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Peripheral Pigmented Retinal Lesions in Stargardt Disease.

ABSTRACT: PURPOSE:To investigate the prevalence of peripheral pigmented retinal lesions and associated clinical findings in patients with Stargardt disease. DESIGN:Retrospective case series. METHODS:Records at a single academic institution were reviewed for patients with genetically confirmed Stargardt disease with peripheral pigmented retinal lesions on wide-field retinal imaging. For this cohort we described demographics, clinical features, and pathogenic variants. RESULTS:Out of 62 patients with Stargardt disease and wide-field retinal imaging, 14 had peripheral pigmented retinal lesions. These flat, subretinal lesions were located in the mid or far periphery and had well-defined borders, resembling congenital hypertrophy of retinal pigment epithelium (CHRPE) lesions. For this group of 14 patients, median age at initial diagnosis of Stargardt disease was 9.5 years, and the median duration of disease was 21.5 years. Median Snellen visual acuity was 20/200, and median central scotoma size was 20.0 degrees. All 14 patients had electroretinographic abnormalities. Four out of 14 patients developed new lesions during clinical follow-up. CONCLUSIONS:Wide-field retinal imaging revealed the presence of peripheral pigmented retinal lesions resembling CHRPE lesions in a subset of patients with genetically confirmed Stargardt disease. Presence of these lesions may be associated with severe phenotypes of the disease.

SUBMITTER: Zhao PY

PROVIDER: S-EPMC5994923 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Peripheral Pigmented Retinal Lesions in Stargardt Disease.

Zhao Peter Y PY Abalem Maria Fernanda MF Nadelman Daniel D Qian Cynthia X CX Branham Kari K Schlegel Dana D Khan Naheed N Heckenlively John R JR Jayasundera Thiran T

American journal of ophthalmology 20171227

<h4>Purpose</h4>To investigate the prevalence of peripheral pigmented retinal lesions and associated clinical findings in patients with Stargardt disease.<h4>Design</h4>Retrospective case series.<h4>Methods</h4>Records at a single academic institution were reviewed for patients with genetically confirmed Stargardt disease with peripheral pigmented retinal lesions on wide-field retinal imaging. For this cohort we described demographics, clinical features, and pathogenic variants.<h4>Results</h4>O ...[more]

PMID: 29288030

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Project description:Importance:Outcome measures that are sensitive to disease progression are needed as clinical end points for future treatment trials in Stargardt disease. Objective:To examine the incidence of atrophic lesions of the retinal pigment epithelium in patients with Stargardt disease as determined by fundus autofluorescence imaging. Design, Setting, and Participants:In this retrospective multicenter cohort study, 217 patients 6 years and older at baseline at tertiary referral centers in Europe, the United States, and the United Kingdom who were harboring disease-causing variants in the adenosine triphosphate (ATP)-binding cassette subfamily A member 4 (ABCA4) gene and who met the following criteria were enrolled: (1) at least 1 well-demarcated area of atrophy with a minimum diameter of 300 µm, with the total area of all atrophic lesions being less than or equal to 12 mm2 in at least 1 eye at the most recent visit, and (2) fundus autofluorescence images for at least 2 visits with a minimum of 6 months between at least 2 visits. Data were collected between August 22, 2013, and December 12, 2014. Data analysis was performed from March 15, 2015, through January 31, 2017. Exposures:Images were evaluated by staff at a central reading center. Areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence (QDAF) were outlined and quantified. Lesion-free survival rates were estimated using Kaplan-Meier survival curves. Main Outcomes and Measures:Incidence of atrophic lesions as determined by fundus autofluorescence. Results:The 217 patients (mean [SD] age, 21.8 [13.3] years; 127 female [57.5%]; 148 white [68.2%]) contributed 390 eyes for which the mean (SD) follow-up time was 3.9 (1.6) years (range, 0.7-12.1 years). Among eyes without DDAF at first visit, the median time to develop a DDAF lesion was 4.9 years (95% CI, 4.3-5.6 years). Among eyes without QDAF, the median time to develop a QDAF lesion was 6.3 years (95% CI, 5.6-9.7 years). Eyes with a lesion of DDAF at the first visit were less likely to develop a QDAF lesion compared with eyes without a lesion of DDAF (hazard ratio, 0.19; 95% CI, 0.05-0.70; P?=?.01). Conclusions and Relevance:An estimated 50% of the eyes without DDAF at first visit will develop the lesion in less than 5 years, suggesting that incidence of DDAF could serve as an outcome measure for treatment trials.

Project description:PurposeTo evaluate demographic, clinical, imaging, and genetic factors associated with retinal pigment epithelium enlargement in Stargardt disease (STGD1) and to measure the agreement between short-wavelength fundus autofluorescence (SW-FAF) and near-infrared fundus autofluorescence (NIR-FAF).MethodsRetrospective cohort study of patients with STGD1 with ≥2 gradable SW-FAF images. RPE-atrophy areas were measured on SW-FAF and NIR-FAF at each visit and regressed against time to obtain the rate of RPE-atrophy enlargement. Agreement between SW-FAF and NIR-FAF with regards to baseline atrophic areas and rates of enlargement was evaluated. Baseline factors predictive of faster SW-FAF RPE-atrophy enlargement were investigated with linear mixed models.ResultsFifty-four eyes of 28 patients (median age: 45 years; 13 males) were included. SW-FAF and NIR-FAF agreed well for slow rates of RPE-atrophy progression, but agreement decreased as the rate increased. Median (interquartile range [IQR]) rate of RPE-atrophy expansion was 0.18 (0.10-0.85) mm2/year on SW-FAF and 0.24 (0.08-0.33) mm2/year on NIR-FAF. Larger baseline RPE-atrophy area (estimate: 0.057 mm2/year, P < 0.001), worse visual acuity (0.305 mm2/year, P = 0.005), multifocal disease (0.401 mm2/year, P = 0.02), and SW-FAF pattern (0.534 mm2/year, P =0 .03) were associated with a faster rate of progression (predictive R 2: 0.65).ConclusionsSW-FAF and NIR-FAF are not interchangeable in the evaluation of RPE-atrophy enlargement, and both imaging modalities may be required for optimal detection of disease progression. A multivariable model based on baseline clinical and imaging information may identify patients at higher risk of fast disease progression.Translational relevanceThe knowledge of the agreement of different FAF modalities, the estimated rates of RPE-atrophy enlargement, and factors predictive of faster anatomic decay in STGD1 may allow tailored clinical management and better clinical trials design.

Project description:BACKGROUND:Retinitis pigmentosa (RP) is an inherited retinal disease characterized by progressive loss of photoreceptor cells. This study aim at exploring the effect of retinal pigment epithelium (RPE) derived from human-induced pluripotent stem cell (hiPSC-RPE) on the retina of retinal degeneration 10 (rd10) mice, which are characterized with progressive photoreceptor death. METHODS:We generated RPE from hiPSCs by sequential supplementation with retinal-inducing factors and RPE specification signaling factors. The three-dimensional (3D) spheroid culture method was used to obtain optimal injectable hiPSC-RPE cells. Subretinal space transplantation was conducted to deliver hiPSC-RPE cells into the retina of rd10 mice. Neurotrophic factor secretion from transplanted hiPSC-RPE cells was detected by enzyme-linked immunosorbent assay (ELISA). Immunostaining, Western blotting, electroretinography (ERG), and visual behavior testing were performed to determine the effects of hiPSC-RPE on the retinal visual function in rd10 mice. RESULTS:Our data demonstrated that hiPSC-RPE cells exhibited classic RPE properties and phenotype after the sequential RPE induction from hiPSCs. hiPSC-RPE cells co-cultured with mouse retinal explants or retinal ganglion cells 5 (RGC5) exhibited decreased apoptosis. The viability and functional properties of hiPSC-RPE cells were enhanced by 3D spheroid culture. Transplanted hiPSC-derived RPE cells were identified by immunostaining with human nuclear antigen staining in the retina of rd10 14?days after subretinal space injection. The pigment epithelium-derived factor level was increased significantly. The expression of CD68, microglial activation marker, reduced after transplantation. The light avoidance behavior and ERG visual function in rd10 mice improved by the transplantation of hiPSC-RPE cells. CONCLUSION:Our findings suggest that injectable hiPSC-RPE cells after 3D spheroid culture can rescue the structure and function of photoreceptors by sub-retinal transplantation, which lay the foundation for future clinical cell therapy to treat RP and other retinal degeneration diseases.

Project description:PurposeStargardt disease is the most common inherited juvenile macular dystrophy and is characterized by yellowish flecks across the posterior pole. The purpose of this study was to investigate fluorescence lifetime changes of retinal flecks over time using fluorescence lifetime imaging ophthalmoscopy.MethodsLongitudinal fluorescence lifetime data of 12 patients with Stargardt disease (mean age ± SEM, 42.25 ± 2.1 years; range, 28-58 years) were acquired using a fluorescence lifetime imaging ophthalmoscope based on a Heidelberg Engineering Spectralis system. Retinal autofluorescence was excited with a 470-nm laser. The emitted fluorescence was detected in two wavelength channels: a short spectral channel (498-560 nm) and a long spectral channel (560-720 nm). The mean retinal autofluorescence lifetimes were calculated and further analyzed with corresponding color fundus images, autofluorescence intensity images, and spectral domain optical coherence tomography. Patients were classified into three subtypes.ResultsAll patients with Stargardt disease displayed characteristic autofluorescence lifetime patterns. Mean fluorescence lifetime values within areas of yellow flecks were significantly prolonged (long spectral channel 484 ps) compared with the surrounding tissue (long spectral channel 297 ps). In 91.6% of the eyes, flecks with short fluorescence lifetimes (long spectral channel 255 ps) were identified. Short lifetime flecks progressed to flecks with characteristic long lifetimes in 75.1% of eyes within a mean interval of 29.2 months (range 3-45 months). Between baseline and follow-up, the rate of newly developed short lifetime flecks (number/per year) based on subtypes was 2.62 in Group 1, 1.43 in Group 2, and 0.81 in Group 3.ConclusionRecent onset flecks in Stargardt disease display short fluorescence lifetimes and convert into longer fluorescence lifetime flecks over time. This transition may represent a change in the composition of retinal deposits with accumulation of lipofuscin and retinoid by-products from the visual cycle. With emerging treatment options, these findings may prove useful to monitor disease progression and therapeutic effects.

Project description:One of the promises in regenerative medicine is to regenerate or replace damaged tissues. The embryonic chick can regenerate its retina by transdifferentiation of the retinal pigmented epithelium (RPE) and by activation of stem/progenitor cells present in the ciliary margin. These two ways of regeneration occur concomitantly when an external source of fibroblast growth factor 2 (FGF2) is present after injury (retinectomy). During the process of transdifferentiation, the RPE loses its pigmentation and is reprogrammed to become neuroepithelium, which differentiates to reconstitute the different cell types of the neural retina. Somatic mammalian cells can be reprogrammed to become induced pluripotent stem cells by ectopic expression of pluripotency-inducing factors such as Oct4, Sox2, Klf4, c-Myc and in some cases Nanog and Lin-28. However, there is limited information concerning the expression of these factors during natural regenerative processes. Organisms that are able to regenerate their organs could share similar mechanisms and factors with the reprogramming process of somatic cells. Herein, we investigate the expression of pluripotency-inducing factors in the RPE after retinectomy (injury) and during transdifferentiation in the presence of FGF2.We present evidence that upon injury, the quiescent (p27(Kip1)+/BrdU-) RPE cells transiently dedifferentiate and express sox2, c-myc and klf4 along with eye field transcriptional factors and display a differential up-regulation of alternative splice variants of pax6. However, this transient process of dedifferentiation is not sustained unless FGF2 is present. We have identified lin-28 as a downstream target of FGF2 during the process of retina regeneration. Moreover, we show that overexpression of lin-28 after retinectomy was sufficient to induce transdifferentiation of the RPE in the absence of FGF2.These findings delineate in detail the molecular changes that take place in the RPE during the process of transdifferentiation in the embryonic chick, and specifically identify Lin-28 as an important factor in this process. We propose a novel model in which injury signals initiate RPE dedifferentiation, while FGF2 up-regulates Lin-28, allowing for RPE transdifferentiation to proceed.

Dataset Information

Peripheral Pigmented Retinal Lesions in Stargardt Disease.

Publications

Peripheral Pigmented Retinal Lesions in Stargardt Disease.

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