA4 patients had higher qAF values than PRPH2/RDS patients, while most patients without mutations in PRPH2/RDS or ABCA4 had qAF levels within the normal range. CONCLUSIONS. The high qAF levels of ABCA4-positive patients are a hallmark of ABCA4-related disease. The reason for high qAF among many PRPH2/RDS-positive patients is not known; higher RPE lipofuscin accumulation may be a primary or secondary effect of the PRPH2/RDS mutation.
关键词： scanning laser ophthalmoscope,PRPH2/RDS,optical coherence tomography,quantitative fundus autofluorescence,retinal pigment epithelium,lipofuscin,recessive Stargardt disease,ABCA4,pattern dystrophy
更新于2025-09-11 14:15:04
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Determination of Rod and Cone Influence to the Early and Late Dynamic of the Pupillary Light Response
摘要： PURPOSE. This study aims to identify which aspects of the pupil light re?ex are most in?uenced by rods and cones independently by analyzing pupil recordings from different mouse models of photoreceptor de?ciency. METHODS. One-month-old wild type (WT), rodless (Rho(cid:2)/(cid:2)), coneless (Cnga3(cid:2)/(cid:2)), or photoreceptor less (Cnga3(cid:2)/(cid:2); Rho(cid:2)/(cid:2) or Gnat1(cid:2)/(cid:2)) mice were subjected to brief red and blue light stimuli of increasing intensity. To describe the initial dynamic response to light, the maximal pupillary constriction amplitudes and the derivative curve of the ?rst 3 seconds were determined. To estimate the postillumination phase, the constriction amplitude at 9.5 seconds after light termination was related to the maximal constriction amplitude. RESULTS. Rho(cid:2)/(cid:2) mice showed decreased constriction amplitude but more prolonged pupilloconstriction to all blue and red light stimuli compared to wild type mice. Cnga3(cid:2)/(cid:2) mice had constriction amplitudes similar to WT however following maximal constriction, the early and rapid dilation to low intensity blue light was decreased. To high intensity blue light, the Cnga3(cid:2)/(cid:2) mice demonstrated marked prolongation of the pupillary constriction. Cnga3(cid:2)/(cid:2); Rho(cid:2)/(cid:2) mice had no pupil response to red light of low and medium intensity. CONCLUSIONS. From speci?c gene defective mouse models which selectively voided the rod or cone function, we determined that mouse rod photoreceptors are highly contributing to the pupil response to blue light stimuli but also to low and medium red stimuli. We also observed that cone cells mainly drive the partial rapid dilation of the initial response to low blue light stimuli. Thus photoreceptor dysfunction can be derived from chromatic pupillometry in mouse models.
关键词： pupillary response,photoreceptors,mouse model,retinal dystrophy
更新于2025-09-11 14:15:04
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Multimodal imaging in a pedigree of X-linked Retinoschisis with a novel RS1 variant
摘要： To describe the clinical phenotype and genetic cause underlying the disease pathology in a pedigree (affected n = 9) with X-linked retinoschisis (XLRS1) due to a novel RS1 mutation and to assess suitability for novel therapies using multimodal imaging.
关键词： X-linked Retinoschisis,Inherited maculopathy,Inherited retinal dystrophy,Retinoschisin
更新于2025-09-10 09:29:36