RESUMO
The purpose of this study was to evaluate the neuroprotective effects of omega-3 polyunsaturated fatty acid (ω3-PUFA) supplementation, alone or in combination with timolol eye drops, in a mouse model of hereditary glaucoma. DBA/2J mice (8.5-month-old) were assigned to an ω3-PUFAs + timolol, ω3-PUFAs only, timolol only, or an untreated group. Treated mice received a daily gavage administration of eicosapentaenoic acid (EPA) and docosahexaenoic acid and/or topical instillation of timolol (0.5%) once a day for 3 months. Blood was analysed regularly to determine ω3-PUFA levels and retinas were histologically analysed. Real-time PCR and Western blot were performed for retinal pro-inflammatory cytokines and macrophages. Blood arachidonic acid/EPA ratio gradually decreased and reached the desired therapeutic range (1-1.5) after 4 weeks of daily gavage with ω3-PUFAs in the ω3-PUFAs + timolol and ω3-PUFAs only groups. Retinal ganglion cell densities were significantly higher in the ω3-PUFAs + timolol (1303.77 ± 139.62/mm2), ω3-PUFAs only (768.40⯱â¯52.44/mm2) and timolol only (910.57⯱â¯57.28/mm2) groups than in the untreated group (323.39⯱â¯95.18/mm2). ω3-PUFA supplementation alone or timolol alone, significantly increased protein expression levels of M1 macrophage-secreted inducible nitric oxide synthase and M2 macrophage-secreted arginase-1 in the retina, which led to significant decreases in the expression levels of tumour necrosis factor-α (TNF-α). ω3-PUFA supplementation alone also resulted in significantly reduced expression of interleukin-18 (IL-18). ω3-PUFA + timolol treatment had no effect on the expression level of any of the aforementioned mediators in the retina. Supplementation with ω3-PUFAs has neuroprotective effect in the retinas of DBA/2J mice that is enhanced when combined with timolol eye drops. The continued inflammation following ω3-PUFAs + timolol treatment suggests that downregulation of IL-18 and TNF-α may not be the only factors involved in ω3-PUFA-mediated neuroprotection in the retina.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Modelos Animais de Doenças , Ácidos Graxos Ômega-3/administração & dosagem , Glaucoma de Ângulo Aberto/prevenção & controle , Doenças do Nervo Óptico/prevenção & controle , Células Ganglionares da Retina/efeitos dos fármacos , Timolol/uso terapêutico , Administração Oftálmica , Animais , Ácido Araquidônico/sangue , Arginase/metabolismo , Western Blotting , Sobrevivência Celular , Combinação de Medicamentos , Ácido Eicosapentaenoico/sangue , Feminino , Glaucoma de Ângulo Aberto/genética , Glaucoma de Ângulo Aberto/metabolismo , Interleucina-18/metabolismo , Pressão Intraocular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Óxido Nítrico Sintase Tipo II/metabolismo , Soluções Oftálmicas , Doenças do Nervo Óptico/genética , Doenças do Nervo Óptico/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Tonometria Ocular , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The authors report the first case of trisomy 18 associated with a clinically detectable optic nerve pit. A female infant with a birth weight of 2,150 g was born by cesarean section to a healthy 40-year-old woman at 38 weeks of gestation. Trisomy 18 had been diagnosed by prenatal genetic testing. Ophthalmologic examination was remarkable for bilateral narrowed palpebral fissures with punctal agenesis, corectopic pupils without reaction to light, bilateral inferior peripapillary retinochoroidal hypopigmentation, and significant optic nerve cupping in the left eye with associated temporal optic nerve pit. It has generally been accepted that optic nerve pits are a congenital anomaly. However, the pathophysiological background of optic nerve pits remains unclear and controversial. This is the first clinical and photographic documentation of an optic nerve pit in a neonate and in Edwards syndrome.
Assuntos
Cromossomos Humanos Par 18 , Disco Óptico/anormalidades , Doenças do Nervo Óptico/congênito , Doenças do Nervo Óptico/genética , Trissomia , Diagnóstico por Imagem , Feminino , Humanos , Recém-NascidoRESUMO
OBJECTIVE: Optic nerve head abnormalities have been reported in some patients with congenital fibrosis of the extraocular muscles (CFEOM). This study prospectively assesses optic nerve head appearance in a consecutive CFEOM cohort. METHODS: All patients with CFEOM referred between 2006 and 2010 and who were mature enough to cooperate with fundus photography were included. Fundus photographs were reviewed with attention to optic nerve head features (eg, cupping >0.6, asymmetric cupping >0.3, optic nerve hypoplasia). Interested participants had CFEOM candidate gene analysis (KIF21A, TUBB3, PHOX2A) for genetic counseling purposes. RESULTS: Ten CFEOM patients (five CFEOM1, five CFEOM3, age range 5-23 years) from eight families (all consanguineous but one) participated. All 10 patients had notable disc excavation (5) or optic nerve hypoplasia (5). CFEOM candidate gene analysis was performed in all patients and revealed a heterozygous p.R954W KIF21A mutation only in the patient who was not from a consanguineous family. CONCLUSIONS: Our observations suggest the optic nerve head can be affected by the orbital dysinnervation that occurs in CFEOM. Because careful clinical optic nerve head assessment is difficult in young patients with CFEOM and associated large angle incomitant strabismus, optic nerve head abnormalities may be under-diagnosed. The absence of mutations in known CFEOM genes in our cohort of consanguineous families suggests further genetic heterogeneity of this group of conditions.
Assuntos
Músculos Oculomotores/patologia , Disco Óptico/anormalidades , Doenças do Nervo Óptico/diagnóstico , Adolescente , Criança , Pré-Escolar , Consanguinidade , Feminino , Fibrose/congênito , Humanos , Cinesinas/genética , Masculino , Mutação , Músculos Oculomotores/inervação , Doenças do Nervo Óptico/genética , Estrabismo/diagnóstico , Estrabismo/genética , Adulto JovemRESUMO
Perry syndrome is a rare form of autosomal dominant Parkinsonism with respiratory failure recently defined as being due to mutations in the DCTN1 gene. We describe a new family carrying a G71R mutation in the DCTN1 gene. The proband displayed a series of distinctive features not previously described in Perry syndrome: a disorder of vertical downward saccades accompanied by progressive midbrain atrophy, predominant nonmotor symptoms responsive to levodopa, distinctive craniocervical levodopa induced dyskinesias, and a good response to high-dose levodopa therapy and respiratory support. The family was initially thought to have autosomal dominant behavioral variant frontotemporal dementia with Parkinsonism. This report expands the clinical definition of this distinctive syndrome.
Assuntos
Sintomas Comportamentais/genética , Proteínas Associadas aos Microtúbulos/genética , Doenças do Nervo Óptico/genética , Transtornos Parkinsonianos/genética , Insuficiência Respiratória/genética , Arginina/genética , Sintomas Comportamentais/complicações , Sintomas Comportamentais/tratamento farmacológico , Análise Mutacional de DNA , Dopaminérgicos/uso terapêutico , Complexo Dinactina , Glicina/genética , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doenças do Nervo Óptico/complicações , Doenças do Nervo Óptico/tratamento farmacológico , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/tratamento farmacológico , Insuficiência Respiratória/complicações , Insuficiência Respiratória/tratamento farmacológicoRESUMO
The primary open-angle glaucoma (POAG) is an optic neuropathy which is influenced by a number of different risk factors. Some of them can induce the transcriptional factor NF-kappaB, a nuclear protein which binds to specific areas of the DNA to stimulate different genes. NF-kappaB can be activated by increased intraocular pressure, increased age, vascular diseases and by oxidative stress. In the case of POAG NF-kappaB might be overstimulated with the induction of uncontrolled biochemical reactions. Treatment strategies for reducing NF-kappaB are to reduce intraocular pressure as well as therapies with statins, omega-3-fatty acids and alpha-lipoic acid. This model is a hypothesis and is intended to provide a basis for further discussions and basic research.
Assuntos
Glaucoma de Ângulo Aberto/fisiopatologia , NF-kappa B/fisiologia , Fatores Etários , Idoso , Endotelina-1/fisiologia , Glaucoma de Ângulo Aberto/genética , Glaucoma de Ângulo Aberto/terapia , Humanos , Pressão Intraocular/genética , Pressão Intraocular/fisiologia , NF-kappa B/genética , Doenças do Nervo Óptico/genética , Doenças do Nervo Óptico/fisiopatologia , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Fatores de Risco , Malha Trabecular/fisiopatologia , Ativação Transcricional/genética , Ativação Transcricional/fisiologiaRESUMO
Autosomal dominant optic atrophy (DOA) is a retinal neuronal degenerative disease characterized by a progressive bilateral visual loss. We report on two affected members of a family with dominantly inherited neuropathy of both optic and auditory nerves expressed by impaired visual acuity, moderate pure tone hearing loss, and marked loss of speech perception. We investigated cochlear abnormalities accompanying the hearing loss and the effects of cochlear implantation. We sequenced OPA1 gene and recorded cochlear receptor and neural potentials before cochlear implantation. Genetic analysis identified R445H mutation in OPA1 gene. Audiological studies showed preserved cochlear receptor outer hair cell activities (otoacoustic emissions) and absent or abnormally delayed auditory brainstem responses (ABRs). Trans-tympanic electrocochleography (ECochG) showed prolonged low amplitude negative potentials without auditory nerve compound action potentials. The latency of onset of the cochlear potentials was within the normal range found for inner hair cell summating receptor potentials. The duration of the negative potential was reduced to normal during rapid stimulation consistent with adaptation of neural sources generating prolonged cochlear potentials. Both subjects had cochlear implants placed with restoration of hearing thresholds, speech perception, and synchronous activity in auditory brainstem pathways. The results suggest that deafness accompanying this OPA1 mutation is due to altered function of terminal unmyelinated portions of auditory nerve. Electrical stimulation of the cochlea activated proximal myelinated portions of auditory nerve to restore hearing.
Assuntos
Percepção Auditiva/fisiologia , Cóclea/fisiopatologia , Nervo Coclear/fisiopatologia , Potenciais Evocados Auditivos do Tronco Encefálico/genética , GTP Fosfo-Hidrolases/genética , Perda Auditiva/genética , Estimulação Acústica , Potenciais de Ação/fisiologia , Adulto , Audiometria de Resposta Evocada , Audiometria de Tons Puros , Vias Auditivas/fisiopatologia , Limiar Auditivo/fisiologia , Criança , Implantes Cocleares , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Feminino , Genótipo , Perda Auditiva/fisiopatologia , Humanos , Pessoa de Meia-Idade , Mutação , Doenças do Nervo Óptico/genéticaRESUMO
PURPOSE: To describe a multigenerational family with autosomal dominant inheritance of cavitary optic nerve head (ONH) anomalies and abnormal ONH vasculature. DESIGN: Description of a single family with inherited eye disease. METHODS: A four-generation pedigree was investigated. Examination included visual acuity, slit-lamp biomicroscopy, intraocular pressure (IOP) measurement, and ophthalmoscopy. Visual fields and fundus photography were obtained when possible. RESULTS: Seventeen clinically affected individuals and two obligate carriers were identified. Most (64.7%) affected persons had bilateral involvement. Visual acuity in affected eyes ranged from 20/20 to no light perception. Although the appearance of affected nerves varied greatly, most lacked a well-formed central retinal artery and instead had multiple radial cilioretinal arteries. Prominent cupping was seen in most affected nerves. Four individuals for whom information was available were treated for glaucoma, but none had documented elevated IOP. Four eyes of two patients demonstrated progressive ONH cupping at normal IOPs. Nine (56.3%) of the 16 individuals for whom we had data had evidence of serous macular detachments; five of these had bilateral macular disease. CONCLUSIONS: A large family with autosomal dominant inheritance of cavitary ONH anomalies and abnormal vasculature is presented. Clinical phenotypes varied markedly. Progressive ONH cupping was documented in four eyes of two patients. Genetic linkage analysis of this family has identified the chromosomal location of a gene responsible for ONH development. This may provide insight into the pathogenesis of glaucomatous ONH damage.
Assuntos
Anormalidades do Olho/diagnóstico , Disco Óptico/anormalidades , Doenças do Nervo Óptico/diagnóstico , Doenças do Nervo Óptico/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Progressão da Doença , Anormalidades do Olho/genética , Feminino , Angiofluoresceinografia , Genes Dominantes , Humanos , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Disco Óptico/irrigação sanguínea , Linhagem , Artéria Retiniana/anormalidades , Transtornos da Visão/genética , Acuidade Visual , Campos VisuaisRESUMO
PURPOSE: To investigate a role of common polymorphisms of the CYP1B1 gene in French patients with primary open-angle glaucoma (POAG). METHODS: Six common CYP1B1 variants, 5 coding and one in promoter, were compared in 224 unrelated French Caucasian POAG patients, excluding those with a CYP1B1 mutation, and in 47 population-matched controls with a normal ophthalmic examination. Allelic associations were assessed with the D' and r2 parameters. An effect of the representative variants on subphenotypes, including the age and the intraocular pressure at diagnosis, the cup to disk ratio, and the visual field alteration, was tested by multivariate analyses. RESULTS: Allele and haplotype frequencies were similar in patients and in controls. Five variants formed two groups with tightly correlated alleles while the sixth one, N453S, was independent. The age and the intraocular pressure at diagnosis were not influenced by any of the variants. In contrast, the 453*Serine allele was associated with decreased cupping of the optic disk (Odds ratio=0.32, 95% CI: 0.15-0.70; p=0.0036) and with a milder alteration of the visual field (p=0.025). CONCLUSIONS: The common N453S coding variant of CYP1B1 is potentially a factor of severity in POAG patients.
Assuntos
Sistema Enzimático do Citocromo P-450/genética , Glaucoma de Ângulo Aberto/genética , Disco Óptico/patologia , Doenças do Nervo Óptico/genética , Polimorfismo de Nucleotídeo Único , Transtornos da Visão/genética , Campos Visuais , Alelos , Hidrocarboneto de Aril Hidroxilases , Citocromo P-450 CYP1B1 , França/epidemiologia , Genótipo , Glaucoma de Ângulo Aberto/etnologia , Humanos , Pressão Intraocular , Reação em Cadeia da Polimerase , Testes de Campo VisualRESUMO
PURPOSE: To investigate the clinical features of subjects with glaucoma with the E50K mutation in the optineurin (OPTN) gene and to compare the onset, severity, and clinical course of these patients with a control group of subjects with glaucoma without this mutation. METHODS: The phenotype of well-characterized subjects from Moorfields Eye Hospital, London, who had been identified as carrying the OPTN E50K mutation was examined. A wide range of structural, psychophysical, and demographic factors were then compared with those in a control group of subjects with glaucoma without this mutation. RESULTS: Eleven subjects with glaucoma with the E50K mutation (nine in two families and two sporadic cases) were studied. All 11 subjects had normal tension glaucoma (NTG), with presenting and highest IOP of 15.3 +/- 3.0 and 16.5 +/- 2.5 mm Hg (+/-SD) on diurnal testing. Compared with 87 NTG control subjects who did not have this mutation, subjects with E50K presented at a younger age (40.8 +/- 15 years, P = 0.0001) and had more advanced optic disc cupping (mean cup-disc ratio +/- SD 0.86 +/- 0.1, P = 0.001) and smaller neuroretinal rim area (+/-SD; 0.5 +/- 0.28 mm2, P = 0.001) at diagnosis. The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003), and all subjects with E50K were found to have progressing visual fields. In addition, seven E50K mutation-carrying individuals in two families (age range, 23-58 years) presented with normal optic discs and visual fields and, as yet, no signs of glaucoma. CONCLUSIONS: In this study, subjects with glaucoma who had the OPTN E50K mutation were found to have NTG that appeared to be more severe than that in a control group of subjects with NTG without this mutation. The findings emphasize the importance of early detection and treatment of glaucoma in such individuals, to minimize visual loss.
Assuntos
Glaucoma de Ângulo Aberto/diagnóstico , Glaucoma de Ângulo Aberto/genética , Mutação , Fator de Transcrição TFIIIA/genética , Adulto , Idoso , Proteínas de Ciclo Celular , Feminino , Cirurgia Filtrante , Glaucoma de Ângulo Aberto/cirurgia , Humanos , Pressão Intraocular , Masculino , Proteínas de Membrana Transportadoras , Pessoa de Meia-Idade , Disco Óptico/patologia , Doenças do Nervo Óptico/diagnóstico , Doenças do Nervo Óptico/genética , Linhagem , Fenótipo , Transtornos da Visão/diagnóstico , Transtornos da Visão/genética , Campos VisuaisRESUMO
BACKGROUND: Primary open-angle glaucoma (POAG) is a leading cause of blindness. High intraocular pressure (IOP) has been shown to be a key risk factor for POAG. Topical application of angiotensin 1-converting enzyme (ACE) inhibitors has been shown to lower IOP, and angiotensin-induced increase in vascular tone has been implicated as a pathogenetic mechanism in glaucomatous cupping and damage to the optic nerve. The objective of this study was to investigate the association between the deletion polymorphism in the ACE gene and ocular signs of POAG. METHODS: Baseline data from the Rotterdam Study was used. The ACE genotype was determined in 6,462 subjects. We used univariate and multiple variable statistical techniques to examine associations between ACE genotype and each of ocular hypertension, glaucomatous optic neuropathy, glaucomatous visual field defects and POAG diagnosis. RESULTS: We found no consistent evidence between ACE genotype and ocular signs of POAG. We did, however, find evidence of an association between ACE genotype and optic disc area, subjects homozygous for the deletion allele tending to have fractionally smaller optic disc areas than those with a single deletion allele subjects, who in turn tended to have fractionally smaller optic discs than those with no deletion alleles (P=0.01). CONCLUSIONS: The data provided little evidence of any association between ocular signs of POAG and the deletion polymorphism of ACE. There was, however, evidence that ACE may be associated with optic disc size-this was an unexpected finding.