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Usher syndrome, the most prevalent cause of combined hereditary vision and hearing impairment, is clinically and genetically heterogeneous. Moreover, several conditions with phenotypes overlapping Usher syndrome have been described. This makes the molecular diagnosis of hereditary deaf-blindness challenging. Here, we performed exome sequencing and analysis on 7 Mexican and 52 Iranian probands with combined retinal degeneration and hearing impairment (without intellectual disability). Clinical assessment involved ophthalmological examination and hearing loss questionnaire. Usher syndrome, most frequently due to biallelic variants in MYO7A (USH1B in 16 probands), USH2A (17 probands), and ADGRV1 (USH2C in 7 probands), was diagnosed in 44 of 59 (75%) unrelated probands. Almost half of the identified variants were novel. Nine of 59 (15%) probands displayed other genetic entities with dual sensory impairment, including Alström syndrome (3 patients), cone-rod dystrophy and hearing loss 1 (2 probands), and Heimler syndrome (1 patient). Unexpected findings included one proband each with Scheie syndrome, coenzyme Q10 deficiency, and pseudoxanthoma elasticum. In four probands, including three Usher cases, dual sensory impairment was either modified/aggravated or caused by variants in distinct genes associated with retinal degeneration and/or hearing loss. The overall diagnostic yield of whole exome analysis in our deaf-blind cohort was 92%. Two (3%) probands were partially solved and only 3 (5%) remained without any molecular diagnosis. In many cases, the molecular diagnosis is important to guide genetic counseling, to support prognostic outcomes and decisions with currently available and evolving treatment modalities.
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Degeneración Retiniana , Síndromes de Usher , Humanos , Irán , Mutación , Linaje , Fenotipo , Degeneración Retiniana/genética , Síndromes de Usher/diagnóstico , Síndromes de Usher/genéticaRESUMEN
This work presents a quick clinical protocol for dark-adapted chromatic (DAC) perimetry as well as a novel clinical tool, scotopic chromatic pupil campimetry (CPC). The goal of the study was to explore the applicability of these methods in a clinical setting, their test-retest repeatability, and the congruence of the results. Local rod sensitivity was assessed at 36 locations within 30° eccentricity of the visual field in 15 healthy subjects (mean age 43 ± 16 years; 7 females and 8 males) with DAC perimetry (red and cyan stimuli) and CPC 2 times in repeated measurements. The duration of individual measurements was 370 ± 5 s for CPC and 366 ± 62 s for DAC perimetry. The intraclass correlation (ICC) coefficient was 0.53 for DAC perimetry cyan stimuli, 0.67 for red stimuli, and 0.93 for CPC. However, the spatial resolution of CPC was substantially smaller than in DAC perimetry. We did not find a correlation of DAC perimetry and CPC measurements on the global or the local level. In comparison to DAC perimetry, CPC shows a superior intervisit repeatability in detecting functional changes in the rod population in an objective way with lower spatial resolution. Our results also indicate that these 2 methods measure the rod function in different ways and could thus constitute complementary scotopic functional diagnostics.
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Pruebas del Campo Visual , Campos Visuales , Adulto , Protocolos Clínicos , Adaptación a la Oscuridad , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
In this retrospective, longitudinal, observational cohort study, we investigated the phenotypic and genotypic features of retinitis pigmentosa associated with variants in the PDE6B gene. Patients underwent clinical examination and genetic testing at a single tertiary referral center, including best-corrected visual acuity (BCVA), kinetic visual field (VF), full-field electroretinography, full-field stimulus threshold, spectral domain optical coherence tomography, and fundus autofluorescence imaging. The genetic testing comprised candidate gene sequencing, inherited retinal disease gene panel sequencing, whole-genome sequencing, and testing for familial variants by Sanger sequencing. Twenty-four patients with mutations in PDE6B from 21 families were included in the study (mean age at the first visit: 32.1 ± 13.5 years). The majority of variants were putative splicing defects (8/23) and missense (7/23) mutations. Seventy-nine percent (38/48) of eyes had no visual acuity impairment at the first visit. Visual acuity impairment was mild in 4% (2/48), moderate in 13% (6/48), and severe in 4% (2/48). BCVA was symmetrical in the right and left eyes. The kinetic VF measurements were highly symmetrical in the right and left eyes, as was the horizontal ellipsoid zone (EZ) width. Regarding the genetic findings, 43% of the PDE6B variants found in our patients were novel. Thus, this study contributed substantially to the PDE6B mutation spectrum. The visual acuity impairment was mild in 83% of eyes, providing a window of opportunity for investigational new drugs. The EZ width was reduced in all patients and was highly symmetric between the eyes, making it a promising outcome measure. We expect these findings to have implications on the design of future PDE6B-related retinitis pigmentosa (RP) clinical trials.
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Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/genética , Mutación , Fenotipo , Retinitis Pigmentosa/genética , Adolescente , Adulto , Niño , Electrorretinografía , Proteínas del Ojo/genética , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Retinitis Pigmentosa/metabolismo , Retinitis Pigmentosa/fisiopatología , Estudios Retrospectivos , Análisis de Secuencia de ADN , Tomografía de Coherencia Óptica , Agudeza Visual , Campos Visuales , Adulto JovenRESUMEN
We aimed to unravel the molecular genetic basis of inherited retinal degeneration (IRD) in a comprehensive cohort of patients diagnosed in the largest center for IRD in Germany. A cohort of 2,158 affected patients from 1,785 families diagnosed with IRD was analyzed by targeted next-generation sequencing (NGS). Patients with single-gene disorders (i.e., choroideremia and retinoschisis) were analyzed by Sanger sequencing and multiplex ligation-dependent probe amplification. Our study cohort accounts for â¼7% of the estimated 30,000 patients with IRD in Germany, thereby providing representative data for both the prevalence of IRDs and the mutation spectrum of IRD genes for the population in Germany. We achieved a molecular diagnostic rate of 35-95%, depending on the clinical entities, with a high detection rate for achromatopsia, retinoschisis, and choroideremia, and a low detection rate for central areolar choroidal dystrophy and macular dystrophy. A total of 1,161 distinct variants were identified, including 501 novel variants, reaffirming the known vast genetic heterogeneity of IRD in a mainly outbred European population. This study demonstrates the clinical utility of panel-based NGS in a large and highly heterogeneous cohort from an outbred population and for the first time gives a comprehensive representation of the genetic landscape of IRDs in Germany. The data are valuable and crucial for the scientific community and healthcare providers, but also for the pharmaceutical industry in the progressing field of personalized medicine and gene therapy.
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Secuenciación de Nucleótidos de Alto Rendimiento , Distrofias Retinianas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Femenino , Alemania , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Fenotipo , Distrofias Retinianas/diagnóstico , Adulto JovenRESUMEN
PURPOSE: Choroideremia (CHM) is a rare inherited retinal degeneration resulting from mutation of the CHM gene, which results in absence of functional Rab escort protein 1 (REP1). We evaluated retinal gene therapy with an adeno-associated virus vector that used to deliver a functional version of the CHM gene (AAV2-REP1). METHODS: THOR (NCT02671539) is a Phase 2, open-label, single-center, randomized study. Six male patients (51-60 years) with CHM received AAV2-REP1, by a single 0.1-mL subretinal injection of 10 genome particles during vitrectomy. Twelve-month data are reported. RESULTS: In study eyes, 4 patients experienced minor changes in best-corrected visual acuity (-4 to +1 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); one gained 17 letters and another lost 14 letters. Control eyes had changes of -2 to +4 letters. In 5/6 patients, improvements in mean (95% confidence intervals) retinal sensitivity (2.3 [4.0] dB), peak retinal sensitivity (2.8 [3.5] dB), and gaze fixation area (-36.1 [66.9] deg) were recorded. Changes in anatomical endpoints were similar between study and control eyes. Adverse events were consistent with the surgical procedure. CONCLUSION: Gene therapy with AAV2-REP1 can maintain, and in some cases, improve, visual acuity in CHM. Longer term follow-up is required to establish whether these benefits are maintained.
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Proteínas Adaptadoras Transductoras de Señales/genética , Coroideremia/terapia , Terapia Genética , Parvovirinae/genética , Retina/fisiopatología , Coroideremia/fisiopatología , Dependovirus , Vectores Genéticos , Humanos , Masculino , Persona de Mediana Edad , Agudeza Visual/fisiología , Pruebas del Campo Visual , Campos Visuales/fisiología , VitrectomíaRESUMEN
INTRODUCTION: The aim of this article was to report on a rebound phenomenon after intravitreal triamcinolone acetonide (IVTA) injection for macular edema secondary to diabetic retinopathy (DR) and central or branch retinal vein occlusion (CRVO/BRVO). METHODS: The data were analyzed retrospectively. Complete ophthalmic examinations, including spectral domain optical coherence tomography, were performed before and 2 months after IVTA injection. The incidence of a rebound phenomenon was defined as an increase in central retinal thickness of >10% from baseline at 2 months after IVTA injection. RESULTS: This retrospective study included 211 consecutive patients (268 eyes). One hundred ninety (71.2%), 39 (14.6%), and 39 (14.6%) eyes had macular edema (ME) due to DR, CRVO, and BRVO. In total, 9.7% of the eyes showed a rebound phenomenon (DR: 9.5%, CRVO: 5.2%, BRVO: 15.4%). The mean number of prior injections of vascular endothelial growth factor inhibitor or corticosteroid agent was statistically significantly higher in the rebound group (6.8 vs. 5.3) than in the nonrebound group (p = 0.01). CONCLUSION: Our study shows that 9.7% of the eyes with ME secondary to DR and RVO developed a rebound phenomenon following IVTA injection, limiting its therapeutic effect. We found an increased number of prior intravitreal pharmacotherapy to be a risk factor for a rebound phenomenon.
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Edema Macular , Oclusión de la Vena Retiniana , Triamcinolona Acetonida , Glucocorticoides/uso terapéutico , Humanos , Inyecciones Intravítreas , Edema Macular/tratamiento farmacológico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Resultado del Tratamiento , Triamcinolona Acetonida/administración & dosificación , Factor A de Crecimiento Endotelial Vascular , Agudeza VisualRESUMEN
PURPOSE: Posterior column ataxia and retinitis pigmentosa (PCARP) is a rare form of syndromic RP associated with mutations in the FLVCR1 gene. Recent evidence has suggested a spectrum in the phenotype depending on the genotype. METHODS: Six individuals with retinitis pigmentosa (RP) carrying mutations in the FLVCR1 gene underwent detailed ophthalmological examinations at the Center for Ophthalmology and two of these also an extensive neurological examination at the Department of Neurology in Tuebingen, Germany. RESULTS: The mutation spectrum in our cohort comprised one nonsense mutation, one 1-bp deletion, two missense variants, and one splice site variant (c.1092+5G>A). Three patients presented with a typical clinical picture of autosomal recessive RP, two patients presented with atypical RP, and one patient presented with a particularly mild form of RP. The findings of the patients that underwent detailed neurological and neurophysiological testing were not suggestive for the presence of progressive PCA, but one patient showed mild cerebellar signs without worsening over time. Five out of six of our cases carry the splice site variant c.1092+5G>A at least on one allele possibly providing evidence as to that this splice site variant may cause a milder form of non-syndromic autosomal recessive RP. CONCLUSIONS: Mutations in FLVCR1 can present with the clinical picture of a non-syndromic autosomal recessive RP (in this case RP without PCA), RP with mild cerebellar signs, but also PCARP. Additionally, we show evidence for a spectrum of the severity of the retinal involvement likely depending on the genotype.
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ADN/genética , Proteínas de Transporte de Membrana/genética , Mutación , Receptores Virales/genética , Retina/patología , Retinitis Pigmentosa/genética , Adolescente , Adulto , Alelos , Análisis Mutacional de ADN , Electrorretinografía , Femenino , Genotipo , Humanos , Masculino , Proteínas de Transporte de Membrana/metabolismo , Persona de Mediana Edad , Linaje , Fenotipo , Receptores Virales/metabolismo , Retina/fisiopatología , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/metabolismo , Trastornos de la Sensación , Degeneraciones Espinocerebelosas , Tomografía de Coherencia Óptica , Adulto JovenRESUMEN
PURPOSE: To characterize choroidal thickness and choroidal reflectivity in the eyes of patients with birdshot chorioretinopathy (BSCR). DESIGN: Cross-sectional observational study. PARTICIPANTS: Two hundred twenty BSCR patients and 59 healthy controls. METHODS: Patients with BSCR and healthy controls underwent imaging of the macula in both eyes with a swept-source optical coherence tomography device (DRI-OCT1 Atlantis; Topcon). Images were exported from the device, and analysis was performed by 2 graders in the Doheny Image Reading Center using Image J software. The choroidal thickness at the foveal center was measured. In addition, the inner and outer boundaries of the choroid and retinal pigment epithelium (RPE) as well as the inner retinal surface all were segmented to allow the brightness and reflectivity of the pixels in the choroid, RPE band, and overlying vitreous to be quantified. An adjusted or normalized choroidal reflectivity, with the RPE as the bright reference standard and the vitreous as the dark reference standard, was computed using the formula: normalized choroidal reflectivity = (choroidal reflectivity-vitreous reflectivity)/RPE reflectivity. MAIN OUTCOME MEASURES: Choroidal reflectivity and choroidal thickness. RESULTS: Three hundred eighty-six eyes in the BSCR group and 59 eyes in the control group were included in this analysis. Higher choroidal reflectivity and lower choroidal thickness were documented in inactive BSCR patients compared with active BSCR and controls (P < 0.01). Active BSCR patients showed lower choroidal thickness compared with controls (P < 0.01). There was a negative correlation between choroidal reflectivity and choroidal thickness (r = -0.793; P < 0.001). On multiple regression analysis, choroidal thickness, age, and disease duration (all P < 0.01) all were significant predictors of choroidal reflectivity. CONCLUSIONS: Choroidal reflectivity and choroidal thickness changes are evident in active and inactive BSCR patients. Novel choroidal parameters such as choroidal reflectivity may warrant further study in the setting of BSCR.
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Coriorretinitis/diagnóstico por imagen , Coroides/diagnóstico por imagen , Coroides/fisiopatología , Tomografía de Coherencia Óptica/métodos , Anciano , Retinocoroidopatía en Perdigonada , Coriorretinitis/fisiopatología , Estudios Transversales , Femenino , Estudios de Seguimiento , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: To establish the extent of the peripheral retinal vasculature in normal eyes using ultra-widefield (UWF) fluorescein angiography. DESIGN: Prospective, observational study. PARTICIPANTS: Fifty-nine eyes of 31 normal subjects, stratified by age, with no evidence of ocular disease in either eye by history and ophthalmoscopic examination. METHODS: Ultra-widefield fluorescein angiographic images were captured centrally and with peripheral steering using the Optos 200Tx (Optos, Dunfermline, United Kingdom). Images obtained at different gaze angles were montaged and corrected for peripheral distortion using a stereographic projection method to provide a single image for grading of the peripheral edge of the visible vasculature. The border of the vascularized retina was expressed as a radial surface distance from the center of the optic disc. The vascularized area was calculated based on this mean peripheral border position for each quadrant. MAIN OUTCOME MEASURES: Mean distance (mm) from the center of optic disc to the peripheral vascular border. RESULTS: In normal eyes, the mean radial surface distance from the center of the optic disc to the peripheral edge of the visible vasculature was 20.3±1.4 mm and the mean area of normal perfused retina was 977.0 mm(2). There was no significant difference between right and left eyes or between male and female participants. However, the distance to the periphery differed depending on the quadrant, with temporal (22.5±0.9 mm) being larger than inferior (20.4±1.7 mm) being larger than superior (19.2±1.5 mm) being larger than nasal (17.4±0.9 mm; P < 0.001) for all interquadrant comparisons. Interestingly, the distances to the perfused vascular border were significantly shorter in older individuals (≥60 years) than in younger subjects. CONCLUSIONS: Ultra-widefield fluorescein angiography is an important tool for studying the extent of peripheral retinal vasculature. With the increasing use of UWF imaging to evaluate and manage patients with retinal vascular disease, the normative data from this study may provide a useful reference when assessing the pathologic significance of findings in the setting of disease.
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Angiografía con Fluoresceína , Vasos Retinianos/anatomía & histología , Adulto , Anciano , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Valores de Referencia , Adulto JovenRESUMEN
PURPOSE: To evaluate manual and semiautomated grading techniques for assessing decreased fundus autofluorescence (DAF) in patients with Stargardt disease phenotype. METHODS: Certified reading center graders performed manual and semiautomated (region finder-based) grading of confocal scanning laser ophthalmoscopy (cSLO) fundus autofluorescence (FAF) images for 41 eyes of 22 patients. Lesion types were defined based on the black level and sharpness of the border: definite decreased autofluorescence (DDAF), well, and poorly demarcated questionably decreased autofluorescence (WDQDAF, PDQDAF). Agreement in grading between the two methods and inter- and intra-grader agreement was assessed by kappa coefficients (κ) and intraclass correlation coefficients (ICC). RESULTS: The mean ± standard deviation (SD) area was 3.07 ± 3.02 mm for DDAF (n = 31), 1.53 ± 1.52 mm for WDQDAF (n = 9), and 6.94 ± 10.06 mm for PDQDAF (n = 17). The mean ± SD absolute difference in area between manual and semiautomated grading was 0.26 ± 0.28 mm for DDAF, 0.20 ± 0.26 mm for WDQDAF, and 4.05 ± 8.32 mm for PDQDAF. The ICC (95% confidence interval) for method comparison was 0.992 (0.984-0.996) for DDAF, 0.976 (0.922-0.993) for WDQDAF, and 0.648 (0.306-0.842) for PDQDAF. Inter- and intra-grader agreement in manual and semiautomated quantitative grading was better for DDAF (0.981-0.996) and WDQDAF (0.995-0.999) than for PDQDAF (0.715-0.993). CONCLUSION: Manual and semiautomated grading methods showed similar levels of reproducibility for assessing areas of decreased autofluorescence in patients with Stargardt disease phenotype. Excellent agreement and reproducibility were observed for well demarcated lesions.
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Mácula Lútea/patología , Degeneración Macular/congénito , Imagen Óptica , Adulto , Atrofia , Femenino , Fondo de Ojo , Humanos , Degeneración Macular/diagnóstico , Masculino , Persona de Mediana Edad , Oftalmoscopía/métodos , Fenotipo , Estudios Prospectivos , Reproducibilidad de los Resultados , Enfermedad de StargardtRESUMEN
PURPOSE: To characterize the vascular structure of Type 3 neovascularization secondary to age-related macular degeneration using optical coherence tomography angiography. METHODS: Optical coherence tomography angiography cube scans (3 mm × 3 mm) were acquired in 29 eyes of 24 patients with Type 3 lesions secondary to age-related macular degeneration using the RTVue XR Avanti with AngioVue, Split-spectrum amplitude-decorrelation, and motion correction technology. Automated layer segmentation boundaries were adjusted to best visualize the neovascular complex on en face projection images. RESULTS: A distinct neovascular complex could be identified in 10 (34%) eyes, all of which were active on optical coherence tomography imaging. In all 10 eyes, the neovascular complex appeared as a small tuft of bright, high-flow tiny vessels with curvilinear morphology located in the outer retinal layers with a feeder vessel communicating with the inner retinal circulation (i.e., deep retinal capillary plexus). The mean (SD) size of the neovascular complex measured 0.07 (± 0.07) mm. CONCLUSION: With optical coherence tomography angiography, it is possible to identify small intraretinal neovascular complexes communicating with the deep retinal capillary plexus in eyes with Type 3 neovascularization secondary to age-related macular degeneration. Qualitative and quantitative analyses of Type 3 neovascular complexes can be performed using optical coherence tomography angiography.
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Angiografía con Fluoresceína/métodos , Neovascularización Retiniana/diagnóstico , Vasos Retinianos/patología , Tomografía de Coherencia Óptica/métodos , Degeneración Macular Húmeda/complicaciones , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/uso terapéutico , Femenino , Humanos , Inyecciones Intravítreas , Masculino , Estudios Prospectivos , Neovascularización Retiniana/etiología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza Visual , Degeneración Macular Húmeda/tratamiento farmacológicoRESUMEN
PURPOSE: To describe the retinal microvasculature of the eyes with nonarteritic retinal artery occlusion (RAO) based on optical coherence tomography angiography. METHODS: Cross-sectional, prospective, observational study performed from September 2014 through February 2015. En face projection of optical coherence tomography angiography images centered at the macula and optic disk of the eyes presenting with RAO were acquired using the RTVue XR Avanti with AngioVue software. Qualitative analysis of the morphology of the superficial and deep retinal capillary plexuses, and radial peripapillary capillaries was performed. Retinal vasculature images using optical coherence tomography angiography were correlated with fluorescein angiography images. RESULTS: Seven patients (seven eyes) were enrolled in the study, including three eyes with central RAO and four eyes with branch RAO. Distinct differences in the distribution of zones of decreased vascular perfusion between the superficial and deep retinal capillary plexus corresponding to areas of delayed dye perfusion on fluorescein angiography were demonstrated in 6 of 7 (86.5%) eyes. CONCLUSION: This small series suggests that optical coherence tomography angiography imaging can accurately discern retinal capillary plexuses at different levels in the eyes with RAO and may be sensitive for more precisely characterizing the extent of macular ischemia and monitoring vascular flow changes during the course of the disease.
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Angiografía con Fluoresceína , Fóvea Central/irrigación sanguínea , Isquemia/diagnóstico , Oclusión de la Arteria Retiniana/diagnóstico , Vasos Retinianos/patología , Tomografía de Coherencia Óptica , Anciano , Anciano de 80 o más Años , Capilares/patología , Estudios Transversales , Femenino , Humanos , Isquemia/fisiopatología , Masculino , Estudios Prospectivos , Flujo Sanguíneo Regional , Oclusión de la Arteria Retiniana/fisiopatología , Agudeza VisualRESUMEN
PURPOSE: To investigate the changes in retinal arterial architecture after treatment with voretigene neparvovec in patients with retinal dystrophy caused by bi-allelic mutations in the RPE65 gene. METHODS: Sixteen eyes treated with voretigene neparvovec at the University Eye Clinic in Tuebingen, Germany, underwent adaptive optics ophthalmoscopy (AO) imaging at baseline and 2 weeks, 1, 3, 6 and 12 months after treatment. Follow-up was performed in six eyes of four patients. For each eye, five different positions at arterial vessels were selected and the wall-to-lumen ratio (WLR), the lumen diameter (LD) and the wall cross-sectional area (WCSA) were measured by the manufacturer's software over the observational period. RESULTS: Vast retinal atrophy dominated all gained AO images. WLR fluctuated in the observation period without statistically significant change. LD and WCSA changed significantly after 2 weeks from the baseline examination and returned to values similar to baseline thereafter. There were no signs of inflammation such as macrophages or perivascular accumulated fluid visible. CONCLUSION: AO imaging of the retinal vessels in RPE65-associated retinal dystrophies (IRD) is challenging. There was no change in the retinal arterial vasculature over the observation period of 12 months that would indicate inflammatory changes. Decrease of the LD and WCSA shortly after treatment might be caused by the perioperative prednisolone intake. AO of retinal vessels can be used as a diagnostic module to complement monitoring the disease and effects of genetic treatments if the acquisition is possible in selected cases.
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Arteriolas , Distrofias Retinianas , Vasos Retinianos , Humanos , Oftalmoscopía , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genéticaRESUMEN
Purpose: To investigate age-dependent wall to lumen ratio (WLR) reference values for healthy individuals in adaptive optics imaging (AO). WLR serves as an objective, dimensionless parameter for the evaluation of structural changes in vessels caused by conditions like arterial hypertension, diabetes or vascular stenosis. Methods: 50 right eyes of healthy individuals were examined by adaptive optics imaging. The central big arterioles and smaller arterial branches at least one disc diameter away from the optic disc, approximately above or below the macula were measured by the manufacturer's software. The wall-lumen-ratio (WLR), the wall cross-sectional area (WCSA) and lumen diameter (LD) were assessed. Subsequent data analysis was performed with a focus on variables including age, gender and blood pressure. Results: Normative values for WLR, WCSA and LD in 5 different age groups could be established. However, no significant differences between the age groups were found. Intra-subject comparisons revealed significantly higher WLRs on peripheral branches when compared to central arterioles. WLR showed in this normotensive cohort no relevant correlation with the systolic, diastolic and mean blood pressure. Gender and intraocular pressure had no influence on the vascular parameters. Conclusion: AO is capable of examining vascular alterations in arterioles at an almost microscopic level. Age did not seem to alter WLR, normotensive blood pressure parameters showed also no significant impact. AO-based vessel analysis may provide clinically useful biomarkers for cardiovascular health and should be tested in future studies.
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BACKGROUND/AAIMS: Congenital stationary night blindness (CSNB) is an inherited retinal disease that is often associated with high myopia and can be caused by pathological variants in multiple genes, most commonly CACNA1F, NYX and TRPM1. High myopia is associated with retinal degeneration and increased risk for retinal detachment. Slowing the progression of myopia in patients with CSNB would likely be beneficial in reducing risk, but before interventions can be considered, it is important to understand the natural history of myopic progression. METHODS: This multicentre, retrospective study explored CSNB caused by variants in CACNA1F, NYX or TRPM1 in patients who had at least 6 measurements of their spherical equivalent of refraction (SER) before the age of 18. A mixed-effect model was used to predict progression of SER overtime and differences between genotypes were evaluated. RESULTS: 78 individuals were included in this study. All genotypes showed a significant myopic predicted SER at birth (-3.076D, -5.511D and -5.386D) for CACNA1F, NYX and TRPM1 respectively. Additionally, significant progression of myopia per year (-0.254D, -0.257D and -0.326D) was observed for all three genotypes CACNA1F, NYX and TRPM1, respectively. CONCLUSIONS: Patients with CSNB tend to be myopic from an early age and progress to become more myopic with age. Patients may benefit from long-term myopia slowing treatment in the future and further studies are indicated. Additionally, CSNB should be considered in the differential diagnosis for early-onset myopia.
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Purpose: Verifying whether specific genotypes causing retinitis pigmentosa (RP) show differences in the preservation of rod and cone function measured by chromatic pupil campimetry (CPC). Methods: 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. Results: 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. Conclusions: 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.
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Retinitis Pigmentosa , Pruebas del Campo Visual , Humanos , Masculino , Pupila , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/genética , Células Fotorreceptoras Retinianas Conos/fisiología , Genotipo , Electrorretinografía/métodos , Proteínas del Ojo/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/genéticaRESUMEN
Purpose: Autosomal recessive retinitis pigmentosa (arRP) can be caused by mutations in the phosphodiesterase 6A (PDE6A) gene. Here, we describe the natural course of disease progression with respect to central retinal function (i.e., visual acuity, contrast sensitivity, and color vision) and establish a detailed genotype--phenotype correlation. Methods: Forty-four patients (26 females; mean age ± SD, 43 ± 13 years) with a confirmed genetic diagnosis of PDE6A-associated arRP underwent comprehensive ophthalmological examinations including best-corrected visual acuity (BCVA) with Early Treatment Diabetic Retinopathy Study charts, contrast sensitivity (CS) with Pelli-Robson charts at distances of 3 m and 1 m, and color vision testing using Roth 28-Hue and Panel D-15 saturated color cups. Results: The most frequently observed variants were c.998+1G>A/p.?, c.304C>A/p.R102S, and c.2053G>A/p.V685M. Central retinal function in patients homozygous for variant c.304C>A/p.R102S was better when compared to patients homozygous for variant c.998+1G>A/p.?, although the former were older at baseline. Central retinal function was similar in patients homozygous for variant c.304C>A/p.R102S and patients heterozygous for variants c.304C>A/p.R102S and c.2053G>A/p.V685M, although the latter were younger at baseline. Annual decline rates in central retinal function were small. Conclusions: We conclude that the severity of the different disease-causing PDE6A mutations in humans with respect to central visual function may be ranked as follows: c.2053G>A/p.V685M in homozygous state (most severe) > c.998+1G>A/p.? in homozygous state > c.304C>A/p.R102S and c.2053G>A/p.V685M in compound-heterozygous state > c.304C>A/p.R102S in homozygous state (mildest). The assessment of treatment efficacy in interventional trials will remain challenging due to small annual decline rates in central retinal function.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6 , Retinitis Pigmentosa , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/genética , Proteínas del Ojo/genética , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Mutación , Linaje , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/genética , Agudeza VisualRESUMEN
AIMS: To determine long-term safety and efficacy outcomes of a subretinal gene therapy for CNGA3-associated achromatopsia. We present data from an open-label, nonrandomised controlled trial (NCT02610582). METHODS: Details of the study design have been previously described. Briefly, nine patients were treated in three escalating dose groups with subretinal AAV8.CNGA3 gene therapy between November 2015 and October 2016. After the first year, patients were seen on a yearly basis. Safety assessment constituted the primary endpoint. On a secondary level, multiple functional tests were carried out to determine efficacy of the therapy. RESULTS: No adverse or serious adverse events deemed related to the study drug occurred after year 1. Safety of the therapy, as the primary endpoint of this trial, can, therefore, be confirmed. The functional benefits that were noted in the treated eye at year 1 were persistent throughout the following visits at years 2 and 3. While functional improvement in the treated eye reached statistical significance for some secondary endpoints, for most endpoints, this was not the case when the treated eye was compared with the untreated fellow eye. CONCLUSION: The results demonstrate a very good safety profile of the therapy even at the highest dose administered. The small sample size limits the statistical power of efficacy analyses. However, trial results inform on the most promising design and endpoints for future clinical trials. Such trials have to determine whether treatment of younger patients results in greater functional gains by avoiding amblyopia as a potential limiting factor.
Asunto(s)
Defectos de la Visión Cromática , Humanos , Defectos de la Visión Cromática/genética , Defectos de la Visión Cromática/terapia , Terapia Genética/métodos , Retina , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genéticaRESUMEN
Introduction: To analyze foveal displacement after macular surgery for idiopathic epiretinal membrane (iERM). Methods: Twenty-eight patients who underwent macular surgery for symptomatic iERM in one eye by one physician were included in this retrospective study. Spectral domain optical coherence tomography (SD-OCT) volume scans were acquired with a Spectralis OCT device (Heidelberg Spectralis). Using the follow-up view mode, the displacement of the fovea was classified and measured according to its postoperative location in the horizontal and/or vertical plane. Results: One day after surgery, 86% of eyes (24/28) showed foveal displacement. Vertical displacement occurred in a superior direction in 50% eyes, and in an inferior direction in 36% of the eyes. The postoperative mean foveal displacement on the vertical plane was 99 ± 82 µm (range, 0-300). Horizontal displacement occurred in a nasal direction in 21%, and temporally in 21%. The postoperative mean foveal displacement on the horizontal plane was 35 ± 45 µm (range, 0-123). One year after the macular surgery 69% of the eyes showed still a foveal dislocation. Discussion: Most of the eyes with iERM showed a foveal dislocation after the macular surgery. Our findings emphasize the necessity to carefully study of the OCT images in such eyes after the surgery as the manually determined postoperative foveal position may be in a different vertical or horizontal plane than the machine-generated pre- and postoperative overlay for the foveal position. Our findings may thus be helpful for surgeons to avoid misinterpretation when evaluating OCT images pre- and postoperatively.