RESUMO
Recent advances in regenerative therapy have placed the treatment of previously incurable eye diseases within arms' reach. Achromatopsia is a severe monogenic heritable retinal disease that disrupts cone function from birth, leaving patients with complete colour blindness, low acuity, photosensitivity and nystagmus. While successful gene-replacement therapy in non-primate models of achromatopsia has raised widespread hopes for clinical treatment, it was yet to be determined if and how these therapies can induce new cone function in the human brain. Using a novel multimodal approach, we demonstrate for the first time that gene therapy can successfully activate dormant cone-mediated pathways in children with achromatopsia (CNGA3- and CNGB3-associated, 10-15 years). To test this, we combined functional MRI population receptive field mapping and psychophysics with stimuli that selectively measure cone photoreceptor signalling. We measured cortical and visual cone function before and after gene therapy in four paediatric patients, evaluating treatment-related change against benchmark data from untreated patients (n = 9) and normal-sighted participants (n = 28). After treatment, two of the four children displayed strong evidence for novel cone-mediated signals in visual cortex, with a retinotopic pattern that was not present in untreated achromatopsia and which is highly unlikely to emerge by chance. Importantly, this change was paired with a significant improvement in psychophysical measures of cone-mediated visual function. These improvements were specific to the treated eye, and provide strong evidence for successful read-out and use of new cone-mediated information. These data show for the first time that gene replacement therapy in achromatopsia within the plastic period of development can awaken dormant cone-signalling pathways after years of deprivation. This reveals unprecedented neural plasticity in the developing human nervous system and offers great promise for emerging regenerative therapies.
Assuntos
Defeitos da Visão Cromática , Humanos , Criança , Defeitos da Visão Cromática/genética , Defeitos da Visão Cromática/terapia , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Eletrorretinografia , Células Fotorreceptoras Retinianas Cones , Terapia GenéticaRESUMO
OBJECTIVES: We report an unusual case of corneal decompensation occurring four decades after complicated cataract extraction with implantation of a Sputnik intraocular lens (IOL) and highlight the clinical and practical issues faced in managing corneal decompensation with a Sputnik IOL. METHODS: A 72-year-old woman presented with deterioration of the vision in her left eye, four decades after intracapsular cataract extraction with Sputnik IOL implantation. Ocular examination revealed diffuse corneal edema and thickened vitreous strands in the anterior chamber. Her best-corrected visual acuity (BCVA) worsened to 6/60 within 3 months. Anterior vitrectomy and inferior iridectomy combined with Desçemet-stripping automated endothelial keratoplasty was performed. RESULTS: The procedure was successful, with the patient achieving best-corrected visual acuity of 6/6 at 8 months postoperatively. CONCLUSION: Corneal decompensation after Sputnik IOL implantation can occur four decades later. When the historical preoperative visual acuity is good in such cases, careful anterior vitrectomy with Desçemet-stripping automated endothelial keratoplasty provides good visual rehabilitation.
Assuntos
Edema da Córnea/terapia , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior , Iridectomia/métodos , Implante de Lente Intraocular/efeitos adversos , Complicações Pós-Operatórias/terapia , Vitrectomia/métodos , Idoso , Feminino , Humanos , Fatores de Tempo , Resultado do TratamentoRESUMO
Achromatopsia is an inherited retinal disease that affects 1 in 30,000-50,000 individuals and is characterised by an absence of functioning cone photoreceptors from birth. This results in severely reduced visual acuity, no colour vision, marked sensitivity to light and involuntary oscillations of the eyes (nystagmus). In most cases, a single gene mutation prevents normal development of cone photoreceptors, with mutations in the CNGB3 or CNGA3 gene being responsible for â¼80â¯% of all patients with achromatopsia. There are a growing number of studies investigating recovery of cone function after targeted gene therapy. These studies have provided some promise for patients with the CNGA3 mutation, but thus far have found limited or no recovery for patients with the CNGB3 mutation. Here, we developed colour-calibrated visual stimuli designed to isolate cone photoreceptor responses. We combined these with adapted fMRI techniques and pRF mapping to identify if cortical responses to cone-driven signals could be detected in 9 adult patients with the CNGB3 mutation after receiving gene therapy. We did not detect any change in brain activity after gene therapy when the 9 patients were analysed as a group. However, on an individual basis, one patient self-reported a change in colour perception, corroborated by improved performance on a psychophysical task designed to selectively identify cone function. This suggests a level of cone sensitivity that was lacking pre-treatment, further supported by a subtle but reliable change in cortical activity within their primary visual cortex.
Assuntos
Defeitos da Visão Cromática , Canais de Cátion Regulados por Nucleotídeos Cíclicos , Terapia Genética , Imageamento por Ressonância Magnética , Mutação , Células Fotorreceptoras Retinianas Cones , Humanos , Adulto , Defeitos da Visão Cromática/genética , Defeitos da Visão Cromática/terapia , Defeitos da Visão Cromática/fisiopatologia , Terapia Genética/métodos , Masculino , Imageamento por Ressonância Magnética/métodos , Feminino , Mutação/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Células Fotorreceptoras Retinianas Cones/fisiologia , Pessoa de Meia-Idade , Adulto Jovem , Estimulação Luminosa/métodos , Percepção de Cores/fisiologia , Córtex Visual/diagnóstico por imagemRESUMO
PURPOSE: To assess the safety and efficacy of AAV8-hCARp.hCNGB3 in participants with CNGB3-associated achromatopsia (ACHM). DESIGN: Prospective, phase 1/2 (NCT03001310), open-label, nonrandomized clinical trial. METHODS: The study enrolled 23 adults and children with CNGB3-associated ACHM. In the dose-escalation phase, adult participants were administered 1 of 3 AAV8-hCARp.hCNGB3 dose levels in the worse-seeing eye (up to 0.5 mL). After a maximum tolerated dose was established in adults, an expansion phase was conducted in children ≥3 years old. All participants received topical and oral corticosteroids. Safety and efficacy parameters, including treatment-related adverse events and visual acuity, retinal sensitivity, color vision, and light sensitivity, were assessed for 6 months. RESULTS: AAV8-hCARp.hCNGB3 (11 adults, 12 children) was safe and generally well tolerated. Intraocular inflammation occurred in 9 of 23 participants and was mainly mild or moderate in severity. Severe cases occurred primarily at the highest dose. Two events were considered serious and dose limiting. All intraocular inflammation resolved following topical and systemic steroids. There was no consistent pattern of change from baseline to week 24 for any efficacy assessment. However, favorable changes were observed for individual participants across several assessments, including color vision (nâ¯=â¯6/23), photoaversion (nâ¯=â¯11/20), and vision-related quality-of-life questionnaires (nâ¯=â¯21/23). CONCLUSIONS: AAV8-hCARp.hCNGB3 for CNGB3-associated ACHM demonstrated an acceptable safety and tolerability profile. Improvements in several efficacy parameters indicate that AAV8-hCARp.hCNGB3 gene therapy may provide benefit. These findings, with the development of additional sensitive and quantitative end points, support continued investigation.
Assuntos
Defeitos da Visão Cromática , Humanos , Adulto , Criança , Pré-Escolar , Defeitos da Visão Cromática/genética , Defeitos da Visão Cromática/terapia , Estudos Prospectivos , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Terapia Genética , InflamaçãoRESUMO
PURPOSE: To describe the nystagmus characteristics of subjects with molecularly confirmed CNGB3-associated achromatopsia and report the spectral domain optical coherence tomography (SD-OCT) findings in these individuals. METHODS: Adults and children with CNGB3-achromatopsia underwent visual acuity testing, ocular motility assessments, video nystagmography, and SD-OCT imaging. Qualitative assessment of foveal structure was performed by grading SD-OCT images into one of five categories. RESULTS: A total of 18 subjects (11 adults) were included. The majority demonstrated a phoria, with manifest strabismus present in only 3 subjects. The predominant nystagmus waveform within the cohort was pure pendular. Nine individuals demonstrated a mixture of waveforms. Nystagmus frequencies were 4-8 cycles/second, with no notable differences in eye movements between adults and children. SD-OCT imaging revealed a continuous ellipsoid zone (EZ) at the fovea in 2 subjects (grade 1) and EZ disruption (grade 2) in the remaining 16. Retinal structure characteristics were symmetrical in both eyes in each subject. CONCLUSIONS: In our study cohort, nystagmus in CNGB3-associated achromatopsia had distinctive features, and the majority of subjects had retinal abnormalities at the fovea on SD-OCT. Early use of SD-OCT in the clinical work-up may eliminate the need for more invasive investigations, such as neuro-imaging.
Assuntos
Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Nistagmo Patológico , Defeitos da Visão Cromática , Fóvea Central , Humanos , Nistagmo Patológico/diagnóstico por imagem , Tomografia de Coerência ÓpticaRESUMO
Purpose: To examine repeatability and reproducibility of foveal cone density measurements in patients with CNGA3- and CNGB3-associated achromatopsia (ACHM) using split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). Methods: Thirty foveae from molecularly confirmed subjects with ACHM, half of whom harbored disease-causing variants in CNGA3 and half in CNGB3, underwent nonconfocal split-detection AOSLO imaging. Cone photoreceptors within the manually delineated rod-free zone were manually identified twice by two independent observers. The coordinates of the marked cones were used for quantifying foveal cone density. Cone density and difference maps were generated to compare cone topography between trials. Results: We observed excellent intraobserver repeatability in foveal cone density estimates, with intraclass correlation coefficients (ICCs) ranging from 0.963 to 0.991 for CNGA3 and CNGB3 subjects. Interobserver reproducibility was also excellent for both CNGA3 (ICC = 0.952; 95% confidence interval [CI], 0.903-1.0) and CNGB3 (ICC = 0.968; 95% CI, 0.935-1.0). However, Bland-Altman analysis revealed bias between observers. Conclusions: Foveal cone density can be measured using the described method with good repeatability and reproducibility both for CNGA3- and CNGB3-associated ACHM. Any degree of bias observed among the observers is of uncertain clinical significance but should be evaluated on a study-specific basis. Translational Relevance: This approach could be used to explore disease natural history, as well as to facilitate stratification of patients and monitor efficacy of interventions for ongoing and upcoming ACHM gene therapy trials.
Assuntos
Defeitos da Visão Cromática , Defeitos da Visão Cromática/diagnóstico , Canais de Cátion Regulados por Nucleotídeos Cíclicos , Fóvea Central/diagnóstico por imagem , Humanos , Reprodutibilidade dos Testes , Células Fotorreceptoras Retinianas ConesRESUMO
Purpose: To investigate the long-term natural history of retinal function of achromatopsia (ACHM). Methods: Subjects with molecularly confirmed ACHM were recruited in a prospective cohort study of mesopic microperimetry. Coefficient of repeatability and intraclass correlation coefficient (ICC) of mean sensitivity (MS) were calculated. Best-corrected visual acuity (BCVA), bivariate contour ellipse area (BCEA), contrast sensitivity (CS), MS, total volume (VTOT), and central field volume (V5°) from volumetric and topographic analyses were acquired. Correlation of functional parameters with structural findings from optical coherence tomography (OCT) was performed. Results: Eighteen subjects were recruited. Mean follow-up was 7.2 years. The MS test-retest repeatability coefficient was 1.65 decibels (dB), and the ICC was 0.973 (95% confidence interval, 0.837-0.98). Mean MS was similar for right and left eyes (16.97dB and 17.14dB, respectively). A negative significant correlation between logMAR BCVA and the retinal sensitivity indices (MS, VTOT, V5°) was found. A significant negative correlation between logCS and MS, VTOT, and V5° was also observed. BCVA and BCEA improved during follow-up. Mean CS, MS, VTOT, and V5° at final follow-up were similar to baseline. MS was similar between CNGA3- and CNGB3-ACHM. Patients with and without the presence of a foveal ellipsoid zone on OCT had similar MS (16.64 dB and 17.17 dB, respectively). Conclusions: We demonstrate a highly reproducible assessment of MS. Retinal function including MS, volumetric indices, and CS are stable in ACHM. Improvement of fixation stability and small changes of BCVA over time may be part of the natural history of the disease.
Assuntos
Defeitos da Visão Cromática/fisiopatologia , Fóvea Central/fisiopatologia , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Campos Visuais/fisiologia , Adolescente , Adulto , Idoso , Criança , Feminino , Seguimentos , Fóvea Central/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Adulto JovemRESUMO
Purpose: The purpose of this study was to report GNAT2-associated achromatopsia (GNAT2-ACHM) natural history, characterize photoreceptor mosaic, and determine a therapeutic window for potential intervention. Methods: Patients with GNAT2-ACHM were recruited from a single tertiary referral eye center (Moorfields Eye Hospital, London, UK). We performed longitudinal clinical evaluation and ophthalmic examination, and multimodal retinal imaging, including adaptive optics scanning light ophthalmoscopy, quantitative analysis of the cone mosaic, and outer nuclear layer (ONL) thickness, including cone densities evaluation in selected regions of interest and comparison with reported healthy controls. Results: All nine subjects (3 women) presented with nystagmus, decreased visual acuity (VA), light sensitivity, and highly variable color vision loss. One patient had normal color vision and better VA. Mean VA was 1.01 (±0.10) logarithms of the minimal angle of resolution (LogMAR) at baseline, and 1.04 (±0.10) LogMAR after a mean follow-up (range) of 7.6 years (1.7-12.8 years). Optical coherence tomography showed preservation of the foveal ellipsoid zone (EZ; n = 8; 88.9%), and EZ disruption (n = 1; 11.1%). Mean ONL thickness (range, ± SD) was 84.72 µm (28.57-113.33, ± 25.46 µm) and 86.47 µm (28.57-113.33, ± 24.65 µm) for right and left eyes, respectively. Mean cone densities (±SD) at 190 µm, 350 µm, and 500 µm from the foveal center, were 48.4 (±24.6), 37.8 (±14.7), and 30.7 (±9.9), ×103 cones/mm2, respectively. Mean cone densities were lower than these of unaffected individuals, but with an overlap. Conclusions: The cone mosaic in GNAT2-ACHM is relatively well preserved, potentially allowing for a wide therapeutic window for cone-directed interventions.
Assuntos
Defeitos da Visão Cromática/genética , Defeitos da Visão Cromática/patologia , Subunidades gama da Proteína de Ligação ao GTP/genética , Células Fotorreceptoras Retinianas Cones/patologia , Adolescente , Adulto , Criança , Testes de Percepção de Cores , Eletrorretinografia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Nistagmo Patológico/diagnóstico , Oftalmoscopia , Imagem Óptica , Linhagem , Fenótipo , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Adulto JovemRESUMO
BACKGROUND: Carbonic anhydrase inhibitors (CAIs) are frequently used as an initial step to treat retinitis pigmentosa-associated cystoid macular oedema (RP-CMO). Interestingly, it has been postulated that CAIs might reduce outer nuclear layer (ONL) fluid more effectively than inner nuclear layer (INL) fluid due to better access to retinal pigment epithelium basolateral membrane than neurosensory retina. This retrospective cohort study explores if an association between spatial distribution of cystoid spaces in RP-CMO and CAI response exists. METHODS: Two independent graders reviewed pretreatment and post-treatment optical coherence tomography (OCT) images of 25 patients (43 eyes) initiated on topical and/or oral CAIs between January 2013 and December 2014. Documentation included the presence/absence of fluid (and layer(s) involved), external limiting membrane, epiretinal membrane (ERM), vitreomacular adhesion/traction, lamellar/full-thickness macular hole and central macular thickness (CMT)/volume. RESULTS: INL fluid was found in all study eyes. All 13 'responders' (at least 11% reduction of CMT after treatment) demonstrated pretreatment ONL fluid. In seven patients (four responders and three non-responders), complete clearance of ONL fluid was achieved despite persistence of INL fluid. ERM presence was similar in responders and non-responders. CONCLUSION: In this study, INL fluid was found to be the most common spatial distribution of RP-CMO. However, patients who were classed as a 'responder' to CAI treatment all demonstrated coexisting ONL fluid on their pretreatment OCT scans. This may be explained by CAIs having better access to retinal pigment epithelium basolateral membrane than neurosensory retina. Our study also suggests a minimal impact on response to CAIs by ERM.
Assuntos
Inibidores da Anidrase Carbônica/uso terapêutico , Edema Macular/etiologia , Retinose Pigmentar/complicações , Acetazolamida/uso terapêutico , Adolescente , Adulto , Idoso , Feminino , Humanos , Edema Macular/diagnóstico por imagem , Edema Macular/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Retinose Pigmentar/diagnóstico por imagem , Retinose Pigmentar/tratamento farmacológico , Estudos Retrospectivos , Sulfonamidas/uso terapêutico , Tiazinas/uso terapêutico , Tiofenos/uso terapêutico , Tomografia de Coerência Óptica , Acuidade Visual , Testes de Campo Visual , Adulto JovemRESUMO
Purpose: To investigate retinal structure in subjects with CNGA3-associated achromatopsia and evaluate disease symmetry and intrafamilial variability. Methods: Thirty-eight molecularly confirmed subjects underwent ocular examination, optical coherence tomography (OCT), and nonconfocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). OCT scans were used for evaluating foveal hypoplasia, grading foveal ellipsoid zone (EZ) disruption, and measuring outer nuclear layer (ONL) thickness. AOSLO images were used to quantify peak foveal cone density, intercell distance (ICD), and the coefficient of variation (CV) of ICD. Results: Mean (±SD) age was 25.9 (±13.1) years. Mean (± SD) best corrected visual acuity (BCVA) was 0.87 (±0.14) logarithm of the minimum angle of resolution. Examination with OCT showed variable disruption or loss of the EZ. Seven subjects were evaluated for disease symmetry, with peak foveal cone density, ICD, CV, ONL thickness, and BCVA not differing significantly between eyes. A cross-sectional evaluation of AOSLO imaging showed a mean (±SD) peak foveal cone density of 19,844 (±13,046) cones/mm2. There was a weak negative association between age and peak foveal cone density (r = -0.397, P = 0.102), as well as between EZ grade and age (P = 0.086). Conclusions: The remnant cone mosaics were irregular and variably disrupted, with significantly lower peak foveal cone density than unaffected individuals. Variability was also seen among subjects with identical mutations. Therefore, subjects should be considered on an individual basis for stratification in clinical trials. Interocular symmetry suggests that both eyes have comparable therapeutic potential and the fellow eye can serve as a valid control. Longitudinal studies are needed, to further examine the weak negative association between age and foveal cone structure observed here.
Assuntos
Defeitos da Visão Cromática/diagnóstico por imagem , Defeitos da Visão Cromática/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Retina/diagnóstico por imagem , Adolescente , Adulto , Criança , Estudos Transversais , Eletrorretinografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oftalmoscopia , Óptica e Fotônica , Células Fotorreceptoras de Vertebrados/patologia , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Adulto JovemRESUMO
Purpose: To perform deep phenotyping of subjects with PDE6C achromatopsia and examine disease natural history. Methods: Eight subjects with disease-causing variants in PDE6C were assessed in detail, including clinical phenotype, best-corrected visual acuity, fundus autofluorescence, and optical coherence tomography. Six subjects also had confocal and nonconfocal adaptive optics scanning light ophthalmoscopy, axial length, international standard pattern and full-field electroretinography (ERG), short-wavelength flash (S-cone) ERGs, and color vision testing. Results: All subjects presented with early-onset nystagmus, decreased best-corrected visual acuity, light sensitivity, and severe color vision loss, and five of them had high myopia. We identified three novel disease-causing variants and provide phenotype data associated with nine variants for the first time. No subjects had foveal hypoplasia or residual ellipsoid zone (EZ) at the foveal center; one had an absent EZ, three had a hyporeflective zone, and four had outer retinal atrophy. The mean width of the central EZ lesion on optical coherence tomography at baseline was 1923 µm. The mean annual increase in EZ lesion size was 48.3 µm. Fundus autofluorescence revealed a central hypoautofluorescence with a surrounding ring of increased signal (n = 5). The mean hypoautofluorescent area at baseline was 3.33 mm2 and increased in size by a mean of 0.13 mm2/year. Nonconfocal adaptive optics scanning light ophthalmoscopy revealed residual foveal cones in only one of two cases. Full-field ERGs were consistent with severe generalized cone system dysfunction but with relative preservation of S-cone sensitivity. Conclusions: PDE6C retinopathy is a severe cone dysfunction syndrome often presenting as typical achromatopsia but without foveal hypoplasia. Myopia and slowly progressive maculopathy are common features. There are few (if any) residual foveal cones for intervention in older adults.
Assuntos
Defeitos da Visão Cromática/genética , Visão de Cores/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Proteínas do Olho/genética , Acuidade Visual , Adolescente , Adulto , Criança , Defeitos da Visão Cromática/diagnóstico , Defeitos da Visão Cromática/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo , Eletrorretinografia , Proteínas do Olho/metabolismo , Feminino , Seguimentos , Previsões , Humanos , Masculino , Pessoa de Meia-Idade , Oftalmoscopia , Fenótipo , Tomografia de Coerência Óptica/métodos , Adulto JovemRESUMO
Achromatopsia is an autosomal recessive condition, characterised by reduced visual acuity, impaired colour vision, photophobia and nystagmus. The symptoms can be profoundly disabling, and there is no cure currently available. However, the recent development of gene-based interventions may lead to improved outcomes in the future. This article aims to provide a comprehensive review of the clinical features of the condition, its genetic basis and the underlying pathogenesis. We also explore the insights derived from animal models, including the implications for gene supplementation approaches. Finally, we discuss current human gene therapy trials.
Assuntos
Defeitos da Visão Cromática , Modelos Animais de Doenças , Terapia Genética , Biologia Molecular , Animais , Defeitos da Visão Cromática/diagnóstico , Defeitos da Visão Cromática/genética , Defeitos da Visão Cromática/terapia , HumanosRESUMO
Purpose: To longitudinally characterize structural retinal changes in achromatopsia (ACHM) over extended follow-up. Methods: Fifty molecularly confirmed ACHM subjects underwent serial spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging. Foveal structure on SD-OCT was graded and compared for evidence of progression, and foveal total retinal thickness (FTRT) and outer nuclear layer (ONL) thickness were serially measured. FAF patterns were characterized and compared over time. Results: Mean SD-OCT follow-up was 61.6 months (age range at baseline, 6-52 years). Forty-five of the subjects had serial FAF (mean follow-up: 48.5 months). Only 6 (12%) of the subjects demonstrated qualitative change on serial foveal SD-OCT scans. Among the entire cohort, there was no statistically significant change over time in FTRT (P = 0.2459) or hyporeflective zone (HRZ) diameter (P = 0.3737). There was a small-but statistically significant-increase in ONL thickness (P = 0.0084). Three different FAF patterns were observed: centrally increased FAF (13/45), normal FAF (14/45), and well-demarcated reduced FAF (18/45), with the latter group displaying a small gradual increase in the area of reduced FAF of 0.055 mm2 over 43.4 months (P = 0.0011). Conclusions: This longitudinal study of retinal structure in ACHM represents the largest cohort and longest follow-up period to date. Our findings support the presiding notion that ACHM is essentially a stationary condition regarding retinal structure, and any change over time is likely to be small, slow, and variable across patients. This may potentially afford a wider window for therapeutic intervention.
Assuntos
Defeitos da Visão Cromática/diagnóstico , Retina/patologia , Adolescente , Adulto , Criança , Defeitos da Visão Cromática/genética , Defeitos da Visão Cromática/fisiopatologia , Feminino , Angiofluoresceinografia , Seguimentos , Fóvea Central , Estudos de Associação Genética , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Testes de Campo Visual , Campos Visuais/fisiologia , Adulto JovemRESUMO
PURPOSE: To characterize a series of 7 patients with cone-rod dystrophy (CORD) and amelogenesis imperfecta (AI) owing to confirmed mutations in CNNM4, first described as "Jalili Syndrome." DESIGN: Retrospective observational case series. METHODS: Seven patients from 6 families with Jalili Syndrome were identified at 3 tertiary referral centers. We systematically reviewed their available medical records, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging (FAF), color fundus photography, and electrophysiological assessments. RESULTS: The mean age at presentation was 6.7 years (range 3-16 years), with 6 male and 1 female patient. CNNM4 mutations were identified in all patients. The mean Snellen best-corrected visual acuity (BCVA) at presentation was 20/246 (range 20/98 to 20/399) in the right eye and 20/252 (range 20/98 to 20/480) in the left. Nystagmus was observed in all 7 patients, and photophobia was present in 6. Funduscopic findings at presentation were variable, ranging from only mild disc pallor to retinal vascular attenuation and macular atrophy. Multimodal imaging demonstrated disease progression in all 7 patients over time. Electroretinography uniformly revealed progressive cone-rod dysfunction. CONCLUSIONS: Jalili Syndrome is a rare CORD associated with AI. We have further characterized its ocular phenotype, including describing SD-OCT, FAF, and electrophysiological features; and report several novel disease-causing sequence variants. Moreover, this study presents novel longitudinal data demonstrating structural and functional progression over time, allowing better informed advice on prognosis.
Assuntos
Amelogênese Imperfeita/diagnóstico , Distrofias de Cones e Bastonetes/diagnóstico , Adolescente , Amelogênese Imperfeita/genética , Proteínas de Transporte de Cátions/genética , Criança , Pré-Escolar , Distrofias de Cones e Bastonetes/genética , Estudos Transversais , Eletrorretinografia , Feminino , Angiofluoresceinografia , Humanos , Estudos Longitudinais , Masculino , Imagem Multimodal , Mutação , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologiaRESUMO
Aspartate is released in the brain during metabolic inhibition and can activate NMDA receptors. We compared the characteristics of aspartate and glutamate release mediated by reversed operation of GLAST glutamate transporters in salamander retinal glial cells, when high [K(+)](o) solution was applied to mimic the ionic conditions of stroke or glaucoma. In the absence of Cl(-), to isolate the transport-associated current of the transporters, reversed uptake of aspartate and glutamate had similar characteristics. Both were increased strongly by depolarisation, inhibited by the transport inhibitor TBOA (DL-threo-beta-benzyloxyaspartate), and activated in a first order manner by intracellular amino acid (in the presence of 20mM [Na(+)](i)) with an EC(50) of 0.8mM for aspartate and 2.3mM for glutamate. In stroke the extracellular pH shifts acid by around a pH unit: this reduced the release of aspartate and glutamate by reversed uptake by a factor of 8-20. The external Cl(-) concentration had only a small effect on the current associated with reversed uptake of aspartate and glutamate. Tamoxifen, which reduces amino acid release through swelling-activated anion channels in glial cells, was found to inhibit reversed uptake with an IC(50) which was >100 microM. Part of the activation of NMDA receptors which occurs in ischaemia is likely to reflect the release of aspartate by reversed uptake.
Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Ácido Aspártico/metabolismo , Animais , Ácido Aspártico/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Estimulação Elétrica/métodos , Ácido Glutâmico/metabolismo , Concentração de Íons de Hidrogênio , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Potenciais da Membrana/efeitos da radiação , Neuroglia/efeitos dos fármacos , Neuroglia/fisiologia , Potássio/metabolismo , Retina/citologia , UrodelosRESUMO
UNLABELLED: We report the case of a woman with pseudoexfoliation who presented with a hyperopic refractive surprise and uncontrolled intraocular pressure (IOP) following cataract surgery and in-the-bag intraocular lens (IOL) implantation in the left eye. Trabeculectomy was performed, and a supplementary (piggyback) sulcus IOL was inserted. At 5 years, the uncorrected distance visual acuity (UDVA) was 20/16 and the IOP was less than 21 mm Hg. Following head trauma, the patient experienced blurred vision. The UDVA was 20/125, correcting to 20/25 with +3.00 -0.75 × 105. The IOL in the capsular bag was not dislocated, but the sulcus IOL was not in the posterior chamber; it was found by ultrasound in the temporal anterior vitreous gel. At-risk patients having supplementary IOL insertion should be warned of this possible late problem. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned.
Assuntos
Migração do Implante de Lente Intraocular/etiologia , Lentes Intraoculares , Pseudofacia/etiologia , Idoso , Migração do Implante de Lente Intraocular/cirurgia , Traumatismos Craniocerebrais/etiologia , Feminino , Humanos , Acuidade Visual/fisiologiaRESUMO
A previously healthy 61-year-old male presented to eye casualty with a left-sided Horner's syndrome. He reported that while offering strong vocal support at a football match 5 days previously, he had suddenly noticed an unusual sensation behind his left eye, accompanied by a left hemifacial headache. He had noted pupillary asymmetry soon after this. Radiological imaging revealed a left internal carotid artery dissection. Anticoagulant therapy was commenced, and all symptoms and signs had fully resolved at 1-month follow-up, with no further complications.
Assuntos
Dissecação da Artéria Carótida Interna/etiologia , Voz , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
A previously healthy 37-year-old woman presented with decreased vision in the right eye, noted suddenly during childbirth. Fundus examination revealed elevation at the right macula, and optical coherence tomography confirmed central serous chorioretinopathy in the right eye. No intervention was undertaken, and the symptoms and clinical findings resolved spontaneously over 2 months.