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Mutations in CEP78 lead to abnormal production of cilia and have previously been identified to cause cone-rod dystrophy (CRD) with progressive sensorineural hearing loss. The authors describe a case of cone dystrophy (CD) with sensorineural hearing loss in a variant that had previously been reported to be of unknown significance and associated with CRD only. This report corroborates the pathogenicity of this variant and highlights that different phenotypes may be associated with one genotype. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].
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PURPOSE: To present the multimodal imaging and functional exam findings in a case of combined Stargardt disease and idiopathic intracranial hypertension. METHODS: The patient was evaluated with multimodal imaging including color fundus photography, short wavelength autofluorescence, spectral domain optical coherence tomography as well as functional testing such as Humphrey visual fields and full-field electroretinogram. RESULTS: A 35-year-old woman was referred for evaluation of bilateral transient visual obscurations over the course of 2 months. Optic disc edema was observed in both eyes as well as a bulls-eye maculopathy with pisciform flecks. Magnetic resonance imaging and subsequent lumbar puncture confirmed a diagnosis of idiopathic intracranial hypertension. Fundus autofluorescence demonstrated hyperautofluorescent flecks surrounding both the macula and the disc. Genetic testing and full-field electroretinogram confirmed a diagnosis of Stargardt disease. Notably, the peripapillary retina was not spared as is frequently seen in Stargardt disease, possibly due to the impact of disc edema in the area. The patient was treated with increasing doses of acetazolamide and familial testing for Stargardt disease was recommended. CONCLUSION: Both Stargardt disease and idiopathic intracranial hypertension are separately rare diseases with common anatomic intersection at the peripapillary retina. Stargardt disease typically spares the peripapillary retina; however, in the present case shows some evidence of peripapillary involvement. This finding suggests some relationship between disc edema due to idiopathic intracranial hypertension and the natural history of Stargardt disease.
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PURPOSE: To present the longitudinal progression of a myopic macular hole with eventual closure and excellent visual recovery over a decade after initial full-thickness hole formation. METHODS: The patient was monitored using time-domain and spectral-domain optical coherence tomography images over 16 years. RESULTS: A 68-year-old man with high myopia was referred for surgical evaluation of a full-thickness macular hole and retinal detachment of his left eye, which were repaired. At initial presentation, the fellow eye demonstrated a lamellar hole, which eventually also progressed to become a full-thickness macular hole. The patient subsequently declined surgery and was observed semiannually over the course of 16 years. At 10 years following initial injury, the full-thickness macular hole closed spontaneously. The visual recovery was excellent with an acuity of 20/25. CONCLUSION: Although surgical intervention remains the mainstay of treatment for macular holes, patients who are not surgical candidates may still have good visual and anatomic outcomes even long after initial hole formation. Lamellar hole epiretinal proliferation material is frequently seen in myopic full-thickness macular holes and may be associated with eventual delayed hole closure due to their slow progression.
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Mutations in collagen-encoding genes have been linked to numerous systemic diseases. Specifically, pathologic alterations in COL4A2 have been linked to Gould syndrome, a hereditary angiopathy affecting the brain, kidneys, and eyes. However, the ocular phenotype associated with COL4A2-associated disease has yet to be fully characterized. In this report, we describe a novel variant in COL4A2 identified in a 48-year-old woman and her 15-year-old daughter. Funduscopic examination demonstrated significant venous and arteriolar tortuosity. Genetic testing revealed a novel variant, c.2321G>A:p.(Gly774Glu), in COL4A2. This vascular phenotype is similar to the familial retinal arterial tortuosity seen in COL4A2-associated Gould syndrome with additional venous involvement. [Ophthalmic Surg Lasers Imaging Retina 2023;54:536-539.].
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Encéfalo , Olho , Feminino , Humanos , Pessoa de Meia-Idade , Adolescente , Testes Genéticos , Mutação , Oftalmoscopia , Síndrome , Colágeno Tipo IV/genéticaRESUMO
Purpose: To describe the phenotype of CLN-associated retinal dystrophy in a subset of patients at the Columbia University Medical Center, United States, and the Hospital das Clínicas de Pernambuco, Brazil, in comparison to the published literature. Methods: Eleven patients with confirmed biallelic variants in the CLN genes were evaluated via dilated fundus examination, clinical imaging, and full-field electroretinogram. A thorough literature search was conducted to determine previously published variants and associated phenotypes. Results: Genetic testing confirmed the presence of variants in CLN3, CLN7/MFSD8, CLN8, and GRN/CLN11. Five novel variants were identified, and four novel phenotypes of previously published alleles were described. The phenotype differed among patients with variants in the same gene and sometimes among patients with the same allele. Conclusions: Substantial phenotypic variability among variants in the CLN genes makes identification of genotype-phenotype or allele-phenotype correlations challenging. Further study is required to establish an extensive database for adequate patient counseling.
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Testes Genéticos , Distrofias Retinianas , Humanos , Mutação , Linhagem , Fenótipo , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genética , Variação Biológica da População , Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genética , Proteínas de Membrana Transportadoras/genéticaRESUMO
BACKGROUND: Spectral-domain optical coherence tomography (SD-OCT) and full-field electroretinography (ERG) allow retinal assessment with vitamin A deficiency (VAD). Using SD-OCT, this study aimed to characterize and follow a novel retinal abnormality in patients with VAD and intramuscular supplementation. METHODS: Patients with VAD were retrospectively reviewed, including SD-OCT and electroretinography. RESULTS: Three patients had VAD following bariatric or colon surgery and varying supplementation. All had nyctalopia, extinguished scotopic rod-specific function with ERG, and decreased serum vitamin A. None demonstrated surface abnormalities. All received intramuscular vitamin A with subjective resolution of symptoms. On SD-OCT, four of six eyes exhibited homogenous foveal hyperreflectivity anterior to retinal pigment epithelium-Bruch complex, reminiscent of a "double carrot", which improved following supplementation. ERG findings demonstrated improved scotopic rod-specific function in all cases; however, photopic function remained diminished in two cases. CONCLUSIONS: Structural improvement of the proposed "double carrot" sign occurs soon after vitamin A supplementation. While scotopic function improves rapidly following supplementation, cone function recovers more slowly. Therefore, foveal changes such as the "double carrot" sign suggest that structural recovery of cones precedes functional recovery.
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Deficiência de Vitamina A , Humanos , Eletrorretinografia/métodos , Retina/diagnóstico por imagem , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Vitamina A/uso terapêutico , Deficiência de Vitamina A/diagnósticoRESUMO
The development of fundus photography and imaging has improved our ability to diagnose and monitor inherited retinal degenerations. Nowadays, color fundus photography has become a staple in evaluating patients with retinitis pigmentosa (RP). Other important multimodal forms of fundus photography used today include red-free fundus photography, short-wavelength autofluorescence, and near-infrared autofluorescence. These photography methodologies provide valuable information on the natural history of disease progression, which in turn can lead to the identification of viable outcome measurements for current and future therapeutic trials. Further advances and developments in the field of fundus imaging will help in our understanding of RP and allied disorders.
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Retinose Pigmentar , Humanos , Retinose Pigmentar/diagnóstico por imagemRESUMO
Optical coherence tomography (OCT) is a noninvasive imaging technology that has gained widespread use in the evaluation of multiple retinal pathologies, including retinitis pigmentosa (RP). OCT allows for visualization of distinct retinal layers and the choroid and facilitates study of morphological features associated with RP. OCT can be used to detect and to track progression of RP, as well as to correlate structural findings with functional manifestations of the disease. This chapter provides a basic overview of OCT technology and details elements of importance in the use of OCT for diagnosis and assessment of progression of RP.
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Retinose Pigmentar , Tomografia de Coerência Óptica , Humanos , Retinose Pigmentar/diagnóstico por imagemRESUMO
Here, we describe affected members of a 2-generation family with a Stargardt disease-like phenotype caused by a 2-base pair deletion insertion, c.1014_1015delGAinsCT;p.(Trp338_Asn339delinsCysTyr), in BEST1. The variant was identified by whole-exome sequencing, and its pathogenicity was verified through chloride channel recording using WT and transfected mutant HEK293 cells. Clinical examination of both patients revealed similar phenotypes at 2 different disease stages that were attributable to differences in their age at presentation. Hyperautofluorescent flecks along the arcades were observed in the proband, while the affected mother exhibited more advanced retinal pigment epithelium (RPE) loss in the central macula. Full-field electroretinogram testing was unremarkable in the daughter; however, moderate attenuation of generalized cone function was detected in the mother. Results from electrooculogram testing in the daughter were consistent with widespread dysfunction of the RPE characteristic of Best disease. Whole-cell patch-clamp recordings revealed a statistically significant decrease in chloride conductance of the mutant compared with WT cells. This report on a mother and daughter with a BEST1 genotype that phenocopies Stargardt disease broadens the clinical spectrum of BEST1-associated retinopathy.
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Bestrofinas , Doença de Stargardt , Humanos , Bestrofinas/genética , Células HEK293 , Doença de Stargardt/genética , Mutação INDEL , FemininoRESUMO
Purpose: To report three cases of retinoschisis in patients with intermediate to advanced choroideremia. Observations: Three patients were referred for evaluation of retinal detachment in the context of an inherited retinal degenerative disease. In all three cases, patients carried variants in the CHM gene suspected to be pathogenic and exhibited the characteristic findings of choroideremia, including pigment clumping and chorioretinal atrophy with scleral exposure and prominent choroidal vessels. Interestingly, these patients were also found to have areas of typical retinoschisis and cystoid degeneration located in the outer plexiform layer of the mid periphery or macula. Retinoschisis was confirmed by spectral domain optical coherence tomography (SD-OCT). Conclusions/Importance: This paper draws attention to the occurrence of retinoschisis in patients with choroideremia. OCT can be used to confirm the presence of retinoschisis rather than retinal detachment, as the clinical exam findings that distinguish the two conditions are not helpful in the setting of advanced chorioretinal atrophy. Although it remains unclear whether patients with choroideremia as a group are at increased risk of retinoschisis, it is possible that abnormal vesicular traffic in the RPE and photoreceptors could contribute to abnormalities in cell adhesion and the extracellular matrix. As gene therapy by subretinal injection of adeno-associated virus becomes the standard of care to slow down or arrest retinal degeneration in choroideremia, it will be critical to carefully screen these patients for retinoschisis prior to surgical intervention and to incorporate any such findings into surgical planning.
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BACKGROUND: Inherited retinal dystrophies describe a heterogeneous group of retinal diseases that lead to the irreversible degeneration of rod and cone photoreceptors and eventual blindness. Recessive loss-of-function mutations in Tubulin Tyrosine Ligase Like 5 (TTLL5) represent a recently described cause of inherited cone-rod and cone dystrophy. This study describes the unusual phenotypes of three patients with autosomal recessive mutations in TTLL5. Examination of these patients included funduscopic evaluation, spectral-domain optical coherence tomography, short-wavelength autofluorescence, and full-field electroretinography (ffERG). Genetic diagnoses were confirmed using whole exome capture. Protein modeling of the identified variants was performed to explore potential genotype-phenotype correlations. RESULTS: Genetic testing revealed five novel variants in TTLL5 in three unrelated patients with retinal dystrophy. Clinical imaging demonstrated features of sectoral cone-rod dystrophy and cone dystrophy, with phenotypic variability seen across all three patients. One patient also developed high-frequency hearing loss during a similar time period as the onset of retinal disease, potentially suggestive of a syndromic disorder. Retinal structure findings were corroborated with functional measures including ffERG findings that supported these diagnoses. Modeling of the five variants suggest that they cause different effects on protein function, providing a potential reason for genotype-phenotype correlation in these patients. CONCLUSIONS: The authors report retinal phenotypic findings in three unrelated patients with novel mutations causing autosomal recessive TTLL5-mediated retinal dystrophy. These findings broaden the understanding of the phenotypes associated with TTLL5-mediated retinal disease and suggest that mutations in TTLL5 should be considered as a potential cause of sectoral retinal dystrophy in addition to cone-rod and cone dystrophies.
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Distrofias Retinianas , Proteínas de Transporte/genética , Eletrorretinografia , Estudos de Associação Genética , Humanos , Mutação/genética , Fenótipo , Distrofias Retinianas/genéticaRESUMO
INTRODUCTION: Mutations in the cone-rod homeobox (CRX) gene, a known cause of inherited retinal dystrophy, are characterized by extensive phenotypic heterogeneity. We describe a novel presentation of rod-cone dystrophy (RCD) phenocopying pigmented paravenous retinochoroidal atrophy associated with a mutation in CRX. CASE DESCRIPTION: A 53-year-old man and his 48-year-old brother presented with a history of progressive vision loss and nyctalopia. Fundus examination revealed a bull's eye lesion with chorioretinal atrophy and intraretinal pigment migration, while spectral-domain optical coherence tomography (SD-OCT) demonstrated retinal thinning with outer retinal atrophy. On short-wavelength autofluorescence (SW-AF) imaging, an atypical paravenous pattern of atrophy with a surrounding hyperautofluorescent border was observed. Full-field electroretinogram (ffERG) revealed a rod-cone pattern of dysfunction. A heterozygous pathogenic variant, c.119G>A:p.(Arg40Gln), in the CRX gene was identified in both brothers and segregated in their family. CONCLUSION: This case report broadens the currently known phenotypic presentations of CRX-associated retinopathy and suggests that mutations in CRX may be associated with pigmented paravenous retinochoroidal atrophy.
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Corioide , Proteínas de Homeodomínio/genética , Distrofias Retinianas , Transativadores/genética , Atrofia/patologia , Corioide/patologia , Eletrorretinografia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Distrofias Retinianas/genética , Tomografia de Coerência ÓpticaRESUMO
Retinal disorders such as retinitis pigmentosa, age-related retinal degeneration, oxygen-induced retinopathy, and ischemia-reperfusion injury cause debilitating and irreversible vision loss. While the exact mechanisms underlying these conditions remain unclear, there has been a growing body of evidence demonstrating the pathological contributions of oxidative stress across different cell types within the eye. Nuclear factor erythroid-2-related factor (Nrf2), a transcriptional activator of antioxidative genes, and its regulator Kelch-like ECH-associated protein 1 (Keap1) have emerged as promising therapeutic targets. The purpose of this review is to understand the protective role of the Nrf2-Keap1 pathway in different retinal tissues and shed light on the complex mechanisms underlying these processes. In the photoreceptors, we highlight that Nrf2 preserves their survival and function by maintaining oxidation homeostasis. In the retinal pigment epithelium, Nrf2 similarly plays a critical role in oxidative stabilization but also maintains mitochondrial motility and autophagy-related lipid metabolic processes. In endothelial cells, Nrf2 seems to promote proper vascularization and revascularization through concurrent activation of antioxidative and angiogenic factors as well as inhibition of inflammatory cytokines. Finally, Nrf2 protects retinal ganglion cells against apoptotic cell death. Importantly, we show that Nrf2-mediated protection of the various retinal tissues corresponds to a preservation of functional vision. Altogether, this review underscores the potential of the Nrf2-Keap1 pathway as a powerful tool against retinal degeneration. Key insights into this elegant oxidative defense mechanism may ultimately pave the path toward a universal therapy for various inherited and environmental retinal disorders.
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Atypical Usher syndrome (USH) is poorly defined with a broad clinical spectrum. Here, we characterize the clinical phenotype of disease caused by variants in CEP78, CEP250, ARSG, and ABHD12.Chart review evaluating demographic, clinical, imaging, and genetic findings of 19 patients from 18 families with a clinical diagnosis of retinal disease and confirmed disease-causing variants in CEP78, CEP250, ARSG, or ABHD12.CEP78-related disease included sensorineural hearing loss (SNHL) in 6/7 patients and demonstrated a broad phenotypic spectrum including: vascular attenuation, pallor of the optic disc, intraretinal pigment, retinal pigment epithelium mottling, areas of mid-peripheral hypo-autofluorescence, outer retinal atrophy, mild pigmentary changes in the macula, foveal hypo-autofluorescence, and granularity of the ellipsoid zone. Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL. ARSG variants resulted in a characteristic pericentral pattern of hypo-autofluorescence with one patient reporting non-congenital SNHL. ABHD12-related disease showed rod-cone dystrophy with macular involvement, early and severe decreased best corrected visual acuity, and non-congenital SNHL ranging from unreported to severe.This study serves to expand the clinical phenotypes of atypical USH. Given the variable findings, atypical USH should be considered in patients with peripheral and macular retinal disease even without the typical RP phenotype especially when SNHL is noted. Additionally, genetic screening may be useful in patients who have clinical symptoms and retinal findings even in the absence of known SNHL given the variability of atypical USH.
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Arilsulfatases/genética , Autoantígenos/genética , Proteínas de Ciclo Celular/genética , Códon sem Sentido/genética , Mutação da Fase de Leitura/genética , Monoacilglicerol Lipases/genética , Síndromes de Usher/genética , Adolescente , Adulto , Idoso , Distrofias de Cones e Bastonetes/diagnóstico , Distrofias de Cones e Bastonetes/genética , Feminino , Testes Genéticos , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Fenótipo , Epitélio Pigmentado da Retina/patologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Síndromes de Usher/diagnóstico por imagem , Acuidade Visual/fisiologia , Adulto JovemRESUMO
Purpose: The purpose of this study was to characterize the phenotypic spectrum of ophthalmic findings in patients with Alagille syndrome. Methods: We conducted a retrospective, observational, multicenter, study on 46 eyes of 23 subjects with Alagille syndrome. We reviewed systemic and ophthalmologic data extracted from medical records, color fundus photography, fundus autofluorescence, optical coherence tomography, visual fields, electrophysiological assessments, and molecular genetic findings. Results: Cardiovascular abnormalities were found in 83% of all cases (of those, 74% had cardiac murmur), whereas 61% had a positive history of hepatobiliary issues, and musculoskeletal anomalies were present in 61% of all patients. Dysmorphic facies were present in 16 patients, with a broad forehead being the most frequent feature. Ocular symptoms were found in 91%, with peripheral vision loss being the most frequent complaint. Median (range) Snellen visual acuity of all eyes was 20/25 (20/20 to hand motion [HM]). Anterior segment abnormalities were present in 74% of the patients; of those, posterior embryotoxon was the most frequent finding. Abnormalities of the optic disc were found in 52%, and peripheral retinal abnormalities were the most frequent ocular finding in this series, found in 96% of all patients. Fifteen JAG1 mutations were identified in 16 individuals; of those, 6 were novel. Conclusions: This study reports a cohort of patients with Alagille syndrome in which peripheral chorioretinal changes were more frequent than posterior embryotoxon, the most frequent ocular finding according to a number of previous studies. We propose that these peripheral chorioretinal changes are a new hallmark to help diagnose this syndrome.
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Síndrome de Alagille/diagnóstico , Oftalmopatias Hereditárias , Disco Óptico , Retina , Adulto , Síndrome de Alagille/genética , Síndrome de Alagille/fisiopatologia , Diagnóstico Diferencial , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/fisiopatologia , Feminino , Angiofluoresceinografia/métodos , Testes Genéticos/métodos , Humanos , Proteína Jagged-1/genética , Masculino , Prontuários Médicos , Mutação , Disco Óptico/anormalidades , Disco Óptico/diagnóstico por imagem , Imagem Óptica/métodos , Retina/anormalidades , Retina/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Testes de Campo Visual/métodosRESUMO
Purpose: The purpose of this paper was to discuss manifestations of primary mitochondrial dysfunctions and whether the retinal pigment epithelium or the photoreceptors are preferentially affected. Methods: A retrospective analysis was performed of patients with clinically and laboratory confirmed diagnoses of maternally inherited diabetes and deafness (MIDD) or Kearns-Sayre syndrome (KSS). Patients underwent full ophthalmic examination, full-field electroretinogram, and multimodal imaging studies, including short-wavelength autofluorescence, spectral domain-optical coherence tomography, and color fundus photography. Results: A total of five patients with MIDD and four patients with KSS were evaluated at two tertiary referral centers. Mean age at initial evaluation was 50.3 years old. Nascent outer retinal tubulations corresponding with faint foci of autofluorescence were observed in two patients with MIDD. Characteristic features of this cohort included a foveal sparing phenotype observed in 13 of 18 eyes (72%), global absence of intraretinal pigment migration, and preserved retinal function on full-field electroretinogram testing in 12 of 16 eyes (75%). One patient diagnosed with MIDD presented with an unusual pattern of atrophy surrounding the parapapillary region and one patient with KSS presented with an atypical choroideremia-like phenotype. Conclusions: MIDD and KSS are phenotypically heterogeneous disorders. Several features of disease suggest that primary mitochondrial dysfunction may first affect the retinal pigment epithelium followed by secondary photoreceptor loss. Similarities between primary mitochondrial degenerations and retinal disorders, such as age-related macular degeneration may suggest a primary role of mitochondria in the pathogenesis of these oligogenic disorders.