RESUMO
PURPOSE: To assess the genotypic diversity in patients with Stargardt disease and to characterise epidemiological and genotypic predictors of phenotype. METHODS: Retrospective, cross-sectional study of 112 patients with Stargardt disease. We evaluated the correlation between age at presentation, best-corrected visual acuity (BCVA), and ABCA4 genotypes. RESULTS: Mean age at presentation was 30 ± 16 years (range 6-78 years) for the 112 patients of 104 families. 98 of 90 families had a probable molecular diagnosis. We found that BCVA is not related to age of presentation in a linear or polynomial manner; that BCVA of patients presenting in the first decade was significantly worse than those presenting in later decades (p=0.04); that patients who harboured two or more mutations presented earlier and had worse BCVA than those with no or 1 mutation identified by any method of testing (n=112, p=3.29 × 10(-6)) or by full sequencing (n=32, p=0.02); that 16 patients with c.5882G>A allele demonstrated better BCVA than the remaining patients (p=0.01); and that 10 patients with the c.5461-10T>C mutation presented earlier (p=0.02 × 10(-5)) and had more severe disease. CONCLUSIONS: Epidemiological and genotypical findings portend visual prognosis in patients with Stargardt disease. Select sequence variations in ABCA4 may confer a specific phenotype. The present data will help in assessing patients for emerging therapies.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Acuidade Visual/fisiologia , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Estudos Transversais , Eletrorretinografia , Feminino , Angiofluoresceinografia , Estudos de Associação Genética , Genótipo , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/genética , Degeneração Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Estudos Retrospectivos , Doença de Stargardt , Tomografia de Coerência Óptica , Adulto JovemRESUMO
PURPOSE: To describe the clinical and molecular findings in ten unrelated African American patients with Stargardt disease. DESIGN: Retrospective, observational case series. METHODS: We reviewed the clinical histories, examinations, and genotypes of 85 patients with molecular diagnoses of Stargardt disease. Three ABCA4 sequence variations identified exclusively in African Americans were evaluated in 300 African American controls and by in silico analysis. RESULTS: ABCA4 sequence changes were identified in 85 patients from 80 families, of which 11 patients identified themselves as African American. Of these 11 patients, 10 unrelated patients shared 1 of 3 ABCA4 sequence variations: c.3602T>G (p.L1201R); c.3899G>A (p.R1300Q); or c.6320G>A (p.R2107H). The minor allele frequencies in the African American control population for each variation were 7.5%, 6.3%, and 2%, respectively. This is comparable to the allele frequency in African Americans in the Exome Variant Server. In contrast, the allele frequency of all three of these variations was less than or equal to 0.05% in European Americans. Although both c.3602T>G and c.3899G>A have been reported as likely disease-causing variations, one of our control patients was homozygous for each variant, suggesting that these are nonpathogenic. In contrast, the absence of c.6320G>A in the control population in the homozygous state, combined with the results of bioinformatics analysis, support its pathogenicity. CONCLUSIONS: Three ABCA4 sequence variations were identified exclusively in 10 unrelated African American patients: p.L1201R and p.R1300Q likely represent nonpathogenic sequence variants, whereas the p.R2107H substitution appears to be pathogenic. Characterization of population-specific disease alleles may have important implications for the development of genetic screening algorithms.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Negro ou Afro-Americano/genética , Variação Genética , Adolescente , Adulto , Sequência de Bases/genética , Eletrorretinografia , Feminino , Angiofluoresceinografia , Frequência do Gene , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Doença de Stargardt , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: To evaluate the efficacy of the pattern scan laser (PASCAL) in treating newly diagnosed high-risk proliferative diabetic retinopathy (PDR). DESIGN: Retrospective comparative case series. SETTING: Institutional. STUDY POPULATION: Eighty-two consecutive eyes of the same number of patients with newly diagnosed high-risk PDR treated with panretinal photocoagulation (PRP) using either argon green laser (41 eyes treated before February 2007) or PASCAL (41 eyes treated February 2007 or thereafter), then followed for at least 6 months. PROCEDURE: Retrospective chart review with attention to main outcome measures, age, sex, race, follow-up interval, insulin dependence, hemoglobin A1c, and total number of lasers spots. MAIN OUTCOME MEASURES: Persistence or recurrence of neovascularization, incidence of vitreous hemorrhage (VH), neovascularization of the iris (NVI), neovascular glaucoma (NVG), and need for vitrectomy. RESULTS: Patients treated with the PASCAL and argon laser received a similar number of spots (1438 vs 1386; P = .59). Patients treated with the PASCAL were more likely to experience persistence or recurrence of neovascularization within 6 months of initial treatment (73% vs 34%; P < .0008). The study was not adequately powered to detect a significant difference in incidence of vitreous hemorrhage, NVI, NVG, or need for vitrectomy. CONCLUSIONS: When using traditional laser settings, PRP performed with the PASCAL is less effective than that performed with traditional argon laser in effecting lasting regression of retinal neovascularization in the setting of previously untreated high-risk PDR. Physicians may need to change treatment parameters when using PASCAL pattern laser therapy for high-risk PDR.
Assuntos
Retinopatia Diabética/cirurgia , Fotocoagulação a Laser , Lasers de Excimer/uso terapêutico , Lasers de Estado Sólido/uso terapêutico , Retina/cirurgia , Neovascularização Retiniana/cirurgia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/fisiopatologia , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Retina/fisiopatologia , Neovascularização Retiniana/fisiopatologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
A 58-year-old man with Darier's disease developed endophthalmitis 3 days following left-sided cataract extraction with intraocular lens implantation. Vitreous cultures were positive for Pseudomonas aeruginosa, similar to previously cultured hyperkeratotic plaques on the patient. Despite emergent vitrectomy and aggressive treatment with systemic, intravitreal, and topical fortified antibiotics, the patient required evisceration 19 days postoperatively. Bacterial overgrowth within hyperkeratotic plaques may increase the risk of endophthalmitis following intraocular surgery in patients with Darier's disease.
Assuntos
Extração de Catarata/efeitos adversos , Catarata/complicações , Doença de Darier/complicações , Endoftalmite/etiologia , Implante de Lente Intraocular/efeitos adversos , Complicações Pós-Operatórias , Doença Aguda , Antibacterianos/uso terapêutico , Endoftalmite/microbiologia , Endoftalmite/patologia , Endoftalmite/cirurgia , Evisceração do Olho , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosaRESUMO
Herein we report a 52-year-old man with subacute right-sided proptosis and diffuse intraconal enhancing abnormality on MRI. Orbital biopsy revealed granulomatous inflammation consistent with idiopathic orbital inflammatory syndrome (IOIS), or orbital pseudotumor. However, further examination under polarizing light microscopy also revealed acetate fiber fragments within the orbit. Prominent speckles within the acetate fibers were identified as titanium by Energy Dispersive X-ray Analysis (EDXA). Acetate impregnated with titanium (as a delustrant) is a common synthetic fiber used in textile and clothing manufacture. The mechanism for entrance into the orbit in this case is not known. Granulomatous idiopathic orbital inflammatory syndrome without local or systemic cause is an uncommon clinical entity, with less than 50 cases reported in the literature. Predominance of lacrimal gland (and thus superficial) involvement in granulomatous IOIS suggests the possibility of occult foreign body in such cases.
Assuntos
Granuloma de Corpo Estranho/etiologia , Granuloma de Corpo Estranho/cirurgia , Pseudotumor Orbitário/diagnóstico , Pseudotumor Orbitário/cirurgia , Titânio/efeitos adversos , Biópsia por Agulha , Análise Química do Sangue , Meios de Contraste , Exoftalmia/diagnóstico , Exoftalmia/etiologia , Seguimentos , Granuloma de Corpo Estranho/diagnóstico , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética/métodos , Masculino , Manometria/métodos , Pessoa de Meia-Idade , Pseudotumor Orbitário/etiologia , Cuidados Pós-Operatórios/métodos , Prednisona/uso terapêutico , Resultado do TratamentoRESUMO
Aicardi syndrome was originally described as a triad of partial or complete agenesis of the corpus callosum, infantile spasms, and pathognomic chorioretinal lacunae. Of approximately 200 cases reported since it was originally described in 1965, there have been no undisputed reports of Aicardi syndrome in a 46 XY male. Thus a dominant X-linked inheritance, presumed lethal in males, has been proposed. Herein we report a 5 year-old 46 XY male with the classic clinical triad of Aicardi syndrome.
Assuntos
Agenesia do Corpo Caloso , Cromossomos Humanos X , Nervo Óptico/anormalidades , Doenças Retinianas/genética , Aberrações dos Cromossomos Sexuais , Espasmos Infantis/genética , Pré-Escolar , Genótipo , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Convulsões/genética , SíndromeRESUMO
Age-related macular degeneration (AMD) affects an estimated 14 million people worldwide, and is the leading cause of severe, irreversible vision loss in individuals over the age of 50 years in Western societies. Choroidal neovascularization (CNV), the hallmark of 'wet', 'exudative' or 'neovascular' AMD, is responsible for approximately 90% of cases of severe vision loss due to AMD. Vascular endothelial growth factor (VEGF) has been shown to play a key role in the regulation of CNV and vascular permeability. Ranibizumab, the current gold standard in the US for the treatment of neovascular AMD, exerts its effect through binding and inhibition of all isoforms of VEGF. Randomized controlled clinical trials have established ranibizumab as the first US FDA-approved therapy for neovascular AMD to result in improvement in visual acuity. Despite impressive outcomes, treatment with ranibizumab requires sustained treatment regimens and frequent intravitreal injections. In this review, we discuss promising emerging therapies for neovascular AMD that aim to improve outcomes, safety and treatment burden through novel mechanisms of action. Currently in phase III clinical trials, VEGF Trap is a receptor decoy that targets VEGF with higher affinity than ranibizumab and other currently available anti-VEGF agents. Another promising therapeutic strategy is the blockade of VEGF effects by inhibition of the tyrosine kinase cascade downstream from the VEGF receptor; such therapies currently in development include vatalanib, TG100801, pazopanib, AG013958 and AL39324. Small interfering RNA technology-based therapies have been designed to downregulate the production of VEGF (bevasiranib) or VEGF receptors (AGN211745) by degradation of specific messenger RNA. Other potential therapies include pigment epithelium-derived factor-based therapies, nicotinic acetylcholine receptor antagonists, integrin antagonists and sirolimus.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Degeneração Macular/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Proteínas do Olho/genética , Humanos , Fatores de Crescimento Neural/genética , Antagonistas Nicotínicos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , RNA Interferente Pequeno/genética , Serpinas/genética , Sirolimo/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/genéticaAssuntos
Neoplasias Oculares/patologia , Linfoma de Célula do Manto/patologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Terapia Combinada , Neoplasias Oculares/terapia , Feminino , Citometria de Fluxo , Humanos , Hibridização in Situ Fluorescente , Linfoma de Célula do Manto/terapia , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Radioimunoterapia , Radioterapia de Alta Energia , Acuidade VisualRESUMO
PURPOSE: To evaluate the short-term test/retest variability in visually normal subjects and patients with retinitis pigmentosa (RP), and to assess the effect of stimulus intensity and baseline amplitude on electroretinogram (ERG) variability. METHODS: Eighteen patients with RP and nine visually normal subjects had a series of three unilateral ERGs, with an inter-visit interval of no less than 2 days and no more than 2 weeks. Responses to dark-adapted and both light-adapted single flash and 32 Hz flicker stimuli were recorded from a dilated eye over a range of stimulus intensities. B-wave amplitudes were compared to baseline amplitudes recorded at initial visit, and the resulting inter-visit percent difference was compared between stimulus intensities. Inter-visit variability was determined by one-way repeated measures analysis of variance using a 95% confidence interval to calculate threshold criteria for significant change. Analysis of variance followed by Bonferroni test for pairwise comparison was used to test for differences in inter-visit variability between two RP patient subgroups (higher versus lower baseline amplitudes) and visually normal subjects. The effect of stimulus intensity on amplitude reproducibility was also assessed. RESULTS: Threshold for significant increase or decrease in inter-visit ERG amplitudes at a 95% confidence level for patients with RP and visually normal subjects was often at or above 25% and not infrequently at or above 40% for certain stimuli and test conditions. While no statistical difference in inter-visit variability was demonstrated between visually normal subjects and patients with RP who were arbitrarily categorized as having relatively higher baseline amplitudes, there was a difference between each of these two groups and a smaller group of patients with RP categorized as having lower baseline amplitudes. Although the authors could not demonstrate that percent inter-visit differences varied with stimulus intensity in either controls or patients with RP, the 32 Hz flicker stimulus generally produced less amplitude variability than either dark- or light-adapted single flash stimuli in patients with RP. CONCLUSIONS: When using ERG amplitude for monitoring either the natural history of functional loss in retinal disease or as an outcome measure during a therapeutic trial, it becomes vital to define inter-visit variability of ERG amplitudes. These findings suggest that a percentage of patients with RP with appreciably lower baseline ERG amplitudes may manifest greater inter-visit ERG amplitude variability than patients with RP with higher baseline amplitudes or controls. Stimulus intensity had no clinically significant effect on inter-visit amplitude variability.
Assuntos
Eletrorretinografia/normas , Retina/fisiologia , Retinose Pigmentar/fisiopatologia , Adulto , Idoso , Assistência Ambulatorial , Intervalos de Confiança , Adaptação à Escuridão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa , Reprodutibilidade dos Testes , Limiar Sensorial/fisiologiaRESUMO
PURPOSE: To determine whether mice that are homozygous for a targeted disruption of the Mer receptor tyrosine kinase gene (mer(kd)) manifest a retinal dystrophy phenotype similar to RCS rats, which carry a mutation in the orthologous gene MERTK: METHODS: Eyes of mer(kd) and C57BL/6 wild-type (WT) mice were examined by light and electron microscopy, whole-eye rhodopsin measurement, and Ganzfeld electroretinography (ERG). RESULTS: The mer(kd) mice showed rapid, progressive degeneration of the photoreceptors (PRs). Features of the phenotype common to mer(kd) mice and RCS rats included the absence or near absence of phagosomes in the retinal pigment epithelium (RPE) at the peak of outer segment (OS) disc shedding, accumulation of debris and whorls of membranes at the RPE-OS interface, transient supernormal rhodopsin content and OS lengths, the presence of OS vacuoles beginning at early ages, and a relatively slow removal of pyknotic PR nuclei. Most PRs were missing, and OS debris was removed by approximately postnatal day (P)45. Scotopic ERG responses were lower than age-matched WT responses and declined with PR loss. Photopic responses were preserved better than scotopic responses, corresponding with preferential cone preservation as judged histologically. ERG amplitudes were usually unmeasurable beyond P40, although a small-amplitude scotopic threshold response (STR) could still be elicited at P253 in some mice when only scattered PR nuclei remained. CONCLUSIONS: Ablation of Mer function in mer(kd) mice results in a retinal phenotype almost identical with that of RCS rats. The similarity in phenotypes between the two rodent models suggests that an RPE phagocytic defect is a feature of all types of retinal degeneration caused by loss of function of Mer tyrosine kinase, perhaps including mutations in human MERTK.
Assuntos
Proteínas Tirosina Quinases/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Proteína Tirosina Quinases , Retina/ultraestrutura , Degeneração Retiniana/enzimologia , Degeneração Retiniana/patologia , Animais , Eletrorretinografia , Immunoblotting , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose , Fagossomos/patologia , Fenótipo , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/metabolismo , Retina/enzimologia , Rodopsina/metabolismo , c-Mer Tirosina QuinaseAssuntos
Camundongos Knockout/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Degeneração Retiniana/genética , Animais , Adaptação à Escuridão , Limiar Diferencial , Eletrorretinografia , Camundongos , Camundongos Knockout/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Retina/patologia , Retina/fisiopatologia , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Degeneração Retiniana/fisiopatologia , c-Mer Tirosina QuinaseRESUMO
The purpose of the study was to evaluate the effects of pre-adaptation and ambient room luminance on the multifocal ERG (mfERG). We recorded mfERGs on 18 normal subjects (average age 32) using a VERIS system, with either 61 or 103 stimulus hexagons. mfERGs were recorded sequentially under different conditions of pre-adaptation and room lighting. Changing pre-adaptation conditions between darkness for 20 min, or light at 1.43 log cd/m2 for 10 min, had essentially no effect on the mfERG, regardless of ambient room lighting. However, mfERG parameters were sensitive to the level of ambient room lighting during the recordings. As room luminance was increased from darkness, there was a gradual attenuation of N1 and P1 amplitudes both centrally and peripherally that approached 25% reduction at 1.6 log cd/m2, and a decrease in P1 time-to-peak. These effects were greatest in the blind spot. The mfERG is largely independent of pre-adaptation conditions, but waveform amplitudes and times-to-peak diminish with increasing ambient room luminance. The exaggerated attenuation of signals in the blind spot with room lighting suggests that mfERGs recorded in the dark are contaminated by light scattered to dark-adapted peripheral retina. The most stable mfERG recording condition appears to be a fully lighted room (1.6 log cd/m2).
Assuntos
Adaptação Ocular/fisiologia , Eletrorretinografia/métodos , Retina/fisiologia , Adolescente , Adulto , Humanos , Iluminação , Pessoa de Meia-IdadeRESUMO
Past studies have shown that acute administration of ciliary neurotrophic factor (CNTF) can prolong the survival of retinal photoreceptor cells that have undergone phototoxic injury or that express gene mutations. Adenovirus-vectored CNTF has also been effective but for all of these treatments, the effect has been transient. On the other hand, adeno-associated virus-vectored minigenes offer considerable promise for long-term survival. The authors sought to provide long-term, CNTF-based protection of mouse photoreceptors expressing a dominant-negative point mutation in the rds gene by using recombinant adeno-associated virus (rAAV) to deliver minigenes that code for a secreted form of CNTF.Secreted CNTF, under control of a cytomegalovirus (CMV) or chick beta actin (CBA) promoter provided long-term, panretinal rescue of photoreceptors following single injections of rAAV vectors into the subretinal compartment. Rescue was much less effective and less reproducible when the vectors were placed in the vitreous compartment. However, there were unexpected side effects that appeared to be dose-related. One side effect was a change in rod photoreceptor nucleus phenotype, featuring an increase in euchromatin and an increase in nuclear size following subretinal injections but not intravitreal injections. These nuclear changes were panretinal when the putatively stronger CBA promoter was used but not panretinal when the CMV promoter was used. In the latter case, the nuclear changes were much more pronounced at the site of injection. Thus, chronic hyperstimulation of retinal cells with CNTF may up-regulate gene expression in photoreceptors. Based on current knowledge of retinal cell targets for CNTF, this effect may be indirect and may not represent direct stimulation of photoreceptors by CNTF.A second side effect was a paradoxical decrease in scotopic a- and b-wave amplitudes and a decrease in photopic b-wave amplitudes in the injected, rescued retina when compared to its contralateral, uninjected counterpart, in spite of the fact that these retinas had more photoreceptors than their untreated mates. The basis for these decreased ERG amplitudes may be related to changes in gene expression. The mechanisms for these side effects and proper doses of CNTF administration should be determined before human clinical trials are considered for the amelioration of inherited retinal degenerations with CNTF.
Assuntos
Fator Neurotrófico Ciliar/fisiologia , Terapia Genética/métodos , Proteínas de Filamentos Intermediários/genética , Glicoproteínas de Membrana , Proteínas do Tecido Nervoso/genética , Mutação Puntual , Degeneração Retiniana/terapia , Adenoviridae/genética , Animais , Fator Neurotrófico Ciliar/genética , Eletrorretinografia , Proteínas do Olho/genética , Vetores Genéticos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Periferinas , Células Fotorreceptoras de Vertebrados/patologia , Retina/fisiopatologia , Degeneração Retiniana/patologia , Degeneração Retiniana/fisiopatologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
To evaluate the ability of the multifocal ERG (mfERG) to detect small defects in the stimulus array was the objective of this paper. Seven normal subjects had mfERGs recorded with a VERIS system. Stimulus arrays composed of 61, 103 or 241 hexagons were covered in part by small masks of different light transmittance properties. Only masks that covered at least one-half of a single 103 hexagon stimulus cell caused a significant reduction in signal. Different-shaped masks of about 5 degrees diameter were detectable using a 61-hexagon array only when they fully covered a stimulus cell. Detection was better, but marginal for some of the masks, with the 103 hexagon array. The 241 hexagon array showed sharp defects for all masks. Masking the stimulus screen is not equivalent to having a pathologic scotoma, but it demonstrates the greatest possible spatial sensitivity of the mfERG system. Thus, the mfERG appears to be able to detect small retinal lesions if they reduce local retinal function by at least 50% and correspond to at least half the area of one stimulus hexagon. Scotomas 5 degrees or smaller would be best detected using a fine (241 hexagon) stimulus array. With coarser stimulus arrays (e.g. 103 or 61 hexagons), the effect of a small scotoma depends on its location relative to the stimulus cells. These issues should be considered when selecting mfERG recording conditions.