RESUMO
We studied the potential of systemically administered aminoglycosides as a therapy for retinal degeneration resulting from premature termination codon (PTC) mutations. Aminoglycosides were systemically delivered to two rodent models of retinal degeneration: a transgenic rat model of dominant disease caused by a PTC in rhodopsin (S334ter); and a mouse model of recessive disease (rd12) caused by a PTC in the retinoid isomerase Rpe65. Initial luciferase reporter assays were undertaken to measure the efficiency of gentamicin-induced read-through in vitro. These experiments indicated that gentamicin treatment induced on average a 5.3% extra read-through of the S334ter PTC in vitro, but did not affect the rd12 PTC. Beginning at postnatal day 5, animals received daily subcutaneous injections of gentamicin or geneticin at a range of doses. The effect of the treatment on retinal degeneration was examined by histopathology and electroretinography (ERG). Systemic treatment with aminoglycoside significantly increased the number of surviving photoreceptors in the S334ter rat model over several weeks of treatment, but was not effective in slowing the retinal degeneration in the rd12 mouse model. Similarly, ERG recordings indicated better preservation of retinal function in the treated S334ter rats, but no difference was observed in the rd12 mice. Daily subcutaneous injection of 12.5mug/g gentamicin was the only regimen that inhibited retinal degeneration without apparent adverse systemic side effects. Reduced effectiveness beyond postnatal day 50 correlated with reduced ocular penetration of drug as seen in gentamicin-Texas red (GTTR) conjugation experiments. We conclude that, in the rat model, an approximately 5% reduction of abnormal truncated protein is sufficient to enhance photoreceptor survival. Such a change in truncated protein is consistent with beneficial effects seen when aminoglycosides has been used in other, non-ocular animal models. In the rd12 mouse, lack of efficacy was seen despite this particular PTC being theoretically more sensitive to aminoglycoside modification. We conclude that aminoglycoside read-through of PTCs in vitro and in vivo cannot be predicted just from genomic context. Because there is considerable genetic heterogeneity amongst retinal degenerations, pharmacologic therapies that are not gene-specific have significant appeal. Our findings suggest that if adverse issues such as systemic toxicity and limited ocular penetration can be overcome, small molecule therapeutics, such as aminoglycosides, which target classes of mutation could hold considerable potential as therapies for retinal disease.
Assuntos
Aminoglicosídeos/uso terapêutico , Retinose Pigmentar/prevenção & controle , Aminoglicosídeos/farmacocinética , Animais , Proteínas de Transporte/genética , Códon sem Sentido , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Eletrorretinografia/efeitos dos fármacos , Proteínas do Olho/genética , Corantes Fluorescentes , Gentamicinas/farmacocinética , Gentamicinas/uso terapêutico , Camundongos , Camundongos Mutantes , Ratos , Ratos Transgênicos , Retina/metabolismo , Retinose Pigmentar/metabolismo , Retinose Pigmentar/patologia , Rodopsina/genética , Xantenos , cis-trans-IsomerasesRESUMO
Outer retinal dystrophies are the major causes of incurable blindness in the Western world. Understanding the etiology of retinal dystrophies has improved remarkably over the past decade. A number of genes, such as RHO, PDE-beta, RDS, TIMP3, MYO7A, RETGC1, RPGR, CRX and ABCR, are now known to be particularly important. Characterization of the genetic basis for disease is leading to new concepts of pathogenesis at the molecular and cellular levels. Such detailed understanding of disease processes is also stimulating a renewed interest in therapeutic strategies.
Assuntos
Cegueira/genética , Células Fotorreceptoras/fisiologia , Doenças Retinianas/genética , Doenças Retinianas/fisiopatologia , Apoptose , Humanos , Células Fotorreceptoras/química , Epitélio Pigmentado Ocular/patologia , Transdução de SinaisRESUMO
AIM: To assess whether macular dysfunction caused by unilateral subretinal neovascular membranes (SRNs) is associated with pupil "evasion" (that is, increased initial rate of re-dilation following a brief light stimulus). METHODS: Comparative observational series. 20 eyes of 10 participants, all with unilateral SRNs and healthy fellow eyes. Dynamic infrared pupillography at seven stimulus intensities (duration 1100 ms, intensities over 2 log unit range). Pupil evasion ratio (PEVR; defined as the ratio of light response amplitude to amount of recovery at the mid-time point of re-dilation expressed as a percentage) was calculated for each stimulus intensity (mean of five recordings). RESULTS: Inter-eye PEVR is significantly reduced in eyes with SRN (that is, greater pupil evasion in SRN eyes: range p = 0.002 to p = 0.05 (paired t test)) and is most apparent at higher stimulus intensities. CONCLUSIONS: PEVR is a novel parameter that is analogous to the pupil escape ratio, but measured following a short rather than a sustained light stimulus. PEVR is significantly altered by macular disease. Clinically PEVR may be used to detect occult unilateral or asymmetric maculopathy in situations such as ocular media opacities like cataract, when pupil reactions are unaffected or augmented, while other tests of retinal function are diminished. PEVR represents altered neuronal firing in cones and macular ganglion cells.
Assuntos
Degeneração Macular/diagnóstico , Reflexo Pupilar , Neovascularização Retiniana/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Técnicas de Diagnóstico Oftalmológico , Feminino , Humanos , Degeneração Macular/etiologia , Degeneração Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa/métodos , Pupila/fisiologia , Neovascularização Retiniana/complicaçõesRESUMO
Congenital colobomata of the eye are important causes of childhood visual impairment and blindness. Ocular coloboma can be seen in isolation and in an impressive number of multisystem syndromes, where the eye phenotype is often seen in association with severe neurological or craniofacial anomalies or other systemic developmental defects. Several studies have shown that, in addition to inheritance, environmental influences may be causative factors. Through work to identify genes underlying inherited coloboma, significant inroads are being made into understanding the molecular events controlling closure of the optic fissure. In general, severity of disease can be linked to the temporal expression of the gene, but this is modified by factors such as tissue specificity of gene expression and genetic redundancy.
Assuntos
Coloboma/genética , Animais , Anoftalmia/genética , Coloboma/embriologia , Coloboma/etiologia , Meio Ambiente , Olho/embriologia , Proteínas do Olho/fisiologia , Regulação da Expressão Gênica , Aconselhamento Genético , Proteínas Hedgehog , Proteínas de Homeodomínio/fisiologia , Humanos , Microftalmia/genética , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados , Proteínas Repressoras/fisiologia , Transativadores/fisiologiaRESUMO
OBJECTIVE: Autosomal dominant drusen is of particular interest because of its phenotypic similarity to age related macular degeneration. Currently, mutation R345W of EFEMP1 and, in a single pedigree, linkage to chromosome 6q14 have been causally related to the disease. We proposed to investigate and quantify the roles of EFEMP1 and the 6q14 locus in dominant drusen patients from the UK and USA. DESIGN: Molecular genetic analysis. PARTICIPANTS: Ten unrelated families and 17 young drusen patients. MAIN OUTCOME MEASURES: Exons 1 and 2 of EFEMP1 were characterised by 5' rapid amplification of cDNA ends and direct sequencing. Exons 1-12 of EFEMP1 were then investigated for mutation by direct sequencing. A HpaII restriction digest test was constructed to detect the EFEMP1 R345W mutation. Marker loci spanning the two dominant drusen linked loci were used to generate haplotype data. RESULTS: Only seven of the 10 families (70%) and one of the 17 sporadic patients (6%) had the R345W mutation. The HpaII restriction digest test was found to be a reliable and quick method for detecting this. No other exonic or splice site mutation was identified. Of the three families without EFEMP1 mutation, two were linked to the 2p16 region. CONCLUSIONS: EFEMP1 R345W accounts for only a proportion of the dominant drusen phenotype. Importantly, other families linked to chromosome 2p16 raise the possibility of EFEMP1 promoter sequence mutation or a second dominant drusen gene at this locus. Preliminary haplotype data suggest that the disease gene at the 6q14 locus is responsible for only a minority of dominant drusen cases.
Assuntos
Proteínas da Matriz Extracelular/genética , Genes Dominantes , Polimorfismo de Nucleotídeo Único , Drusas Retinianas/genética , Adulto , Cromossomos Humanos Par 2 , Cromossomos Humanos Par 6 , Estudos de Coortes , Feminino , Ligação Genética , Variação Genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Radiografia , Drusas Retinianas/diagnóstico por imagemRESUMO
PURPOSE: Subretinal transplantation of stem-cell-derived photoreceptor precursor cells (PPCs) is a promising and innovative approach to treating a range of blinding diseases. However, common barriers to efficient preclinical transplantation comes in the form of suboptimal graft architecture, limited graft survival, and immune-rejection, each of which cannot be assessed using conventional in vivo imaging (i.e., rodent ophthalmoscopy). With the majority of PPCs reported to die within the first few weeks after transplantation, understanding the mechanisms of graft failure, and ultimately devising preventative methods, currently relies on lengthy end point histology. To address these limitations, we hypothesized that combining two imaging modalities, optical coherence tomography (OCT) and fluorescence confocal scanning laser ophthalmoscopy (fcSLO), could provide a more rapid and comprehensive view of PPC engraftment. METHODS: Human ESC-derived PPCs were transplanted into 15 retinal dystrophic rats that underwent bimodal imaging at 0, 8, and 15 days posttransplant. RESULTS: Bimodal imaging provided serial detection of graft: placement, architecture, and survival; each undetectable under ophthalmoscopy. Bimodal imaging determined graft placement to be either: subretinal (n=7), choroidal (n=4), or vitreal (n=4) indicating neural retinal perforation. Graft architecture was highly variable at the time of transplantation, with notable redistribution over time, while complete, or near complete, graft loss was observed in the majority of recipients after day 8. Of particular importance was detection of vitreal aggregates overlying the graft-possibly an indicator of host-site inflammation and rejection. CONCLUSION: Early real-time feedback of engraftment has the potential to greatly increase efficiency of preclinical trials in cell-based retinal therapeutics.
Assuntos
Sobrevivência de Enxerto/fisiologia , Células-Tronco Embrionárias Humanas/transplante , Células Fotorreceptoras de Vertebrados/transplante , Degeneração Retiniana/cirurgia , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Imuno-Histoquímica , Microscopia Confocal , Oftalmoscopia/métodos , Células Fotorreceptoras de Vertebrados/citologia , Pontos Quânticos , Ratos , Tomografia de Coerência Óptica/métodos , Transplante HeterólogoRESUMO
BACKGROUND/AIMS: To report the generation of a new mouse model for a genetically determined corneal abnormality that occurred in transgenesis experiments. METHODS: Transgenic mice expressing mutant forms of Rab27a, a GTPase that has been implicated in the pathogenesis of choroideremia, were generated. RESULTS: Only one transgenic line (T27aT15) exhibited an unexpected eye phenotype. T27aT15 mice developed corneal opacities, usually unilateral, and cataracts, resulting in some cases in phthisical eyes. Histologically, the corneal stroma was thickened and vacuolated, and both epithelium and endothelium were thinned. The posterior segment of the eye was also affected with abnormal pigmentation, vessel narrowing, and abnormal leakage of dye upon angiography but was histologically normal. CONCLUSION: Eye abnormality in T27aT15 mice results from random insertional mutagenesis of the transgene as it was only observed in one line. The corneal lesion observed in T27aT15 mice most closely resembles posterior polymorphous corneal dystrophy and might result from the disruption of the equivalent mouse locus.
Assuntos
Distrofias Hereditárias da Córnea/genética , Modelos Animais , Mutagênese Insercional , Proteínas rab de Ligação ao GTP/genética , Animais , Distrofias Hereditárias da Córnea/patologia , Angiofluoresceinografia , Fundo de Olho , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Proteínas rab27 de Ligação ao GTPRESUMO
Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c(w59) mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c(w59) embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed. Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c(w59) mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Células Fotorreceptoras Retinianas Cones/patologia , Degeneração Retiniana/genética , Proteínas de Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Morte Celular/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo , Técnicas de Silenciamento de Genes , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Células Fotorreceptoras Retinianas Cones/metabolismo , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismoAssuntos
Engenharia Genética/tendências , Retinose Pigmentar/genética , Animais , Modelos Animais de Doenças , Humanos , Mutação/genética , Fenótipo , Células Fotorreceptoras/fisiologia , Retina/citologia , Retina/fisiopatologia , Retinose Pigmentar/fisiopatologia , Rodopsina/genética , Roedores , SuínosRESUMO
Nr2e1 encodes a stem cell fate determinant of the mouse forebrain and retina. Abnormal regulation of this gene results in retinal, brain, and behavioral abnormalities in mice. However, little is known about the functionality of human NR2E1. We investigated this functionality using a novel knock-in humanized-mouse strain carrying a single-copy bacterial artificial chromosome (BAC). We also documented, for the first time, the expression pattern of the human BAC, using an NR2E1-lacZ reporter strain. Unexpectedly, cerebrum and olfactory bulb hypoplasia, hallmarks of the Nr2e1-null phenotype, were not fully corrected in animals harboring one functional copy of human NR2E1. These results correlated with an absence of NR2E1-lacZ reporter expression in the dorsal pallium of embryos and proliferative cells of adult brains. Surprisingly, retinal histology and electroretinograms demonstrated complete correction of the retina-null phenotype. These results correlated with appropriate expression of the NR2E1-lacZ reporter in developing and adult retina. We conclude that the human BAC contained all the elements allowing correction of the mouse-null phenotype in the retina, while missing key regulatory regions important for proper spatiotemporal brain expression. This is the first time a separation of regulatory mechanisms governing NR2E1 has been demonstrated. Furthermore, candidate genomic regions controlling expression in proliferating cells during neurogenesis were identified.
Assuntos
Encéfalo/anormalidades , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Retina/anormalidades , Animais , Encéfalo/embriologia , Encéfalo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Introdução de Genes , Genoma , Humanos , Óperon Lac , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Nucleares Órfãos , Fenótipo , Retina/embriologia , Retina/metabolismoAssuntos
Proteínas do Olho/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Sequências Reguladoras de Ácido Nucleico/genética , Retinopatia da Prematuridade/genética , Alelos , Pré-Escolar , Análise Mutacional de DNA , Doenças em Gêmeos/genética , Mecanismo Genético de Compensação de Dose , Éxons/genética , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Regiões Promotoras Genéticas/genética , Sítios de Splice de RNA/genética , Retinopatia da Prematuridade/fisiopatologia , Gêmeos/genéticaAssuntos
Fundo de Olho , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêutico , Neovascularização Retiniana/tratamento farmacológico , Adulto , Humanos , Masculino , Síndrome , Verteporfina , Transtornos da Visão/tratamento farmacológico , Transtornos da Visão/etiologiaRESUMO
PURPOSE: To re-assess the value of argon laser treatment for macular oedema in ischaemic branch retinal vein occlusion (I-BRVO). METHODS: Case series consisting of three patients with macular oedema following I-BRVO. Three patients were studied including two patients where ischaemia extended to include the foveal avascular zone (FAZ), with additional retinal neovascularisation in one of these. Heavy, overlapping areas of treatment were applied to the ischaemic retina up to 500 microns from the fovea. RESULTS: All cases in the series benefited from significantly improved visual acuity. In one case laser was given several years after the initial retinal vasculopathy. CONCLUSIONS: Argon laser treatment may improve visual acuity in I-BRVO even with severe ischaemia extending into the FAZ. Treatment intensity must be sufficient to destroy ischaemic retina. Visual benefit may last for several years, and treatment can be undertaken several years after I-BRVO. The benefit to visual acuity of argon laser treatment in I-BRVO needs to be re-assessed in a prospective study.
Assuntos
Fotocoagulação a Laser/métodos , Oclusão da Veia Retiniana/cirurgia , Acuidade Visual/fisiologia , Feminino , Angiofluoresceinografia , Humanos , Edema Macular/cirurgia , Masculino , Pessoa de Meia-Idade , Oclusão da Veia Retiniana/fisiopatologiaRESUMO
We have identified a highly polymorphic intragenic marker composed of two dinucleotide repeats in an intron of the human interferon regulatory factor (IRF3) gene. This polymorphic marker has allowed us to map IRF3 to the boundary of 19q13.3-13.4 between the polymorphic markers D19S604 and D19S206 close to KLK1. An intron is present in a homologous position in the mouse Irf3 gene, but lacks the dinucleotide repeats present in the human intron. Syntenic conservation between this region of 19q13.3-13.4 maps Irf3 to either mouse chromosome 7 or 17.
Assuntos
Cromossomos Humanos Par 19 , Proteínas de Ligação a DNA/genética , Polimorfismo Genético , Fatores de Transcrição/genética , Alelos , Sequência de Aminoácidos , Sequência de Bases , Mapeamento Cromossômico , DNA Complementar , Frequência do Gene , Marcadores Genéticos , Humanos , Fator Regulador 3 de Interferon , Dados de Sequência MolecularRESUMO
In this study, we report the identification and characterisation of a novel carbonic anhydrase related-protein. We have determined that the full length coding sequence of an anonymous expressed sequenced tag, D19S799E, encodes a novel carbonic anhydrase related-protein (CARP-2) that is 328 amino acids in length. This peptide exhibits between 23.1-28.8% amino acid identity with the seven active human carbonic anhydrase (CA) isozymes. Four substitutions of key amino acids in the catalytic domain of CAs (equivalent to His94Arg, His96Leu, His119Gln, and Thr199Ser) are likely to render CARP-2 inactive as a carbonic anhydrase. Northern blot analysis of 23 human tissues indicates that CARP2 is expressed abundantly in the brain with moderate expression also present in spinal cord and thyroid. D19S799E (and thus CARP2) has previously been localised close to the polymorphic marker D19S412 and the genes DBP and FUT1/FUT2 on 19q13. 3.
Assuntos
Anidrases Carbônicas/química , Anidrases Carbônicas/genética , Cromossomos Humanos Par 19/genética , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Sequência de Bases , Anidrases Carbônicas/biossíntese , Mapeamento Cromossômico , Regulação da Expressão Gênica , Humanos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/biossíntese , Especificidade de Órgãos/genética , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
Syndromic Hirschsprung disease has been associated with mutations in ZFHX1B, a Smad-interacting transcriptional repressor protein. Tissue in situ hybridization has demonstrated strong expression of ZFHX1B in the developing eye, suggesting that some mutations in this gene may cause visual loss. However, none of the reported mutations have been associated with an ocular phenotype. We describe a patient with Down syndrome and Hirschsprung disease with high myopia and ocular coloboma affecting the iris and retina. In addition to trisomy 21, a novel, de novo heterozygous A to G transition in exon 8 of the ZFHX1B gene was identified, which results in a R953G amino acid substitution. This abnormality was not seen in a screen of 200 chromosomes from ethnically matched, normal controls. The arginine residue at position 953 is an extremely conserved amino acid throughout evolution. This is the first report associating Hirschsprung disease and severe eye defects with a specific genetic mutation and is the first report of a mutation in ZFHX1B causing a developmental ocular anomaly.
Assuntos
Anormalidades Múltiplas/genética , Síndrome de Down/patologia , Oftalmopatias/patologia , Doença de Hirschsprung/patologia , Proteínas de Homeodomínio/genética , Mutação de Sentido Incorreto , Proteínas Repressoras/genética , Anormalidades Múltiplas/patologia , Sequência de Bases , Criança , Coloboma/patologia , DNA/química , DNA/genética , Análise Mutacional de DNA , Feminino , Humanos , Cariotipagem , Masculino , Miopia/patologia , Homeobox 2 de Ligação a E-box com Dedos de ZincoRESUMO
PURPOSE: Validating the current protocol of Amsler chart grid surveillance for the early detection of subretinal neovascular membrane(SRN) in age-related macular degeneration(AMD), and investigating its value in facilitating early laser therapy. METHODS: A retrospective pilot study. SETTING: Central London eye hospital with dedicated 24-h ophthalmic casualty serving West and West-central London. PARTICIPANTS: 100 consecutive AMD patients who attended casualty with vision loss fulfilling the following criteria: patients had received and been instructed in the use of Amsler charts according to the unit's dispensation protocol,fluorescein angiography which confirmed new SRN. Patients presented over 20 months. Outcome measures were detection of SRN by the Amsler chart, and laser treatment of SRN. RESULTS: The Amsler chart surveillance protocol had detected SRN in 29 of the 100 patients. The surveillance protocol detected less than 30% of the specific patients who subsequently underwent laser treatment. A statistically significant difference was seen on comparing the ages of patients in whom the screening protocol was successful versus those in whom it was unsuccessful (student's t-test,P<3.2 x 103). Younger patients were more likely to be detected using the Amsler chart. A one-tailed Z2 test approached, but did not achieve, statistical significance (Z2 = 1.057,P <0.3) suggesting that patients who have already lost vision to SRN in one eye might not be more likely to be detected using the surveillance protocol than patients in whom SRN was affecting their first eye. In all, 38% of surveillance responders went on to receive laser therapy, compared with 37% of surveillance nonresponders. CONCLUSIONS: The current Amsler chart surveillance protocol is suboptimal for detecting SRN in AMD, and a proportion of cases suitable for early laser therapy may be missing rapid detection. The results are especially important since recent advances in laser therapy for SRN require early detection for optimal effectiveness.
Assuntos
Terapia a Laser/métodos , Degeneração Macular/diagnóstico , Neovascularização Retiniana/diagnóstico , Testes Visuais/métodos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Humanos , Degeneração Macular/etiologia , Degeneração Macular/cirurgia , Pessoa de Meia-Idade , Projetos Piloto , Neovascularização Retiniana/complicações , Neovascularização Retiniana/cirurgia , Estudos Retrospectivos , Autocuidado/métodos , Resultado do TratamentoRESUMO
OBJECTIVE: Little is known of the cytopathology of photoreceptors in human inherited retinal dystrophies that initially affect the central retina, including the macula. The current study sought to determine the cytologic features of dysfunctional cone and rod photoreceptors, as well as the pattern of degeneration of the cells in representative cases of central retinal dystrophy. STUDY DESIGN: Comparative human tissue study. MATERIALS: Four human donor eyes with the following forms of central retinal dystrophy: cone-rod dystrophy (CRD), central areolar choroidal dystrophy, Bardet-Biedl syndrome, and cone dystrophy-cerebellar ataxia. The cytologic features of retinal photoreceptors in these eyes were compared with those in an eye with retinitis pigmentosa and six normal human eyes. METHODS AND OUTCOME MEASURES: Immunocytochemistry and electron microscopy were used to evaluate the retinal histopathology in the donor eyes. RESULTS: Cone numbers were decreased in the case of CRD, particularly in the central and far peripheral retina, and both cone and rod outer segments were slightly shortened. Occasional degenerate cones had dense cytoplasm and pyknotic nuclei dislocated sclerad to the external-limiting membrane. The most prominent alteration in this retina was marked enlargement and distortion of the cone photoreceptor pedicles, which contained reduced numbers of synaptic vesicles. The retina with central areolar choroidal dystrophy contained a few cones with similarly abnormal synapses. However, comparable cone synapse abnormalities were not observed in the cases of Bardet-Biedl syndrome, cone dystrophy-cerebellar ataxia, retinitis pigmentosa, or in the normal retinas. CONCLUSIONS: The functional consequences of the cone synapse abnormalities in CRD are not known but may correlate with the electroretinographic abnormalities documented in some cases of CRD. To our knowledge, comparable synapse changes have not been noted in either rods or cones in other forms of retinal dystrophy, including retinitis pigmentosa, suggesting that different cytopathologic mechanisms may be involved.