Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 96
Filtrar
Mais filtros

Tipo de documento
Intervalo de ano de publicação
1.
Graefes Arch Clin Exp Ophthalmol ; 259(11): 3311-3320, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34357417

RESUMO

PURPOSE: To evaluate reliability and repeatability of computer-assisted measurements of cone photoreceptor metrics on Heidelberg Engineering Spectralis™ High Magnification Module (HMM™) Automatic Real-time Tracking (ART™) images. METHODS: We analyzed HMM™ images in three separate study arms. Computer-assisted cone identification software was validated using an open-access adaptive optics (AO) dataset. We compared results of the first arm to data from AO and histology. We evaluated intersession repeatability of our computer-assisted cone analysis in the second arm. We assessed the capability of HMM™ to visualize cones in the presence of pathology in the third arm. RESULTS: We included 10 healthy subjects in the first arm of our study, 5 additional healthy participants in the second arm and 5 patients in the third arm. In total, we analyzed 225 regions of interest on HMM™ images. We were able to automatically identify cone photoreceptors and assess corresponding metrics at all eccentricities between 2 and 9° from the fovea. Cone density significantly declined with increasing eccentricity (p = 4.890E-26, Friedman test). With increasing eccentricity, we found a significant increase in intercell distance (p = 2.196E-25, Friedman test) and nearest neighbor distance (p = 1.997E-25, Friedman test). Cone hexagonality ranged between 71 and 85%. We found excellent automated intersession repeatability of cone density counts and spacing measurements. In pathology, we were also able to repeatedly visualize photoreceptors. CONCLUSION: Computer-assisted cone photoreceptor analysis on Spectralis™ HMM™ images is feasible, and most cone metrics show excellent repeatability. HMM™ imaging may be useful for photoreceptor analysis as progression marker in outer retinal disease.


Assuntos
Fóvea Central , Células Fotorreceptoras Retinianas Cones , Contagem de Células , Computadores , Humanos , Oftalmoscopia , Óptica e Fotônica , Reprodutibilidade dos Testes
2.
Retina ; 40(8): 1565-1573, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31356496

RESUMO

PURPOSE: To investigate hyperreflective foci (HF) on spectral-domain optical coherence tomography in patients with Type 1 diabetes mellitus across different stages of diabetic retinopathy (DR) and diabetic macular edema (DME) and to study clinical and morphological characteristics associated with HF. METHODS: Spectral-domain optical coherence tomography scans and color fundus photographs were obtained of 260 patients. Spectral-domain optical coherence tomography scans were graded for the number of HF and other morphological characteristics. The distribution of HF across different stages of DR and DME severity were studied. Linear mixed-model analysis was used to study associations between the number of HF and clinical and morphological parameters. RESULTS: Higher numbers of HF were found in patients with either stage of DME versus patients without DME (P < 0.001). A trend was observed between increasing numbers of HF and DR severity, although significance was only reached for moderate nonproliferative DR (P = 0.001) and proliferative DR (P = 0.019). Higher numbers of HF were associated with longer diabetes duration (P = 0.029), lower high-density lipoprotein cholesterol (P = 0.005), and the presence of microalbuminuria (P = 0.005). In addition, HF were associated with morphological characteristics on spectral-domain optical coherence tomography, including central retinal thickness (P = 0.004), cysts (P < 0.001), subretinal fluid (P = 0.001), and disruption of the external limiting membrane (P = 0.018). CONCLUSION: The number of HF was associated with different stages of DR and DME severity. The associations between HF and clinical and morphological characteristics can be of use in further studies evaluating the role of HF as a biomarker for disease progression and treatment response.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Retinopatia Diabética/etiologia , Edema Macular/etiologia , Fotografação , Retina/patologia , Tomografia de Coerência Óptica , Adulto , Idoso , Retinopatia Diabética/classificação , Retinopatia Diabética/diagnóstico por imagem , Feminino , Humanos , Edema Macular/classificação , Edema Macular/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Retina/diagnóstico por imagem , Microscopia com Lâmpada de Fenda , Acuidade Visual/fisiologia
3.
Graefes Arch Clin Exp Ophthalmol ; 257(6): 1147-1157, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30903310

RESUMO

PURPOSE: To raise awareness of Stargardt disease (STGD1) patients without fundus abnormalities. METHODS: Medical records were evaluated for age at onset, initial symptoms and diagnosis, reason for delay of diagnosis, age at STGD1 diagnosis, best-corrected visual acuity (BCVA), ophthalmoscopy, fundus photography, fundus autofluorescence (FAF), fluorescein angiography (FA), spectral-domain optical coherence tomography (SD-OCT), full-field electroretinography (ffERG), color vision test, and the presence of ABCA4 variants. RESULTS: In 11.1% of our STGD1 cohort of 280 patients, no fundus abnormalities were observed at first ophthalmic consultation. The median age at onset was 8 years (range, 1-18). There was a median delay in diagnosis of 3 years (range, 0-19) in 27 out of 31 patients, which resulted in a median age at diagnosis of 12 years (range, 7-26). Patients were misdiagnosed with amblyopia, myopia, optic disk pathology, mental health problems, tension headache, neuritis bulbaris, and uveitis. Subtle abnormalities, such as lipofuscin accumulation, were seen on FAF at an earlier disease stage than in ophthalmoscopy. On SD-OCT, this included a thickened external limiting membrane. Color vision tests showed red-green insufficiency in 79% of patients. Reduced ERG amplitudes were only present in 26% (N = 8) and a dark choroid sign in 65% of the patients. Visual acuity considerably fluctuated in the first 5 years after onset. The majority of the patients (65%) carried a least one variant with a severe effect on ABCA4 function. CONCLUSIONS: Childhood-onset STGD1 patients were diagnosed with a delay of median 3 years. The presence of accurate competence, equipment, and the possibility for genetic screening is required; therefore, we recommend to refer children with visual complaints without initial fundus abnormalities to a specialized ophthalmologic center. In particular, to diagnose patients at an early stage of disease is of increased importance with the advent of new therapeutic possibilities.


Assuntos
Eletrorretinografia/métodos , Angiofluoresceinografia/métodos , Degeneração Macular/congênito , Epitélio Pigmentado da Retina/patologia , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Erros de Diagnóstico , Feminino , Fundo de Olho , Testes Genéticos , Humanos , Lactente , Degeneração Macular/diagnóstico , Degeneração Macular/genética , Degeneração Macular/metabolismo , Masculino , Oftalmoscopia , Doença de Stargardt , Adulto Jovem
4.
Int J Mol Sci ; 19(3)2018 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-29518907

RESUMO

Leber congenital amaurosis (LCA) is a rare inherited retinal disorder affecting approximately 1:50,000 people worldwide. So far, mutations in 25 genes have been associated with LCA, with CEP290 (encoding the Centrosomal protein of 290 kDa) being the most frequently mutated gene. The most recurrent LCA-causing CEP290 mutation, c.2991+1655A>G, causes the insertion of a pseudoexon into a variable proportion of CEP290 transcripts. We previously demonstrated that antisense oligonucleotides (AONs) have a high therapeutic potential for patients homozygously harbouring this mutation, although to date, it is unclear whether rescuing one single allele is enough to restore CEP290 function. Here, we assessed the AON efficacy at RNA, protein and cellular levels in samples that are compound heterozygous for this mutation, together with a protein-truncating mutation in CEP290. We demonstrate that AONs can efficiently restore splicing and increase protein levels. However, due to a high variability in ciliation among the patient-derived cell lines, the efficacy of the AONs was more difficult to assess at the cellular level. This observation points towards the importance of the severity of the second allele and possibly other genetic variants present in each individual. Overall, AONs seem to be a promising tool to treat CEP290-associated LCA, not only in homozygous but also in compound heterozygous carriers of the c.2991+1655A>G variant.


Assuntos
Alelos , Antígenos de Neoplasias/genética , Heterozigoto , Amaurose Congênita de Leber/genética , Mutação , Proteínas de Neoplasias/genética , Oligonucleotídeos Antissenso , Splicing de RNA , Antígenos de Neoplasias/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular , Proteínas do Citoesqueleto , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Amaurose Congênita de Leber/metabolismo , Masculino , Proteínas de Neoplasias/metabolismo
5.
Ophthalmology ; 123(1): 32-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26386849

RESUMO

PURPOSE: To describe the complications associated with hydrogel explants and to describe the indications, surgical technique, and risks involved in the removal of a hydrogel explant. DESIGN: Single-center, retrospective interventional case series. PARTICIPANTS: Patients who underwent surgical removal of a symptomatic, swollen hydrogel explant. METHODS: We reviewed the medical records of 457 consecutive patients (467 eyes in total) who underwent surgical removal of a symptomatic, swollen episcleral MIRAgel (MIRA Inc., Waltham, MA) explant at the Radboud University Medical Center from 1998 to 2011. We reviewed the initial symptoms, clinical findings, surgical aspects, and intraoperative and postoperative complications. MAIN OUTCOME MEASURES: Presenting symptoms, retinal redetachment rate, and intraoperative scleral perforation. RESULTS: The median interval between initial placement of the hydrogel explant and removal of the explant was 159 months. More than 34% of the episcleral hydrogel explants developed symptomatic swelling and required surgical removal. Intraoperative scleral perforation or retinal redetachment related to the removal of the explant occurred in 11% of patients. CONCLUSIONS: The percentage of explants that ultimately develop symptomatic swelling is considerably higher than reported previously. A swollen hydrogel explant can be removed many years after the primary detachment surgery, and 11% of cases develop intraoperative scleral perforation or retinal redetachment.


Assuntos
Remoção de Dispositivo/métodos , Poli-Hidroxietil Metacrilato/análogos & derivados , Complicações Pós-Operatórias/cirurgia , Descolamento Retiniano/cirurgia , Recurvamento da Esclera/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Poli-Hidroxietil Metacrilato/efeitos adversos , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Recurvamento da Esclera/métodos , Acuidade Visual , Adulto Jovem
6.
Hum Mutat ; 36(1): 43-7, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25363634

RESUMO

Variants in ABCA4 are responsible for autosomal-recessive Stargardt disease and cone-rod dystrophy. Sequence analysis of ABCA4 exons previously revealed one causative variant in each of 45 probands. To identify the "missing" variants in these cases, we performed multiplex ligation-dependent probe amplification-based deletion scanning of ABCA4. In addition, we sequenced the promoter region, fragments containing five deep-intronic splice variants, and 15 deep-intronic regions containing weak splice sites. Heterozygous deletions spanning ABCA4 exon 5 or exons 20-22 were found in two probands, heterozygous deep-intronic variants were identified in six probands, and a deep-intronic variant was found together with an exon 20-22 deletion in one proband. Based on ophthalmologic findings and characteristics of the identified exonic variants present in trans, the deep-intronic variants V1 and V4 were predicted to be relatively mild and severe, respectively. These findings are important for proper genetic counseling and for the development of variant-specific therapies.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Estudos de Associação Genética/métodos , Degeneração Macular/congênito , Retinose Pigmentar/genética , Éxons , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Íntrons , Degeneração Macular/genética , Masculino , Linhagem , Análise de Sequência de DNA , Deleção de Sequência , Doença de Stargardt
7.
Am J Hum Genet ; 90(1): 102-9, 2012 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-22177090

RESUMO

Cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. By using homozygosity mapping in an individual with autosomal-recessive (ar) RP from a consanguineous family, we identified three sizeable homozygous regions, together encompassing 46 Mb. Next-generation sequencing of all exons, flanking intron sequences, microRNAs, and other highly conserved genomic elements in these three regions revealed a homozygous nonsense mutation (c.497T>A [p.Leu166(∗)]) in C8orf37, located on chromosome 8q22.1. This mutation was not present in 150 ethnically matched control individuals, single-nucleotide polymorphism databases, or the 1000 Genomes database. Immunohistochemical studies revealed C8orf37 localization at the base of the primary cilium of human retinal pigment epithelium cells and at the base of connecting cilia of mouse photoreceptors. C8orf37 sequence analysis of individuals who had retinal dystrophy and carried conspicuously large homozygous regions encompassing C8orf37 revealed a homozygous splice-site mutation (c.156-2A>G) in two siblings of a consanguineous family and homozygous missense mutations (c.529C>T [p.Arg177Trp]; c.545A>G [p.Gln182Arg]) in siblings of two other consanguineous families. The missense mutations affect highly conserved amino acids, and in silico analyses predicted that both variants are probably pathogenic. Clinical assessment revealed CRD in four individuals and RP with early macular involvement in two individuals. The two CRD siblings with the c.156-2A>G mutation also showed unilateral postaxial polydactyly. These results underline the importance of disrupted ciliary processes in the pathogenesis of retinal dystrophies.


Assuntos
Genes Recessivos , Mutação , Proteínas/genética , Distrofias Retinianas/genética , Adolescente , Idade de Início , Sequência de Bases , Criança , Pré-Escolar , Mapeamento Cromossômico , Consanguinidade , Análise Mutacional de DNA , Éxons , Feminino , Humanos , Lactente , Íntrons , Masculino , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Epitélio Pigmentado da Retina/metabolismo
8.
Mol Vis ; 21: 461-76, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25999674

RESUMO

PURPOSE: To determine the efficacy of multiple versions of a commercially available arrayed primer extension (APEX) microarray chip for autosomal recessive retinitis pigmentosa (arRP). METHODS: We included 250 probands suspected of arRP who were genetically analyzed with the APEX microarray between January 2008 and November 2013. The mode of inheritance had to be autosomal recessive according to the pedigree (including isolated cases). If the microarray identified a heterozygous mutation, we performed Sanger sequencing of exons and exon-intron boundaries of that specific gene. The efficacy of this microarray chip with the additional Sanger sequencing approach was determined by the percentage of patients that received a molecular diagnosis. We also collected data from genetic tests other than the APEX analysis for arRP to provide a detailed description of the molecular diagnoses in our study cohort. RESULTS: The APEX microarray chip for arRP identified the molecular diagnosis in 21 (8.5%) of the patients in our cohort. Additional Sanger sequencing yielded a second mutation in 17 patients (6.8%), thereby establishing the molecular diagnosis. In total, 38 patients (15.2%) received a molecular diagnosis after analysis using the microarray and additional Sanger sequencing approach. Further genetic analyses after a negative result of the arRP microarray (n = 107) resulted in a molecular diagnosis of arRP (n = 23), autosomal dominant RP (n = 5), X-linked RP (n = 2), and choroideremia (n = 1). CONCLUSIONS: The efficacy of the commercially available APEX microarray chips for arRP appears to be low, most likely caused by the limitations of this technique and the genetic and allelic heterogeneity of RP. Diagnostic yields up to 40% have been reported for next-generation sequencing (NGS) techniques that, as expected, thereby outperform targeted APEX analysis.


Assuntos
Genes Recessivos , Testes Genéticos/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Retinose Pigmentar/genética , Estudos de Coortes , Análise Mutacional de DNA/métodos , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Retinose Pigmentar/diagnóstico , Estudos Retrospectivos
9.
Ophthalmology ; 122(2): 335-44, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25444351

RESUMO

OBJECTIVE: To describe the phenotype and genotype of patients with early-onset Stargardt disease. DESIGN: Retrospective cohort study. PARTICIPANTS: Fifty-one Stargardt patients with age at onset ≤10 years. METHODS: We reviewed patient medical records for age at onset, medical history, initial symptoms, best-corrected visual acuity (BCVA), ophthalmoscopy, fundus photography, fundus autofluorescence (FAF), fluorescein angiography (FA), spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinography (ffERG). The ABCA4 gene was screened for mutations. MAIN OUTCOME MEASURES: Age at onset, BCVA, fundus appearance, FAF, FA, SD-OCT, ffERG, and presence of ABCA4 mutations. RESULTS: The mean age at onset was 7.2 years (range, 1-10). The median times to develop BCVA of 20/32, 20/80, 20/200, and 20/500 were 3, 5, 12, and 23 years, respectively. Initial ophthalmoscopy in 41 patients revealed either no abnormalities or foveal retinal pigment epithelium (RPE) changes in 10 and 9 patients, respectively; the other 22 patients had foveal atrophy, atrophic RPE lesions, and/or irregular yellow-white fundus flecks. On FA, there was a "dark choroid" in 21 out of 29 patients. In 14 out of 50 patients, foveal atrophy occurred before flecks developed. On FAF, there was centrifugal expansion of disseminated atrophic spots, which progressed to the eventual profound chorioretinal atrophy. Spectral-domain OCT revealed early photoreceptor damage followed by atrophy of the outer retina, RPE, and choroid. On ffERG in 26 patients, 15 had normal amplitudes, and 11 had reduced photopic and/or scotopic amplitudes at their first visit. We found no correlation between ffERG abnormalities and the rate of vision loss. Thirteen out of 25 patients had progressive ffERG abnormalities. Finally, genetic screening of 44 patients revealed ≥2 ABCA4 mutations in 37 patients and single heterozygous mutations in 7. CONCLUSIONS: In early-onset Stargardt, initial ophthalmoscopy can reveal no abnormalities or minor retinal abnormalities. Yellow-white flecks can be preceded by foveal atrophy and may be visible only on FAF. Although ffERG is insufficient for predicting the rate of vision loss, abnormalities can develop. Over time, visual acuity declines rapidly in parallel with progressive retinal degeneration, resulting in profound chorioretinal atrophy. Thus, early-onset Stargardt lies at the severe end of the spectrum of ABCA4-associated retinal phenotypes.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Análise Mutacional de DNA , Genótipo , Degeneração Macular/congênito , Fenótipo , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Eletrorretinografia , Feminino , Angiofluoresceinografia , Humanos , Lactente , Degeneração Macular/diagnóstico , Degeneração Macular/epidemiologia , Degeneração Macular/genética , Masculino , Pessoa de Meia-Idade , Oftalmoscopia , Estudos Retrospectivos , Doença de Stargardt , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Adulto Jovem
10.
Retina ; 35(9): 1778-85, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25901838

RESUMO

PURPOSE: This study investigated whether pain from intravitreal injections (IVIs) can be reduced by injecting with a 33-G needle instead of the commonly used 30-G needle. Additionally, several pain-related psychological factors were explored as predictors of outcome. METHODS: This randomized crossover trial included 36 patients who received injections with both needles in randomized order. After the injection, patients rated IVI pain on a 0 to 10 scale. Before injection, distress and pain expectations were assessed. Afterward, patients rated the IVI procedure and anticipated consequences. In addition, we assessed the force necessary to penetrate the sclera for both needles in porcine eyes. RESULTS: The 33-G needle did not result in lower IVI pain (2.8 vs. 3.1, P = 0.758) but tended to cause less vitreal reflux (0 vs. 5 times, P = 0.054). Factors related to more pain were distress, expecting IVI pain and discomfort, dissatisfaction with the preparation procedure, anticipating negative consequences, and female gender. Patients regarded povidone-iodine disinfection as particularly unpleasant. Exploration of the needles' mechanical properties showed that 33-G needles penetrate the sclera more easily. CONCLUSION: The thinner 33-G needle does not reduce IVI pain but may limit scleral damage. Future efforts could be aimed at optimizing patient information, reducing distress, and the use of better tolerable disinfectants.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Dor Ocular/etiologia , Injeções Intravítreas/instrumentação , Agulhas , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Desenho de Equipamento , Dor Ocular/diagnóstico , Feminino , Humanos , Edema Macular/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Medição da Dor , Oclusão da Veia Retiniana/tratamento farmacológico , Inquéritos e Questionários , Degeneração Macular Exsudativa/tratamento farmacológico
11.
Am J Hum Genet ; 89(2): 253-64, 2011 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-21835304

RESUMO

A fundamental challenge in analyzing exome-sequence data is distinguishing pathogenic mutations from background polymorphisms. To address this problem in the context of a genetically heterogeneous disease, retinitis pigmentosa (RP), we devised a candidate-gene prioritization strategy called cis-regulatory mapping that utilizes ChIP-seq data for the photoreceptor transcription factor CRX to rank candidate genes. Exome sequencing combined with this approach identified a homozygous nonsense mutation in male germ cell-associated kinase (MAK) in the single affected member of a consanguineous Turkish family with RP. MAK encodes a cilium-associated mitogen-activated protein kinase whose function is conserved from the ciliated alga, Chlamydomonas reinhardtii, to humans. Mutations in MAK orthologs in mice and other model organisms result in abnormally long cilia and, in mice, rapid photoreceptor degeneration. Subsequent sequence analyses of additional individuals with RP identified five probands with missense mutations in MAK. Two of these mutations alter amino acids that are conserved in all known kinases, and an in vitro kinase assay indicates that these mutations result in a loss of kinase activity. Thus, kinase activity appears to be critical for MAK function in humans. This study highlights a previously underappreciated role for CRX as a direct transcriptional regulator of ciliary genes in photoreceptors. In addition, it demonstrates the effectiveness of CRX-based cis-regulatory mapping in prioritizing candidate genes from exome data and suggests that this strategy should be generally applicable to a range of retinal diseases.


Assuntos
Cílios/genética , Éxons/genética , Mutação/genética , Proteínas Serina-Treonina Quinases/genética , Sequências Reguladoras de Ácido Nucleico/genética , Retinose Pigmentar/genética , Análise de Sequência de DNA , Adulto , Sequência de Aminoácidos , Animais , Mapeamento Cromossômico , Cílios/enzimologia , Feminino , Genes Recessivos/genética , Loci Gênicos/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/patologia , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Retinose Pigmentar/enzimologia , Rodopsina/genética , Transativadores/metabolismo , Transcrição Gênica , Adulto Jovem
12.
Mol Vis ; 20: 753-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24940029

RESUMO

PURPOSE: The gene encoding nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) was recently found to be mutated in a subset of patients with Leber congenital amaurosis (LCA) with macular atrophy. The aim of this study was to determine the occurrence and frequency of NMNAT1 mutations and associated phenotypes in different types of inherited retinal dystrophies. METHODS: DNA samples of 161 patients with LCA without genetic diagnosis were analyzed for variants in NMNAT1 using Sanger sequencing. Variants in exon 5 of NMNAT1, which harbors the majority of the previously identified mutations, were screened in 532 additional patients with retinal dystrophies. This cohort encompassed 108 persons with isolated or autosomal recessive cone-rod dystrophy (CRD), 271 with isolated or autosomal recessive retinitis pigmentosa (RP), and 49 with autosomal dominant RP, as well as 104 persons with LCA in whom the causative mutation was previously identified. RESULTS: Compound heterozygous alterations were found in six patients with LCA and in one person with early-onset RP. All except one carried the common p.E257K variant on one allele. Macular atrophy was absent in one patient, who carried this variant in combination with a truncating mutation on the other allele. The p.E257K alteration was also found in a heterozygous state in five individuals with LCA and one with RP while no mutation was detected on the other allele. Two individuals with LCA carried other NMNAT1 variants in a heterozygous state, whereas no NMNAT1 variants in exon 5 were identified in individuals with CRD. The p.E257K variant was found to be enriched in a heterozygous state in individuals with LCA (0.94%) compared to Caucasian controls (0.18%), although the difference was statistically insignificant (p=0.12). CONCLUSIONS: Although macular atrophy can occur in LCA and CRD, no NMNAT1 mutations were found in the latter cohort. NMNAT1 variants were also not found in a large group of patients with sporadic or autosomal recessive RP. The enrichment of p.E257K in a heterozygous state in patients with LCA versus controls suggests that this allele could act as a modifier in other genetic subtypes of LCA.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Amaurose Congênita de Leber/enzimologia , Amaurose Congênita de Leber/genética , Nicotinamida-Nucleotídeo Adenililtransferase/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Adulto Jovem
13.
Ophthalmology ; 121(8): 1620-7, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24697911

RESUMO

OBJECTIVE: To identify the genetic causes underlying autosomal recessive retinitis pigmentosa (arRP) and to describe the associated phenotype. DESIGN: Case series. PARTICIPANTS: Three hundred forty-seven unrelated families affected by arRP and 33 unrelated families affected by retinitis pigmentosa (RP) plus noncongenital and progressive hearing loss, ataxia, or both, respectively. METHODS: A whole exome sequencing (WES) analysis was performed in 2 families segregating arRP. A mutational screening was performed in 378 additional unrelated families for the exon-intron boundaries of the ABHD12 gene. To establish a genotype-phenotype correlation, individuals who were homozygous or compound heterozygotes of mutations in ABHD12 underwent exhaustive clinical examinations by ophthalmologists, neurologists, and otologists. MAIN OUTCOME MEASURES: DNA sequence variants, best-corrected visual acuity, visual field assessments, electroretinogram responses, magnetic resonance imaging, and audiography. RESULTS: After a WES analysis, we identified 4 new mutations (p.Arg107Glufs*8, p.Trp159*, p.Arg186Pro, and p.Thr202Ile) in ABHD12 in 2 families (RP-1292 and W08-1833) previously diagnosed with nonsyndromic arRP, which cosegregated with the disease among the family members. Another homozygous mutation (p.His372Gln) was detected in 1 affected individual (RP-1487) from a cohort of 378 unrelated arRP and syndromic RP patients. After exhaustive clinical examinations by neurologists and otologists, the 4 affected members of the RP-1292 had no polyneuropathy or ataxia, and the sensorineural hearing loss and cataract were attributed to age or the normal course of the RP, whereas the affected members of the families W08-1833 and RP-1487 showed clearly symptoms associated with polyneuropathy, hearing loss, cerebellar ataxia, RP, and early-onset cataract (PHARC) syndrome. CONCLUSIONS: Null mutations in the ABHD12 gene lead to PHARC syndrome, a neurodegenerative disease including polyneuropathy, hearing loss, cerebellar ataxia, RP, and early-onset cataract. Our study allowed us to report 5 new mutations in ABHD12. This is the first time missense mutations have been described for this gene. Furthermore, these findings are expanding the spectrum of phenotypes associated with ABHD12 mutations ranging from PHARC syndrome to a nonsyndromic form of retinal degeneration.


Assuntos
Ataxia/genética , Catarata/genética , Exoma/genética , Monoacilglicerol Lipases/genética , Mutação de Sentido Incorreto , Polineuropatias/genética , Retinose Pigmentar/genética , Adulto , Idoso , Ataxia/diagnóstico , Ataxia/fisiopatologia , Audiometria , Catarata/diagnóstico , Catarata/fisiopatologia , Eletrorretinografia , Feminino , Genes Recessivos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Monoacilglicerol Lipases/química , Linhagem , Fenótipo , Polineuropatias/diagnóstico , Polineuropatias/fisiopatologia , Estrutura Secundária de Proteína , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/fisiopatologia , Análise de Sequência de DNA , Acuidade Visual/fisiologia , Campos Visuais/fisiologia
14.
Acta Ophthalmol ; 102(5): 513-520, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38146841

RESUMO

PURPOSE: To describe clinical characteristics and management in a large cohort of patients with retinal detachment due to a giant retinal tear (GRT). METHODS: We performed a retrospective cohort study with 222 eyes of 206 patients with a primary and non-traumatic GRTs between 2005 and 2022. We analysed the relevant clinical and surgical data from these patients. RESULTS: Eighty-six per cent (n = 177) of patients were male. We observed no relation between refractive error and GRT size (Spearman's rho: r = -0.018, p = 0.83). We achieved a primary and final treatment success in 77%, respectively 92%, of eyes. The final visual outcome was 20/40 or better in 65% and 36% of eyes in fovea-on and fovea-off GRTs respectively. Thirty-five per cent (n = 73) of patients developed a retinal detachment in the fellow eye. The median time until a retinal detachment in the fellow eye occurred after GRT was 20 months, and 10% developed within 1 month. A prediction model for the development of retinal detachment in the fellow eye resulted in a receiver operating characteristics curve with an area under the curve of 0.68 (95% CI: 0.57-0.78, p = 0.001). CONCLUSION: We observed a highly significant gender imbalance in patients with a non-traumatic GRT. One third of patients developed a retinal detachment bilaterally. Ten per cent of fellow eye's retinal detachment that develop after GRT, occur within 1 month. Clinical parameters showed limited predictive value for a retinal detachment in the fellow eye. These findings suggest an underlying genetic factor.


Assuntos
Descolamento Retiniano , Perfurações Retinianas , Acuidade Visual , Humanos , Masculino , Estudos Retrospectivos , Feminino , Fatores de Risco , Pessoa de Meia-Idade , Acuidade Visual/fisiologia , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/cirurgia , Descolamento Retiniano/etiologia , Perfurações Retinianas/diagnóstico , Perfurações Retinianas/cirurgia , Perfurações Retinianas/etiologia , Adulto , Idoso , Vitrectomia/métodos , Adulto Jovem , Idoso de 80 Anos ou mais , Adolescente , Seguimentos
15.
Hum Mutat ; 34(11): 1537-1546, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23946133

RESUMO

This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ∼2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.


Assuntos
Proteínas do Olho/genética , Estudos de Associação Genética , Amaurose Congênita de Leber/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Retinose Pigmentar/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Consanguinidade , Feminino , Angiofluoresceinografia , Genótipo , Humanos , Lactente , Recém-Nascido , Amaurose Congênita de Leber/diagnóstico , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Retina/patologia , Retinose Pigmentar/diagnóstico , Adulto Jovem
16.
Am J Hum Genet ; 86(5): 783-8, 2010 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-20398884

RESUMO

With a worldwide prevalence of 1 in 4,000, retinitis pigmentosa (RP) is the most common form of hereditary retinal degeneration. More than 30 genes and loci have been implicated in nonsyndromic autosomal-recessive (ar) RP. Genome-wide homozygosity mapping was conducted in one Dutch and one Israeli family affected by arRP. The families were found to share a 5.9 Mb homozygous region on chromosome 2p23.1-p23.3. A missense variant in one of the genes residing in this interval, C2ORF71, has recently been reported to be associated with RP. C2ORF71, encoding a putative protein of 1,288 amino acids, was found to be specifically expressed in human retina. Furthermore, RT-PCR analysis revealed that in the mouse eye, C2orf71 is expressed as early as embryonic day 14. Mutation analysis detected a 1 bp deletion (c.946 del; p.Asn237MetfsX5) segregating with RP in the Dutch family, whereas a nonsense mutation (c.556C > T; p.Gln186X) was identified in the Israeli family. Microsatellite-marker analysis in additional Israeli families revealed cosegregation of a C2ORF71-linked haplotype in one other family, in which a 13 bp deletion (c.2756_2768 del; p.Lys919ThrfsX) was identified. Clinically, patients with mutations in C2ORF71 show signs of typical RP; these signs include poor night vision and peripheral field loss, typical retinal bone-spicule-type pigment deposits, pale appearance of the optic disk, and markedly reduced or completely extinguished electroretinograms. In conclusion, truncating mutations in C2ORF71 were identified in three unrelated families, thereby confirming the involvement of this gene in the etiology of arRP.


Assuntos
Mutação , Proteínas/genética , Retina/metabolismo , Retinose Pigmentar/genética , Animais , Mapeamento Cromossômico , Análise Mutacional de DNA , Proteínas do Olho/genética , Haplótipos , Homozigoto , Humanos , Camundongos , Repetições de Microssatélites , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Graefes Arch Clin Exp Ophthalmol ; 251(5): 1373-82, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23250478

RESUMO

BACKGROUND: Primary vitreous floaters can be highly bothersome in some patients. In the case of persistently bothersome floaters, pars plana vitrectomy may be the most effective treatment. The aim of this study is to evaluate the incidence of complications, and patient satisfaction, after pars plana vitrectomy for disabling primary vitreous opacities. METHODS: We included a total of 110 eyes that underwent pars plana vitrectomy between February 1998 and August 2010. Fifty-seven eyes (51.8%) underwent 20-gauge vitrectomy, whereas 53 eyes (48.2%) underwent 23-gauge vitrectomy. In a retrospective manner, we assessed intraoperative and postoperative complications. There was a considerable range of time between surgery and questionnaire (range: 4-136 months). Patient satisfaction was assessed by a questionnaire based on a modified NEI VFQ-25 questionnaire. RESULTS: A retinal detachment occurred in 10.9% of cases, and the incidence did not differ significantly between the 20-gauge and 23-gauge vitrectomy groups. In 4.5% of the eyes, a retinal detachment developed within the first 3 months, and 6.4% occurred later in the postoperative period. Cystoid macular edema occurred in 5.5%, and an epiretinal membrane was seen postoperatively in 3.6% of cases. Development of glaucoma requiring glaucoma surgery, a macular hole, and postoperative scotoma, each occurred in 0.9% of cases. No cases of endophthalmitis occurred. Eighty-five percent of patients were satisfied or very satisfied with the results of the vitrectomy. Eighty-four percent of all patients were completely cured from their troublesome vitreous floaters, and an additional 9.3% of patients were less troubled by vitreous floaters. Ten patients (9.3%) were dissatisfied, and six of these patients (5.6%) had a serious complication that resulted in permanent visual loss. CONCLUSIONS: Pars plana vitrectomy is an effective approach to treat primary vitreous floaters, resulting in a high rate of patient satisfaction. Postoperative complications may be more frequent than previously reported, so patients should be well-informed about the complication rate before reaching informed consent about this surgical intervention. Additional preventive measures should be considered to reduce this complication rate.


Assuntos
Oftalmopatias/cirurgia , Satisfação do Paciente/estatística & dados numéricos , Vitrectomia , Corpo Vítreo/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Complicações Intraoperatórias , Masculino , Microcirurgia/métodos , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Refração Ocular/fisiologia , Perfil de Impacto da Doença , Resultado do Tratamento , Acuidade Visual/fisiologia
18.
Acta Ophthalmol ; 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38041245

RESUMO

PURPOSE: High Magnification Module (HMM™, Heidelberg Engineering, Heidelberg, Germany) imaging is a novel technique, designed to visualize the retina at a cellular level. To assess the potential of HMM™-based metrics as endpoints for future trials, we evaluated correlations between structural HMM™ cone metrics, spectral-domain OCT (SD-OCT, Heidelberg Engineering, Heidelberg, Germany) and retinal sensitivity on microperimetry (MP, MAIA, CenterVue, Padova, Italy) in healthy subjects and p.(Arg142Trp) PRPH2-associated Central Areolar Choroidal Dystrophy (CACD) patients. METHODS: We projected a default 10° MP grid on composite HMM™ images and performed automated cone density (CD), intercell distance (ICD) and nearest neighbour distance (NND) analysis at stimuli located at 3° and 5° retinal eccentricity. We manually measured intrasubject outer retinal thickness on SD-OCT in absolute and relative scotomas, located outside of focal atrophy. RESULTS: We included 15 CACD patients and five healthy subjects. We found moderate-to-strong correlations of HMM™ metrics and MP sensitivity at 3° eccentricity from the fovea. We found the outer retina at the locations of absolute scotomas to be statistically significant thinner (p = 0.000003, one-sample t-test), as the outer retinal thickness at locations of relative scotomas. Interestingly, HMM™ metrics of these areas did not differ significantly. CONCLUSIONS: We found significant correlations between structural photoreceptors metrics on HMM™ imaging and retinal sensitivity on MP in healthy subjects and CACD patients. A multimodal approach, combining SD-OCT, MP and HMM™ imaging, allows for detailed mapping of retinal photoreceptor integrity and restitution potential, important data that could serve as biomarkers in future clinical trials.

19.
Prog Retin Eye Res ; 97: 101158, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-36621380

RESUMO

Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-ß pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention.


Assuntos
Descolamento Retiniano , Humanos , Descolamento Retiniano/genética , Acuidade Visual , Estudos de Associação Genética
20.
Br J Ophthalmol ; 107(2): 248-253, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34348923

RESUMO

AIMS: To describe the prevalence of the Charles Bonnet syndrome (CBS) and search for potential CBS risk factors in a Dutch Stargardt disease (STGD1) cohort. METHODS: Eighty-three patients with STGD1 were screened for CBS. They underwent a full eye examination. All patients completed the social functioning domain of the 36-Item Short Form Health Survey questionnaire. Participants suspected of CBS were interviewed to further evaluate their visual hallucinations. RESULTS: CBS prevalence was 8.4%. Six out of seven patients with CBS were women. CBS was not associated with age (p=0.279, Mann-Whitney). Patients with CBS had a significant lower social functioning score (p<0.05, Mann-Whitney). All seven patients with CBS were in the category of vision impairment (visual acuity <6/12, but ≥3/60). Moreover, first hallucinations manifested after a drop in visual acuity. The retinal atrophic area of the worst eye tended to be lower in the CBS group (range 0.11-9.86 mm2) as compared with controls (range 0-180 mm2). There was no relation between the position of the scotoma and the location of the visual hallucinations. CONCLUSION: The relative high CBS prevalence in STGD1 suggests that CBS may be more prevalent in younger ophthalmic patients than currently presumed. In this specific group of patients, we established social isolation and acquired vision impairment as risk factors for CBS. There was a female preponderance among patients with CBS. Age and retinal pigment epithelium atrophy were not identified as significant risk factors. We should actively diagnose CBS in patients of any age who fulfil the criteria for the category vision impairment, especially in cases where social isolation is suspected.


Assuntos
Síndrome de Charles Bonnet , Humanos , Feminino , Masculino , Síndrome de Charles Bonnet/complicações , Doença de Stargardt , Prevalência , Alucinações/diagnóstico , Alucinações/epidemiologia , Alucinações/complicações , Fatores de Risco , Transtornos da Visão/diagnóstico , Transtornos da Visão/epidemiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA