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Patients with inherited retinal dystrophies (IRDs) were recruited from two understudied populations: Mexico and Pakistan as well as a third well-studied population of European Americans to define the genetic architecture of IRD by performing whole-genome sequencing (WGS). Whole-genome analysis was performed on 409 individuals from 108 unrelated pedigrees with IRDs. All patients underwent an ophthalmic evaluation to establish the retinal phenotype. Although the 108 pedigrees in this study had previously been examined for mutations in known IRD genes using a wide range of methodologies including targeted gene(s) or mutation(s) screening, linkage analysis and exome sequencing, the gene mutations responsible for IRD in these 108 pedigrees were not determined. WGS was performed on these pedigrees using Illumina X10 at a minimum of 30X depth. The sequence reads were mapped against hg19 followed by variant calling using GATK. The genome variants were annotated using SnpEff, PolyPhen2, and CADD score; the structural variants (SVs) were called using GenomeSTRiP and LUMPY. We identified potential causative sequence alterations in 61 pedigrees (57%), including 39 novel and 54 reported variants in IRD genes. For 57 of these pedigrees the observed genotype was consistent with the initial clinical diagnosis, the remaining 4 had the clinical diagnosis reclassified based on our findings. In seven pedigrees (12%) we observed atypical causal variants, i.e. unexpected genotype(s), including 4 pedigrees with causal variants in more than one IRD gene within all affected family members, one pedigree with intrafamilial genetic heterogeneity (different affected family members carrying causal variants in different IRD genes), one pedigree carrying a dominant causative variant present in pseudo-recessive form due to consanguinity and one pedigree with a de-novo variant in the affected family member. Combined atypical and large structural variants contributed to about 20% of cases. Among the novel mutations, 75% were detected in Mexican and 50% found in European American pedigrees and have not been reported in any other population while only 20% were detected in Pakistani pedigrees and were not previously reported. The remaining novel IRD causative variants were listed in gnomAD but were found to be very rare and population specific. Mutations in known IRD associated genes contributed to pathology in 63% Mexican, 60% Pakistani and 45% European American pedigrees analyzed. Overall, contribution of known IRD gene variants to disease pathology in these three populations was similar to that observed in other populations worldwide. This study revealed a spectrum of mutations contributing to IRD in three populations, identified a large proportion of novel potentially causative variants that are specific to the corresponding population or not reported in gnomAD and shed light on the genetic architecture of IRD in these diverse global populations.
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Etnicidade/genética , Degeneração Retiniana/genética , Consanguinidade , Análise Mutacional de DNA/métodos , Exoma/genética , Proteínas do Olho/genética , Feminino , Estudos de Associação Genética/métodos , Ligação Genética/genética , Genótipo , Humanos , Masculino , México , Mutação/genética , Paquistão , Linhagem , Retina/patologia , Sequenciamento do Exoma/métodos , Sequenciamento Completo do Genoma/métodosRESUMO
Pre-mRNA splicing factors are crucial in regulating transcript diversity, by removing introns from eukaryotic transcripts, an essential step in gene expression. Splicing of pre-mRNA is catalyzed by spliceosomes. CWC27 is a cyclophilin associated with spliceosome, in which genetic defects of its components have been linked to spliceosomopathies with clinical phenotypes including skeletal developmental defects, retinitis pigmentosa (RP), short stature, skeletal anomalies, and neurological disorders. We report two siblings (male and female) of Mexican descent with a novel homozygous frameshift variant in CWC27 and aim to highlight the cardinal features among the previously described 12 cases as well as expand the currently recognized phenotypic spectrum. Both siblings presented with a range of ocular and extraocular manifestations including novel features such as solitary kidney and tarsal coalition in the male sibling, together with gait abnormalities, and Hashimoto's thyroiditis in the female sibling. Finally, we highlight ectodermal involvement including sparse scalp hair, eyebrows and lashes, pigmentary differences, nail dysplasia, and dental anomalies as a core phenotype associated with the CWC27 spliceosomopathy.
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Precursores de RNA , Retinose Pigmentar , Feminino , Humanos , Masculino , Ciclofilinas/genética , Ciclofilinas/metabolismo , Peptidilprolil Isomerase/genética , Retinose Pigmentar/genética , Precursores de RNA/genética , Splicing de RNA/genética , Spliceossomos/genética , México/etnologiaRESUMO
PURPOSE: Late-onset retinal degeneration (L-ORD) is a rare retinal dystrophy with anterior segment (AS) abnormalities, including long anterior zonules (LAZ) and iris atrophy. This investigation evaluates AS changes in a L-ORD cohort. METHODS: Prospective, longitudinal study including L-ORD individuals (Ser163Arg) with ocular exam and standard slit-lamp photographs between 2011 and 2022. AS images were merged and assessed for LAZ number and zonule-free zone (ZFZ) radius. Further clinical findings such as iris atrophy patterns were reported descriptively. RESULTS: Twelve eyes of 6 patients (4 males, median age = 60.5 years) were included, showing a median of 160 (11-372) LAZs, mainly localized superiorly (39%) and inferiorly (24%). There was a high inter-ocular correlation (rs = 0.94, p < 0.01), no difference in LAZ count between eyes (p = 0.82), and an inverse relationship between LAZ and age (r = - 0.82; p < 0.05). The ZFZ had median 2.1 mm (1.3-5.4), with no inter-ocular difference (p = 0.31). Iris transillumination defects occurred in 11/12 eyes, with 4 major patterns identified: pupillary ruff rarefaction (10/12), patchy atrophy (6/12), notched defects (6/12), and radial streaks (2/12). In a short-term follow-up of 5.9 years, 4 eyes showed a reduction in LAZ count to median 139.5 (67-169) (p = 0.50) and a concomitant increase in ZFZ measurement to median 2.2 (1.7-2.6) (p = 0.17). CONCLUSION: This study confirms symmetric LAZs count and ZFZ in L-ORD, with ZFZ measurements smaller than in previous cohorts. A reduction in LAZs count and an increase in ZFZ with age were suggested longitudinally, yet findings need further evaluation as follow-up was limited to two cases.
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Doenças da Íris , Degeneração Retiniana , Masculino , Humanos , Pessoa de Meia-Idade , Estudos Longitudinais , Estudos Prospectivos , Degeneração Retiniana/diagnóstico , Degeneração Retiniana/genética , Mutação , Atrofia , ColágenoRESUMO
PURPOSE: To understand the baseline and longitudinal microperimetry characteristics in foveal-sparing atrophic late-onset retinal degeneration. METHOD: Prospective, cross-sectional, longitudinal study in which patients from the retina clinics of two academic teaching hospitals were included. Mesopic microperimetry was performed using a Nidek MP-1 micro-perimeter. Mean total, foveal, inner ring, and outer ring sensitivities were analyzed. RESULTS: A total of 20 eyes from 10 patients had baseline data. The subset of 10 eyes from five patients had follow-up data. The mean baseline macular sensitivity was 10.02 dB (± 5.26) with findings showing symmetry between both eyes. In the follow-up cohort, there was a significant loss of outer ring (0.83 dB per year; P = 0.0001), inner ring (0.67 dB per year; P = 0.034), and foveal sensitivity (0.92 dB loss per year; P = 0.015), whereas the mean sensitivity decreased significantly (0.66 dB per year; P = 0.0008) at 4-year follow-up. The drop in mean sensitivity was associated with significant increases in the number of deep scotoma points (6.20, P = 0.037) and a decrease in the number of normal points (-6.30, P = 0.022). CONCLUSION: Microperimetry is a useful tool for macular function follow-up to measure disease progression in late-onset retinal degeneration.
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Retina , Testes de Campo Visual , Humanos , Estudos Longitudinais , Estudos Prospectivos , Estudos Transversais , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: To refine the retinal phenotypes of suspected pentosan polysulfate sodium toxicity using ultra-widefield imaging. METHODS: Patients with complete dosing profiles who visited the ophthalmology department and with ultra-widefield and optical coherence tomography imaging records were identified using electronic health records at a large academic center. Retinal toxicity was initially identified using previously published imaging criteria, while grading was categorized using both previously reported and new classification systems. RESULTS: One hundred and four patients were included in this study. Twenty-six (25%) were identified as having toxicity from PPS. The mean duration of exposure and cumulative dose between the retinopathy group (162.7 months, 1,803.2 g) were longer and higher compared with the nonretinopathy group (69.7 months, 972.6 g) (both P < 0.001). There was variability of extramacular phenotype in the retinopathy group, with four eyes having only peripapillary involvement and six eyes having far peripheral extension. CONCLUSION: Retinal toxicity in the setting of prolonged exposure and increased cumulative dosing from PPS therapy produces phenotypic variability. Providers should be aware of the extramacular component of toxicity when screening patients. Understanding the different retinal phenotypes may prevent continued exposure and reduce the risk of vision-threatening foveal-involving disease.
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Poliéster Sulfúrico de Pentosana , Doenças Retinianas , Humanos , Poliéster Sulfúrico de Pentosana/efeitos adversos , Angiofluoresceinografia/métodos , Retina , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/diagnóstico , Tomografia de Coerência Óptica/métodos , FenótipoRESUMO
PURPOSE: To assess genetic associations for pentosan polysufate sodium maculopathy. METHODS: Genetic testing for inherited retinal dystrophy genes using exome testing and for 14 age-related macular degeneration-associated single nucleotide polymorphisms (SNPs) using panel testing were performed. In addition, full-field electroretinograms (ffERG) were obtained to identify any cone-rod dystrophy. RESULTS: Eleven of 15 patients were women, with a mean age of 69 (range 46-85). Inherited retinal dystrophy exome testing in five patients revealed six pathogenic variants, but failed to confirm inherited retinal dystrophy in any patient genetically. FfERG performed in 12 patients demonstrated only nonspecific a- and b-wave abnormalities in 11 cases and was normal in one case. For age-related macular degeneration single nucleotide polymorphisms, CFH rs3766405 ( P = 0.003) and CETP ( P = 0.027) were found to be statistically significantly associated with pentosan polysulfate maculopathy phenotype compared with the control population. CONCLUSION: Pentosan polysulfate maculopathy is not associated with Mendelian inherited retinal dystrophy genes. However, several age-related macular degeneration risk alleles were identified to be associated with maculopathy compared with their frequency in the normal population. This suggests a role for genes in disease pathology, particularly the alternative complement pathway. These findings would benefit from further investigation to understand the risk of developing maculopathy in taking pentosan polysulfate.
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Distrofias de Cones e Bastonetes , Cistite Intersticial , Degeneração Macular , Distrofias Retinianas , Feminino , Masculino , Humanos , Poliéster Sulfúrico de Pentosana/efeitos adversos , Degeneração Macular/induzido quimicamente , Degeneração Macular/diagnóstico , Degeneração Macular/genéticaRESUMO
INTRODUCTION: The aim of this study was to investigate retinal layer thickness and vessel density differences between patients with reticular pseudodrusen (RPD) and intermediate dry age-related macular degeneration (iAMD). METHODS: Participants included in the study were patients diagnosed by retinal specialists with RPD, iAMD, and both RPD and iAMD at our academic referral center, seen from May 2021 until February 2022. The central 3 mm retinal thickness was measured using spectral-domain optical coherence tomography (Heidelberg Spectralis HRA+OCT System; Heidelberg Engineering, Heidelberg, Germany). Individual retinal thickness measurements were obtained from the innermost layer (nerve fiber layer) until the outermost layer (retinal pigment epithelium [RPE]). Each thickness measurement was subdivided into nine Early Treatment Diabetic Retinopathy Study (ETDRS) sectors. For the vessel density, OCT angiography from the Heidelberg Spectralis System was measured using proprietary third-party software (AngioTool; National Institutes of Health, National Cancer Institute, Bethesda, MD). Clinical and demographic characteristics were compared across the three groups (iAMD, RPD, iAMD and RPD) and analyzed with necessary adjustments. Linear mixed-effects models with necessary corrections were employed to compare continuous eye-level measurements between our three groups as well as in pairwise fashion using the R statistical programming software (R version 4.2.1). RESULTS: A total of 25 eyes of 17 patients with RPD, 20 eyes of 15 patients with iAMD, and 14 eyes of 9 patients with both iAMD and RPD were analyzed. Retinal thickness analysis identified that the superior inner (p = 0.028) and superior outer (p = 0.027) maculas of eyes with both iAMD and RPD were significantly thinner than those with iAMD alone. In eyes with RPD, the superior inner and superior outer RPE (p = 0.011 and p = 0.05, respectively), outer plexiform layer (p = 0.003 and p = 0.013, respectively), and inner nuclear layer (p = 0.034 and p = 0, respectively) were noted to be thinner compared to eyes with iAMD alone. In addition, the macular deep capillary plexus vessel density was significantly reduced in eyes with RPD compared to eyes with iAMD (p = 0.017). CONCLUSION: Patients with RPD had inner retinal structural as well as vascular changes compared to iAMD patients. Inner retinal vascular attenuation should be investigated further to see if there is a causal association with retinal thinning.
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Atrofia Geográfica , Degeneração Macular , Drusas Retinianas , Humanos , Corioide , Drusas Retinianas/diagnóstico , Retina , Degeneração Macular/diagnóstico , Tomografia de Coerência Óptica/métodosRESUMO
Inherited retinal diseases (IRDs) are a leading cause of irreversible visual loss in the developed world. The primary driver of pathology in IRDs is pathogenic genetic variant. However, there is increasing evidence, from recent studies, for a role of the immune system in disease mechanism, particularly retinal microglia. Microglia are the primary immune cells in the retina and actively contribute to disease pathogenesis when activated locally by phagocytosing photoreceptors, inducing inflammation and signaling infiltration of circulating monocytes. In this article, we discuss the evidence for the contribution of retinal microglia to IRD pathogenesis reported so far using mice model.
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Degeneração Retiniana , Doenças Retinianas , Camundongos , Animais , Microglia/patologia , Degeneração Retiniana/genética , Retina/patologia , Doenças Retinianas/genética , Doenças Retinianas/patologia , Neuroglia/patologia , Monócitos/patologiaRESUMO
Late-onset retinal degeneration (L-ORD) is an autosomal dominant macular dystrophy resulting from mutations in the gene CTRP5/C1QTNF5. A mouse model (Ctrp5+/-) for the most common S163R developed many features of human clinical disease. We generated a novel homozygous Ctrp5 gene knock-out (Ctrp5-/-) mouse model to further study the mechanism of L-ORD. The retinal morphology of these mice was evaluated by retinal imaging, light microscopy, and transmission electron microscopy (TEM) at 6, 11, and 18.5 mo. Expression of Ctrp5 was analyzed using immunostaining and qRT-PCR. The Ctrp5-/- mice showed lack of both Ctrp5 transcript and protein. Presence of a significantly larger number of autofluorescent spots was observed in Ctrp5-/- mice compared to the WT (P < 0.0001) at 19 mo. Increased RPE stress with vacuolization and thinning was observed as early as 6 mo in Ctrp5-/- mice. Further, ultrastructural analyses revealed a progressive accumulation of basal laminar sub-RPE deposits in Ctrp5-/- mice from 11 mo. The Ctrp5-/- mice shared retinal and RPE pathology that matches with that previously described for Ctrp5+/- mice suggesting that pathology in these mice results from the loss of functional CTRP5 and that the presence of CTRP5 is critical for normal RPE and retinal function.
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Degeneração Macular , Degeneração Retiniana , Camundongos , Humanos , Animais , Degeneração Retiniana/patologia , Retina/patologia , Degeneração Macular/patologia , Mutação , Epitélio Pigmentado da Retina/patologiaRESUMO
BACKGROUND: Retinitis pigmentosa (RP) represents a group of progressive, genetically heterogenous blinding diseases. Recently, relationships between measures of retinal function and structure are needed to help identify outcome measures or biomarkers for clinical trials. The ability to align retinal multimodal images, taken on different platforms, will allow better understanding of this relationship. We investigate the efficacy of artificial intelligence (AI) in overlaying different multimodal retinal images in RP patients. METHODS: We overlayed infrared images from microperimetry on near-infra-red images from scanning laser ophthalmoscope and spectral domain optical coherence tomography in RP patients using manual alignment and AI. The AI adopted a two-step framework and was trained on a separate dataset. Manual alignment was performed using in-house software that allowed labelling of six key points located at vessel bifurcations. Manual overlay was considered successful if the distance between same key points on the overlayed images was ≤1/2°. RESULTS: Fifty-seven eyes of 32 patients were included in the analysis. AI was significantly more accurate and successful in aligning images compared to manual alignment as confirmed by linear mixed-effects modelling (p < 0.001). A receiver operating characteristic analysis, used to compute the area under the curve of the AI (0.991) and manual (0.835) Dice coefficients in relation to their respective 'truth' values, found AI significantly more accurate in the overlay (p < 0.001). CONCLUSION: AI was significantly more accurate than manual alignment in overlaying multimodal retinal imaging in RP patients and showed the potential to use AI algorithms for future multimodal clinical and research applications.
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Inteligência Artificial , Retinose Pigmentar , Humanos , Retina , Retinose Pigmentar/diagnóstico , Tomografia de Coerência Óptica/métodos , Acuidade VisualRESUMO
PURPOSE: There are limited real-world data on long-term mortality and visual outcomes in patients treated with anti-vascular endothelial growth factor (VEGF) for exudative age-related macular degeneration (exudative AMD). We assessed 10-year mortality and clinical outcomes in exudative AMD patients treated with intravitreal therapy (IVT) anti-VEGF injections on a pro-re-nata (PRN) regime following a standard loading regime. METHODS: Retrospective cohort study of the first 216 exudative AMD patients receiving IVT anti-VEGF for exudative AMD at a public tertiary referral hospital in Scotland. Main outcome measures were mortality, cause of death and best-corrected visual acuity (BCVA). RESULTS: A total of 216 patients were included. Mean age at presentation was 79.1 years [standard deviation (SD) 6.9]. Mean follow-up duration was 6.6 years (SD 3.2) during which there was a mean 24.3 Early Treatment Diabetic Retinopathy Study (ETDRS) letter loss in BCVA (P < 0.0001). Patients received a mean of 2.2 (SD 1.8) injections per year of follow-up. Overall, 52.6% (113/216) died during the period studied. Observed annual mortality incidence risk was 6.5% (SD 3.1) and was found to be significantly lower (P = 0.0064) than the expected annual death incidence risk (9.6%, SD 1.5) based on age and sex standardised Scottish mortality risk. The most common causes of death were malignancies (21.3%) and infection (20.0%). CONCLUSIONS: This study highlights the relatively good long-term prognosis in vision and mortality in exudative AMD treated with a PRN regime in the real world. Although the majority lost vision, the rate of decline was significantly slower than that which would have been experienced in the pre-anti-VEGF era and reassuringly standardised mortality risk was lower than the national average.
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Degeneração Macular , Ranibizumab , Inibidores da Angiogênese/efeitos adversos , Seguimentos , Humanos , Degeneração Macular/tratamento farmacológico , Ranibizumab/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Acuidade VisualRESUMO
INTRODUCTION: Few studies have explored Multicolor™ imaging (MCI) in evaluating retinal vascular diseases, particularly branch retinal vein occlusion (BRVO). This study aimed to compare the identification of retinal vessel whitening in BRVO using MCI by scanning confocal laser versus conventional white flash color fundus photography (CFP). METHODS: Paired images of consecutive patients diagnosed with BRVO who underwent same-day MCI and CFP were reviewed. Visualization of vessel whitening on MCI and CFP was graded and scored using a scale by two masked graders. A longitudinal analysis of the vessel grading score was performed to evaluate the vessel whitening detection by MCI. A correlation analysis was conducted between vessel whitening on MCI and the measured area of retinal ischemia on fluorescein angiography to evaluate the MCI performance. RESULTS: Forty-four eyes of 41 patients (mean age 69±14 years; 61% female) were analyzed. MCI demonstrated superior vessel whitening visibility score than CFP (p<0.001). Longitudinal analysis showed no significant changes in vessel whitening visibility scores over a mean follow-up time of 430 ± 648 days (p=0.655). There was a significantly positive correlation between the grading score of vessels whitening by MCI and the area of ischemia by fluorescein angiography (r2=0.15; p=0.036). CONCLUSION: MCI appears to provide a superior detection of whitening BRVO compared to CFP, serving as a rapid and non-invasive correlate of retinal ischemia.
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Inherited retinal degenerations (IRDs) are a group of genetically heterogeneous conditions with a broad phenotypic heterogeneity. Here, we report detection and validation of the underlying cause of progressive retinal degeneration in a nuclear family of European descent with a single affected individual. Whole genome sequencing of the proband and her unaffected sibling identified a novel intron 8 donor splice site variant (c.1296 + 1G>A) and a novel 731 base pair deletion encompassing exon 9 (Chr2:g.112751488_112752218 del) resulting in c.1297_1451del; p.K433_G484fsTer3 in the Mer tyrosine kinase protooncogene (MERTK), which is highly expressed in the retinal pigment epithelium (RPE). The proband carried both variants in the heterozygous state, which segregated with disease in the pedigree. These MERTK variants are predicted to result in the defective splicing of exon 8 and loss of exon 9 respectively. To evaluate the impact of these novel variants, peripheral blood mononuclear cells of the proband and her parents were reprogrammed to humaninduced pluripotent stem cell (hiPSC) lines, which were subsequently differentiated to hiPSC-RPE. Analysis of the proband's hiPSC-RPE revealed the absence of both MERTK transcript and its respective protein as well as abnormal phagocytosis when compared with the parental hiPSC-RPE. In summary, whole genome sequencing identified novel compound heterozygous variants in MERTK as the underlying cause of progressive retinal degeneration in a simplex case. Further, analysis using an hiPSC-RPE model established the functional impact of novel MERTK mutations and revealed the potential mechanism underlying pathology in the proband.
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Células-Tronco Pluripotentes Induzidas , Degeneração Retiniana , Feminino , Humanos , Leucócitos Mononucleares/patologia , Mutação , Fagocitose , Degeneração Retiniana/genética , Degeneração Retiniana/patologia , Epitélio Pigmentado da Retina/patologia , Sequenciamento Completo do Genoma , c-Mer Tirosina Quinase/genéticaRESUMO
PURPOSE: To identify quantifiable markers of disease progression in patients with foveal-sparing atrophic late-onset retinal degeneration using fundus autofluorescence and spectral-domain optical coherence tomography imaging. METHODS: Natural history study evaluating patients within a 3-year interval. Disease progression was assessed based on the area of retinal atrophy, macular topographic distribution of lesions, retinal and choroidal thickness and volume, and choroidal vascularity index. RESULTS: Twenty-four eyes (12 individuals) were included for fundus autofluorescence, and 31 eyes (16 individuals) for spectral-domain optical coherence tomography studies. Measurements were symmetrical between eyes of the same patient. The area of atrophy significantly enlarged (P = 0.002), with a growth rate of 2.67 mm2/year (SD: 2.13; square rooted: 0.57 mm/year, SD = 0.34). Baseline area of atrophy and progression both correlated with age. Most atrophic lesions were found in the temporal macula and progressed nasally at follow-up. Central choroidal and retinal thicknesses and volume in late-onset retinal degeneration cases were significantly reduced compared with controls, but only central retinal thickness decreased significantly at follow-up. CONCLUSION: This study identifies the area of atrophy and central retinal thickness, but not chorioretinal volume or choroidal thickness, as markers of short-term progression in late-onset retinal degeneration. These findings may be useful for disease monitoring and late-onset retinal degeneration interventional studies.
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Angiofluoresceinografia/métodos , Fóvea Central/patologia , Degeneração Retiniana/diagnóstico , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Atrofia , Corioide/diagnóstico por imagem , Feminino , Seguimentos , Fundo de Olho , Humanos , Masculino , Pessoa de Meia-Idade , Oftalmoscopia , Epitélio Pigmentado da Retina/patologia , Estudos Retrospectivos , Fatores de TempoRESUMO
Whole genome sequencing (WGS) was performed to identify the variants responsible for inherited retinal degeneration (IRD) in a Caucasian family. Segregation analysis of selected rare variants with pathogenic potential identified a set of compound heterozygous changes p.Arg266*:c.796C>T and p.Ala568Thr:c.1702G>A in the intraflagellar transport protein-88 (IFT88) gene segregating with IRD. Expression of IFT88 with the p.Arg266* and p.Ala568Thr mutations in mIMDC3 cells by transient transfection and in HeLa cells by introducing the mutations using CRISPR-cas9 system suggested that both mutations result in the formation of abnormal ciliary structures. The introduction of the IFT88 p.Arg266* variant in the homozygous state in HeLa cells by CRISPR-Cas9 genome-editing revealed that the mutant transcript undergoes nonsense-mediated decay leading to a significant depletion of IFT88 transcript. Additionally, abnormal ciliogenesis was observed in these cells. These observations suggest that the rare and unique combination of IFT88 alleles observed in this study provide insight into the physiological role of IFT88 in humans and the likely mechanism underlying retinal pathology in the pedigree with IRD.
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Ciliopatias/genética , Degeneração Retiniana/genética , Proteínas Supressoras de Tumor/genética , Sequenciamento Completo do Genoma , Alelos , Sistemas CRISPR-Cas/genética , Ciliopatias/fisiopatologia , Feminino , Edição de Genes , Predisposição Genética para Doença , Células HeLa , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Retina/patologia , Degeneração Retiniana/fisiopatologiaRESUMO
PURPOSE: Transplantation of human embryonic stem cell (hESC)-derived retinal pigment epithelial (RPE) cells offers the potential for benefit in macular degeneration. Previous trials have reported improved visual acuity (VA), but lacked detailed analysis of retinal structure and function in the treated area. DESIGN: Phase 1/2 open-label dose-escalation trial to evaluate safety and potential efficacy (clinicaltrials.gov identifier, NCT01469832). PARTICIPANTS: Twelve participants with advanced Stargardt disease (STGD1), the most common cause of macular degeneration in children and young adults. METHODS: Subretinal transplantation of up to 200 000 hESC-derived RPE cells with systemic immunosuppressive therapy for 13 weeks. MAIN OUTCOME MEASURES: The primary end points were the safety and tolerability of hESC-derived RPE cell administration. We also investigated evidence of the survival of transplanted cells and measured retinal structure and function using microperimetry and spectral-domain OCT. RESULTS: Focal areas of subretinal hyperpigmentation developed in all participants in a dose-dependent manner in the recipient retina and persisted after withdrawal of systemic immunosuppression. We found no evidence of uncontrolled proliferation or inflammatory responses. Borderline improvements in best-corrected VA in 4 participants either were unsustained or were matched by a similar improvement in the untreated contralateral eye. Microperimetry demonstrated no evidence of benefit at 12 months in the 12 participants. In one instance at the highest dose, localized retinal thinning and reduced sensitivity in the area of hyperpigmentation suggested the potential for harm. Participant-reported quality of life using the 25-item National Eye Institute Visual Function Questionnaire indicated no significant change. CONCLUSIONS: Subretinal hyperpigmentation is consistent with the survival of viable transplanted hESC-derived RPE cells, but may reflect released pigment in their absence. The findings demonstrate the value of detailed analysis of spatial correlation of retinal structure and function in determining with appropriate sensitivity the impact of cell transplantation and suggest that intervention in early stage of disease should be approached with caution. Given the slow rate of progressive degeneration at this advanced stage of disease, any protection against further deterioration may be evident only after a more extended period of observation.
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Células-Tronco Embrionárias Humanas/transplante , Degeneração Macular/congênito , Epitélio Pigmentado da Retina/transplante , Adulto , Eletrorretinografia , Feminino , Angiofluoresceinografia , Humanos , Imunossupressores/uso terapêutico , Degeneração Macular/diagnóstico por imagem , Degeneração Macular/fisiopatologia , Degeneração Macular/terapia , Masculino , Pessoa de Meia-Idade , Células Fotorreceptoras de Vertebrados/fisiologia , Qualidade de Vida , Perfil de Impacto da Doença , Microscopia com Lâmpada de Fenda , Doença de Stargardt , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Testes de Campo Visual , Campos Visuais/fisiologiaRESUMO
BACKGROUND: To assess the effect of switching patients previously incompletely treated with ranibizumab (RBZ) to aflibercept (AFL) using a pro re nata (PRN) treatment strategy in neovascular age-related macular degeneration (nvAMD). METHODS: A retrospective case series was conducted on patients who had persistent or recurrent intra- and/or sub-retinal fluid treated initially with RBZ and subsequently switched to AFL. The main outcome measures were best corrected visual acuity (BCVA) and central retinal thickness (CRT) measured at different stages of the study. Friedman analysis of variance and Wilcoxon test were used to examine differences in BCVA and CRT. RESULTS: Two hundred and seven eyes from 182 patients were included. BCVA and CRT improved significantly initially following 3 RBZ injections with a mean gain of 3.7 letters (p < 0.001) and a mean loss of 69 µm (p < 0.001) respectively. Following PRN RBZ therapy and immediately prior to switching to AFL (mean 129 weeks), there was a mean loss of 6.7 letters (p < 0.001) BCVA and a mean gain of 24 µm (p < 0.001) CRT. AFL loading resulted in a mean improvement of 0.7 letters (p = 0.28) BCVA and 55 µm (p < 0.001) CRT. At final follow-up following AFL PRN therapy (mean 85 weeks), there was a mean loss of 8.9 letters (p < 0.001) BCVA and a mean gain of 12 µm (p < 0.05) CRT. CONCLUSION: AFL loading resulted in a significant anatomical improvement but no significant change in visual acuity. However, the benefits of switching were gradually lost over time with AFL PRN dosing despite an increased injection rate when compared with RBZ PRN treatment. TRIAL REGISTRATION: Not applicable.
Assuntos
Protocolos Clínicos , Substituição de Medicamentos/métodos , Ranibizumab/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Acuidade Visual , Degeneração Macular Exsudativa/tratamento farmacológico , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Feminino , Seguimentos , Humanos , Injeções Intravítreas , Masculino , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Estudos Retrospectivos , Fatores de Tempo , Tomografia de Coerência Óptica , Resultado do Tratamento , Degeneração Macular Exsudativa/diagnósticoRESUMO
BACKGROUND: Plasmodium knowlesi causes severe malaria, but its pathogenesis is poorly understood. Retinal changes provide insights into falciparum malaria pathogenesis but have not been studied in knowlesi malaria. METHODS: An observational study was conducted in Malaysian adults hospitalized with severe (n = 20) and nonsevere (n = 24) knowlesi malaria using indirect ophthalmoscopy (n = 44) and fundus photography (n = 29). RESULTS: The patients' median age was 44 years (range, 18-74 years). No coma or deaths occurred. Photography detected retinal changes in 11 of 12 patients (92%) with severe and 14 of 17 (82%) with nonsevere knowlesi malaria. Nonspecific retinal whitening occurred in 3 (35%) and 5 (29%) patients with severe and nonsevere disease, respectively; hemorrhages in 2 (17%) and 3 (18%); loss of retinal pigment epithelium in 1 (8%) and 4 (24%); and drusen in 9 (71%) and 12 (75%). All changes were mild, with no significant differences between severe and nonsevere disease. Patients with retinal hemorrhages had lower platelet counts than those without (median, 22 vs 43 × 10(9)/L; P= .04). CONCLUSIONS: The paucity of specific retinal findings associated with disease severity in knowlesi malaria contrasts with the retinopathy of severe adult falciparum malaria with and without coma, suggesting that falciparum-like microvascular sequestration in the brain is not a major component in severe knowlesi malaria pathogenesis.
Assuntos
Malária/complicações , Plasmodium knowlesi , Retina/patologia , Doenças Retinianas , Vasos Retinianos/patologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Malária/epidemiologia , Malásia/epidemiologia , Masculino , Pessoa de Meia-Idade , Doenças Retinianas/epidemiologia , Doenças Retinianas/etiologia , Doenças Retinianas/patologia , Adulto JovemRESUMO
BACKGROUND: Malarial retinopathy is an important finding in Plasmodium falciparum cerebral malaria, since it strengthens diagnostic accuracy, predicts clinical outcome and appears to parallel cerebral disease processes. Several angiographic features of malarial retinopathy have been described, but observations in different populations can only be reliably compared if consistent methodology is used to capture and grade retinal images. Currently no grading scheme exists for fluorescein angiographic features of malarial retinopathy. METHODS: A grading scheme for fluorescein angiographic images was devised based on consensus opinion of clinicians and researchers experienced in malarial retinopathy in children and adults. Dual grading were performed with adjudication of admission fluorescein images from a large cohort of children with cerebral malaria. RESULTS: A grading scheme is described and standard images are provided to facilitate future grading studies. Inter-grader agreement was >70 % for most variables. Intravascular filling defects are difficult to grade and tended to have lower inter-grader agreement (>57 %) compared to other features. CONCLUSIONS: This grading scheme provides a consistent way to describe retinal vascular damage in paediatric cerebral malaria, and can facilitate comparisons of angiographic features of malarial retinopathy between different patient groups, and analysis against clinical outcomes. Inter-grader agreement is reasonable for the majority of angiographic signs. Dual grading with expert adjudication should be used to maximize accuracy.
Assuntos
Angiografia/métodos , Processamento de Imagem Assistida por Computador/métodos , Malária Cerebral/complicações , Malária Falciparum/complicações , Doenças Retinianas/diagnóstico , Doenças Retinianas/patologia , Coloração e Rotulagem/métodos , Adulto , Feminino , Fluoresceína/análise , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
BACKGROUND: In visceral leishmaniasis (VL), retinal changes have previously been noted but not described in detail and their clinical and pathological significance are unknown. A prospective observational study was undertaken in Mymensingh, Bangladesh aiming to describe in detail visible changes in the retina in unselected patients with VL. METHODS: Patients underwent assessment of visual function, indirect and direct ophthalmoscopy and portable retinal photography. The photographs were assessed by masked observers including assessment for vessel tortuosity using a semi-automated system. RESULTS: 30 patients with VL were enrolled, of whom 6 (20%) had abnormalities. These included 5 with focal retinal whitening, 2 with cotton wool spots, 2 with haemorrhages, as well as increased vessel tortuosity. Visual function was preserved. CONCLUSIONS: These changes suggest a previously unrecognized retinal vasculopathy. An inflammatory aetiology is plausible such as a subclinical retinal vasculitis, possibly with altered local microvascular autoregulation, and warrants further investigation.