RESUMO
PURPOSE: To study the phenotype in two families with genetically identified autosomal dominant retinitis pigmentosa (adRP) focusing on macular structure and function. METHODS: Clinical data were collected at the Department of Ophthalmology, Lund University, Sweden, for affected and unaffected family members from two pedigrees with adRP. Examinations included optical coherence tomography (OCT), full-field electroretinography (ffERG), and multifocal electroretinography (mfERG). Molecular genetic screening was performed for known mutations associated with adRP. RESULTS: The mode of inheritance was autosomal dominant in both families. The members of the family with a mutation in the PRPF31 (p.IVS6+1G>T) gene had clinical features characteristic of RP, with severely reduced retinal rod and cone function. The degree of deterioration correlated well with increasing age. The mfERG showed only centrally preserved macular function that correlated well with retinal thinning on OCT. The family with a mutation in the RHO (p.R135W) gene had an extreme intrafamilial variability of the phenotype, with more severe disease in the younger generations. OCT showed pathology, but the degree of morphological changes was not correlated with age or with the mfERG results. The mother, with a de novo mutation in the RHO (p.R135W) gene, had a normal ffERG, and her retinal degeneration was detected merely with the reduced mfERG. CONCLUSIONS: These two families demonstrate the extreme inter- and intrafamilial variability in the clinical phenotype of adRP. This is the first Swedish report of the clinical phenotype associated with a mutation in the PRPF31 (p.IVS6+1G>T) gene. Our results indicate that methods for assessment of the central retinal structure and function may improve the detection and characterization of the RP phenotype.
Assuntos
Proteínas do Olho/genética , Genes Dominantes , Macula Lutea/fisiologia , Mutação , Retinose Pigmentar/genética , Retinose Pigmentar/fisiopatologia , Adolescente , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Análise Mutacional de DNA , Eletrorretinografia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Retinose Pigmentar/epidemiologia , Rodopsina/genética , Suécia , Tomografia de Coerência Óptica , Acuidade Visual , Adulto JovemRESUMO
Retinitis pigmentosa (RP) refers to a genetically heterogeneous group of progressive neurodegenerative diseases that result in dysfunction and/or death of rod and cone photoreceptors in the retina. So far, 18 genes have been identified for autosomal-dominant (ad) RP. Here, we describe an adRP locus (RP42) at chromosome 7p15 through linkage analysis in a six-generation Scandinavian family and identify a disease-causing mutation, c.449G-->A (p.S150N), in exon 6 of the KLHL7 gene. Mutation screening of KLHL7 in 502 retinopathy probands has revealed three different missense mutations in six independent families. KLHL7 is widely expressed, including expression in rod photoreceptors, and encodes a 75 kDa protein of the BTB-Kelch subfamily within the BTB superfamily. BTB-Kelch proteins have been implicated in ubiquitination through Cullin E3 ligases. Notably, all three putative disease-causing KLHL7 mutations are within a conserved BACK domain; homology modeling suggests that mutant amino acid side chains can potentially fill the cleft between two helices, thereby affecting the ubiquitination complexes. Mutations in an identical region of another BTB-Kelch protein, gigaxonin, have previously been associated with giant axonal neuropathy. Our studies suggest an additional role of the ubiquitin-proteasome protein-degradation pathway in maintaining neuronal health and in disease.
Assuntos
Autoantígenos/genética , Genes Dominantes , Mutação de Sentido Incorreto/genética , Polimorfismo de Nucleotídeo Único/genética , Retinose Pigmentar/genética , Sequência de Aminoácidos , Autoantígenos/metabolismo , Cromossomos Humanos Par 7/genética , Ensaio de Imunoadsorção Enzimática , Perfilação da Expressão Gênica , Ligação Genética , Humanos , Immunoblotting , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Retinose Pigmentar/metabolismo , Retinose Pigmentar/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência de AminoácidosRESUMO
UNLABELLED: To evaluate the influence of hard exudates on macular function in patients with diabetic retinopathy. METHODS: Thirty seven eyes from 27 diabetic patients, aged 57 +/- 14 years, diabetes duration 12.5 +/- 9 years, not previously treated with photocoagulation, underwent fundus photography, multifocal electroretinography (mfERG) and optical coherence tomography (OCT). Hard exudates were graded from fundus photography with superimposed OCT and a superimposed hexagonal pattern (mfERG) by one retinal specialist, unaware of mfERG and OCT results. We defined three groups; A = eyes with exudates in the analyzed zone, B = eyes with no exudates in the analyzed zone but elsewhere, and C = eyes with no exudates. The mfERG responses and OCT values from five defined areas in the macula were compared. RESULTS: MfERG showed that the implicit time was significantly prolonged in group A compared to group C in the central, middle and outer areas and in the nasal and temporal area (p = 0.045, 0.019, 0.017 and 0.035 and 0.016 respectively), in group B compared to group C in the central area (p = 0.016), and in group A compared to group B in the outer area (p = 0.035). Amplitude differed between group A and C in the middle area and outer area (14.2 +/- 5.2 nV/deg(2) vs 21.1 +/- 8.7 nV/deg(2), p = 0.037 and 14.1 +/- 3.9 nV/deg(2) vs 17.7 +/- 7.1 nV/deg(2) , p = 0.02 respectively), and between group B and C in the temporal area 14.5 +/- 2.2 nV/deg(2) vs 20.0 +/- 8.7 nV/deg(2), p = 0.017). Macular thickness assessed with OCT was similar between the groups. CONCLUSIONS: In eyes with diabetic retinopathy, hard exudates prolong the implicit time assessed with mfERG, compared to eyes without hard exudates, and independently of macular thickness. These results indicate that the hard exudates in the macular region, even at a distance from the fovea centre, have a deleterious effect on macular function.
Assuntos
Retinopatia Diabética/fisiopatologia , Eletrorretinografia , Exsudatos e Transudatos/fisiologia , Macula Lutea/fisiopatologia , Pressão Sanguínea , Angiofluoresceinografia , Hemoglobinas Glicadas/análise , Humanos , Pessoa de Meia-Idade , Fotografação , Tomografia de Coerência Óptica , Acuidade Visual/fisiologiaRESUMO
PURPOSE: To investigate retinal function after reduction of intraocular pressure (IOP) by filtration surgery in patients with medically uncontrolled glaucoma. METHODS: Eleven patients (11 eyes) with medically uncontrolled glaucoma underwent trabeculectomy. Clinical investigation, visual field (testing with standard automated perimetry (SAP-Humphrey), optical coherence tomography (OCT), full-field electroretinography (full-field ERG) and multifocal electroretinography (mfERG) were performed preoperatively as well as 2 and 6 months after surgery. DESIGN: Interventional prospective, consecutive case series. RESULTS: No significant reduction was seen in mean log MAR visual acuity 2 or 6 months after filtration surgery. The mean preoperative intraocular pressure of 27.1 (+/-6.2) mmHg decreased to 19.0(+/-6.1) mmHg 2 months after surgery and to 17.1 (+/- 3.4) mmHg 6 months after surgery (both p = 0.001). The reduction in IOP significantly decreased the number of anti-glaucoma agents used, from 3.7 +/- 1.6 at baseline to 0.8 +/- 0.9 2 months after surgery and to 1.3 +/- 1.2 6 months after surgery (p = 0.004 and p = 0.008 respectively). The results of SAP, OCT and full-field ERG did not show any significant difference between pre- and postoperative values at any point in time. No significant improvement was found with regard to the first positive peak (P(1)) amplitudes in the macular retina (area 1) or in the perimacular retina/periphery (area 2) when measured with mfERG 2 months after surgery. The mfERG examinations revealed significantly improved P(1) amplitudes 6 months after surgery in both area 1 and area 2, compared with the preoperative values (p = 0.042 and p = 0.014 respectively). The implicit time of P(1) decreased significantly 6 months after surgery in area 2 compared with the preoperative values (p = 0.023). CONCLUSION: A significant lowering of IOP seems to improve the function of the central retina, as demonstrated by increased amplitudes and reduced implicit times assessed with mfERG.
Assuntos
Glaucoma de Ângulo Aberto/fisiopatologia , Glaucoma de Ângulo Aberto/cirurgia , Retina/fisiopatologia , Trabeculectomia , Idoso , Idoso de 80 Anos ou mais , Eletrorretinografia , Feminino , Humanos , Pressão Intraocular/fisiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tomografia de Coerência Óptica , Transtornos da Visão/fisiopatologia , Acuidade Visual/fisiologia , Testes de Campo Visual , Campos Visuais/fisiologiaRESUMO
BACKGROUND: To investigate, in a rabbit model, the effect of two different doses of vigabatrin (VGB) on retinal function and morphology. METHODS: Twenty-nine rabbits of mixed strain were divided into two groups, receiving either high-dose (n = 15) or low-dose (n = 14) oral VGB treatment (cumulative dose 29.8 +/- 2.9 g and 14.2 +/- 0.6 g respectively). Ten rabbits receiving water served as control animals. The rabbits underwent three baseline ff-ERG measurements before initiation of VGB medication and two ff-ERG registrations during treatment, after 8 and 12-14 weeks respectively. At the end of the study, the expression of protein kinase C-alpha (PKC-alpha), gamma amino butyric acid (GABA) A receptors, vimentin, glial fibrillary acidic protein (GFAP) and peanut agglutinin (PNA) was examined in retinal sections from all rabbits. RESULTS: In animals of the high-dose group, the ff-ERG measurements revealed a significant decrease of isolated rod b-wave amplitudes, combined rod-cone b-wave amplitudes and amplitudes of oscillatory potentials (OPs); OP1, OP2 and OP3. In the low-dose group, the b-wave amplitudes of combined rod-cone responses as well as OP2 and OP3 were significantly reduced. PKC-alpha labeling demonstrated a dose-related translocation of the enzyme in rod bipolar cells, also revealing a significant decline of the number of PKC-alpha labeled rod bipolar cells in treated animals. Vimentin labeling showed a dose-related deviant labeling pattern of Müller cells, with strikingly low labeling intensity in the outer parts of the cells; in the outer limiting membrane (OLM) as well as the outer nuclear layer (ONL). Labeling with antibodies against GABA A receptors and GFAP, as well as PNA staining, revealed no differences between treated animals and controls. CONCLUSIONS: In this study, VGB medication was associated, in a dose-related manner, with a decrease of ff-ERG amplitudes as well as with altered protein expression in rod bipolar cells and Müller cells, suggesting alterations of inner retinal function. The dose-related morphological and electrophysiological changes indicate a retinal pathology that may explain the constricted visual fields seen in some patients treated with VGB.
Assuntos
Anticonvulsivantes/toxicidade , Eletrorretinografia/efeitos dos fármacos , Inibidores Enzimáticos/toxicidade , Proteína Quinase C-alfa/metabolismo , Retina/efeitos dos fármacos , Doenças Retinianas/induzido quimicamente , Vigabatrina/toxicidade , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Técnica Indireta de Fluorescência para Anticorpo , Proteína Glial Fibrilar Ácida/metabolismo , Microscopia de Fluorescência , Aglutinina de Amendoim/metabolismo , Coelhos , Receptores de GABA-A/metabolismo , Retina/enzimologia , Retina/fisiopatologia , Doenças Retinianas/enzimologia , Doenças Retinianas/fisiopatologia , Vigabatrina/administração & dosagem , Vimentina/metabolismoRESUMO
PURPOSE: To study the toxicology of rifabutin in the rabbit eye with emphasis on retinal function and histopathology. METHODS: Seven rabbits received a daily dose of rifabutin during 15 months. Six rabbits receiving only the vehicle were used as controls. Repeated standardized full-field electroretinograms (ERG) were assessed. After discontinuing treatment, the rabbits were killed and the cornea, the lens, and the sectioned retina was studied. Immunhistochemistry directed against vimentin, glial fibrillaryacidic protein (GFAP), protein kinase C (PKC), and peanut agglutinin (PNA) was performed. RESULTS: Rifabutin was detected in serum of the treated rabbits. During treatment, the full-field ERG demonstrated significantly reduced b-wave amplitudes in the total rod-cone response as well as in the isolated rod and cone response compared with the recordings before treatment. The control rabbits did not demonstrate a reduction of the ERG amplitudes. The treated rabbits developed a discoloration of the lens, not seen in the control group. No retinal pathology was demonstrated using immunohistochemical methods. CONCLUSION: Rifabutin causes a discoloration of the lens and reduces both rod and cone function in rabbits, but does not alter retinal morphology. Previous reports on ocular side effects caused by rifabutin are supported by the results of this study.
Assuntos
Antibacterianos/toxicidade , Eletrorretinografia/efeitos dos fármacos , Cristalino/efeitos dos fármacos , Retina/efeitos dos fármacos , Doenças Retinianas/induzido quimicamente , Rifabutina/toxicidade , Animais , Antibacterianos/farmacocinética , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Proteína Glial Fibrilar Ácida/metabolismo , Cristalino/metabolismo , Cristalino/patologia , Masculino , Proteína Quinase C/metabolismo , Coelhos , Retina/metabolismo , Retina/fisiopatologia , Doenças Retinianas/metabolismo , Doenças Retinianas/fisiopatologia , Rifabutina/farmacocinética , Vimentina/metabolismoRESUMO
OBJECTIVES: To characterize the clinical phenotype and to study the course of disease in patients with Alström syndrome, with an emphasis on retinal function assessed with full-field electroretinography (ERG). METHODS: Three age- and sex-matched patients with Alström syndrome were selected from our retinitis pigmentosa register for repeated ophthalmologic examinations that included tests for color vision and visual fields using Goldmann perimetry and for repeated assessment of full-field ERGs. RESULTS: Electroretinography demonstrated cone-rod degeneration in all 3 patients. A concomitant impairment of color vision and visual fields was also observed as well as marked variation in retinal function and in disease severity. CONCLUSIONS: Full-field ERGs confirmed that Alström syndrome is associated with a cone-rod type of retinal degeneration. In this study, we have shown a striking variability in retinal function and disease onset and severity, which has, to our knowledge, not been described previously in Alström syndrome.
Assuntos
Anormalidades Múltiplas/fisiopatologia , Eletrorretinografia , Células Fotorreceptoras de Vertebrados/fisiologia , Retinose Pigmentar/fisiopatologia , Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular , Criança , Defeitos da Visão Cromática/fisiopatologia , Análise Mutacional de DNA , Feminino , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Mutação , Obesidade/genética , Obesidade/fisiopatologia , Fenótipo , Reação em Cadeia da Polimerase , Proteínas/genética , Retinose Pigmentar/genética , Síndrome , Transtornos da Visão/fisiopatologia , Testes de Campo Visual , Campos Visuais/fisiologiaRESUMO
PURPOSE: To characterize the phenotype of members of a Swedish family with Best macular dystrophy and two distinct mutations in VMD2. METHODS: Venous blood samples were obtained from six family members and screened for mutations in VMD2. Six individuals were examined clinically, four of whom were further investigated with full-field electroretinography (ERG), electro-oculography (EOG), multifocal electroretinography (mfERG), and optical coherence tomography (OCT). RESULTS: The VMD2 mutations resulting in Arg141His and Tyr29stop were identified in family members. Two individuals harbored both mutations, one mutation in each VMD2 allele. These two family members had an abnormal EOG and their full-field ERG demonstrated widespread degeneration with a prolonged implicit time in the cone 30-Hz flicker ERG. MfERG verified reduction of the central retinal function and OCT demonstrated intraretinal fluid, swelling, and thickening of the outer retina-RPE-choroid complex (ORCC). CONCLUSION: A previously undescribed severe form of Best macular dystrophy is associated with compound heterozygous mutations in VMD2.
Assuntos
Proteínas do Olho/genética , Mutação , Degeneração Retiniana/genética , Adulto , Idoso , Alelos , Bestrofinas , Criança , Canais de Cloreto , Análise Mutacional de DNA , Eletroculografia , Eletrorretinografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Epitélio Pigmentado Ocular/fisiopatologia , Reação em Cadeia da Polimerase , Retina/fisiopatologia , Degeneração Retiniana/fisiopatologia , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) have recently been discovered to cause a form of autosomal dominant retinitis pigmentosa (adRP). Such mutations are estimated to account for approximately 2-5% of the adRP cases among Americans of European origin and Europeans. Aiming towards an understanding of the molecular background of retinitis pigmentosa, this paper describes the phenotype of a Swedish family with a mutation in IMPDH1. METHODS: Venous blood samples were obtained from 12 family members and screened for mutations in IMPDH1. Six individuals with the mutation were examined clinically and with full-field electroretinography (ERG), dark adaptometry, multifocal electroretinography (mfERG), and optical coherence tomography (OCT). Also reviewed were the clinical findings and ERGs obtained 14 years earlier. RESULTS: The proband and eight other relatives from three generations were found to harbor the Asp226Asn mutation in IMPDH1. These individuals, from three generations, showed clinical and electrophysiological signs of retinitis pigmentosa. The cone responses to the full-field, 30-Hz flicker ERG demonstrated an unusual pattern, with implicit times within normal limits or only slightly prolonged. Rod ERG responses, however, were undetectable. OCT showed intraretinal fluid and swelling, changes that were more pronounced in younger individuals. mfERG showed residual preserved central function. The older the individual, the smaller the area of preserved central function. CONCLUSION: In this family with a mutation in IMPDH1, we found a specific phenotype with rod function affected more than cone function, foveal edema, and central retinal function preserved for a long period of time. Foveal edema could be a pathogenic feature in this form of retinal degeneration.
Assuntos
IMP Desidrogenase/genética , Mutação Puntual , Retinose Pigmentar/genética , Adolescente , Adulto , Análise Mutacional de DNA , Adaptação à Escuridão , Eletrorretinografia , Feminino , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Retinose Pigmentar/enzimologia , Retinose Pigmentar/fisiopatologia , Suécia , Tomografia de Coerência ÓpticaRESUMO
OBJECTIVE: To characterize the clinical phenotype, with emphasis on electrophysiology and blood flow measurements, of a family with dominant optic nerve atrophy and an identified mutation in the OPA1 gene. METHODS: Seven family members were examined. Ophthalmological evaluation included testing of visual acuity, ophthalmolscopy, kinetic perimetry, color vision testing, full-field electroretinography (ERG), multifocal electroretinography (MERG), and multifocal visual evoked potential (MVEP). Retrobulbar arterial blood flow and retinal capillary perfusion was measured in three patients using scanning laser Doppler flowmetry (SLDF) and color Doppler imaging techniques. PCR-SSCP and DNA sequencing determined the presence of a mutation in exon 18 of the OPA1 gene. RESULTS: The clinical characteristics varied considerably in the family. The ERG and the MERG demonstrated normal retinal function, while the MVEP was abnormal in all examined patients. Retinal and optic nerve head capillary perfusion was significantly decreased in the three patients examined with SLDF. Retrobulbar blood flow velocities were significantly decreased in the central retinal and ophthalmic arteries. In all seven examined subjects, a microdeletion (1756-1767del(12 bp)) in the OPA1 gene was identified. CONCLUSION: Patients with a mutation in the OPA1 gene have a very variable phenotype. MVEP and blood flow measurements are two new objective methods for an easier detection of this specific genetic optic nerve atrophy.
Assuntos
GTP Fosfo-Hidrolases/genética , Mutação , Atrofia Óptica Autossômica Dominante/genética , Atrofia Óptica Autossômica Dominante/fisiopatologia , Retina/fisiologia , Adolescente , Adulto , Velocidade do Fluxo Sanguíneo , Criança , Eletrorretinografia , Potenciais Evocados Visuais , Feminino , Humanos , Fluxometria por Laser-Doppler , Masculino , Pessoa de Meia-Idade , Artéria Oftálmica/fisiologia , Disco Óptico/irrigação sanguínea , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Fluxo Sanguíneo Regional , Artéria Retiniana/fisiologia , Ultrassonografia Doppler em Cores , Acuidade VisualRESUMO
PURPOSE: To describe new disease-causing RP2 and RPGR-ORF15 mutations and their corresponding clinical phenotypes in Swedish families with X-linked retinitis pigmentosa (XLRP) and to establish genotype-phenotype correlations by studying the clinical spectrum of disease in families with a known molecular defect. METHODS: Seventeen unrelated families with RP and an apparent X-linked pattern of disease inheritance were identified from the Swedish RP registry and screened for mutations in the RP2 and RPGR (for the RP3 disease) genes. These families had been previously screened for the RPGR exons 1-19, and disease-causing mutations were identified in four of them. In the remaining 13 families, we sequenced the RP2 gene and the newly discovered RPGR-ORF exon. Detailed clinical evaluations were then obtained from individuals in the three families with identified mutations. RESULTS: Mutations in RP2 and RPGR-ORF15 were identified in three of the 13 families. Clinical evaluations of affected males and carrier females demonstrated varying degrees of retinal dysfunction and visual handicap, with early onset and severe disease in the families with mutations in the ORF15 exon of the RPGR gene. CONCLUSIONS: A total of seven mutations in the RP2 and RPGR genes have been discovered so far in Swedish XLRP families. All affected individuals express a severe form of retinal degeneration with visual handicap early in life, although the degree of retinal dysfunction varies both in hemizygous male patients and in heterozygous carrier females. Retinal disease phenotypes in patients with mutations in the RPGR-ORF15 were more severe than in patients with mutations in RP2 or other regions of the RPGR.
Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos X/genética , Proteínas do Olho , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação/genética , Proteínas/genética , Retinose Pigmentar/genética , Adulto , Idoso , Análise Mutacional de DNA , Eletrorretinografia , Éxons/genética , Feminino , Proteínas de Ligação ao GTP , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Fases de Leitura Aberta , Linhagem , Suécia , Acuidade Visual , Campos VisuaisRESUMO
PURPOSE: To investigate the clinical value of assessment of peripapillary retinal nerve fibre layer (RNFL) thickness with OCT in addition to the evaluation of retinal function measured by full-field electroretinography (ff-ERG) in patients with suspected vigabatrin (VGB)-attributed visual field defects. METHODS: Visual fields from adult patients in our clinical follow-up program for VGB medication were analysed. Twelve patients with suspected VGB-attributed visual field defects were selected for the study. They were re-examined with computerized kinetic perimetry, ff-ERG and OCT (2D circle scan). RESULTS: Constricted visual fields were found in all patients. Comparative analysis of ff-ERG parameters showed reduced b-wave amplitudes for the isolated and the combined rod and cone responses (p < 0.0001). The a-wave, reflecting photoreceptor activity, was reduced (p = 0.001), as well as the summed amplitude of oscillatory potentials (p = 0.029), corresponding to inner retinal function. OCT measurements demonstrated attenuation of the RNFL in nine of 12 patients, most frequently superiorly and/or inferiorly. No temporal attenuation was found. Significant positive correlations were found between the total averaged RNFL thickness, superior and inferior RNFL thickness and reduced ff-ERG parameters. Positive correlations were also found between RNFL thickness and isopter areas. CONCLUSION: OCT measurements can detect attenuation of the RNFL in patients exposed to VGB medication. RNFL thickness correlates with reduced ff-ERG parameters and isopter areas of constricted visual fields, indicating that VGB is retino-toxic on several levels, from photoreceptors to ganglion cells. The study also supports previous studies, suggesting that OCT measurement of the RNFL thickness may be of clinical value in monitoring patients on vigabatrin therapy.
Assuntos
Anticonvulsivantes/efeitos adversos , Eletrorretinografia , Fibras Nervosas/patologia , Retina/fisiopatologia , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica , Vigabatrina/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/efeitos dos fármacos , Disco Óptico/efeitos dos fármacos , Disco Óptico/patologia , Refração Ocular , Retina/efeitos dos fármacos , Células Ganglionares da Retina/efeitos dos fármacos , Transtornos da Visão/induzido quimicamente , Acuidade Visual , Testes de Campo Visual , Campos Visuais/efeitos dos fármacosRESUMO
AIM: To study the effects of the tumor necrosis factor alpha inhibitor adalimumab on rabbit retina after injection into the vitreous body. METHODS: Forty-eight rabbits of mixed strain (9-12 months old, weighing ≈ 3.5 kg) were randomized into four groups. Adalimumab was injected at one of two concentrations (1.25 mg or 2.5 mg) into the eyes of two groups, and balanced salt solution into the eyes of the third group. The fourth group acted as controls. Full-field electroretinography (ffERG) was performed before injection and 1 and 6 weeks post-injection. At 6 weeks post-injection the rabbits were euthanized and the sectioned retinas were studied. Retinal histology was studied with hematoxylin-eosin staining. Immunohistochemical analysis was performed on rods, cones, rod bipolar cells, horizontal cells, amacrine cells and Müller cells. RESULTS: No significant difference in ffERG amplitudes or implicit times was observed between the four groups at any time point. Histological and immunohistochemical findings were similar in all groups. CONCLUSIONS: Injection of adalimumab into the vitreous body of healthy rabbits, at doses up to 2.5 mg, does not appear to be toxic to the rabbit retina.
Assuntos
Anti-Inflamatórios/toxicidade , Anticorpos Monoclonais Humanizados/toxicidade , Retina/efeitos dos fármacos , Retina/fisiopatologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Animais , Calbindinas/metabolismo , Eletrorretinografia , Técnica Indireta de Fluorescência para Anticorpo , Proteína Glial Fibrilar Ácida/metabolismo , Injeções Intravítreas , Parvalbuminas/metabolismo , Proteína Quinase C-alfa/metabolismo , Coelhos , Retina/metabolismo , Rodopsina/metabolismoRESUMO
AIM: To study the effects of intravitreally injected triamcinolone acetonide (TA) and/or its preservative benzyl alcohol (BA) in healthy rabbit retina. METHODS: Forty-eight rabbits (aged 4 months, body weight ≈3 kg) were randomized into four groups (n = 12). They were examined with electroretinography (ERG) prior to drug exposure, and then injected intravitreally with a combination of TA and BA, TA without BA, BA alone or a balanced saline solution (BSS). The electroretinograms were assessed 1 week and 7 weeks post-injection. The rabbits were euthanized and the sectioned retinas were studied. Immunohistochemical analysis was performed on rods, cones, rod bipolar cells, horizontal cells, amacrine cells and Müller cells. RESULTS: Rabbits injected with BA showed a significantly lower rod-mediated b-wave amplitude than the controls 1 week after injection. TA-injected rabbits demonstrated significantly higher a- and b-wave amplitudes in the total retinal response than the controls 1 week post-injection. The rabbits injected with TA + BA demonstrated a significantly higher b-wave amplitude in the total retinal response than the controls 1 week after injection. The significantly higher a-wave amplitude in the total retinal response remained in the TA-injected rabbits 7 weeks after injection. Immunohistochemistry revealed that protein kinase C alpha (PKC α) was down-regulated in both the perikarya and the axons of bipolar cells in histological sections from rabbit retina injected with TA + BA, BA and TA. CONCLUSIONS: Intravitreal injection of the preservative BA reduces the isolated rod-mediated retinal response in the rabbit, transiently and selectively. Intravitreal injection of TA increases the total retinal response in the rabbit up to seven weeks after injection. The effects observed are not only limited to retinal function, but also include changes in the expression of PKC α in rod bipolar cells, indicating drug-related interference with normal retinal physiology in the healthy rabbit eye.
Assuntos
Anti-Inflamatórios/farmacologia , Álcool Benzílico/farmacologia , Conservantes Farmacêuticos/farmacologia , Retina/efeitos dos fármacos , Triancinolona Acetonida/farmacologia , Células Amácrinas/citologia , Células Amácrinas/efeitos dos fármacos , Anestésicos Locais/farmacologia , Animais , Biomarcadores , Eletrorretinografia/efeitos dos fármacos , Células Ependimogliais/citologia , Células Ependimogliais/efeitos dos fármacos , Humanos , Injeções Intravítreas , Coelhos , Distribuição Aleatória , Retina/citologia , Retina/fisiologia , Células Bipolares da Retina/citologia , Células Bipolares da Retina/efeitos dos fármacos , Células Fotorreceptoras Retinianas Cones/citologia , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Células Horizontais da Retina/citologia , Células Horizontais da Retina/efeitos dos fármacos , Células Fotorreceptoras Retinianas Bastonetes/citologia , Células Fotorreceptoras Retinianas Bastonetes/efeitos dos fármacosRESUMO
PURPOSE/AIM: To explore changes in morphology and function in the rabbit retina after intravitreal high-dose injection of three commonly used VEGF inhibitors. MATERIALS AND METHODS: Forty-eight rabbits of mixed strain (6 months of age, body weight ≈ 3 kg) were randomized into four groups (n = 12). They were examined with full-field electroretinography (ERG) and with multifocal electroretinography (mf ERG) prior to drug exposure. The rabbits were then injected intravitreally with bevacizumab, ranibizumab, pegaptanib, or with a balanced saline solution. The dose of VEGF inhibitor was chosen to achieve a vitreous concentration approximately three times higher than the one clinically used in the adult human eye. ERG was then performed 8 weeks postinjection, and mf ERG 9 weeks postinjection. After 9 weeks, the rabbits were sacrificed and the sectioned retina was studied. Immunohistochemical analysis was performed of rods, cones, rod bipolar cells, horizontal cells, and amacrine cells. RESULTS: Rabbits injected with VEGF inhibitors all showed significantly lower amplitude of the dark-adapted b-wave rod-mediated response to dim light, compared to the rabbits injected with BSS. The a wave (reflecting photoreceptor function) in the response to single flash white light was however not affected. Immunohistochemistry revealed a significant reduction in PKC labeling of rod bipolar cells in pegaptanib and ranibizumab injected eyes whereas bevacizumab injected eyes displayed normal PKC labeling. No apparent morphological change was seen with markers for remaining retinal cells. CONCLUSIONS: Our results indicate that the use of high-dose intravitreal VEGF inhibitors in the rabbit eye affects rod-mediated retinal function and PKC expression in rod bipolars cells for at least 9 weeks after drug administration. The three VEGF inhibitors influence the retina slightly differently. These results are important for the understanding of drug action and when devising therapeutical strategies in new areas such as retinopathy of prematurity where vitreous volume is significantly lower compared to the adult eye.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Aptâmeros de Nucleotídeos/administração & dosagem , Eletrorretinografia , Retina/patologia , Retina/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/administração & dosagem , Animais , Bevacizumab , Modelos Animais de Doenças , Imuno-Histoquímica , Injeções Intravítreas , Degeneração Macular/tratamento farmacológico , Degeneração Macular/patologia , Degeneração Macular/fisiopatologia , Coelhos , Ranibizumab , Retina/efeitos dos fármacosRESUMO
PURPOSE: To evaluate retinal function in children taking vigabatrin and to explore the influence of age and dose parameters on the results of full-field electroretinography (ff-ERG). METHODS: The ff-ERGs from 14 children receiving vigabatrin were compared with ff-ERGs from healthy controls. Treated children were further grouped according to age (pre-school = 12-71 months; older = 72-228 months). Parameters of drug dosage were compared. RESULTS: Treated children showed rod and cone dysfunction reflected by reduced b-wave amplitudes for the isolated rod response, the combined rod-cone response, and the 30-Hz flicker response. The a-wave amplitude and implicit time for the combined rod-cone response, reflecting photoreceptor function, were also altered. Further evaluation of age groups revealed similar findings in the pre-school group but not in the older group. Alterations in ff-ERG were seen in 57% of the treated children. Pre-school children had received significantly higher daily drug doses with start of medication at younger age. No differences were found concerning cumulative doses or duration of medication. CONCLUSION: Alterations in ff-ERG are as frequent in children as in adults and the results indicate that exposure to high daily doses of vigabatrin may be associated with increased risk of retinal dysfunction, including photoreceptor damage, not previously shown in children. Thus, recommendations of careful follow-up for children receiving vigabatrin are supported.
Assuntos
Anticonvulsivantes/efeitos adversos , Eletrorretinografia/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Retina/fisiopatologia , Doenças Retinianas/induzido quimicamente , Vigabatrina/efeitos adversos , Adolescente , Anticonvulsivantes/administração & dosagem , Criança , Pré-Escolar , Fenômenos Eletrofisiológicos , Feminino , Humanos , Lactente , Masculino , Estimulação Luminosa , Células Fotorreceptoras de Vertebrados/fisiologia , Doenças Retinianas/fisiopatologia , Convulsões/tratamento farmacológico , Espasmos Infantis , Vigabatrina/administração & dosagemRESUMO
PURPOSE: To present the clinical and electrophysiological findings in four members of a family with Best vitelliform macular dystrophy (BVMD) and angle-closure glaucoma (ACG). METHODS: Four members of a family with BVMD were examined clinically, including visual acuity, slit-lamp examination, biomicroscopy, Goldmann applanation tonometry and gonioscopy. Measurements of the anterior chamber depth and axial length, visual field, optical coherence tomography, full-field electroretinography, multifocal electroretinography and electrooculography were performed. In addition molecular genetic analysis of the bestrophin-1 gene (BEST1), the microphthalmia-associated transcription factor gene (MITF) and the cone-rod homeobox gene (CRX) were performed. RESULTS: Four family members with the c.253T>C p.Y85H mutation in the BEST1 gene and BVMD in different stages also exhibited anterior segment abnormalities such as shallow anterior chambers (two cases), and reduced axial lengths in all cases. Microphthalmos (axial length ≤ 20mm) was found in the index patient and in her son. Hyperopia was found in all four examined patients. Closed angles/narrow angles were observed in patients with microphthalmos. The index patient developed ACG at the age of 12 years. Her son inherited microphthalmos, severe hyperopia, and narrow angles. He is at risk of developing ACG. No pathogenic mutation of the MITF or the CRX genes was detected in the index patient. CONCLUSIONS: BVMD could be associated with anterior segment abnormalities such as shallow anterior chambers, closed/narrow anterior chamber angles and ACG. Ophthalmologists should be aware of the association between ACG and BVMD. Examination of the anterior segment, gonioscopy and intraocular pressure control are recommended in patients with BVMD.
Assuntos
Segmento Anterior do Olho/anormalidades , Canais de Cloreto/genética , Proteínas do Olho/genética , Glaucoma de Ângulo Fechado/genética , Mutação de Sentido Incorreto , Distrofia Macular Viteliforme/genética , Adulto , Idoso , Segmento Anterior do Olho/diagnóstico por imagem , Bestrofinas , Criança , Análise Mutacional de DNA , Eletrorretinografia , Feminino , Glaucoma de Ângulo Fechado/diagnóstico , Gonioscopia , Proteínas de Homeodomínio/genética , Humanos , Pressão Intraocular/fisiologia , Masculino , Fator de Transcrição Associado à Microftalmia/genética , Microscopia Acústica , Linhagem , Reação em Cadeia da Polimerase , Tomografia de Coerência Óptica , Tonometria Ocular , Transativadores/genética , Acuidade Visual/fisiologia , Campos Visuais , Distrofia Macular Viteliforme/diagnósticoRESUMO
PURPOSE: To describe morphological and functional changes in a single patient with multifocal Best vitelliform macular dystrophy (BVMD) and to perform a genotype/phenotype correlation. METHODS: The proband with multifocal BVMD and three of her family members were examined with electrooculography (EOG), full-field electroretinography (full-field ERG), multifocal electroretinography (mfERG) and optical coherence tomography (OCT). Genomic DNA was screened for mutation in the BEST1 gene by DNA sequencing analysis. RESULTS: The proband was observed regularly during a follow-up period of 4 years. Full-field ERG demonstrated reduced and delayed responses of both rods and cones. OCT demonstrated intra- and subretinal fluid which seemed to fluctuate with periods of stress, similar to that seen in chronic central serous chorioretinopathy. Two distinct heterozygous BEST1 mutations were identified in the proband, the recurrent p.R141H mutation and the p.P233A mutation. Heterozygous p.R141H mutations were also identified in two family members, while p.P233A was a de novo mutation. Abnormal EOG findings were observed in both the proband and in the carriers of p.R141H. Heterozygous carriers showed delayed implicit times in a- and b-waves of combined total rod and cone full-field ERG responses. CONCLUSIONS: The p.R141H mutation is frequently seen together with multifocal vitelliform retinopathy and biallelic mutations in BEST1. Our results show that carriers of the p.R141H mutation are clinically unaffected but present with abnormal EOG and full-field ERG findings. A patient with biallelic mutations of the BEST1 gene, causing multifocal BVMD with progressive, widespread functional disturbance of the retina, confirmed by full-field and mfERG is described.
Assuntos
Canais de Cloreto/genética , Proteínas do Olho/genética , Mutação , Retina/fisiopatologia , Distrofia Macular Viteliforme/fisiopatologia , Adolescente , Bestrofinas , Análise Mutacional de DNA , Eletroculografia , Eletrorretinografia , Feminino , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Análise de Sequência de DNA , Tomografia de Coerência Óptica , Distrofia Macular Viteliforme/genéticaRESUMO
OBJECTIVE: To characterize visual function in defined genotypes including siblings with Usher syndrome. METHODS: Thirteen patients with phenotypically different subtypes of Usher syndrome, including 3 families with affected siblings, were selected. Genetic analysis and ophthalmological examinations including visual fields, full-field electroretinography (ERG), multifocal electroretinography (mf ERG), and optical coherence tomography (OCT) were assessed. The patients' degree of visual handicap was evaluated by a questionnaire (ADL). RESULTS: Twelve of thirteen patients were genotyped as Usher 1B, 1D, 1F, 2A, 2C or 3A. In 12 of 13 patients examined with ERG the 30 Hz flickering light response revealed remaining cone function. In 3 of the patients with Usher type 1 mf ERG demonstrated a specific pattern, with a sharp distinction between the area with reduced function and the central area with remaining macular function and normal peak time. OCT demonstrated loss of foveal depression with distortion of the foveal architecture in the macula in all patients. The foveal thickness ranged from 159 to 384 µm and was not correlated to retinal function. Three siblings shared the same mutation for Usher 2C but in contrast to previous reports regarding this genotype, 1 of them diverged in phenotype with substantially normal visual fields, almost normal OCT and mf ERG findings, and only moderately reduced rod and cone function according to ERG. CONCLUSIONS: Evaluation of visual function comprising both the severity of the rod cone degeneration and the function in the macular region confirm phenotypical heterogeneity within siblings and between different genotypes of Usher syndrome.
Assuntos
Genótipo , Fenótipo , Síndromes de Usher/genética , Adolescente , Adulto , Idoso , Proteínas Relacionadas a Caderinas , Caderinas/genética , Criança , Eletrorretinografia , Proteínas da Matriz Extracelular/genética , Feminino , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Miosinas/genética , Linhagem , Receptores Acoplados a Proteínas G/genética , Retina/fisiopatologia , Irmãos , Inquéritos e Questionários , Tomografia de Coerência Óptica , Síndromes de Usher/fisiopatologia , Acuidade Visual/fisiologia , Campos Visuais/fisiologiaRESUMO
PURPOSE: To evaluate the retinal function, with emphasis on phenotype and rate of progression, in infants and children with different genotypes of Usher syndrome. METHODS: Fourteen children (2-10 years of age) with retinitis pigmentosa and hearing impairment were examined with full-field electroretinography (ERG) during general anesthesia, ophthalmologic examination, and genetic analysis. Five children were repeatedly examined (follow-up 5-10 years) with full-field ERG under local anesthesia and in 2 children multifocal ERG and optical coherence tomography (OCT) were performed. These results were compared to full-field ERG data from 58 children without retinal eye disorder. RESULTS: Six children were genotyped as Usher 1B, 2A, and 3A. Full-field ERG demonstrated early alterations corresponding to a rod-cone dystrophy in all children. A remaining rod function could be verified in the majority of the children up to 4 years of age. After 4 years of age, there was a further deterioration of the rod function; the progress was severe in Usher types 1 and 2 and moderate in Usher type 3. In all children, the cone function was moderately reduced, in a few cases almost normal. The results from the 58 children without retinal disorder confirm that full-field ERG during general anesthesia is reliable. Multifocal ERG confirmed a preserved central cone function and in OCT there were discrete structural alterations. CONCLUSIONS: Full-field ERG during general anesthesia in children with Usher syndrome demonstrates variable phenotypes and different degrees in rate of progression during childhood.