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With a common aim of restoring physiological function of defective cells, optogenetics and targeted gene therapies have shown great clinical potential and novelty in the branch of personalized medicine and inherited retinal diseases (IRDs). The basis of optogenetics aims to bypass defective photoreceptors by introducing opsins with light-sensing capabilities. In contrast, targeted gene therapies, such as methods based on CRISPR-Cas9 and RNA interference with noncoding RNAs (i.e., microRNA, small interfering RNA, short hairpin RNA), consists of inducing normal gene or protein expression into affected cells. Having partially leveraged the challenges limiting their prompt introduction into the clinical practice (i.e., engineering, cell or tissue delivery capabilities), it is crucial to deepen the fields of knowledge applied to optogenetics and targeted gene therapy. The aim of this in-depth and novel literature review is to explain the fundamentals and applications of optogenetics and targeted gene therapies, while providing decision-making arguments for ophthalmologists. First, we review the biomolecular principles and engineering steps involved in optogenetics and the targeted gene therapies mentioned above by bringing a focus on the specific vectors and molecules for cell signalization. The importance of vector choice and engineering methods are discussed. Second, we summarize the ongoing clinical trials and most recent discoveries for optogenetics and targeted gene therapies for IRDs. Finally, we then discuss the limits and current challenges of each novel therapy. We aim to provide for the first time scientific-based explanations for clinicians to justify the specificity of each therapy for one disease, which can help improve clinical decision-making tasks.
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INTRODUCTION: Choroideremia (CHM) is an X-linked inherited retinal disease mostly affecting males. However, women with phenotypic and/or genotypic evidence of CHM may develop degenerative visual disability with advancing age. Our objective was to determine the visual impacts of phenotypic and/or genotypic evidence of CHM in women and its associated psychosocial burden and influence on activities of daily living (ADLs). METHODS: We conducted an international cross-sectional survey from April to December 2022 using an e-questionnaire distributed through not-for-profit stakeholder organizations and social media plat-forms. RESULTS: With a total of 55 respondents (n = 55), most women with phenotypic and/or genotypic evidence of CHM (76%) reported a change in their visual acuity. When assessing its impact on ADLs, Pearson's correlation coefficient showed a negative correlation between driving (p = 0.046) and mobility capabil-ities (0.046) with the respondent's age. More than half of women reported being afraid, anxious, and stressed, with women below the age of 50 years old reporting a significantly higher level of distress and hopelessness (p = 0.003), anxiety (p = 0.00007), issues with relaxing (p = 0.025), and negative personal thoughts (p = 0.042). CONCLUSION: Overall, this survey outlines both physical and psychological burden of being a woman with phenotypic and/or genotypic evidence of CHM. Given the limited clinical research in females affected by CHM, this patient-centered survey is a crucial advocacy tool for these individuals.
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Coroideremia , Desprendimiento de Retina , Perforaciones de la Retina , Humanos , Coroideremia/complicaciones , Coroideremia/diagnóstico , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/etiología , Desprendimiento de Retina/cirugía , Perforaciones de la Retina/diagnóstico , Perforaciones de la Retina/etiología , Perforaciones de la Retina/cirugíaRESUMEN
OBJECTIVE: To understand the physical, psychosocial, and practical challenges faced by Canadian patients with inherited retinal diseases (IRDs) and their families. DESIGN: Mixed methods. PARTICIPANTS: A total of 408 Canadians living with or caring for someone with an IRD (mean ageâ¯=â¯51.4 ± 16.7 years) completed an online survey. Twenty cohort respondents participated in additional telephone interviews. METHODS: The online survey was comprised of questions concerning demographics, self-reported vision, genetic testing, information preferences, health care experiences, treatment goals, and disease impact on daily life. Recruitment occurred through Fighting Blindness Canada's community database. Survey dissemination also occurred via social media and not-for-profit stakeholder outreach. Subsequent to survey completion, a subset of respondents participated in semistructured telephone interviews to further elucidate illness experience. RESULTS: Respondents identified having 1 of more than 14 IRDs, with 72% specifying retinitis pigmentosa. Sixty-eight percent reported being legally blind, and more than 85% self-reported moderate to low vision or worse. IRDs impacted daily functioning, with 53% of respondents indicating that they affected employment or education. Psychological challenges were evident, with more than 70% worried about coping with daily life and more than 60% indicating fear and stress. Qualitative data described hopelessness around suitable work, loss of independence, and challenges with social interaction. Sixty-five percent reported a negative impact on family life. Many had not accessed social support services because of a lack of perceived need, awareness, or availability. CONCLUSION: Canadian patients with IRDs report moderate to severe visual impairment, and both patients and their families describe an impact on psychosocial well-being and functioning during daily activities. Vision rehabilitation with a psychosocial approach is necessary, alongside facilitating access to emerging treatments.
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Retinitis Pigmentosa , Baja Visión , Humanos , Adulto , Persona de Mediana Edad , Anciano , Canadá/epidemiología , Adaptación Psicológica , Encuestas y Cuestionarios , Trastornos de la VisiónRESUMEN
The electroretinogram (ERG) represents the biopotential evoked by the retina in response to a light stimulus. The flash evoked ERG (fERG) is the ERG modality most frequently used clinically to diagnose and monitor retinal disorders. We hereby present a new method to record spontaneous retinal activity, without the use of a flash stimulus, that we named the resting-state ERG (rsERG). The recordings were done in normal subjects under light- and dark-adaptation and with different background light conditions (i.e., variations of wavelength and intensity). Additionally, rsERG recordings were obtained in five patients with retinopathies. The signals were subsequently analyzed in the frequency domain, extracting both periodic (i.e., frequency peaks) and aperiodic (i.e., background trend) components of the signal. The later was further assessed through a multifractal analysis using Wavelet Leaders. Results show that, irrespective of the recording conditions used, the rsERG always includes the same 90 Hz component; a frequency component also present in the fERG response, suggesting a retinally-intrinsic origin. However, in addition, the fERGs also includes a low-frequency component which is absent in the rsERGs, a finding supporting a retinally-induced origin. Comparing rsERGs with fERGs in selected patients with various retinal disorders indicates that the two retinal signals are not always similarly affected (either as a result of underlying retinal pathology or otherwise), suggesting an added value in the assessment of retinal function. Thus, the rsERG could have a similar role in clinical visual electrophysiology as that of the resting-state EEG in neurology namely, to quantify changes in spontaneous activity that result from a given disease processes.
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Rhegmatogenous retinal detachment in choroideremia is a rare occurrence. The authors present a case of a 23-year-old man with choroideremia with a near-total rhegmatogenous retinal detachment. Fundus examination did not reveal any retinal breaks, but extensive preoperative optical coherence tomography detected a small posterior hole along the superior arcades. The retinal detachment was successfully managed with vitrectomy, perfluorooctane to confirm the absence of any peripheral breaks, endolaser, and 20% sulfur hexafluoride gas. Similar extramacular holes were found in the patient's other eye. Patients with choroideremia may develop posterior retinal breaks leading to retinal detachment.
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Coroideremia , Desprendimiento de Retina , Perforaciones de la Retina , Adulto , Coroideremia/complicaciones , Coroideremia/diagnóstico , Humanos , Masculino , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/etiología , Desprendimiento de Retina/cirugía , Perforaciones de la Retina/diagnóstico , Perforaciones de la Retina/etiología , Perforaciones de la Retina/cirugía , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Vitrectomía , Adulto JovenRESUMEN
Purpose: To investigate whether vascular endothelial growth factor (VEGF)-suppression durations contribute to our understanding of clinical trial outcomes by simulating vitreous molar concentrations (Cvm) of intravitreal aflibercept (IVT-AFL) and brolucizumab (IVT-BRO) using pharmacokinetic (PK) modeling. Methods: A PK model simulated Cvm after single-dose IVT-AFL, IVT-BRO, and ranibizumab (IVT-RAN), and extrapolated intraocular VEGF-suppression thresholds and durations. Vitreous PK after multidose regimens used in studies of IVT-AFL versus IVT-BRO were simulated and compared with best-corrected visual acuity (BCVA) data. Results: Cvm peaked higher (Cmax) and decreased more quickly to the VEGF-suppression threshold and minimum (Cmin) levels with IVT-BRO than with IVT-AFL, consistent with their molar doses calculated using molecular weights and vitreous half-lives (26 kDa and 115 kDa; 4.4-5.1 and 9.1-11 days, respectively). The mean VEGF suppression durations were 71 days for IVT-AFL 2 mg and 51 (48-59) days for IVT-BRO 6 mg. Based on dosing in OSPREY (matched dosing to week [w]32 for both agents; thereafter, IVT-AFL every eight weeks [q8w] and IVT-BRO q12w for the last two doses [w32âw44 and w44âw56]), IVT-BRO showed wider Cmax-Cmin fluctuations than IVT-AFL. The IVT-BRO Cmin fell below the VEGF-suppression threshold at timepoints near w56, when decreases in BCVA were also observed. The IVT-AFL vitreous Cmin remained above the suppression threshold through w56, where BCVA gains were maintained. Conclusions: The PK-modeled mean VEGF-suppression duration for IVT-BRO was substantially shorter than that published for IVT-AFL and may not be sufficient to effectively suppress VEGF throughout q12w dosing. Translational Relevance: The PK modeling suggests that more patients may be maintained on ≥q12w dosing with IVT-AFL than with IVT-BRO.
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Inhibidores de la Angiogénesis , Factor A de Crecimiento Endotelial Vascular , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados , Humanos , Inyecciones Intravítreas , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión , Agudeza VisualRESUMEN
These recommendations, produced by a group of Canadian retina experts, have been developed to assist both retina specialists and general ophthalmologists in the management of vision-threatening neovascular age-related macular degeneration (nAMD). The recommendations are based on published evidence as well as collective experience and expertise in routine clinical practice. We provide an update on practice principles for optimal patient care, focusing on identified imaging biomarkers, in particular retinal fluid, as well as current and emerging therapeutic approaches. Algorithms for delivering high-quality care and improving long-term patient outcomes are provided, with an emphasis on timely and appropriate treatment to preserve and maintain vision. In the context of nAMD, increasing macular fluid or leakage on fluorescein angiography (FA) may indicate disease activity regardless of its location. Early elimination of intraretinal fluid (IRF) is of particular relevance as it is a prognostic indicator of worse visual outcomes. Robust referral pathways for second opinion and peer-to-peer consultations must be in place for cases not responding to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy.
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Degeneración Macular , Degeneración Macular Húmeda , Inhibidores de la Angiogénesis/uso terapéutico , Biomarcadores , Canadá , Humanos , Inyecciones Intravítreas , Degeneración Macular/tratamiento farmacológico , Ranibizumab/uso terapéutico , Tomografía de Coherencia Óptica , Factor A de Crecimiento Endotelial Vascular , Agudeza Visual , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/tratamiento farmacológicoAsunto(s)
ADN/genética , Errores Innatos del Metabolismo/complicaciones , Mutación , Enfermedades de la Retina/etiología , Enfermedades de la Retina/metabolismo , Transcobalaminas/genética , Adulto , Análisis Mutacional de ADN , Femenino , Humanos , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Enfermedades Raras , Enfermedades de la Retina/genética , Transcobalaminas/metabolismoRESUMEN
PURPOSE: To provide a comprehensive review of the ocular manifestations, outcomes, and genetic findings in patients with Coats-like retinitis pigmentosa (RP). DESIGN: Multicenter, retrospective, nonconsecutive case series. PARTICIPANTS: Patients with a diagnosis of RP demonstrating Coats-like exudative vitreoretinopathy between January 1, 2008, and October 1, 2019. METHODS: Evaluation of ocular findings at RP diagnosis and at time of presentation of Coats-like exudative vitreoretinopathy, pedigree analysis, genetic testing, retinal imaging, and anatomic outcomes after treatment. MAIN OUTCOME MEASURES: Visual acuity, ophthalmoscopy results, OCT results, fluorescein angiography results, and identification of genetic mutations. RESULTS: Nine patients diagnosed with RP and demonstrating Coats-like exudative vitreoretinopathy were included. Median age at time of RP diagnosis was 8 years (range, 1-22 years), and median age at presentation of Coats-like exudative vitreoretinopathy was 18 years (range, 1-41 years). Seven patients were female, and 2 were male. The genetic cause of disease was identified in 6 patients. Three patients demonstrated Coats-like fundus findings at the time of RP diagnosis. Exudative retinal detachment (ERD) localized to the infratemporal periphery was present in all patients, with bilateral disease observed in 7 patients. In all treated patients, focal laser photocoagulation was used to treat leaking telangiectasias and to limit further ERD expansion. Cystoid macular edema refractory to carbonic anhydrase inhibitor therapy and ultimately amenable to treatment with intravitreal anti-vascular endothelial growth factor injection was observed in 4 patients. CONCLUSIONS: Coats-like vitreoretinopathy is present in up to 5% of all RP patients. The term Coats-like RP is used colloquially to describe this disease state, which can present at the time of RP diagnosis or, more commonly, develops late during the clinical course of patients with longstanding RP. Coats-like RP is distinct from Coats disease in that exudative pathologic features occur exclusively in the setting of a coexisting RP diagnosis, is restricted to the infratemporal retina, can affect both eyes, and does not demonstrate a male gender bias. Given the risk of added vision loss posed by exudative vitreoretinopathy in patients with RP, a heightened awareness of this condition is critical in facilitating timely intervention.
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Crioterapia/métodos , Pruebas Genéticas/métodos , Coagulación con Láser/métodos , Retina/patología , Telangiectasia Retiniana/diagnóstico , Retinitis Pigmentosa/diagnóstico , Agudeza Visual , Adolescente , Adulto , Niño , Preescolar , Diagnóstico Diferencial , Electrorretinografía , Exudados y Transudados , Femenino , Angiografía con Fluoresceína/métodos , Estudios de Seguimiento , Fondo de Ojo , Humanos , Lactante , Masculino , Linaje , Retinitis Pigmentosa/genética , Estudios Retrospectivos , Tomografía de Coherencia Óptica/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
SIGNIFICANCE: Charles Bonnet syndrome is commonly encountered and diagnosed in low-vision patients. It can be distressing for some of them, as there is no known effective treatment of this condition. Although there is a growing interest in retinal implants for blind patients with severe retinal diseases, the effect of these devices on Charles Bonnet syndrome visual hallucinations remains undocumented. PURPOSE: The aim of this study was to report changes in the Charles Bonnet syndrome of a patient with retinitis pigmentosa after implantation of the Argus II retinal prosthesis. CASE REPORT: A 65-year-old patient with retinitis pigmentosa and no light perception was frequently experiencing Charles Bonnet syndrome. In the hope of improving his vision, he received an Argus II retinal prosthesis in 2018 and participated in a 10-week rehabilitation program at the Institut Nazareth et Louis-Braille. The nature and the frequency of his Charles Bonnet syndrome were documented with the Questionnaire de repérage du syndrome de Charles Bonnet (a French questionnaire used to screen for Charles Bonnet syndrome) before the surgery and for 70 weeks after it. The patient's visual acuity and visual fields were monitored during the same period. Additional tests were administered to document the visual, psychological, and cognitive states of the patient throughout the study. CONCLUSIONS: Although this case report confirmed that Argus II retinal prosthesis improves the performance of blind patients in visual tests, the improvement was not associated with a decrease in the symptoms of Charles Bonnet syndrome.
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Ceguera/rehabilitación , Síndrome de Charles Bonnet/fisiopatología , Implantación de Prótesis , Prótesis Visuales , Anciano , Ceguera/etiología , Humanos , Masculino , Retinitis Pigmentosa/complicaciones , Encuestas y Cuestionarios , Agudeza Visual/fisiología , Campos Visuales/fisiologíaRESUMEN
Telemedicine-based remote digital fundus imaging (RDFI-TM) offers a promising platform for the screening of retinopathy of prematurity. RDFI-TM addresses some of the challenges faced by ophthalmologists in examining this vulnerable population in both low- and high-income countries. In this review, we studied the evidence on the use of RDFI-TM and analyzed the practical framework for RDFI-TM systems. We assessed the novel technological advances that can be deployed within RDFI-TM systems including noncontact imaging systems, smartphone-based imaging tools, and deep learning algorithms.
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OBJECTIVE: To measure the difference in intraocular pressure (IOP) before and after pharmacologic mydriasis in normal subjects using Goldmann applanation tonometer (GAT) and the Diaton transpalpebral tonometer (DT). DESIGN: Prospective case series study. PARTICIPANTS: Sixty-seven adult patients attending a tertiary general ophthalmology eye care center. METHODS: Patients were recruited based on a lack of glaucoma history and normal anterior segment on slit lamp examination. IOP measurements predilation and postdilation were collected. Predilation, both eyes were measured using GAT followed immediately by DT. Forty-five minutes post pharmacologic mydriasis, the measurements were repeated sequentially in the same order. Central corneal thickness (CCT) and additional parameters were also collected to corroborate the absence of glaucoma. RESULTS: Using GAT, the mean IOP predilation was 16.7 ± 3.1 mm Hg OD and 16.12 ± 3.0 mm Hg OS. The mean difference between predilation and postdilation time-points was -1.1 ± 2.5 mm Hg in the right eye and -0.7 ± 2.3 mm Hg in the left eye. Using DT, the mean IOP predilation was 12.8 ± 3.8 mm Hg OD and 13.2 ± 3.5 mm Hg OS. The mean difference between predilation and postdilation time points was -0.8 ± 4.0 mm Hg in the right eye and -0.7 ± 3.6 mm Hg in the left eye. There was a larger fluctuation of postdilation measurements using DT. The difference in IOP measured by the 2 instruments was statistically significant both predilation and postdilation (paired sample analysis pre-correlation 0.38 pâ¯=â¯0.002; post correlation 0.40 pâ¯=â¯0.001). CONCLUSIONS: The use of pharmacologic mydriasis affected the reliability of IOP measurements which was decreased when taken postdilation by both GAT and DT. The poor agreement between GAT and DT values indicates an intrinsic difference between the two types of instrumentation.
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Presión Intraocular/fisiología , Midriáticos/farmacología , Pupila/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Paquimetría Corneal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reproducibilidad de los Resultados , Tonometría OcularRESUMEN
BACKGROUND: Inadequate screening of treatment-warranted retinopathy of prematurity (ROP) can lead to devastating visual outcomes. Especially in resource-poor communities, the use of an affordable, portable, and easy to use smartphone-based non-contact fundus photography device may prove useful for screening for high-risk ROP. This study evaluates the feasibility of screening for high-risk ROP using a novel smartphone-based fundus photography device, RetinaScope. METHODS: Retinal images were obtained using RetinaScope on a cohort of prematurely born infants during routine examinations for ROP. Images were reviewed by two masked graders who determined the image quality, the presence or absence of plus disease, and whether there was retinopathy that met predefined criteria for referral. The agreement between image-based assessments was compared to the gold standard indirect ophthalmoscopic assessment. RESULTS: Fifty-four eyes of 27 infants were included. A wide-field fundus photograph was obtained using RetinaScope. Image quality was acceptable or excellent in 98% and 95% of cases. There was substantial agreement between the gold standard and photographic assessment of presence or absence of plus disease (Cohen's κ = 0.85). Intergrader agreement on the presence of any retinopathy in photographs was also high (κ = 0.92). CONCLUSIONS: RetinaScope can capture digital retinal photographs of prematurely born infants with good image quality for grading of plus disease.
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Técnicas de Diagnóstico Oftalmológico , Tamizaje Neonatal/métodos , Fotograbar/métodos , Retinopatía de la Prematuridad/diagnóstico , Teléfono Inteligente , Telemedicina/métodos , Femenino , Edad Gestacional , Humanos , Recién Nacido , Masculino , Estudios Prospectivos , Reproducibilidad de los ResultadosRESUMEN
PURPOSE: An important, unmet clinical need is for cost-effective, reliable, easy-to-use, and portable retinal photography to evaluate preventable causes of vision loss in children. This study presents the feasibility of a novel smartphone-based retinal imaging device tailored to imaging the pediatric fundus. METHODS: Several modifications for children were made to our previous device, including a child-friendly 3D printed housing of animals, attention-grabbing targets, enhanced image stitching, and video-recording capabilities. Retinal photographs were obtained in children undergoing routine dilated eye examination. Experienced masked retina-specialist graders determined photograph quality and made diagnoses based on the images, which were compared to the treating clinician's diagnosis. RESULTS: Dilated fundus photographs were acquired in 43 patients with a mean age of 6.7 years. The diagnoses included retinoblastoma, Coats' disease, commotio retinae, and optic nerve hypoplasia, among others. Mean time to acquire five standard photographs totaling 90-degree field of vision was 2.3 ± 1.1 minutes. Patients rated their experience of image acquisition favorably, with a Likert score of 4.6 ± 0.8 out of 5. There was 96% agreement between image-based diagnosis and the treating clinician's diagnosis. CONCLUSIONS: We report a handheld smartphone-based device with modifications tailored for wide-field fundus photography in pediatric patients that can rapidly acquire fundus photos while being well-tolerated. TRANSLATIONAL RELEVANCE: Advances in handheld smartphone-based fundus photography devices decrease the technical barrier for image acquisition in children and may potentially increase access to ophthalmic care in communities with limited resources.
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We report an unusual phenotype in a child with a clinical diagnosis of recessive Stargardt disease (STGD1) and two pathogenic variants in the ABCA4 gene. Typically, the diagnosis of early-onset STGD1 is challenging because children may present with a variety of fundus changes and a variable rate of progression. At the time of his initial visit, the 6-year-old boy presented with 20/200 OD (right eye) and 20/150 OS (left eye), symmetrical mild foveal atrophy without flecks on fundus exam, and foveal hypoautofluorescence surrounded by a homogeneous hyperautofluorescent background on wide-field fundus autofluorescence. Over 4 years of follow-up, the retinal atrophy continued to progress, resulting in two well-defined and concentric hyperautofluorescent rings: one ring located at the posterior pole and the other located around the peripapillary region. Visual acuity also deteriorated to counting fingers at 4ft OD and 20/500 OS. To the best of our knowledge, this phenotype has not been previously described with the ABCA4 gene.
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Transportadoras de Casetes de Unión a ATP/genética , Variación Genética , Degeneración Macular/congénito , Retina/patología , Niño , Angiografía con Fluoresceína , Fondo de Ojo , Humanos , Degeneración Macular/diagnóstico , Degeneración Macular/genética , Degeneración Macular/fisiopatología , Masculino , Imagen Óptica , Fenotipo , Estudios Retrospectivos , Enfermedad de Stargardt , Tomografía de Coherencia Óptica , Trastornos de la Visión/genética , Trastornos de la Visión/fisiopatología , Agudeza Visual/fisiología , Campos Visuales/fisiologíaRESUMEN
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.