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Inherited retinal dystrophies encompass a diverse group of disorders affecting the structure and function of the retina, leading to progressive visual impairment and, in severe cases, blindness. Electrophysiology testing has emerged as a valuable tool in assessing and diagnosing those conditions, offering insights into the function of different parts of the visual pathway from retina to visual cortex and aiding in disease classification. This review provides an overview of the application of electrophysiology testing in the non-macular inherited retinal dystrophies focusing on both common and rare variants, including retinitis pigmentosa, progressive cone and cone-rod dystrophy, bradyopsia, Bietti crystalline dystrophy, late-onset retinal degeneration, and fundus albipunctatus. The different applications and limitations of electrophysiology techniques, including multifocal electroretinogram (mfERG), full-field ERG (ffERG), electrooculogram (EOG), pattern electroretinogram (PERG), and visual evoked potential (VEP), in the diagnosis and management of these distinctive phenotypes are discussed. The potential for electrophysiology testing to allow for further understanding of these diseases and the possibility of using these tests for early detection, prognosis prediction, and therapeutic monitoring in the future is reviewed.
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This case report presents a 26-year-old female patient diagnosed with fundus albipunctatus (FAP), a rare form of congenital stationary night blindness. The patient's clinical history and retinal findings spanning 23 years are consistent with FAP. The patient has profound night blindness, photophobia, and mild color vision changes with preserved best-corrected visual acuity (BCVA). Small white dots are present throughout the fundus, sparing the central macula. Electroretinograms (ERG) are consistent with congenital stationary night blindness (CSNB) and suggest a lack of rod response. Ophthalmic imaging has remained stable over time. Genetic testing revealed two biallelic missense mutations in the LRAT gene, c.197G>A (p.Gly66Glu) and c.557A>C (p.Lys186Thr). LRAT mutations are known to contribute to other retinal conditions but have not been previously associated with FAP. While there are currently no available treatments for FAP, this report expands our understanding of the genetic landscape of FAP to include LRAT and provides clinical data to support this finding.
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Inherited retinal dystrophies (IRDs) are a group of heterogeneous diseases caused by genetic mutations that specifically affect the function of the rod, cone, or bipolar cells in the retina. Electroretinography (ERG) is a diagnostic tool that measures the electrical activity of the retina in response to light stimuli, and it can help to determine the function of these cells. A normal ERG response consists of two waves, the a-wave and the b-wave, which reflect the activity of the photoreceptor cells and the bipolar and Muller cells, respectively. Despite the growing availability of next-generation sequencing (NGS) technology, identifying the precise genetic mutation causing an IRD can be challenging and costly. However, certain types of IRDs present with unique ERG features that can help guide genetic testing. By combining these ERG findings with other clinical information, such as on family history and retinal imaging, physicians can effectively narrow down the list of candidate genes to be sequenced, thereby reducing the cost of genetic testing. This review article focuses on certain types of IRDs with unique ERG features. We will discuss the pathophysiology and clinical presentation of, and ERG findings on, these disorders, emphasizing the unique role ERG plays in their diagnosis and genetic testing.
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Inherited retinal diseases (IRD) are a group of heterogeneous disorders, most of which lead to blindness with limited therapeutic options. Pathogenic variants in RBP4, coding for a major blood carrier of retinol, retinol-binding protein 4, are responsible for a peculiar form of IRD. The aim of this study was to investigate if retinal function of an RBP4-related IRD patient can be improved by retinol administration. Our patient presented a peculiar white-dot retinopathy, reminiscent of vitamin A deficient retinopathy. Using a customized next generation sequencing (NGS) IRD panel we discovered a novel loss-of-function homozygous pathogenic variant in RBP4: c.255G >A, p.(Trp85*). Western blotting revealed the absence of RBP4 protein in the patient's serum. Blood retinol levels were undetectable. The patient was put on a high-dose oral retinol regimen (50,000 UI twice a week). Subjective symptoms and retinal function markedly and sustainably improved at 5-months and 1-year follow-up. Here we show that this novel IRD case can be treated by oral retinol administration.
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Distrofias Retinianas , Vitamina A , Humanos , Retina/metabolismo , Distrofias Retinianas/tratamento farmacológico , Distrofias Retinianas/genética , Proteínas Plasmáticas de Ligação ao Retinol/genética , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Vitamina A/uso terapêuticoRESUMO
BACKGROUND: The aim of this study is to identify the genetic defects in a Chinese family with fundus albipunctatus. METHODS: Complete ophthalmic examinations, including slit-lamp biomicroscopy, dilated indirect ophthalmoscopy, fundus photography, autofluorescence, swept source optical coherence tomography (SS-OCT) and full-field electroretinography (ffERG) were performed. Genomic DNA was extracted from blood samples and whole genome sequencing was performed. Variants were validated with Sanger sequencing. RESULTS: Six members in this Chinese family, including three affected individuals and three controls, were recruited in this study. The ophthalmic examination of three recruited patients was consistent with fundus albipunctatus. Three variants, a novel frameshift deletion c.39delA [p.(Val14CysfsX47] and a haplotype of two rare missense variants, c.683G > A [p.(Arg228Gln)] along with c.710A > G [p.(Tyr237Cys], within the retinal dehydrogenase 5 (RDH5) gene were found to segregate with fundus albipunctatus in this family in an autosomal recessive matter. CONCLUSION: We identified novel compound heterozygous variants in RDH5 responsible for fundus albipunctatus in a large Chinese family. The results of our study further broaden the genetic defects of RDH5 associated with fundus albipunctatus.
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Oxirredutases do Álcool , Cegueira Noturna , Distrofias Retinianas , Oxirredutases do Álcool/genética , China , Eletrorretinografia , Humanos , Mutação , Linhagem , Reação em Cadeia da Polimerase , Retinal Desidrogenase , Doenças Retinianas , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: Fundus albipunctatus is an inherited cause of congenital stationary night blindness. The objective of this report is to describe structural changes occurring in a macular phenotype of a novel RDH5 mutation producing fundus albipunctatus using high-resolution in vivo imaging. A 62-year-old male with longstanding night blindness underwent imaging and genetic evaluation. High-resolution images of the photoreceptor mosaic were compared to those of a healthy subject. Results of a comprehensive ophthalmic evaluation and genetic testing with imaging including fundus photography, spectral-domain optical coherence tomography (OCT), fluorescein angiography (FA), OCT angiography (OCT-A), and adaptive optics scanning light ophthalmoscopy (AOSLO) are described. OBSERVATIONS: The patient presented with visual acuity of 20/25 in both eyes and longstanding poor dark adaptation. Anterior segment examination was unremarkable. Fundoscopy revealed well circumscribed bilateral perifoveal mottling and atrophy in both eyes. Discrete white-yellow flecks were present beyond the vascular arcades extending to the far periphery. Genetic testing revealed a novel compound heterozygous RDH5 mutation (c.388C > T, p.Gln130*; c.665T > C, p.Leu222Pro). OCT demonstrated perifoveal photoreceptor and outer retinal irregularities, which corresponded to a window defect with late staining on FA. OCT-A demonstrated normal retinal vasculature with patchy areas of non-perfusion in the choriocapillaris. Macular abnormalities in both eyes were imaged using AOSLO to assess cone and rod photoreceptor architecture. While clinical features are consistent with a primary rod disorder, confocal AOSLO showed a paucity of normal cones with a small spared central island in both eyes. Rods appeared larger and more irregular throughout the macula. Non-confocal split detection AOSLO imaging revealed the presence of cone inner segments in dark regions of confocal imaging, indicating some degree of photoreceptor preservation. CONCLUSIONS AND IMPORTANCE: The AOSLO imaging of this particular macular phenotype of fundus albipunctatus demonstrates some of the structural photoreceptor abnormalities that occur in this condition, adding insight to the variable presentation of RDH5 retinopathy. The presence of preserved inner segment architecture suggests the possibility that gene therapy could play a future role in treating this condition.
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The article describes a clinical case of a 14-year old patient with RDH5 mutations (OMIM *601617) in patient with fundus albipunctatus (OMIM #136880) and characteristic biomarkers of this disease with previously described pathogenic variant of nucleotic sequence in exon 3 of the RDH5 gene (NM_002905.3:c.500G>A), causing a missense change (p.Arg167His) in heterozygous state and previously not described pathogenic variant of nucleotic sequence in exon 5 of the RDH5 gene (NM_002905.3:c.838C>T), leading to a missense change (p.Arg280Cys) in heterozygous state with characteristic biomarkers of the disease. Best-corrected visual acuity (BCVA) was 20/20. Nyctalopia was accompanied by reduced b-wave of scotopic (dark-adapted 0.01) ERG and decreased amplitude of a- and b-waves of maximum (dark-adapted 3) ERG. Decreased amplitude of the a- and b-waves of photopic (light-adapted 3) ERG and the amplitude of high-frequency (light-adapted 30 Hz) Flicker ERG shows the involvement of retinal cone system in the process. Fundus autofluorescence imaging of both eyes produced fuzzy and grainy images with slight hyperfluorescence of retinal flecks. Optical coherence tomography showed focal thickening centered in the photoreceptor outer segment corresponding to the multiple discrete albipunctate dots.
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Eletrorretinografia , Cegueira Noturna , Adolescente , Oxirredutases do Álcool/genética , Humanos , Mutação , Doenças Retinianas , Tomografia de Coerência ÓpticaRESUMO
Congenital stationary night blindness (CSNB) is a group of rare, mainly stationary disorders of the retina, resulting from dysfunction of several specific and essential visual processing mechanisms. The inheritance is often recessive and as such, CSNB may be more common among populations with a high degree of consanguinity. Here, we present a topic update and a review of the clinical and molecular genetic spectrum of CSNB in Saudi Arabia. Since a major review article on CSNB in 2015, which described 17 genes underlying CSNB, an additional four genes have been incriminated in autosomal recessive CSNB: RIMS2, GNB3, GUCY2D and ABCA4. These have been associated with syndromic cone-rod synaptic disease, ON bipolar cell dysfunction with reduced cone sensitivity, CSNB with dysfunction of the phototransduction (Riggs type) and CSNB with cone-rod dystrophy, respectively. In Saudi Arabia, a total of 24 patients with CSNB were identified, using a combination of literature search and retrospective study of previously unpublished cases. Recessive mutations in TRPM1 and CABP4 accounted for the majority of cases (5 and 13 for each gene, respectively). These genes were associated with complete (cCSNB) and incomplete (icCSNB), respectively, and were associated with high myopia in the former and hyperopia in the latter. Four novel mutations were identified. For the first time, we describe the fundus albipunctatus in two patients from Saudi Arabia, caused by recessive mutation in RDH5 and RPE65, where the former in addition featured findings compatible with cone dystrophy. No cases were identified with any dominantly inherited CSNB.
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Proteínas de Ligação ao Cálcio/genética , DNA/genética , Oftalmopatias Hereditárias/epidemiologia , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Mutação , Miopia/epidemiologia , Cegueira Noturna/epidemiologia , Retina/fisiopatologia , Canais de Cátion TRPM/genética , Proteínas de Ligação ao Cálcio/metabolismo , Análise Mutacional de DNA , Eletrorretinografia , Oftalmopatias Hereditárias/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Incidência , Miopia/congênito , Miopia/genética , Cegueira Noturna/congênito , Cegueira Noturna/genética , Linhagem , Fenótipo , Arábia Saudita/epidemiologia , Canais de Cátion TRPM/metabolismoRESUMO
Background: Retinitis punctate albescens (RPA) is a rare form of retinal dystrophy characterized by congenital stationary night blindness and a characteristic fundus appearance. Missense or nonsense mutations in RDH5 in homozygous or heterozygous state have been implicated in RPA.Material and methods: Two consanguineous Pakistani kindreds with the highly variable manifestation of RPA were studied. Whole-exome sequencing was applied to the index subjects in both families. Sanger sequencing of the candidate RDH5 variant was carried out. Pathogenicity of the detected variant was assessed through bioinformatics tools.Results: The ophthalmic examination through full-field electroretinogram of affected patients in both families was consistent with RPA. A novel splice donor variant at the first exon/intron boundary of RDH5 (NM_002905.3: c.-33 + 2dup) segregated in recessive fashion with the clinical phenotype in both families. One of the heterozygous variant carriers was also observed to have a milder expression of retinal flecks. Haplotype analysis surrounding the splice variant and pattern of runs of homozygosity were suggestive of common ancestry in these families.Conclusion: This is the first report of any pathogenic splice variant at first exon/intron boundary implicated in RPA and suggests another mechanism through which RDH5 variants could be associated with eye phenotype. This study also highlights the importance of a thorough phenotypic evaluation of heterozygous mutation carriers who may exhibit milder symptoms.
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Oxirredutases do Álcool/genética , Consanguinidade , Mutação , Sítios de Splice de RNA/genética , Doenças Retinianas/genética , Doenças Retinianas/patologia , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Linhagem , PrognósticoRESUMO
PURPOSE: Retinoid isomerohydrolase RPE65 has received a tremendous amount of attention due to successful clinical gene therapy for Leber congenital amaurosis (LCA) cases caused by RPE65 mutations. This study aimed to evaluate the frequency of RPE65 mutations and the associated phenotypes based on exome sequencing. METHODS: RPE65 variants were collected from exome sequencing data obtained from 2133 probands with different forms of hereditary retinal degeneration (HRD). Clinical data were collected from probands with homozygous or compound heterozygous variants in RPE65. Associated phenotypes were characterized based on clinical data. RESULTS: Biallelic RPE65 mutations were detected in 18 families, including eight with LCA, five with early-onset retinal degeneration, four with fundus albipunctatus-like (FA-like) changes and one with high hyperopia. These cases accounted for approximately 3.0% (8/269) of LCA and 0.8% (18/2133) of HRD cases. An almost identical FA-like change was identified in seven patients from four unrelated families with RPE65 mutations. Classification of mutations suggested that FA-like changes may be associated with biallelic missense mutations in RPE65. CONCLUSION: Fundus albipunctatus-like (FA-like) change, a common characteristic fundus sign in RPE65 biallelic mutations, was unexpected but was confirmed by the finding that affected siblings from different families exhibited similar phenotypes. These results enrich our understanding of RPE65 mutation frequencies and their associated phenotypic variants.
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Variação Biológica da População/genética , Amaurose Congênita de Leber/genética , Taxa de Mutação , Mutação/genética , Doenças Retinianas/genética , Distrofias Retinianas/genética , cis-trans-Isomerases/genética , Povo Asiático/genética , Criança , Pré-Escolar , China , Análise Mutacional de DNA , Eletrorretinografia , Feminino , Humanos , Lactente , Amaurose Congênita de Leber/diagnóstico , Masculino , Linhagem , Doenças Retinianas/diagnóstico , Distrofias Retinianas/diagnóstico , Sequenciamento do ExomaRESUMO
Fundus autofluorescence (FAF) is a non-invasive retinal imaging modality used in clinical practice to non-invasively map changes at the level of the retinal pigment epithelium (RPE)/photoreceptor complex and alterations of macular pigment distribution. This imaging method is based on the visualization of intrinsic fluorophores and may be easily and rapidly used in routine patient care. Excessive accumulation of lipofuscin granules in the lysosomal compartment of RPE cells represents a common downstream pathogenic pathway in various hereditary and complex retinal diseases. The clinical applications of FAF continue to expand. It is now an essential tool for evaluating macular dystrophies and various hereditary retinal disorders. Fundus autofluorescence (FAF) may detect abnormalities beyond those detected on funduscopic examination, fluorescein angiography (FA) or optical coherence tomography (OCT). Fundus autofluorescence (FAF) imaging is particularly helpful for differential diagnosis, detection and extent delineation of involved retinal areas, genotype-phenotype correlations and monitoring of changes overtime. Given its ease of use, non-invasive nature and value in characterizing retinal disease, FAF enjoys increasing clinical relevance. This review summarizes basic principles and FAF findings in various hereditary retinal diseases.
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Angiofluoresceinografia/métodos , Imagem Óptica/métodos , Doenças Retinianas/diagnóstico , Doenças Retinianas/genética , Epitélio Pigmentado da Retina/patologia , Fundo de Olho , Humanos , Tomografia de Coerência ÓpticaRESUMO
The visual system produces visual chromophore, 11-cis-retinal from dietary vitamin A, all-trans-retinol making this vitamin essential for retinal health and function. These metabolic events are mediated by a sequential biochemical process called the visual cycle. Retinol dehydrogenases (RDHs) are responsible for two reactions in the visual cycle performed in retinal pigmented epithelial (RPE) cells, photoreceptor cells and Müller cells in the retina. RDHs in the RPE function as 11-cis-RDHs, which oxidize 11-cis-retinol to 11-cis-retinal in vivo. RDHs in rod photoreceptor cells in the retina work as all-trans-RDHs, which reduce all-trans-retinal to all-trans-retinol. Dysfunction of RDHs can cause inherited retinal diseases in humans. To facilitate further understanding of human diseases, mouse models of RDHs-related diseases have been carefully examined and have revealed the physiological contribution of specific RDHs to visual cycle function and overall retinal health. Herein we describe the function of RDHs in the RPE and the retina, particularly in rod photoreceptor cells, their regulatory properties for retinoid homeostasis and future therapeutic strategy for treatment of retinal diseases.
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Oxirredutases do Álcool/metabolismo , Células Ependimogliais/enzimologia , Doenças Retinianas/enzimologia , Epitélio Pigmentado da Retina/enzimologia , Células Fotorreceptoras Retinianas Bastonetes/enzimologia , Retinaldeído/metabolismo , Visão Ocular , Vitamina A/metabolismo , Oxirredutases do Álcool/genética , Animais , Predisposição Genética para Doença , Humanos , Mutação , Oxirredução , Fenótipo , Doenças Retinianas/genética , Doenças Retinianas/fisiopatologia , Doenças Retinianas/terapia , Epitélio Pigmentado da Retina/fisiopatologiaRESUMO
Congenital stationary night blindness (CSNB) refers to a group of genetically and clinically heterogeneous retinal disorders. Seventeen different genes with more than 360 different mutations and more than 670 affected alleles have been associated with CSNB, including genes coding for proteins of the phototransduction cascade, those important for signal transmission from the photoreceptors to the bipolar cells or genes involved in retinoid recycling in the retinal pigment epithelium. This article describes the phenotypic characteristics of different forms of CSNB that are necessary for accurate diagnosis and to direct and improve genetic testing. An overview of classical and recent methods used to identify specific CSNB genotypes is provided and a meta-analysis of all previously published and novel data is performed to determine the prevalence of disease-causing mutations. Studies of the underlying molecular pathogenic mechanisms based on cell culture techniques and animal studies are outlined. The article highlights how the study of CSNB has increased understanding of the mechanisms of visual signalling in the retina, likely to prove important in developing future treatments for CSNB and other retinal disorders.
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Oftalmopatias Hereditárias , Proteínas do Olho/genética , Doenças Genéticas Ligadas ao Cromossomo X , Miopia , Cegueira Noturna , Animais , Modelos Animais de Doenças , Eletrorretinografia , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/fisiopatologia , Oftalmopatias Hereditárias/terapia , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Terapia Genética/métodos , Genótipo , Humanos , Mutação , Miopia/diagnóstico , Miopia/genética , Miopia/fisiopatologia , Miopia/terapia , Cegueira Noturna/diagnóstico , Cegueira Noturna/genética , Cegueira Noturna/fisiopatologia , Cegueira Noturna/terapia , FenótipoRESUMO
Electrophysiological techniques allow clinical investigations to include a 'dissection' of the visual system. Using suitable electrophysiological techniques, the 'dissection' allows function to be ascribed to the different photoreceptors (rod and cone photoreceptors), retinal layers, retinal location or the visual pathway up to the visual cortex. Combined with advances in genetics, retinal biochemistry, visual fields and ocular imaging, it is now possible to obtain a better understanding of diseases affecting the retina and visual pathways. This paper reviews core electrophysiological principles that can complement other examination techniques, including advanced ocular imaging, and help the interpretation of other clinical data and thus, refine and guide clinical diagnosis.
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Eletrorretinografia , Potenciais Evocados Visuais/fisiologia , Vias Visuais/fisiologia , Defeitos da Visão Cromática/fisiopatologia , Humanos , Neurite Óptica/fisiopatologia , Doenças Retinianas/fisiopatologia , Retinose Pigmentar/fisiopatologia , Visão OcularRESUMO
The hyperosmolarity response of the standing potential was recorded in retinitis pigmentosa (20 eyes), central (pericentral) retinitis pigmentosa (4 eyes), pigmented paravenous retinochoroidal atrophy (2 eyes), fundus albipunctatus (8 eyes), and Stargardt's disease (or fundus flavimaculatus) (14 eyes). The light peak/dark trough ratio (the L/D ratio) and the Diamox response were also determined.The hyperosmolarity response was greatly suppressed (less than M-4SD; M and SD indicate respectively the mean and the standard deviation in normal control subjects) in all examined eyes with retinitis pigmentosa (20 eyes) including retinitis pigmentosa sine pigmento (8 eyes), central (pericentral) retinitis pigmentosa (4 eyes), and pigmented paravenous retinochoroidal atrophy (2 eyes). The L/D ratio was larger than 1.26 (M-2.5 SD) in the half of the eyes with the above-described diseases.The hyperosmolarity response was abnormal (less than M-2 SD) in 4 of 8 eyes with fundus albipunctatus. The L/D ratio was normal in all 8 eyes.The hyperosmolarity response was abnormal (less than M-2 SD) in all 14 eyes with Stargardt's disease or fundus flavimaculatus. The L/D ratio was abnormal in 5 of these 14 eyes.The hyperosmolarity response was more frequently abnormal than the L/D ratio in the chorioretinal dystrophies mentioned above, and hence is useful particularly for early diagnosis of these disorders.