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PURPOSE: The c.1430A > G (Asp477Gly) variant in RPE65 has been reported in Irish and Scottish families with either an autosomal dominant retinal dystrophy (adRD) that resembles choroideremia, a vitelliform macular dystrophy or an isolated macular atrophy. We report novel features on multimodal imaging and the natural history of a family harbouring this variant in combination with the BEST1 c.37C > T (Arg13Cys) variant. METHODS: Members of a family with an adRD were examined clinically to ascertain phenotype and underwent genetic testing. Multimodal imaging included widefield colour fundus photography, quantitative autofluorescence (qAF) and spectral domain optical coherence tomography. Electrophysiology and microperimetry were also performed. RESULTS: Vision loss was attributed to foveal atrophy in the proband and choroidal neovascularisation and a vitello-eruptive lesion in one affected son. Peripheral retinal white dots corresponding to subretinal deposits were seen in three patients. The median qAF8 values in the proband (I:1) were low (40 and 101 in OD and OS) at age 79. Similarly, the qAF8 values for the middle son (II:2) were also low (100 and 87 in ODS and OS) at age 60. Electrophysiology showed disproportionate reduction in Arden ratio prior to the gradual loss of full-field responses. Microperimetry demonstrated an enlarging scotoma in the proband. CONCLUSIONS: The coexistence of the pathogenic BEST1 c.37C > T variant may modify clinical features observed in RPE65 adRD. This study expands our understanding of RPE65 adRD as a retinoid cycle disorder supported by the reduced qAF, fine white retinal dots and corresponding subretinal deposits on OCT in affected members.
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Bestrofinas , Distrofias Retinianas , Distrofia Macular Viteliforme , cis-trans-Isomerases , Idoso , Bestrofinas/genética , Eletrorretinografia , Angiofluoresceinografia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genética , Tomografia de Coerência Óptica , cis-trans-Isomerases/genéticaRESUMO
The International Society for Clinical Electrophysiology of Vision (ISCEV) standard for full-field electroretinography (ERG) describes a minimum procedure for testing generalized retinal function but encourages more extensive testing. This extended protocol describes a method of assessing the function of the short-wavelength-sensitive cone (S-cone) retinal pathway, using a short-wavelength flash superimposed on a background that saturates the rods and adapts the L/M-cones to elicit a response, known as the S-cone ERG. Stimulus parameters such as the strength and luminance of the flash and background, respectively, and their spectral and temporal characteristics are specified. As a complement to the ISCEV standard, testing the S-cone ERG enables further characterization of light-adapted retinal function and may refine diagnosis of some retinal disorders. Typical applications are described including use in the diagnosis of rod monochromacy and S-cone monochromacy, identification and investigation of cone On-bipolar cell dysfunction and use of the technique to confirm the diagnosis of enhanced S-cone syndrome.
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Eletrofisiologia/normas , Eletrorretinografia/normas , Células Fotorreceptoras Retinianas Cones/fisiologia , Opsinas de Bastonetes/fisiologia , Sociedades Médicas/normas , Adaptação Ocular , Calibragem/normas , Protocolos Clínicos , Humanos , Agências Internacionais , Estimulação Luminosa , Distrofias Retinianas/fisiopatologia , Visão OcularRESUMO
PURPOSE: Mutation of the CLN3 gene, associated with juvenile neuronal ceroid lipofuscinosis, has recently been associated with late-onset, non-syndromic retinal dystrophy. Herein we describe the multimodal imaging, immunological and systemic features of an adult with compound heterozygous CLN3 mutations. METHODS: A 50-year-old female with non-syndromic retinal dystrophy from the age of 36 years underwent multimodal retinal imaging, electroretinography, neuroimaging, immunological studies and genetic testing. CLN3 transcripts were amplified from patient leukocytes by reverse transcriptase polymerase chain reaction and characterized by Sanger sequencing. RESULTS: Visual acuity declined to 6/12 and 6/76 due to asymmetrical central scotoma. ERG responses became electronegative and patient's serum contained anti-retinal antibodies. Final visual acuity stabilized at 6/60 bilaterally 3 years after peri-ocular steroid and rituximab infusion. Genetic testing revealed compound heterozygous CLN3 mutations: the 1.02 kb deletion and a novel missense mutation (c.175G>A). In silico, analyses predicted the c.175G>A mutation disrupted an exonic splice enhancer site in exon 3. In patient leukocytes, CLN3 expression was reduced and novel CLN3 transcripts lacking exon 3 were detected. CONCLUSIONS: Our case study shows that (1) non-syndromic CLN3 disease leads to rod and delayed primary cone degeneration resulting in constricting peripheral field and enlarging central scotoma and, (2) the c.175G>A CLN3 mutation, altered splicing of the CLN3 gene. Overall, we provide comprehensive clinical characterization of a patient with non-syndromic CLN3 disease.
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Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genética , Mutação de Sentido Incorreto , Lipofuscinoses Ceroides Neuronais/genética , Distrofias Retinianas/genética , Autoanticorpos/sangue , Autoantígenos/imunologia , Western Blotting , Eletrorretinografia , Éxons , Feminino , Humanos , Pessoa de Meia-Idade , Imagem Multimodal , Lipofuscinoses Ceroides Neuronais/diagnóstico , Lipofuscinoses Ceroides Neuronais/imunologia , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Linhagem , Retina/imunologia , Retina/fisiopatologia , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/imunologia , Distrofias Retinianas/fisiopatologia , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Acuidade Visual/fisiologiaRESUMO
PURPOSE: To characterize the ultrastructural and functional correlates of hydroxychloroquine (HCQ)-induced subclinical bull's eye lesion seen on near-infrared reflectance (NIR) imaging. METHODS: An asymptomatic 54-year-old male taking HCQ presented with paracentral ring-like scotoma, abnormal multifocal electroretinography (mfERG) and preserved ellipsoid zone on optical coherence tomography (OCT). Dense raster OCT was performed to create en face reflectivity maps of the interdigitation zone. Macular Integrity Assessment (MAIA) microperimetry and mfERG findings were compared with NIR imaging, en face OCT, retinal thickness profiles and wave-guiding cone density maps derived from flood-illumination adaptive optics (AO) retinal photography. RESULTS: The bull's eye lesion is an oval annular zone of increased reflectivity on NIR with an outer diameter of 1450 µm. This region corresponds exactly to an area of preserved interdigitation zone reflectivity in en face OCT images and of normal cone density on AO imaging. Immediately surrounding the bull's eye lesion is an annular zone (3°-12° eccentricity) of depressed retinal sensitivity on MAIA and reduced amplitude density on mfERG. Wave-guiding cone density at 2° temporal was 25,400 per mm2. This declined rapidly to 12,900 and 1200 per mm2 at 3° and 4°. CONCLUSION: Multimodal imaging illustrated pathology in the area surrounding the NIR bull's eye, characterized by reduced reflectance, wave-guiding cone density and retinal function. Further studies are required to investigate whether the bull's eye on NIR imaging and en face OCT is prominent or consistent enough for diagnostic use.
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Antirreumáticos/toxicidade , Fóvea Central/efeitos dos fármacos , Hidroxicloroquina/toxicidade , Doenças Retinianas/induzido quimicamente , Escotoma/induzido quimicamente , Eletrorretinografia , Angiofluoresceinografia , Fóvea Central/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Retina/fisiopatologia , Células Fotorreceptoras Retinianas Cones/patologia , Doenças Retinianas/diagnóstico por imagem , Doenças Retinianas/fisiopatologia , Escotoma/diagnóstico por imagem , Escotoma/fisiopatologia , Tomografia de Coerência Óptica/métodos , Testes de Campo VisualRESUMO
PURPOSE: Paraneoplastic retinopathy can be the first manifestation of systemic malignancy. A subset of paraneoplastic retinopathy is characterized by negative-type electroretinography (ERG) without fundus abnormality. Here we describe the multimodal imaging and clinico-pathological correlation of a unique case of acute progressive paravascular placoid neuroretinopathy with suspected retinal depolarizing bipolar cell dysfunction preceding the diagnosis of metastatic small cell carcinoma of the prostate. METHODS: ERG was performed according to the International Society for Clinical Electrophysiology of Vision standards. Imaging modalities included near-infrared reflectance, blue-light autofluorescence, fluorescein and indocyanine green angiographies, spectral domain optical coherence tomography, ultra-widefield colour and green-light autofluorescence imaging, microperimetry and adaptive optics imaging. Patient serum was screened for anti-retinal antibodies using western blotting. Immunostaining and histological analyses were performed on sections from human retinal tissues and a patient prostate biopsy. RESULTS: Serial multimodal retinal imaging, microperimetry and adaptive optics photography demonstrated a paravascular distribution of placoid lesions characterized by hyper-reflectivity within the outer nuclear layer resembling type 2 acute macular neuroretinopathy. There was no visible lesion within the inner nuclear layer despite electronegative-type ERG. Six months later, the patient presented with metastatic small cell carcinoma of the prostate. Tumour cells were immunopositive for glyceraldehyde-3-phosphate dehydrogenase, enolase and recoverin as well as neuroendocrine markers. The patient's serum reacted to cytoplasmic and nuclear antigens in the prostate biopsy and in human retina. Anti-retinal antibodies against several antigens were detected by both commercial and in-house western blots. CONCLUSIONS: A spectrum of autoreactive anti-retinal antibodies is associated with a unique phenotype of acute progressive paravascular placoid neuroretinopathy resulting in degeneration of photoreceptor cells, inner retinal dysfunction and classic electronegative ERG in paraneoplastic retinopathy. Detailed clinical, functional and immunological phenotyping of paraneoplastic retinopathy illustrated the complex mechanism of paraneoplastic syndrome.
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Eletrorretinografia , Síndromes Paraneoplásicas/diagnóstico , Retina/patologia , Doenças Retinianas/diagnóstico , Doença Aguda , Humanos , Masculino , Pessoa de Meia-Idade , Imagem MultimodalRESUMO
PURPOSE: To illustrate altered fundus autofluorescence in rubella retinopathy and to investigate their relationships with photoreceptor structure and function using multimodal imaging. METHODS: The authors report four cases of rubella retinopathy aged 8, 33, 42, and 50 years. All patients had dilated clinical fundus examination; wide-field color photography; blue, green, and near-infrared autofluorescence imaging and spectral domain optical coherence tomography. Two patients also underwent microperimetry and adaptive optics imaging. En face optical coherence tomography, cone mosaic, and microperimetry were coregistered with autofluorescence images. The authors explored the structure-function correlation. RESULTS: All four patients had a "salt-and-pepper" appearance on dilated fundus examination and wide-field color photography. There were variable-sized patches of hypoautofluorescence on both blue and near-infrared excitation in all four patients. Wave-guiding cones were visible and retinal sensitivity was intact over these regions. There was no correlation between hypoautofluorescence and regions of attenuated ellipsoid and interdigitation zones. Hyperautofluorescent lesions were also noted and some of these were pseudo-vitelliform lesions. CONCLUSION: Patchy hypoautofluorescence on near-infrared excitation can be a feature of rubella retinopathy. This may be due to abnormal melanin production or loss of melanin within retinal pigment epithelium cells harboring persistent rubella virus infection. Preservation of the ellipsoid zone, wave-guiding cones, and retinal sensitivity within hypoautofluorescent lesions suggest that these retinal pigment epithelium changes have only mild impact on photoreceptor cell function.
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Células Fotorreceptoras Retinianas Cones/patologia , Doenças Retinianas/fisiopatologia , Rubéola (Sarampo Alemão)/complicações , Adulto , Criança , Angiofluoresceinografia , Fundo de Olho , Humanos , Pessoa de Meia-Idade , Células Fotorreceptoras Retinianas Cones/fisiologia , Doenças Retinianas/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Testes de Campo Visual , Campos Visuais/fisiologiaRESUMO
BACKGROUND: The articular surface replacement (ASR) was recalled in 2010 because of higher than expected revision rates. Patients reported symptoms of neurologic dysfunction including poor vision. This cohort study, using objective measurements, aimed to establish whether a higher incidence of visual function defects exists in ASR patients. METHODS: Thirty-three ASR patients and 33 non-ASR controls (control 1) were recruited. Data were compared with normative population data from the visual electrophysiology database (control 2). Patients underwent investigations for serum cobalt levels, psychophysical visual tests, and extensive electrophysiological visual testing. RESULTS: After excluding 2 subjects with pre-existing eye disease, data from 33 ASR patients were compared with the 2 control cohorts. The median serum cobalt level in the ASR group (median, 52 nmol/L [interquartile range, 14-151 nmol/L]) was significantly higher than that in the control 1 cohort (median, 7 nmol/L [interquartile range, 5-14 nmol/L]; P < .0001). The photoreceptor function of patients with an ASR of the hip showed significantly larger electroretinography mixed rod-cone b-wave amplitudes than both control 1 and control 2 cohorts (P = .0294 and .0410, respectively). Abnormalities in macular function as reflected by multifocal and scotopic electroretinography were more prevalent in control 1 (P = .0445 and .0275, respectively). Optic nerve pathway measurements using visual-evoked potential latency was significantly longer in the ASR group compared with those in the control 2 cohort (P = .0201). There were no statistical differences in visual acuity. CONCLUSION: A statistically significant disturbance in visual electrophysiology was found in the ASR group when compared with the control groups. These differences did not translate to identifiable clinical visual deficits. Orthopedic surgeons need to be aware of the possibility of visual dysfunction in patients with ASR and other metal-on-metal hip arthroplasties; however, routine visual testing is not recommended.
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Cobalto/efeitos adversos , Prótese de Quadril/efeitos adversos , Transtornos da Visão/induzido quimicamente , Vias Visuais/efeitos dos fármacos , Idoso , Artroplastia de Quadril/efeitos adversos , Artroplastia de Quadril/instrumentação , Cobalto/sangue , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Desenho de PróteseRESUMO
PURPOSE: The effect of elevated serum cobalt on the human visual system has not yet been established. In light of recent reports of visual problems with elevated cobalt in association with hip prostheses, this review examines the literature for evidence regarding the effects of cobalt on human visual function. METHODS: A systematic literature review was undertaken in July 2013. The electronic databases of PubMed (1955 to July week 1 2013), Cochrane Library and EMBASE were searched. Only human studies or case reports written in English were included. RESULTS: Eight case reports were identified. Five case reports involved patients with metal hip arthroplasties, two cases involved patients exposed to environmental cobalt, and one case involved a patient treated medically for anaemia with cobalt chloride. No human prospective studies were identified. CONCLUSIONS: Several case reports showed that high serum cobalt may be associated with both irreversible and reversible visual loss, optic neuropathy and atrophy, electrophysiological evidence of abnormal retinal and retinal pigment epithelium function and fluorescein angiographic evidence of abnormal choroidal perfusion.
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Artroplastia de Quadril/instrumentação , Cobalto/efeitos adversos , Próteses Articulares Metal-Metal/efeitos adversos , Doenças do Nervo Óptico/induzido quimicamente , Doenças Retinianas/induzido quimicamente , Transtornos da Visão/induzido quimicamente , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Masculino , Transtornos da Visão/fisiopatologiaRESUMO
Purpose: To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene. Methods: A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype-phenotype correlations. Results: The median age at symptom onset was 40 years (range, 4-78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). Symptom onset was earlier in retinitis pigmentosa as compared with pseudo-Stargardt pattern dystrophy (34 vs 44 years; P = 0.004). The median visual acuity was 0.18 logMAR (interquartile range, 0-0.54 logMAR) and 0.18 logMAR (interquartile range 0-0.42 logMAR) in the right and left eyes, respectively. ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). Twenty-two variants were novel. The central areolar choroidal dystrophy phenotype was associated with 13 missense variants. The remaining variants showed marked phenotypic variability. Conclusions: We described six distinct FAF phenotypes associated with variants in the PRPH2 gene. One FAF phenotype may have multiple ERG phenotypes, demonstrating a discordance between structure and function. Given the vast spectrum of PRPH2 disease our findings are useful for future clinical trials.
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Eletrorretinografia , Periferinas , Fenótipo , Distrofias Retinianas , Acuidade Visual , Humanos , Periferinas/genética , Pessoa de Meia-Idade , Adulto , Masculino , Feminino , Adolescente , Distrofias Retinianas/genética , Distrofias Retinianas/fisiopatologia , Distrofias Retinianas/diagnóstico , Idoso , Acuidade Visual/fisiologia , Criança , Adulto Jovem , Pré-Escolar , Tomografia de Coerência Óptica , Mutação , Angiofluoresceinografia , Estudos de Associação Genética , Estudos Retrospectivos , Análise Mutacional de DNA , DNA/genética , LinhagemRESUMO
Purpose: Biallelic crumbs cell polarity complex component 1 (CRB1) mutations can present as Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), or cystic maculopathy. This study reports a novel phenotype of asymptomatic fenestrated slit maculopathy (AFSM) and examines macular volume profile and microperimetry as clinical trial end points in CRB1-associated retinopathies. Methods: Twelve patients from nine families with CRB1 mutation were recruited. Ultra-widefield (UWF) color fundus photography and autofluorescence (AF), spectral-domain optical coherence tomography (SD-OCT), microperimetry, and adaptive optics (AO) imaging were performed. Macular volume profiles were compared with age-matched healthy controls. Genotyping was performed using APEX genotyping microarrays, targeted next-generation sequencing, and Sanger sequencing. Results: We identified one patient with LCA, five patients with RP, and four patients with macular dystrophy (MD) with biallelic CRB1 mutations. Two siblings with compound heterozygote genotype (c.[2843G>A]; [498_506del]) had AFSM characterized by localized outer retinal disruption on SD-OCT and parafoveal cone loss on AO imaging despite normal fundus appearance, visual acuity, and foveal sensitivity. UWF AF demonstrated preserved para-arteriolar retinal pigment epithelium (PPRPE) in all patients with RP. Microperimetry documented preserved central retinal function in six patients. The ratio of perifoveal-to-foveal retinal volume was greater than controls in 89% (8/9) of patients with RP or MD, whereas central subfield and total macular volume were outside normal limits in 67% (6/9). Conclusions: AO imaging was helpful in detecting parafoveal cone loss in asymptomatic patients. Macular volume profile and microperimetry parameters may have utility as CRB1 trials end points. Translational Relevance: Macular volume and sensitivity can be used as structural and functional end points for trials on CRB1-associated RP and MD.
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Proteínas do Olho , Retinose Pigmentar , Proteínas do Olho/genética , Humanos , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , Retina , Retinose Pigmentar/diagnóstico , Testes de Campo VisualRESUMO
Adaptive optics flood illumination ophthalmoscopy (AO-FIO) is an established imaging tool in the investigation of retinal diseases. However, the clinical interpretation of AO-FIO images can be challenging due to varied image quality. Therefore, image quality assessment is essential before interpretation. An image assessment tool will also assist further work on improving the image quality, either during acquisition or post processing. In this paper, we describe, validate and compare two automated image quality assessment methods; the energy of Laplacian focus operator (LAPE; not commonly used but easily implemented) and convolutional neural network (CNN; effective but more complex approach). We also evaluate the effects of subject age, axial length, refractive error, fixation stability, disease status and retinal location on AO-FIO image quality. Based on analysis of 10,250 images of 50 × 50 µm size, at 41 retinal locations, from 50 subjects we demonstrate that CNN slightly outperforms LAPE in image quality assessment. CNN achieves accuracy of 89%, whereas LAPE metric achieves 73% and 80% (for a linear regression and random forest multiclass classifier methods, respectively) compared to ground truth. Furthermore, the retinal location, age and disease are factors that can influence the likelihood of poor image quality.
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BACKGROUND: Heterozygous c.440 G > T mutation in the S-antigen visual arrestin (SAG) gene has been described as a cause of autosomal dominant retinitis pigmentosa (adRP) in a series of patients of Hispanic origin. This study presents the early and late clinical features and disease progression rates in an Australian family with SAG adRP. MATERIALS AND METHODS: An observational case series of four family members with adRP. They were examined clinically, with multi-modal retinal imaging and electroretinography (ERG) to ascertain phenotype. Disease progression rate was measured using optical coherence tomography (OCT) and fundus autofluorescence (FAF). A retinal dystrophy panel was used for the proband and cascade testing with targeted Sanger sequencing was conducted in other available family members. RESULTS: The proband presented at 36 years of age with profoundly reduced full-field ERG responses despite a sector RP phenotype. This progressed to a classic RP pattern over several decades leaving a small residual island of central visual field. The horizontal span of the residual outer nuclear layer and the area of hyperautofluorescent ring contracted at a rate of 8-11% and 9-14% per year, respectively. DNA sequencing confirmed the segregation of SAG c.440 G > T mutation with disease. CONCLUSION: SAG adRP presents with a reduced full-field ERG response consistent with a rod-cone dystrophy in mid-life despite a sector RP phenotype. Centripetal progression of the disease into the macula can be tracked by OCT and FAF imaging.
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Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação a DNA/genética , Mutação , Retinose Pigmentar/patologia , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Austrália , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Retinose Pigmentar/etiologia , Retinose Pigmentar/metabolismo , Campos VisuaisRESUMO
Purpose: Microperimetry measures differential light sensitivity (DLS) at specific retinal locations. The aim of this study is to examine the variation in DLS across the macula and the contribution to this variation of cone distribution metrics and retinal eccentricity. Methods: Forty healthy eyes of 40 subjects were examined by microperimetry (MAIA) and adaptive optics imaging (rtx1). Retinal DLS was measured using the grid patterns: foveal (2°-3°), macular (3°-7°), and meridional (2°-8° on horizontal and vertical meridians). Cone density (CD), distribution regularity, and intercone distance (ICD) were calculated at the respective test loci coordinates. Linear mixed-effects regression was used to examine the association between cone distribution metrics and loci eccentricity, and retinal DLS. Results: An eccentricity-dependent reduction in DLS was observed on all MAIA grids, which was greatest at the foveal-parafoveal junction (2°-3°) (-0.58 dB per degree, 95% confidence interval [CI]; -0.91 to -0.24 dB, P < 0.01). Retinal DLS across the meridional grid changed significantly with each 1000 cells/deg2 change in CD (0.85 dB, 95% CI; 0.10 to 1.61 dB, P = 0.03), but not with each arcmin change in ICD (1.36 dB, 95% CI; -2.93 to 0.20 dB, P = 0.09). Conclusions: We demonstrate significant variation in DLS across the macula. Topographical change in cone separation is an important determinant of the variation in DLS at the foveal-parafoveal junction. We caution the extrapolation of changes in DLS measurements to cone distribution because the relationship between these variables is complex. Translational Relevance: Cone density is an independent determinant of DLS in the foveal-parafoveal junction in healthy eyes.
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Fotofobia , Células Fotorreceptoras Retinianas Cones , Contagem de Células , Voluntários Saudáveis , Humanos , Acuidade VisualRESUMO
Background: Mutations in the RCC1 and BTB domain-containing protein 1 (RCBTB1) gene have been implicated in a rare form of retinal dystrophy. Herein, we report the clinical features of a 45-year-old Singaporean-Chinese female and her presymptomatic sibling, who each possesses compound heterozygous mutations in RCBTB1. Expression of RCBTB1 in patient-derived cells was evaluated.Materials and Methods: The natural history was documented by a series of ophthalmic examinations including electroretinography, fundus autofluorescence imaging, spectral-domain optical coherence tomography, visual field, microperimetry, and adaptive optics retinal imaging. Patient DNA was genetically analysed using a 537-gene Next Generation Sequencing panel and targeted Sanger sequencing. Expression of RCBTB1 in lymphocytes, fibroblasts, and induced pluripotent stem cells (iPSC) derived from the proband and healthy controls was characterized by quantitative PCR, Sanger sequencing, and western blotting.Results: The proband presented with left visual distortion at age 40 due to extrafoveal chorioretinal atrophy. Atrophy expanded at 1.3 (OD) and 1.0 (OS) mm2/year. Total macular volume declined by 0.09 (OD) and 0.13 (OS) mm3/year. Microperimetry demonstrated enlarging scotoma in both eyes. Generalised cone dysfunction was demonstrated by electroretinography. A retinal dystrophy panel testing revealed biallelic frameshifting mutations, c.170delG (p.Gly57Glufs*12) and c.707delA (p.Asn236Thrfs*11) in RCBTB1. The level of RCBTB1 mRNA expression was reduced in patient-derived lymphocytes compared to controls. RCBTB1 protein was detected in control fibroblasts and iPSC but was absent in patient-derived cells.Conclusions: Atrophy expansion rate and macular volume change are feasible endpoints for monitoring RCBTB1-associated retinopathy. We provide further functional evidence of pathogenicity for two disease-causing variants using patient-derived iPSCs.
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Fatores de Troca do Nucleotídeo Guanina/genética , Mutação/genética , Distrofias Retinianas/genética , Povo Asiático/etnologia , Povo Asiático/genética , Western Blotting , Eletrorretinografia , Feminino , Fibroblastos/metabolismo , Angiofluoresceinografia , Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Linfócitos/metabolismo , Pessoa de Meia-Idade , Fenótipo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Singapura/epidemiologiaRESUMO
BACKGROUND: Mutations in the splicing factor pre-messenger RNA processing factor 31 (PRPF31) gene cause autosomal dominant retinitis pigmentosa 11 (RP11) through a haplo-insufficiency mechanism. We describe the phenotype and progression of microperimetry and autofluorescence endpoints in an Indigenous Australian RP11 family. PATIENTS AND METHODS: Ophthalmic examination, optical coherence tomography, fundus autofluorescence and microperimetry were performed at baseline and every 6-12 months. Baseline and annual change in best-corrected visual acuity (BCVA), microperimetry mean sensitivity (MS) and number of scotoma loci, residual ellipsoid zone (EZ) span and hyperautofluorescent ring (HAR) area were reported. Next-generation and Sanger sequencing were performed in available members. RESULTS: 12 affected members from three generations were examined. Mean (SD, range) age at onset of symptoms was 11 (4.5, 4-19) years. MS declined steadily from the third decade and EZ span and HAR area declined rapidly during the second decade. Serial microperimetry showed negligible change in MS over 2-3 years. However, mean EZ span, near-infrared and short-wavelength HAR area reduction was 203 (6.4%) µm/year, 1.8 (8.7%) mm2/year and 1.1 (8.6%) mm2/year, respectively. Genetic testing was performed on 11 affected and 10 asymptomatic members and PRPF31 c.1205 C > A (p.Ser402Ter) mutation was detected in all affected and two asymptomatic members (non-penetrant carriers). CONCLUSIONS: Our findings suggest that in the studied cohort, the optimal window for therapeutic intervention is the second decade of life and residual EZ span and HAR area can be considered as efficacy outcome measures. Further studies on larger samples with different PRPF31 mutations and longer follow-up duration are recommended.
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Proteínas do Olho/genética , Mutação , Imagem Óptica/métodos , Fenótipo , Retinose Pigmentar/patologia , Tomografia de Coerência Óptica/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Progressão da Doença , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Retinose Pigmentar/diagnóstico por imagem , Retinose Pigmentar/genética , Acuidade Visual , Testes de Campo Visual , Adulto JovemRESUMO
X-linked Retinoschisis is a leading cause of juvenile macular degeneration. Four Western Australian families affected by X-Linked Retinoschisis were analysed using DNA and clinical information from the Australian Inherited Retinal Disease (IRD) Register and DNA Bank. By direct sequencing of the RS1 gene, three genetic variants were identified; 52+1G > T, 289T > G and 416delA. 289T > G has not been previously reported and is likely to cause a substitution of a membrane binding residue (W92G) in the functional discoidin domain. All clinically diagnosed individuals showed typical electronegative ERGs. The 52+1G > T obligate carrier also recorded a bilaterally abnormal rod ERG and mildly abnormal photopic responses. mfERG trace arrays showed reduced response densities in the paramacular region extending futher temporally for each eye.
Assuntos
Retinosquise/genética , Sequência de Aminoácidos , Sequência de Bases , Análise Mutacional de DNA , Eletrorretinografia , Proteínas do Olho/química , Proteínas do Olho/genética , Família , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Dados de Sequência Molecular , Mutação/genética , Linhagem , Retinosquise/fisiopatologia , Alinhamento de Sequência , Austrália OcidentalRESUMO
BACKGROUND: Deletion-insertion (delins) variants in the retina-specific ATP-binding cassette transporter gene, subfamily A, member 4 (ABCA4) accounts for <1% in Stargardt disease. The consequences of these delins variants on splicing cannot be predicted with certainty without supporting in vitro data. METHODS: Candidate ABCA4 variants were revealed by genetic and segregation analysis of a family with pseudodominant Stargardt disease using a commercial panel and Sanger sequencing. RNA extracted from patient-derived fibroblasts was analyzed by RT-PCR to evaluate splicing behavior of the ABCA4 variants. RESULTS: Affected members carrying the novel c.6031_6044delinsAGTATTTAACCAATATTT variant in exon 44 presented with contrasting phenotypes; from early-onset cone-rod dystrophy to late-onset macular dystrophy. This variant resulted in a 56-nucleotide deletion in the mutant allele by activation of a cryptic splice acceptor site which disrupts the reading frame and results in a premature termination codon (p.Ile2003LeufsTer41). If translated, the crucial functional domains near the C-terminus would be truncated from the ABCA4 protein. CONCLUSION: This work demonstrates the intrafamilial phenotypic variability in a pseudodominant Stargardt disease pedigree and the use of patient-derived fibroblasts to evaluate the effect of a novel ABCA4 delins variant on splicing to complement in silico pathogenicity assessment.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Mutação INDEL , Fenótipo , Doença de Stargardt/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Células Cultivadas , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Splicing de RNA , Doença de Stargardt/patologiaRESUMO
Foveal retinoschisis is rarely found in women. An 11-year-old girl, from non-consanguineous parents, presented with bilateral visual loss from isolated foveal retinoschisis as confirmed by a normal fluorescein angiogram and characteristic optical coherence tomogram. Psychophysical and electrophysiological studies demonstrated mild contrast sensitivity loss, dyschromatopsia and normal full field electroretinographic responses. Visual acuity, foveal retinoschisis, electroretinography, electro-oculography and visual evoked responses remained stable after 13 years but a reduction in pattern electroretinography amplitude was noted. No mutation was found in the coding regions of the RS1 gene. Isolated foveal retinoschisis may be a form of macular dystrophy. Longer-term follow up may contribute to our understanding of this rare disease.