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PURPOSE: To describe the clinical and genetic findings in a patient with autosomal recessive bestrophinopathy (ARB) and his healthy parents. METHODS: The patient and his healthy non-consanguineous parents underwent detailed ophthalmic evaluations including electro-oculography (EOG), spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) imaging. Mutation analysis of the BEST1 gene was performed by Sanger sequencing. RESULTS: The FAF images showed multiple spots of increased autofluorescence, and the sites of these spots corresponded to the yellowish deposits detected by ophthalmoscopy. SD-OCT showed cystoid macular changes and a shallow serous macular detachment. The Arden ratio of the EOG was markedly reduced to 1.1 in both eyes. Genetic analysis of the proband detected two sequence variants of the BEST1 gene in the heterozygous state: a novel variant c.717delG, p.V239VfsX2 and an already described c.763C>T, p.R255W variant associated with Best vitelliform macular dystrophy and ARB. The proband's father carried the c.717delG, p.V239VfsX2 variant in the heterozygous state, and the mother carried the c.763C>T, p.R255W variant in the heterozygous state. The parents who were heterozygous for the BEST1 variants had normal visual acuity, EOG, SD-OCT, and FAF images. CONCLUSIONS: In a truncating BEST1 mutation, the phenotype associated with ARB is most likely due to a marked decrease in the expression of BEST1 promoted by the nonsense-mediated decay surveillance mechanism, and it may depend on the position of the premature termination of the codon created.
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Canais de Cloreto/genética , Oftalmopatias Hereditárias , Proteínas do Olho/genética , Retina , Doenças Retinianas , Adaptação Ocular/fisiologia , Adulto , Bestrofinas , Análise Mutacional de DNA , Eletroculografia , Eletrorretinografia , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/patologia , Oftalmopatias Hereditárias/fisiopatologia , Feminino , Angiofluoresceinografia , Fundo de Olho , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Oftalmoscopia/métodos , Pais , Fenótipo , Retina/patologia , Retina/fisiopatologia , Doenças Retinianas/genética , Doenças Retinianas/patologia , Doenças Retinianas/fisiopatologia , Tomografia de Coerência Óptica , Acuidade Visual , Distrofia Macular Viteliforme/patologiaRESUMO
BACKGROUND: To report functional and high-resolution retinal imaging abnormalities, including adaptive optics (AO) throughout the course of acute macular neuroretinopathy (AMNR). METHODS: Two female patients (four eyes) with a diagnosis of AMNR were observed at the Clinical Investigation Center, CHNO des Quinze-Vingts, Paris, France. The patients underwent detailed ophthalmic examination including best-corrected visual acuity, slit-lamp examination, kinetic and static perimetry, full-field and multifocal electroretinogram, infrared reflectance, autofluorescence imaging and spectral-domain optical coherence tomography (SD-OCT) and AO fundus imaging at presentation and during follow-up. RESULTS: Both cases showed concomitant loss of integrity of the outer retinal structures on SD-OCT, and marked abnormalities on AO imaging with disruption of the visibility of the cone mosaic. In the first case, photoreceptor damage was seen to progress during several weeks before healing. In both cases, there were persistent morphological abnormalities of photoreceptors 1 year after onset. CONCLUSION: This study further highlights the value of AO fundus imaging to facilitate detection, mapping, and monitoring of damage to the cone outer segments during AMNR. In particular, residual damage to the cone mosaic can be precisely documented.
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Células Fotorreceptoras de Vertebrados/patologia , Doenças Retinianas/diagnóstico por imagem , Doenças Retinianas/fisiopatologia , Doença Aguda , Adolescente , Diagnóstico por Imagem , Eletrorretinografia , Feminino , Angiofluoresceinografia , Humanos , Escotoma/fisiopatologia , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Adulto JovemRESUMO
PURPOSE: To characterize the peripheral cones in the images obtained by spectral-domain optical coherence tomography (OCT), swept source OCT, and adaptive optics fundus camera in a patient with peripheral cone dystrophy. METHODS: A 28-year-old Japanese man underwent detailed ophthalmic evaluations including high-resolution imaging of the fundus of both eyes. RESULTS: The decimal best-corrected visual acuity was 1.2 in both eyes. The results of slit-lamp biomicroscopy and ophthalmoscopy were essentially normal. Fluorescein and indocyanine green angiographies did not show any hyper- or hypofluorescent areas of the retina. Goldmann perimetry showed full peripheral visual fields but relative central scotomas within the central 20°. The results of the Humphrey Visual Field Analyzer showed a limited preservation of the central sensitivity. Color vision tests showed no errors in both eyes. Spectral-domain OCT showed attenuation of both the ellipsoid and interdigitation zones throughout the macular region except the center of the fovea. The scotopic full-field ERGs were normal, but the photopic ERGs were markedly reduced. Regular cone mosaics were not observed especially more than 450 µm radius from the fovea in the adaptive optics retinal images. The parafoveal cone densities were severely decreased in both eyes. CONCLUSIONS: Our findings indicate that the peripheral cone dystrophy diagnosed by full-field ERGs and perimetry is due to a reduction in the density of parafoveal and peripheral cones.
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Imagem Multimodal , Células Fotorreceptoras Retinianas Cones/patologia , Retinose Pigmentar/diagnóstico , Adulto , Corantes , Eletrorretinografia , Angiofluoresceinografia , Humanos , Verde de Indocianina , Masculino , Fotografação , Retinose Pigmentar/fisiopatologia , Tomografia de Coerência Óptica/métodos , Acuidade Visual/fisiologia , Testes de Campo Visual , Campos Visuais/fisiologiaRESUMO
PURPOSE: To report new findings in a case of ocular siderosis explored by high resolution angiography and adaptive optics (AO). METHODS: We report data on a 40-year-old man with an intraocular foreign body (IOFB) embedded in the sclera after hammering. RESULTS: Nine months after this accident, the patient presented with full-field electroretinogram (FF-ERG) abnormalities. Subsequent IOFB extraction was performed. One month after the surgery, high resolution angiography showed for the first time small iron particles all over the inner retinal surface. Spreading of these deposits was followed by inflammatory prepapillary new vessels and venous retinal vasculatis, which spontaneously resolved within a few months. ERG responses became slightly electronegative at this time. Clearance of the iron particles was followed over a year with AO and ERG recording. AO revealed an arterial tropism with a decrease in the amount of particles overtime, which may be consistent with macrophagic activity. CONCLUSION: High resolution angiography and AO are new tools, combined with electrophysiology, to better understand ocular siderosis pathophysiology.
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Corpos Estranhos no Olho/diagnóstico , Ferimentos Oculares Penetrantes/diagnóstico , Ferro , Retina/fisiopatologia , Doenças Retinianas/diagnóstico , Esclera/lesões , Siderose/diagnóstico , Adulto , Eletrorretinografia , Corpos Estranhos no Olho/fisiopatologia , Corpos Estranhos no Olho/cirurgia , Ferimentos Oculares Penetrantes/fisiopatologia , Ferimentos Oculares Penetrantes/cirurgia , Humanos , Masculino , Doenças Retinianas/fisiopatologia , Doenças Retinianas/cirurgia , Siderose/fisiopatologia , Siderose/cirurgia , Tomografia de Coerência Óptica , Acuidade Visual , VitrectomiaRESUMO
The Retinal Pigment Epithelium (RPE) plays a prominent role in diseases such as age-related macular degeneration, but imaging individual RPE cells is challenging due to their high absorption and low autofluorescence emission. The RPE lies beneath the highly reflective photoreceptor layer (PR) and contains absorptive pigments, preventing direct backscattered light detection when the PR layer is intact. Here, we used near-infrared autofluorescence adaptive optics scanning laser ophthalmoscopy (NIRAF AOSLO) and transscleral flood imaging (TFI) in the same healthy eyes to cross-validate these approaches. Both methods revealed a consistent RPE mosaic pattern and appeared to reflect a distribution of fluorophores consistent with findings from histological studies. Interestingly, even in apparently healthy RPE, we observed dynamic changes over months, suggesting ongoing cellular activity or alterations in fluorophore distribution. These findings emphasize the value of NIRAF AOSLO and TFI in understanding RPE morphology and dynamics.
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OBJECTIVE: Cystoid macular edema (CME) in retinitis pigmentosa (RP) is an important complication causing visual dysfunction. We investigated the effect of CME on photoreceptors in RP patients with previous or current CME, using an adaptive optics (AO) fundus camera. METHODS: We retrospectively observed the CME and ellipsoid zone (EZ) length (average of horizontal and vertical sections) by optical coherence tomography. The density and regularity of the arrangement of photoreceptor cells (Voronoi analysis) were examined at four points around 1.5° from superior to inferior and temporal to nasal. We also performed a multivariate analysis using CME duration, central macular thickness and transversal length of CME. RESULTS: We evaluated 18 patients with previous or current CME (18 eyes; age, 48.7 ± 15.6 years) and 24 patients without previous or current CME (24 eyes; age, 46.0 ± 14.5 years). There were no significant differences in age, logMAR visual acuity, or EZ length. In groups with and without CME, cell density was 11967 ± 3148 and 16239 ± 2935 cells/mm2, and sequence regularity was 85.5 ± 3.4% and 88.5 ± 2.8%, respectively; both parameters were significantly different. The correlation between photoreceptor density and age was more negative in group with CME. The CME group tended toward greater reductions in duration of CME. CONCLUSION: Complications of CME in RP patients may lead to a decrease in photoreceptor density and regularity. Additionally, a longer duration of CME may result in a greater reduction in photoreceptor density.
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Edema Macular , Retinose Pigmentar , Humanos , Adulto , Pessoa de Meia-Idade , Edema Macular/complicações , Estudos Retrospectivos , Retinose Pigmentar/complicações , Retinose Pigmentar/diagnóstico por imagem , Fóvea Central , Tomografia de Coerência Óptica/métodos , Células FotorreceptorasRESUMO
This study tested if a high-resolution, multi-modal, multi-scale retinal imaging instrument can provide novel information about structural abnormalities in vivo. The study examined 11 patients with very mild to moderate non-proliferative diabetic retinopathy (NPDR) and 10 healthy subjects using fundus photography, optical coherence tomography (OCT), OCT angiography (OCTA), adaptive optics scanning laser ophthalmoscopy (AO-SLO), adaptive optics OCT and OCTA (AO-OCT(A)). Of 21 eyes of 11 patients, 11 had very mild NPDR, 8 had mild NPDR, 2 had moderate NPDR, and 1 had no retinopathy. Using AO-SLO, capillary looping, inflections and dilations were detected in 8 patients with very mild or mild NPDR, and microaneurysms containing hyperreflective granular elements were visible in 9 patients with mild or moderate NPDR. Most of the abnormalities were seen to be perfused in the corresponding OCTA scans while a few capillary loops appeared to be occluded or perfused at a non-detectable flow rate, possibly because of hypoperfusion. In one patient with moderate NPDR, non-perfused capillaries, also called ghost vessels, were identified by alignment of corresponding en face AO-OCT and AO-OCTA images. The combination of multiple non-invasive imaging methods could identify prominent microscopic abnormalities in diabetic retinopathy earlier and more detailed than conventional fundus imaging devices.
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Capilares , Retinopatia Diabética , Oftalmoscopia , Tomografia de Coerência Óptica , Humanos , Tomografia de Coerência Óptica/métodos , Retinopatia Diabética/diagnóstico por imagem , Retinopatia Diabética/patologia , Feminino , Masculino , Oftalmoscopia/métodos , Pessoa de Meia-Idade , Capilares/diagnóstico por imagem , Capilares/patologia , Adulto , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/patologia , Idoso , Angiofluoresceinografia/métodosRESUMO
We present a compact multi-modal and multi-scale retinal imaging instrument with an angiographic functional extension for clinical use. The system integrates scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT) and OCT angiography (OCTA) imaging modalities and provides multi-scale fields of view. For high resolution, and high lateral resolution in particular, cellular imaging correction of aberrations by adaptive optics (AO) is employed. The entire instrument has a compact design and the scanning head is mounted on motorized translation stages that enable 3D self-alignment with respect to the subject's eye by tracking the pupil position. Retinal tracking, based on the information provided by SLO, is incorporated in the instrument to compensate for retinal motion during OCT imaging. The imaging capabilities of the multi-modal and multi-scale instrument were tested by imaging healthy volunteers and patients.
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Pupila , Retina , Humanos , Oftalmoscopia/métodos , Óptica e Fotônica , Retina/diagnóstico por imagem , Tomografia de Coerência Óptica/métodosRESUMO
Purpose: Maternally inherited diabetes and deafness (MIDD) is caused by a heteroplasmic m.3243A>G mutation in the mitochondrial DNA. The main ocular feature in MIDD is macular dystrophy. The purpose of this study was to identify the phenotypical characteristics of a patient with MIDD by multimodal high-resolution imaging analyses.Methods: A detailed history and ophthalmic examination were performed on a 39-year-old patient with MIDD. Multi-modal imaging included fundus photography, fundus autofluorescence imaging, fluorescein angiography, spectral-domain optical coherence tomography, OCT-angiography, and adaptive optics imaging. The PCR-invader and whole exome sequencing (WES) methods were performed on the DNA of the patient.Results: A 39-year-old woman with sensorineural hearing loss, diabetes mellitus presented with atrophic perifoveal changes and MIDD was suspected. The PCR-invader and WES methods showed that the patient had a m.3243A>G mutation in the mitochondrial DNA with 29% and 16.7% of the heteroplasmy in the peripheral blood, respectively. Morphological analyses revealed that the areas of photoreceptor degeneration and chorioretinal atrophy were present mainly in the perifoveal region. Multifocal ERGs showed that the perifoveal responses were reduced. Goldmann visual field was significant for a cecocentral scotoma in the right eye and an enlarged blind spot in the left eye. The central isopter was constricted bilaterally. The results of high-resolution retinal imaging by AO revealed that the densities of the cone photoreceptor were significantly reduced in the fovea where no obvious atrophy of the RPE and choroid was observed.Conclusions: Our findings indicate that WES analysis can be used to detect the m.3243A>G mutation in the mtDNA. The results of multimodal imaging analyses indicated that the primary dysfunction of the photoreceptors in the fovea might precede the dysfunction of the RPE in patient with MIDD.
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DNA Mitocondrial/genética , Surdez/genética , Diabetes Mellitus Tipo 2/genética , Degeneração Macular/genética , Mitocôndrias/genética , Doenças Mitocondriais/genética , Mutação/genética , Adulto , Surdez/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Eletrorretinografia , Feminino , Angiofluoresceinografia , Humanos , Degeneração Macular/diagnóstico , Doenças Mitocondriais/diagnóstico , Imagem Multimodal , Imagem Óptica , Linhagem , Reação em Cadeia da Polimerase , Tomografia de Coerência Óptica , Testes de Campo Visual , Campos Visuais , Sequenciamento do ExomaRESUMO
Purpose: Drusen are dynamic sub-RPE deposits that are risk factors for late-stage age-related macular degeneration (AMD). Here we show a new imaging method using flood-illumination adaptive optics (FIAO) that reveal drusen with high contrast and resolution. Methods: A fovea-centered 4° × 4° FIAO image and eight surrounding images with gaze displaced by ±2° vertically and horizontally were acquired. Clinical color fundus and spectral-domain optical coherence tomography were acquired for clinical grading and comparison. Custom software registered overlapping FIAO images and fused the data statistically to generate a fovea-centered 4° × 4° gaze-dependent image. Our dataset included 15 controls (aged 31-72) and 182 eyes from 104 AMD patients (aged 56-92), graded as either normal aging (n = 7), and early (n = 12), intermediate (n = 108) and late AMD (n = 42); 27 had subretinal drusenoid deposits (SDDs), and 83 were imaged longitudinally. Results: No gaze varying structures were detected in young eyes. In aging eyes with no evidence of age-related changes, putative drusen <20 µm in diameter were visible. Gaze-dependent images revealed more drusen and many smaller drusen than visible in color fundus images. Longitudinal images showed expansion and fusion of drusen. SDDs were lower contrast, and RPE atrophy did not yield a consistent signal. Conclusions: Gaze-dependent imaging in a commercially available FIAO fundus camera combined with image registration and postprocessing permits visualization of drusen and their progression with high contrast and resolution. Translational Relevance: This new technique offers promise as a robust and sensitive method to detect, map, quantify, and monitor the dynamics of drusen in aging and AMD.
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Iluminação , Drusas Retinianas , Inundações , Angiofluoresceinografia , Humanos , Oftalmoscopia , Drusas Retinianas/diagnóstico por imagemRESUMO
PURPOSE: The hexokinase 1 (HK1) gene encodes one of the four human hexokinases that play essential roles in glucose metabolism. Recently, several cases of E847K mutation in the HK1 gene were reported to cause inherited retinal dystrophy. The purpose of this study was to identify the phenotypical characteristics of patients with a recurrent E847K mutation in the HK1 gene. METHODS: Three generations of one family with autosomal dominant retinitis pigmentosa were examined. Whole exome sequencing was performed on the DNA. Fundus imaging by an adaptive optics fundus camera was used to obtain high-resolution photoreceptor images. RESULTS: Fundus examination of the proband showed degeneration of the mid-peripheral retina, and SD-OCT images showed an absence of the ellipsoid zone (EZ) and interdigitation zone (IZ) in the parafovea and more peripherally. SD-OCT images of the mother of the proband showed an absence of the EZ and IZ, and fundus autofluorescence images showed hypo-autofluorescence surrounding the macular region. One daughter of the proband had only mild night blindness, however, the density of the cone photoreceptors was reduced in the parafoveal region. Whole exome sequencing identified a heterozygous variant, E847K, in the HK1 gene. This variant was found to co-segregate with the disease in three family members. CONCLUSIONS: Although the systemic phenotypes were found to be associated with the HK1 mutations, only the E847K mutation can cause a non-syndromic photoreceptor degeneration. Our study strengthened the hypothesis that the amino acid E847 might play a critical role in the maintenance of the morphology and function of the photoreceptors.
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Genes Dominantes , Hexoquinase/genética , Mutação , Cegueira Noturna/patologia , Células Fotorreceptoras Retinianas Cones/metabolismo , Retinose Pigmentar/patologia , Feminino , Angiofluoresceinografia , Humanos , Masculino , Pessoa de Meia-Idade , Cegueira Noturna/etiologia , Linhagem , Fenótipo , Retinose Pigmentar/etiologiaRESUMO
BACKGROUND: The GUCY2D (guanylate cyclase 2D) gene encodes a photoreceptor guanylate cyclase (GC-E), that is predominantly expressed in the cone outer segments. Mutations in the GUCY2D lead to severe retinal disorders such as autosomal dominant cone-rod dystrophy (adCRD) and autosomal recessive Leber congenital amaurosis type 1. The purpose of this study was to identify the phenotype of a Japanese patient with a probably pathogenic GUCY2D variant. METHODS: Detailed ophthalmic examinations were performed, and whole exome sequencing was performed on DNA obtained from the patient. The variants identified by exome sequencing and targeted analysis were further confirmed by direct sequencing. RESULTS: A 47-year-old man had atrophic and pigmentary changes in the macula of both eyes. Amplitudes and implicit times on full-field electroretinograms (ERGs) were within normal limits; however, the densities of multifocal ERGs in the central area were reduced in both eyes. Whole exome sequencing identified heterozygous variant c.2527G>C, p.Glu843Gln in the GUCY2D gene within the mutation hot spot for adCRD. The allelic frequencies of this variant are extremely low and, according to American College of Medical Genetics and Genomics standards and guidelines, the variants are classified as likely pathogenic. CONCLUSIONS: This is the first report of a heterozygous variant, c.2527G>C, p.Glu843Gln, in the GUCY2D, in a patient presenting with mild macular dystrophy without a general reduction in cone function. Our findings expand the spectrum of the clinical phenotypes of GUCY2D-adCRD and help clarify the morphological and functional changes caused by defects of dimerization of GC-E in the phototransduction cascade.
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Estudos de Associação Genética , Guanilato Ciclase/genética , Degeneração Macular/genética , Mutação , Receptores de Superfície Celular/genética , HumanosRESUMO
PURPOSE: To report the results after 4 years of follow-up in a previously presented first case of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) sheet autologous transplantation using multimodal imaging. DESIGN: Follow-up of a single case. PARTICIPANT: A patient with exudative age-related macular degeneration and polypoidal choroidal vasculopathy. METHODS: Transplantation of an autologous iPSC-derived RPE cell sheet after removal of choroidal neovascularization (CNV) in September 2014. MAIN OUTCOME MEASURES: The function of the graft was assessed 4 years after surgery by color fundus photography, spectral-domain (SD) OCT, fluorescein angiography, indocyanine green angiography, and an adaptive optics (AO) retinal camera. RESULTS: At the 4-year follow-up, the transplanted autologous iPSC-derived RPE sheet had survived beneath the retina with slight expansion of the pigmented area and no adverse events. The outer nuclear layer above and adjacent to the graft showed acceptable thickness and an organized structure. Fluorescein angiography and SD OCT suggested the presence of vessel-like structures confined to the grafted area associated with the remaining trunk vessel of preoperative polypoidal choroidal vasculopathy but with no exudative changes. Visual acuity has been stable with no additional injections of anti-vascular endothelial growth factor agent. The choroidal volume at the graft site is relatively preserved when compared with the volume outside this site without RPE after removal of the CNV. Indocyanine green angiography revealed a preserved choriocapillaris around the iPSC-derived RPE sheet. Dark cell-like structures with a predominantly hexagonal arrangement were observed by AO imaging in an area located near the margin of the graft sheet. The average intercell distance was found to be stable over time. CONCLUSIONS: Thus far, the grafted iPSC-derived RPE sheet has survived for 4 years and seems to support photoreceptors and choroidal vessels. The morphologic characteristics of the RPE are observed at the transplant site.
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Procedimentos Cirúrgicos Oftalmológicos/métodos , Células-Tronco Pluripotentes/transplante , Epitélio Pigmentado da Retina/transplante , Acuidade Visual , Degeneração Macular Exsudativa/cirurgia , Idoso , Feminino , Angiofluoresceinografia/métodos , Seguimentos , Fundo de Olho , Humanos , Epitélio Pigmentado da Retina/citologia , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Transplante Autólogo , Degeneração Macular Exsudativa/diagnósticoRESUMO
BACKGROUND AND OBJECTIVE: To characterize the photoreceptors and choroidal morphology of heterozygous female carriers of choroideremia who typically do not have any visual defects but can have severe funduscopic changes. PATIENTS AND METHODS: This was a clinical case series study. Detailed ophthalmic examinations were performed on six female carriers from four families with choroideremia. The subfoveal choroidal thickness (SFCT) was determined by spectral-domain optical coherence tomography (SD-OCT) and the cone photoreceptor density by adaptive optics (AO) retinal imaging. SFCT and cone densities of the carriers were compared to that of normal eyes of healthy subjects. RESULTS: The mean age of the carriers was 42.5 years. Fundus photographs showed diffuse, patchy depigmentation; however, the SFCT was within the normal limits. AO retinal imaging revealed preserved cone densities at temporal eccentricities from 2 to 8 angular degrees. CONCLUSIONS: The findings indicate that despite the presence of distinctive depigmentation of the retinal pigment epithelium in female carriers of choroideremia, their cone photoreceptor densities and SFCT are well-preserved. These observations may account for the good visual acuity and lack of an awareness of visual disturbances. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:76-85.].
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Coroideremia/diagnóstico por imagem , Oftalmoscopia/métodos , Retina/diagnóstico por imagem , Células Fotorreceptoras Retinianas Cones , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Coroideremia/genética , Técnicas de Diagnóstico Oftalmológico , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Acuidade Visual , Adulto JovemRESUMO
Background: The GNAT1 gene encodes the alpha-subunit of transducin in rod photoreceptors and is an important part of the phototransduction cascade. Defects in GNAT1 are very rare but have been identified in autosomal dominant and recessive congenital stationary night blindness (CSNB) and autosomal recessive rod-cone dystrophy. The purpose of this study was to determine the phenotype-genotype relationship in a non-consanguineous Japanese family with a GNAT1 mutation.Methods: Detailed ophthalmic examinations were performed on the patients and their family members. Whole exome sequencing (WES) was applied to the DNA obtained from the family members. Sanger sequencing and co-segregation analyses were performed to identify the most likely pathogenic variant.Results: Two female (13- and 11-years) and one male (15-years) patients from a family had night blindness from their childhood. The fundus had a mild golden appearance regardless of the state of light- or dark-adaptation. Electroretinographic (ERG) analyses showed that the scotopic a-wave was extinguished, and the mixed rod-cone responses were severely reduced with an electronegative form in patients. The shapes of the dark-adapted ERGs were similar to those recorded from patients with Oguchi disease. We identified a homozygous in-frame deletion c.818_820delAGA, p.Lys273del in the GNAT1 gene. Variants were verified by Sanger sequencing and co-segregated with the disease in five members of the family.Conclusions: Our findings indicate that a recessive GNAT1 mutation found in this family could be the cause of the golden appearance of the fundus and negative ERGs with reduced a-waves, and nearly absent b-waves in the mixed rod-cone ERGs.
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Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/patologia , Fundo de Olho , Deleção de Genes , Homozigoto , Mutação , Cegueira Noturna/genética , Cegueira Noturna/patologia , Transducina/genética , Adolescente , Criança , Eletrorretinografia , Feminino , Humanos , Masculino , Linhagem , Fenótipo , PrognósticoRESUMO
BACKGROUND: CEP250 encodes the C-Nap1 protein which belongs to the CEP family of proteins. C-Nap1 has been reported to be expressed in the photoreceptor cilia and is known to interact with other ciliary proteins. Mutations of CEP250 cause atypical Usher syndrome which is characterized by early-onset sensorineural hearing loss (SNHL) and a relatively mild retinitis pigmentosa. This study tested the hypothesis that the mild cone-rod dystrophy (CRD) and SNHL in a non-consanguineous Japanese family was caused by CEP250 mutations. METHODS: Detailed ophthalmic and auditory examinations were performed on the proband and her family members. Whole exome sequencing (WES) was used on the DNA obtained from the proband. RESULTS: Electrophysiological analysis revealed a mild CRD in two family members. Adaptive optics (AO) imaging showed reduced cone density around the fovea. Auditory examinations showed a slight SNHL in both patients. WES of the proband identified compound heterozygous variants c.361C>T, p.R121*, and c.562C>T, p.R188* in CEP250. The variants were found to co-segregate with the disease in five members of the family. CONCLUSIONS: The variants of CEP250 are both null variants and according to American College of Medical Genetics and Genomics (ACMG) standards and guideline, these variants are classified into the very strong category (PVS1). The criteria for both alleles will be pathogenic. Our data indicate that mutations of CEP250 can cause mild CRD and SNHL in Japanese patients. Because the ophthalmological phenotypes were very mild, high-resolution retinal imaging analysis, such as AO, will be helpful in diagnosing CEP250-associated disease.
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Povo Asiático/genética , Autoantígenos/genética , Proteínas de Ciclo Celular/genética , Distrofias de Cones e Bastonetes/genética , Perda Auditiva Neurossensorial/genética , Mutação , Adulto , Distrofias de Cones e Bastonetes/diagnóstico , Distrofias de Cones e Bastonetes/fisiopatologia , Análise Mutacional de DNA , Eletrorretinografia , Exoma/genética , Feminino , Perda Auditiva Neurossensorial/diagnóstico , Testes Auditivos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Oftalmoscopia , Linhagem , Reação em Cadeia da Polimerase , Retina/fisiopatologia , Acuidade Visual , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: To report the clinical features of Japanese patients at Stage 1 and 2 of central areolar choroidal dystrophy (CACD). PATIENTS AND METHODS: Five family members had comprehensive ophthalmic examinations including adaptive optics (AO) retinal imaging. Mutation analysis of the PRPH2 gene was performed by Sanger sequencing. The protocol conformed to the tenets of the Declaration of Helsinki and was approved by the institutional review board of The Jikei University School of Medicine. RESULTS: Four family members had a heterozygous PRPH2 mutation, p.R172Q; however, one member with a mutation did not show any ophthalmological abnormalities. Two patients had mild parafoveal retinal dystrophy and a reduction of cone density determined by AO analysis. CONCLUSION: The results indicate that the parafoveal cone photoreceptors can be affected even at the early stage of CACD. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1115-1126.].
Assuntos
Doenças da Coroide/diagnóstico , Angiofluoresceinografia/instrumentação , Mutação , Óptica e Fotônica , Periferinas/genética , Retina/patologia , Tomografia de Coerência Óptica/instrumentação , Adulto , Doenças da Coroide/genética , Doenças da Coroide/metabolismo , Progressão da Doença , Eletrorretinografia , Feminino , Fundo de Olho , Humanos , Masculino , Pessoa de Meia-Idade , Oftalmoscópios , Linhagem , Periferinas/metabolismo , Retina/fisiopatologia , Células Fotorreceptoras Retinianas Cones/patologia , Adulto JovemRESUMO
Purpose. To report the morphological and functional changes associated with a regression of foveoschisis in a patient with X-linked retinoschisis (XLRS). Methods. A 42-year-old man with XLRS underwent genetic analysis and detailed ophthalmic examinations. Functional assessments included best-corrected visual acuity (BCVA), full-field electroretinograms (ERGs), and multifocal ERGs (mfERGs). Morphological assessments included fundus photography, spectral-domain optical coherence tomography (SD-OCT), and adaptive optics (AO) fundus imaging. After the baseline clinical data were obtained, topical dorzolamide was applied to the patient. The patient was followed for 24 months. Results. A reported RS1 gene mutation was found (P203L) in the patient. At the baseline, his decimal BCVA was 0.15 in the right and 0.3 in the left eye. Fundus photographs showed bilateral spoke wheel-appearing maculopathy. SD-OCT confirmed the foveoschisis in the left eye. The AO images of the left eye showed spoke wheel retinal folds, and the folds were thinner than those in fundus photographs. During the follow-up period, the foveal thickness in the SD-OCT images and the number of retinal folds in the AO images were reduced. Conclusions. We have presented the detailed morphological changes of foveoschisis in a patient with XLRS detected by SD-OCT and AO fundus camera. However, the findings do not indicate whether the changes were influenced by topical dorzolamide or the natural history.
RESUMO
The purpose of this study was to determine whether an autosomal recessive cone dystrophy was caused by a homozygous RP1L1 mutation. A family including one subject affected with cone dystrophy and four unaffected members without evidence of consanguinity underwent detailed ophthalmic evaluations. The ellipsoid and interdigitation zones on the spectral-domain optical coherence tomography images were disorganized in the proband. The proband had a reduced amplitude of cone and flicker full-field electroretinograms (ERGs). Focal macular ERGs and multifocal ERGs were severely reduced in the proband. A homozygous RP1L1 mutation (c.3628T>C, p.S1210P) was identified in the proband. Family members who were heterozygous for the p.S1210P mutation had normal visual acuity and normal results of clinical evaluations. To investigate other putative pathogenic variant(s), a next-generation sequencing (NGS) approach was applied to the proband. NGS identified missense changes in the heterozygous state of the PCDH15, RPGRIP1, and GPR98 genes. None of these variants cosegregated with the phenotype and were predicted to be benign reinforcing the putative pathogenicity of the RP1L1 homozygous mutation. The AO images showed a severe reduction of the cone density in the proband. Our findings indicate that a homozygous p.S1210P exchange in the RP1L1 gene can cause cone dystrophy.
Assuntos
Proteínas do Olho/genética , Genes Recessivos , Mutação de Sentido Incorreto , Degeneração Retiniana/genética , Substituição de Aminoácidos , Feminino , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Células Fotorreceptoras Retinianas Cones/patologia , Degeneração Retiniana/patologia , Tomografia de Coerência ÓpticaRESUMO
The purpose of this study was to determine the retinal morphology of eyes with Bietti crystalline dystrophy (BCD) associated with a CYP4V2 mutation using high-resolution imaging techniques. Three subjects with BCD underwent detailed ophthalmic examinations. High-resolution fundus images were obtained with an adaptive optics (AO) fundus camera. A common homozygous mutation was detected in the three patients. Funduscopic examination of the three patients revealed the presence of crystalline deposits in the retina, and all of the crystalline deposits were also detected in the infrared (IR) images. The crystals observed in the IR images were seen as bright reflective plaques located on the RPE layer in the SD-OCT images. The clusters of hyperreflective signals in the AO images corresponded to the crystals in the IR images. High-magnification AO images revealed that the clusters of hyperreflective signals consisted of circular spots that are similar to the signals of cone photoreceptors. Most of these circular spots were detected in healthy areas in the FAF images. There is a possibility that circular spots observed by AO are residual cone photoreceptors located over the crystals.