RESUMO
BACKGROUND AND OBJECTIVES: Stargardt disease produces lipofuscin accumulation predisposing to subretinal fibrosis (SRFib) after ocular trauma. Noninvasive imaging techniques allow in vivo assessment. The purpose of this study is to determine the prevalence of SRFib in a cohort of Stargardt patients, the presence of history of ocular trauma, the clinical features and possible genotype-phenotype associations in Stargardt patients with SRFib. METHODS: We evaluated retrospectively 106 Stargardt patients and analysed the multimodal imaging and the genotype of patients with SRFib. RESULTS: Six patients exhibited SRFib, three of them with history of ocular trauma. Multimodal imaging showed extensive SRFib principally in the temporal midperipheral retina with no fluid associated. SRFib was better defined by short wavelength autofluorescence and spectral domain optical coherence tomography and appeared clinically stable over time. There was no particular genotype associated to SRFib. CONCLUSION: SRFib occurs in a significant percentage of patients with Stargardt disease and can be diagnosed through multimodal imaging regardless the history of trauma, further sustaining the importance of an appropriate imaging in such patients. No genotype-phenotype association has been established, supporting the traumatic etiology in half of cases. The remaining cases may be classified as idiopathic or have a minimal trauma occurring early in life that may be not recalled by the patients.
Assuntos
Lipofuscina , Tomografia de Coerência Óptica , Fibrose , Angiofluoresceinografia/métodos , Humanos , Imagem Multimodal , Fenótipo , Prevalência , Estudos Retrospectivos , Doença de Stargardt , Tomografia de Coerência Óptica/métodosRESUMO
Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.
Assuntos
Proteínas do Olho/metabolismo , Proteínas de Homeodomínio/metabolismo , Distrofias Retinianas/genética , Retinose Pigmentar/genética , Transativadores/metabolismo , Idoso , Animais , Proteínas Correpressoras/metabolismo , Códon sem Sentido , Estudos de Coortes , Hibridização Genômica Comparativa , Consanguinidade , Análise Mutacional de DNA , Exoma , Feminino , Regulação da Expressão Gênica , Genes Recessivos , Homozigoto , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Mapeamento de Interação de Proteínas , Retina/metabolismo , Retina/fisiopatologia , Distrofias Retinianas/etiologia , Distrofias Retinianas/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Retinose Pigmentar/etiologia , Retinose Pigmentar/metabolismo , Espanha , Fatores de Transcrição/metabolismoRESUMO
Mutations in the gene encoding the transcription factor neural retina leucine zipper (NRL) are known to cause autosomal dominant (adRP) or recessive (arRP) retinitis pigmentosa (RP). In an adRP Spanish family, we detected a novel sequence variation (c.287T>C) in the NRL gene that results in the p.M96T protein change. A functional test of the ability of NRL, in conjunction with cone-rod homeobox (CRX), to transactivate a human rhodopsin (RHO) promoter was used to evaluate the pathogenic mechanisms of NRL. We found upregulation of the RHO promoter by p.M96T protein similar to that shown by other missense NRL mutations that cause adRP. Affected RP patients of the family carry the nucleotide change, although two other family members that also carry the c.287T>C variation remain asymptomatic. This result complicates the genetic counselling of the family. The pathogenic mechanisms associated with adRP NRL mutations appear to be caused by a gain of function. To suppress the negative effect of an NRL mutant, the suppression and replacement strategy seems to be the most suitable therapeutic approach capable of overcoming the mutational heterogeneity associated with NRL-linked adRP. Thus, we evaluated this methodology in the NRL gene for the first time.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Proteínas do Olho/genética , Mutação de Sentido Incorreto , RNA Interferente Pequeno/genética , Retinose Pigmentar/genética , Adulto , Idoso , Sequência de Aminoácidos , Animais , Células COS , Chlorocebus aethiops , Genes Dominantes , Heterogeneidade Genética , Variação Genética , Proteínas de Homeodomínio/genética , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Rodopsina/genética , Transativadores/genética , Ativação Transcricional , Regulação para CimaRESUMO
OBJECTIVE: Quantify and define post-surgical pain after pterygium surgery with conjunctival autografts. MATERIAL AND METHODS: The study included 17 patients. The parameters analysed were, gender, age, pterygium TCL classification, primary characteristics or relapse, usage of isolated tissue adhesive or extra fixation with stitches. A visual analogue pain scale was used immediately after surgery, on the days 2 and 3 post-surgery, and the characteristics of the pain and the frequency of it in days 2 and 3 following the surgery. RESULTS: A total of 17 eyes of 17 patients were operated. The majority of patients (52.9%) showed moderate pain on the visual analogue scale immediately after surgery. On day 2 after surgery the pain level was mild in the majority of patients with characteristics of sharp pain and lash pain predominantly. On day 3 after surgery, mild pain was also predominant, with characteristics of stinging and lash pain in majority of patients. CONCLUSIONS: Using scales and pain characteristics we can quantify and define post-surgical pain after pterygium surgery with conjunctival auto-grafts resection immediately after surgery and in the following days.
Assuntos
Túnica Conjuntiva/transplante , Dor Pós-Operatória/diagnóstico , Pterígio/cirurgia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/etiologia , Medição da Dor , Dor Pós-Operatória/classificação , Dor Pós-Operatória/etiologia , Estudos Prospectivos , Técnicas de Sutura , Cápsula de Tenon/cirurgia , Adesivos Teciduais , Transplante AutólogoRESUMO
ObjetivoCuantificar y definir el dolor postquirúrgico tras cirugía de pterigión mediante resección con autoinjerto conjuntival.Material y métodosEn el estudio se han incluido 17 pacientes. Los parámetros analizados han sido sexo, edad, clasificación TCL del pterigión, carácter primario o recidiva del mismo, uso de adhesivo tisular aislado o con fijación extra con puntos de sutura, escala visual analógica de dolor inmediato a la cirugía, en el día 2 y en el 3 postcirugía, al igual que las características del dolor e intervalo del mismo en los días 2 y 3 postcirugía.ResultadosSe intervinieron 17 ojos de 17 pacientes. En relación a los datos obtenidos en la escala analógica visual para el dolor, en los resultados inmediatos a la cirugía la mayor parte de los pacientes (52,9%) presentaron dolor moderado. En el día 2 postcirugía el nivel de dolor fue predominantemente leve, con características de pinchazo y latigazo de forma mayoritaria. En el día 3 postcirugía, de nuevo destacó el dolor de grado leve, con características de escozor y latigazo en mayor porcentaje.ConclusionesMediante la utilización de escalas de nivel y características de dolor podemos cuantificar y definir el dolor postquirúrgico tras cirugía de pterigión mediante resección con autoinjerto conjuntival en el postoperatorio inmediato y días sucesivos(AU)
ObjectiveQuantify and define post-surgical pain after pterygium surgery with conjunctival autografts.Material and methodsThe study included 17 patients. The parameters analysed were, gender, age, pterygium TCL classification, primary characteristics or relapse, usage of isolated tissue adhesive or extra fixation with stitches. A visual analogue pain scale was used immediately after surgery, on the days 2 and 3 post-surgery, and the characteristics of the pain and the frequency of it in days 2 and 3 following the surgery.ResultsA total of 17 eyes of 17 patients were operated. The majority of patients (52.9%) showed moderate pain on the visual analogue scale immediately after surgery. On day 2 after surgery the pain level was mild in the majority of patients with characteristics of sharp pain and lash pain predominantly. On day 3 after surgery, mild pain was also predominant, with characteristics of stinging and lash pain in majority of patients.ConclusionsUsing scales and pain characteristics we can quantify and define post-surgical pain after pterygium surgery with conjunctival auto-grafts resection immediately after surgery and in the following days(AU)
Assuntos
Humanos , Pterígio/cirurgia , Transplante Autólogo , Túnica Conjuntiva/transplante , Dor Pós-Operatória/epidemiologia , /métodosRESUMO
Patients with Usher syndrome type II (USH2) show moderate-to-severe hearing loss (HL), retinitis pigmentosa and normal vestibular function. The progression of HL remains controversial. To evaluate whether a phenotype-genotype correlation exists regarding the issue of progression of HL, only USH2 patients with a defined genotype were selected. Ophthalmologic, vestibular and audiometric examination along with a mutation analysis of the USH2A gene (exons 1--21) was performed in twenty-eight Spanish USH2 patients. Ten different pathogenic mutations and 17 sequence variants not associated with the disease were found. Six of the 10 mutations are novel. Disease alleles were identified in 13 of the 28 families tested. Eight of these 13 families had a mutation found in both alleles. In the other five families, only one mutation was identified. The phenotypic data provide evidence for the existence of phenotypic differences between patients with the same genotype. These differences were observed at both the interfamilial and intrafamilial levels.
Assuntos
Proteínas da Matriz Extracelular/genética , Frequência do Gene , Perda Auditiva Neurossensorial/genética , Mutação , Retinose Pigmentar/genética , Adulto , Criança , Códon sem Sentido , Análise Mutacional de DNA , Feminino , Mutação da Fase de Leitura , Genótipo , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Polimorfismo Genético , Espanha , SíndromeAssuntos
Proteínas do Olho/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso , Receptores de Superfície Celular/genética , Receptores Acoplados a Proteínas G , Retinose Pigmentar/genética , Proteínas de Ligação ao Retinol/genética , DNA/química , DNA/genética , Análise Mutacional de DNA , Saúde da Família , Feminino , Genes Recessivos/genética , Humanos , Masculino , Mutação , Linhagem , Polimorfismo Conformacional de Fita Simples , Proteínas Celulares de Ligação ao RetinolAssuntos
Genes Recessivos/genética , Homozigoto , Canais Iônicos/genética , Mutação/genética , Retinose Pigmentar/genética , Adulto , Consanguinidade , Canais de Cátion Regulados por Nucleotídeos Cíclicos , DNA/genética , Análise Mutacional de DNA/métodos , Proteínas do Olho/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Núcleo Familiar , Linhagem , EspanhaAssuntos
Substituição de Aminoácidos/genética , Proteínas do Olho/genética , Genes Dominantes/genética , Proteínas de Filamentos Intermediários/genética , Degeneração Macular/genética , Glicoproteínas de Membrana , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Arginina/genética , Cisteína/genética , Eletroforese em Gel de Poliacrilamida , Histidina/genética , Humanos , Periferinas , Reação em Cadeia da Polimerase , Degeneração Retiniana/genética , Triptofano/genética , Tirosina/genéticaRESUMO
We present clinical and cytogenetic studies of a female patient affected with choroideremia, mild sensorineural deafness, and primary amenorrhea showing a balanced translocation between chromosomes X and 4. The breakpoint was precisely defined applying FISH techniques: 46,X,t(X;4)(q21.2;p16.3).ish t(X;4)(D4S96+, D4F26+; wcpX+). The X-chromosomal breakpoint was located within a region where both the choroideremia locus and a deafness locus (DFN3/POU3F4) have been mapped. The presence of X-linked disorders in this balanced carrier of X-autosomal translocations (XAT) can be explained either by the disruption of the structural coding or regulatory sequences of the gene(s) or by the submicroscopic deletion of this region leading to a contiguous gene deletion syndrome. The primary ovarian failure (POF) found in the present case has been already observed in XAT when the breakpoint is within a previously defined critical region (Xq13-26). A position effect is postulated as a possible explanation.
Assuntos
Coroideremia/genética , Surdez/genética , Perda Auditiva Neurossensorial/genética , Insuficiência Ovariana Primária/genética , Translocação Genética , Cromossomo X , Adulto , Coroideremia/complicações , Coroideremia/patologia , Bandeamento Cromossômico , Cromossomos Humanos Par 4 , Sondas de DNA , Surdez/complicações , Surdez/patologia , Feminino , Angiofluoresceinografia , Ligação Genética , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/patologia , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Insuficiência Ovariana Primária/complicações , Insuficiência Ovariana Primária/patologiaRESUMO
Autosomal dominant retinitis pigmentosa (adRP) may be caused by point mutations in the rhodopsin gene in up to 20% of Spanish families. Most of the rhodopsin mutations causing adRP have been reported in the heterozygous state. We describe a patient with adRP who is homozygous for a missense mutation at codon 188 in the second intradiscal domain of rhodopsin. All her sons are heterozygous for the mutation and show an RP phenotype suggesting complete penetrance for this mutation. The homozygous carrier of the mutation Gly-188-Arg in the rhodopsin gene showed a later subjective onset of symptoms than the heterozygotes, suggesting that the photoreceptor degeneration induced by the mutation is not dramatically influenced by mutant allele dosage.
Assuntos
Heterozigoto , Homozigoto , Mutação de Sentido Incorreto , Retinose Pigmentar/genética , Rodopsina/genética , Adulto , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Progressão da Doença , Eletroculografia , Eletroforese em Gel de Poliacrilamida , Eletrorretinografia , Feminino , Angiofluoresceinografia , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Reação em Cadeia da Polimerase , Retina/fisiopatologia , Retinose Pigmentar/fisiopatologia , Campos VisuaisRESUMO
The Usher syndrome (USH) is a group of autosomal recessive diseases characterized by congenital sensorineural hearing loss and retinitis pigmentosa. Three clinically distinct forms of Usher syndrome have so far been recognized and can be distinguished from one another by assessing auditory and vestibular function. Usher syndrome type II (USH2) patients have congenital moderate-to-severe nonprogressive hearing loss, retinitis pigmentosa, and normal vestibular function. Genetic linkage studies have revealed genetic heterogeneity among the three types of USH, with the majority of USH2 families showing linkage to the USH2A locus in 1q41. The USH2A gene (MIM 276901) has been identified: three mutations, 2314delG, 2913delG, and 4353-54delC, were initially reported in USH2A patients, the most frequent of which is the 2314delG mutation. It has been reported that this mutation can give rise to typical and atypical USH2 phenotypes. USH2 cases represent 62% of all USH cases in the Spanish population, and 95% of these cases have provided evidence of linkage to the USH2A locus. In the present study, the three reported mutations were analyzed in 59 Spanish families with a diagnosis of USH type II. The 2314delG was the only mutation identified in our population: it was detected in 25% of families and 16% of USH2 chromosomes analyzed. This study attempts to estimate the prevalence of this common mutation in a homogeneous Spanish population.
Assuntos
Sequência de Bases , Proteínas da Matriz Extracelular/genética , Perda Auditiva Neurossensorial/genética , Retinose Pigmentar/genética , Deleção de Sequência/genética , Alelos , Mapeamento Cromossômico , Análise Mutacional de DNA , Primers do DNA/química , Feminino , Haplótipos , Perda Auditiva Neurossensorial/etnologia , Análise Heteroduplex , Humanos , Masculino , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo Conformacional de Fita Simples , Prevalência , Retinose Pigmentar/etnologia , Espanha/epidemiologiaRESUMO
PURPOSE: To assess the contribution of TULP1 to autosomal recessive retinitis pigmentosa (arRP). METHODS: Fifteen exons of the gene were screened by single-strand conformation polymorphism analysis of 7 (of 49) arRP pedigrees showing cosegregation with TULP1 locus markers. RESULTS: In one of the seven families two allelic mutations, IVS4-2delAGA and c.937delC, were found in exons 5 and 10, respectively. CONCLUSIONS: Two novel mutations in TULP1 were found to be associated with arRP. That they both compromise the gene product supports their pathogenicity. This gene was present in no more than 2% of a panel of 49 Spanish families affected by arRP.
Assuntos
Proteínas do Olho/genética , Mutação Puntual , Retinose Pigmentar/genética , Sequência de Aminoácidos , Sequência de Bases , Éxons , Feminino , Deleção de Genes , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Análise de Sequência de DNARESUMO
Mutations in the rhodopsin cause of retinitis pigmentosa autosomal dominant (ADRP). We report a large family affected with ADRP. Analysis by denaturant gradient gel electrophoresis and direct DNA sequence detected an heterozygous G to T transversion in the exon 3 of the rhodopsin gene. This mutation damages a restriction site for Taq I enzyme and produces the change Asp-190-Tyr in rhodopsin. All carriers of the mutation show a regional RP phenotype. This mutation is responsible for the disease in this family.
Assuntos
Aberrações Cromossômicas/genética , Expressão Gênica/genética , Mutação Puntual/genética , Retinose Pigmentar/genética , Rodopsina/genética , Cromossomo X/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pré-Escolar , Transtornos Cromossômicos , Citogenética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
A Spanish family affected with autosomal dominant retinitis pigmentosa (ADRP) with a diffuse phenotype showed a mutation in the rhodopsin gene. The mutation was the transition T-->C in codon 186, which has been reported once before in an American patient (Dryja et al., Proc Natl Acad Sci USA 1991;88:9370-9374). This change replaces a serine by a proline in the second intradiscal loop of the protein, generating a molecule that is probably folding- and transport-defective.
Assuntos
Mutação Puntual , Retinose Pigmentar/genética , Rodopsina/genética , Adulto , Análise Mutacional de DNA , Eletrorretinografia , Feminino , Fundo de Olho , Genes Dominantes , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Prolina , Retinose Pigmentar/diagnóstico , Serina , Espanha , Campos VisuaisRESUMO
We present two siblings with retinitis pigmentosa, mental retardation, markedly short stature, and brachydactyly. This association of clinical findings appears to be distinct from previously described syndromes and seems to represent the pleiotropic effects of a single autosomal recessive gene.
Assuntos
Deformidades Congênitas do Pé/genética , Transtornos do Crescimento/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Retinose Pigmentar/genética , Adulto , Feminino , Deformidades Congênitas do Pé/patologia , Deformidades Congênitas da Mão/diagnóstico por imagem , Deformidades Congênitas da Mão/patologia , Humanos , Masculino , Pessoa de Meia-Idade , RadiografiaRESUMO
A Spanish family with three Usher I syndrome-affected members was linked to markers located on chromosome 11q. A search for mutations on the myosin VIIA gene revealed a novel mutation (Cys628STOP) on exon 16 segregating with the disorder in a homozygous state. This nonsense mutation could be responsible for the disease since it leads to a truncated protein that presumably has no function.
Assuntos
Códon de Terminação/genética , Cisteína/genética , Surdez/genética , Miosinas/genética , Retinose Pigmentar/genética , DNA/análise , DNA/química , DNA/genética , Análise Mutacional de DNA , Surdez/congênito , Dineínas , Éxons/genética , Feminino , Genes Recessivos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Miosina VIIa , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Retinose Pigmentar/congênito , SíndromeRESUMO
We present a Spanish family affected with autosomal dominant pigmentary retinosis in which we have identified the mutation responsible for the disease (Pro347Leu) within the rhodopsin (RHO) gene. Complete ophthalmological and electrophysiological studies were performed in 14 members of this family. The molecular study, performed by SSCP analysis of the 5 exon and the promotor region of the rhodopsin gene, direct sequentiation and restriction analysis with the enzyme Mspl, showed a C-->T change in the second base of 347 codon of RHO gene. This mutation predicts a change of proline by leucine at this position. Every patient with the mutation showed a phenotype of diffuse, early onset and severe pigmentary retinosis with a little intrafamiliar variation. The Pro347Leu mutation, that has been very frequently described among all the populations, has been identified as a cause of RP in an Spanish family.