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1.
Sci Rep ; 14(1): 15189, 2024 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956231

RESUMO

Variants in the retinitis pigmentosa GTPase regulator (RPGR) gene are responsible for the majority of X-linked retinitis pigmentosa cases, which not only affects male patients but also some heterozygous females. Vision-related disability and anxiety of patients with RPGR-associated retinal degeneration have never been explored before. This study aimed to evaluate self-reported visual function and vision-related anxiety in a Portuguese cohort of male and female patients with RPGR-associated retinal degeneration using two validated patient-reported outcome measures. Cross-sectional data of thirty-two genetically-tested patients was examined, including scores of the Michigan retinal degeneration questionnaire (MRDQ) and Michigan vision-related anxiety questionnaire. Patients were classified according to retinal phenotypes in males (M), females with male phenotype (FM), and females with radial or focal pattern. Both M and FM revealed higher rod-function and cone-function anxiety scores (p < 0.017). Most MRDQ disability scores were higher in M and FM (p < 0.004). Overall, positive correlations (p < 0.004) were found between every MRDQ domain and both anxiety scores. In RPGR-associated retinal degeneration, males and females with male phenotype show similar levels of increased vision-related anxiety and disability. Every MRDQ visual function domain showed a strong correlation with anxiety scores.


Assuntos
Ansiedade , Proteínas do Olho , Degeneração Retiniana , Autorrelato , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Degeneração Retiniana/fisiopatologia , Proteínas do Olho/genética , Estudos Transversais , Retinose Pigmentar/fisiopatologia , Retinose Pigmentar/psicologia , Retinose Pigmentar/genética , Idoso , Fenótipo , Adulto Jovem , Inquéritos e Questionários
2.
Int J Mol Sci ; 25(11)2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38891946

RESUMO

Retinitis pigmentosa (RP) is an inherited retinal dystrophy caused by the loss of photoreceptors and retinal pigment epithelial atrophy, leading to severe visual impairment or blindness. RP can be classified as nonsyndromic or syndromic with complex clinical phenotypes. Three unrelated Polish probands affected with retinitis pigmentosa coexisting with cerebellar ataxia were recruited for this study. Clinical heterogeneity and delayed appearance of typical disease symptoms significantly prolonged the patients' diagnostic process. Therefore, many clinical and genetic tests have been performed in the past. Here, we provide detailed clinical and genetic analysis results of the patients. Whole-exome sequencing (WES) and targeted NGS analysis allow the identification of four novel and two previously reported variants in the following genes: ABHD12, FLVCR1, and PNPLA6. The use of next-generation sequencing (NGS) methods finally allowed for confirmation of the clinical diagnosis. Ultra-rare diseases such as PHARC, PCARP, and Oliver-McFarlane syndromes were diagnosed in patients, respectively. Our findings confirmed the importance of the application of next-generation sequencing methods, especially in ultra-rare genetic disorders with overlapping features.


Assuntos
Sequenciamento do Exoma , Retinose Pigmentar , Humanos , Retinose Pigmentar/genética , Retinose Pigmentar/diagnóstico , Masculino , Feminino , Linhagem , Sequenciamento de Nucleotídeos em Larga Escala , Adulto , Ataxia Cerebelar/genética , Ataxia Cerebelar/diagnóstico , Proteínas de Membrana Transportadoras/genética , Monoacilglicerol Lipases/genética , Mutação , Ataxia/genética , Ataxia/diagnóstico , Fenótipo , Aciltransferases , Catarata , Fosfolipases , Polineuropatias
3.
Invest Ophthalmol Vis Sci ; 65(6): 5, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38833260

RESUMO

Purpose: The purpose of this study was to evaluate self-reported functional vision (FV) and the impact of vision loss in patients with USH2A-associated retinal degeneration using a patient-reported outcome (PRO) measure, the Michigan Retinal Degeneration Questionnaire (MRDQ), to correlate MRDQ scores with well-established visual function measurements. Design: An observational cross-sectional study (n = 93) of participants who had Usher Syndrome Type 2 (USH2, n = 55) or autosomal recessive non-syndromic retinitis pigmentosa (ARRP; n = 38) associated with biallelic variants in the USH2A gene. Methods: The study protocol was approved by all ethics boards and informed consent was obtained from each participant. Participants completed the MRDQ at the 48-month study follow-up visit. Disease duration was self-reported by participants. One-way ANOVA was used to compare subgroups (clinical diagnosis, age, disease duration, and full-field stimulus threshold [FST] Blue-Red mediation) on mean scores per domain. Spearman correlation coefficients were used to assess associations between MRDQ domains and visual/retinal function assessments. Results: Of the study sample, 58% were female participants and the median disease duration was 13 years. MRDQ domains were sensitive to differences between subgroups of clinical diagnosis, age, disease duration, and FST Blue-Red mediation. MRDQ domains correlated with static perimetry, microperimetry, full-field stimulus testing, and best-corrected visual acuity (BCVA). Conclusions: Self-reported FV measured by the MRDQ, when applied to USH2 and ARRP participants, had good distributional characteristics and correlated well with visual function tests. MRDQ adds a new dimension of understanding on vision-related functioning and establishes this PRO tool as an informative measure in evaluating USH2A outcomes.


Assuntos
Proteínas da Matriz Extracelular , Autorrelato , Síndromes de Usher , Acuidade Visual , Humanos , Feminino , Masculino , Estudos Transversais , Pessoa de Meia-Idade , Acuidade Visual/fisiologia , Proteínas da Matriz Extracelular/genética , Adulto , Síndromes de Usher/genética , Síndromes de Usher/fisiopatologia , Síndromes de Usher/diagnóstico , Inquéritos e Questionários , Degeneração Retiniana/genética , Degeneração Retiniana/fisiopatologia , Degeneração Retiniana/diagnóstico , Idoso , Adulto Jovem , Qualidade de Vida , Adolescente , Retinose Pigmentar/genética , Retinose Pigmentar/fisiopatologia , Retinose Pigmentar/diagnóstico
4.
Mol Genet Genomic Med ; 12(6): e2481, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38867642

RESUMO

PURPOSE: To characterize the phenotype and genotype of a Chinese family with autosomal-dominant retinitis pigmentosa (RP) accompanied by iris coloboma. METHODS: The proband, a 34-year-old male, was examined with his family by using fundus photography, optical coherence tomography (OCT), autofluorescence, and full-field electroretinography (ffERG). Genetic analyses were conducted through whole-exome sequencing (WES) to screen for variations. RESULTS: Three members of this Chinese family were shown to be bilateral iris coloboma. The male proband and his mother exhibited typical RP feature. The proband's late grandfather had been documented manifestation of iris coloboma. The mode of inheritance was confirmed to be autosomal dominance. Through linkage analysis and WES, a heterozygous variation in the miR-204 gene (n.37C>T), a noncoding RNA gene, was identified in these three members. CONCLUSIONS: In this third independent and the first Asian family, the existence of a miR-204 variant associated with RP accompanied by iris coloboma was confirmed. Our findings reinforce the significance of miR-204 as an important factor influencing visual function in the retina. When phenotypes like RP accompanied by iris coloboma in an autosomal-dominant pattern, including in Chinese patients, miR-204 aberrations should be considered.


Assuntos
Coloboma , MicroRNAs , Linhagem , Retinose Pigmentar , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Coloboma/genética , Coloboma/patologia , População do Leste Asiático , Iris/anormalidades , Iris/patologia , MicroRNAs/genética , Fenótipo , Retinose Pigmentar/genética
5.
PLoS One ; 19(6): e0304261, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38870197

RESUMO

PURPOSE: Patients with Retinitis Pigmentosa (RP) commonly experience sleep-related issues and are susceptible to stress. Moreover, variatiaons in their vision are often linked to anxiety, stress and drowsiness, indicating that stress and sleep deprivation lead to a decline in vision, and vision improves when both are mitigated. The objective of this study was to investigate the utility of salivary biomarkers as biochemical indicators of anxiety and sleep deprivation in RP patients. METHODS: Seventy-eight RP patients and 34 healthy controls were included in this observational study. Anxiety and sleep-quality questionnaires, a complete ophthalmological exam for severity grading and, the collection of salivary samples from participants were assessed for participants. The activity of biomarkers was estimated by ELISA, and statistical analysis was performed to determine associations between the parameters. Associations between underlying psychological factors, grade of disease severity, and biomarkers activity were also examined. RESULTS: Fifty-two (67%) of patients had a severe RP, and 26 (33%) had a mild-moderate grade. Fifty-eight (58,9%) patients reported severe levels of anxiety and 18 (23.,1%) a high level. Forty-six (59%) patients obtained pathological values in sleep-quality questionaries and 43 (55.1%) in sleepiness. Patients with RP exhibited significant differences in testosterone, cortisol, sTNFαRII, sIgA and melatonin as compared to controls and patients with a mild-moderate and advanced stage of disease showed greater differences. In covariate analysis, patients with a severe anxiety level also showed greater differences in mean salivary cortisol, sTNFαRII and melatonin and male patients showed lower IgA levels than female. CONCLUSIONS: The present findings suggest that salivary biomarkers could be suitable non-invasive biochemical markers for the objective assessment of sleep deprivation and anxiety in RP patients. Further research is needed to characterize the effects of untreated negative psychological states and sleep deprivation on increased variability of vision and disease progression, if any.


Assuntos
Biomarcadores , Retinose Pigmentar , Saliva , Privação do Sono , Humanos , Masculino , Feminino , Saliva/química , Saliva/metabolismo , Biomarcadores/metabolismo , Biomarcadores/análise , Retinose Pigmentar/metabolismo , Adulto , Pessoa de Meia-Idade , Privação do Sono/metabolismo , Estresse Psicológico/metabolismo , Ansiedade/metabolismo , Estudos de Casos e Controles , Hidrocortisona/análise , Hidrocortisona/metabolismo
6.
Biomolecules ; 14(6)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38927058

RESUMO

The retina, a tissue of the central nervous system, is vital for vision as its photoreceptors capture light and transform it into electrical signals, which are further processed before they are sent to the brain to be interpreted as images. The retina is unique in that it is continuously exposed to light and has the highest metabolic rate and demand for energy amongst all the tissues in the body. Consequently, the retina is very susceptible to oxidative stress. VDAC, a pore in the outer membrane of mitochondria, shuttles metabolites between mitochondria and the cytosol and normally protects cells from oxidative damage, but when a cell's integrity is greatly compromised it initiates cell death. There are three isoforms of VDAC, and existing evidence indicates that all three are expressed in the retina. However, their precise localization and function in each cell type is unknown. It appears that most retinal cells express substantial amounts of VDAC2 and VDAC3, presumably to protect them from oxidative stress. Photoreceptors express VDAC2, HK2, and PKM2-key proteins in the Warburg pathway that also protect these cells. Consistent with its role in initiating cell death, VDAC is overexpressed in the retinal degenerative diseases retinitis pigmentosa, age related macular degeneration (AMD), and glaucoma. Treatment with antioxidants or inhibiting VDAC oligomerization reduced its expression and improved cell survival. Thus, VDAC may be a promising therapeutic candidate for the treatment of these diseases.


Assuntos
Retina , Canais de Ânion Dependentes de Voltagem , Humanos , Canais de Ânion Dependentes de Voltagem/metabolismo , Retina/metabolismo , Animais , Estresse Oxidativo , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia , Mitocôndrias/metabolismo , Retinose Pigmentar/metabolismo , Retinose Pigmentar/patologia
7.
PLoS One ; 19(6): e0305812, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38913662

RESUMO

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy and a major cause of blindness. RP is caused by several variants of multiple genes, and genetic diagnosis by identifying these variants is important for optimizing treatment and estimating patient prognosis. Next-generation sequencing (NGS), which is currently widely used for diagnosis, is considered useful but is known to have limitations in detecting copy number variations (CNVs). In this study, we re-evaluated CNVs in EYS, the main causative gene of RP, identified via NGS using multiplex ligation-dependent probe amplification (MLPA). CNVs were identified in NGS samples of eight patients. To identify potential CNVs, MLPA was also performed on samples from 42 patients who were undiagnosed by NGS but carried one of the five major pathogenic variants reported in Japanese EYS-RP cases. All suspected CNVs based on NGS data in the eight patients were confirmed via MLPA. CNVs were found in 2 of the 42 NGS-undiagnosed RP cases. Furthermore, results showed that 121 of the 661 patients with RP had EYS as the causative gene, and 8.3% (10/121 patients with EYS-RP) had CNVs. Although NGS using the CNV calling criteria utilized in this study failed to identify CNVs in two cases, no false-positive results were detected. Collectively, these findings suggest that NGS is useful for CNV detection during clinical diagnosis of RP.


Assuntos
Variações do Número de Cópias de DNA , Proteínas do Olho , Sequenciamento de Nucleotídeos em Larga Escala , Retinose Pigmentar , Humanos , Retinose Pigmentar/genética , Retinose Pigmentar/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Feminino , Masculino , Proteínas do Olho/genética , Pessoa de Meia-Idade , Adulto , Reação em Cadeia da Polimerase Multiplex/métodos
8.
Genes (Basel) ; 15(6)2024 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-38927727

RESUMO

Mutations in the gene SCAPER (S phase Cyclin A-Associated Protein residing in the Endoplasmic Reticulum) have recently been associated with retinitis pigmentosa (RP) and intellectual disability (ID). In 2011, a possible involvement of SCAPER in human diseases was discovered for the first time due to the identification of a homozygous mutation causing ID in an Iranian family. Later, five studies were published in 2019 that described patients with autosomal recessive syndromic retinitis pigmentosa (arRP) accompanied by ID and attention-deficit/hyperactivity disorder (ADHD). This present study describes three patients from an Arab consanguineous family in Israel with similar clinical features of the SCAPER syndrome. In addition, new manifestations of ocular symptoms, nystagmus, glaucoma, and elevator palsy, were observed. Genetic testing of the patients and both parents via whole-exome sequencing revealed the homozygous mutation c.2023-2A>G in SCAPER. Phenotypic and genotypic descriptions for all available cases described in the literature including our current three cases (37 cases) were carried out, in addition to a bioinformatics analysis for all the genetic variants that was undertaken. Our study confirms and extends the clinical manifestations of SCAPER-related disorders.


Assuntos
Biologia Computacional , Deficiência Intelectual , Mutação , Linhagem , Fenótipo , Retinose Pigmentar , Adolescente , Adulto , Feminino , Humanos , Proteínas de Transporte/genética , Biologia Computacional/métodos , Consanguinidade , Sequenciamento do Exoma , Genes Recessivos , Homozigoto , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Peptídeos e Proteínas de Sinalização Intercelular , Retinose Pigmentar/genética , Retinose Pigmentar/patologia
9.
Genes (Basel) ; 15(6)2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38927740

RESUMO

Retinitis pigmentosa (RP) is a heterogeneous inherited retinal disorder. Mutations in KIZ cause autosomal recessive (AR) RP. We aimed to characterize the genotype, expression pattern, and phenotype in a large cohort of KIZ cases. Sanger and whole exome sequencing were used to identify the KIZ variants. Medical records were reviewed and analyzed. Thirty-one patients with biallelic KIZ mutations were identified: 28 homozygous for c.226C>T (p.R76*), 2 compound heterozygous for p.R76* and c.3G>A (p.M1?), and one homozygous for c.247C>T (p.R83*). c.226C>T is a founder mutation among patients of Jewish descent. The clinical parameters were less severe in KIZ compared to DHDDS and FAM161A cases. RT-PCR analysis in fibroblast cells revealed the presence of four different transcripts in both WT and mutant samples with a lower percentage of the WT transcript in patients. Sequence analysis identified an exonic sequence enhancer (ESE) that includes the c.226 position which is affected by the mutation. KIZ mutations are an uncommon cause of IRD worldwide but are not rare among Ashkenazi Jews. Our data indicate that p.R76* affect an ESE which in turn results in the pronounced skipping of exon 3. Therefore, RNA-based therapies might show low efficacy since the mutant transcripts are spliced.


Assuntos
Mutação , Retinose Pigmentar , Humanos , Retinose Pigmentar/genética , Retinose Pigmentar/patologia , Feminino , Masculino , Adulto , Judeus/genética , Sequenciamento do Exoma/métodos , Linhagem , Proteínas do Olho/genética , Fenótipo , Pessoa de Meia-Idade , Adolescente
10.
Sci Rep ; 14(1): 10551, 2024 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-38719929

RESUMO

Our purpose was to elucidate the genotype and ophthalmological and audiological phenotype in TUBB4B-associated inherited retinal dystrophy (IRD) and sensorineural hearing loss (SNHL), and to model the effects of all possible amino acid substitutions at the hotspot codons Arg390 and Arg391. Six patients from five families with heterozygous missense variants in TUBB4B were included in this observational study. Ophthalmological testing included best-corrected visual acuity, fundus examination, optical coherence tomography, fundus autofluorescence imaging, and full-field electroretinography (ERG). Audiological examination included pure-tone and speech audiometry in adult patients and auditory brainstem response testing in a child. Genetic testing was performed by disease gene panel analysis based on genome sequencing. The molecular consequences of the substitutions of residues 390 and 391 on TUBB4B and its interaction with α-tubulin were predicted in silico on its three-dimensional structure obtained by homology modelling. Two independent patients had amino acid exchanges at position 391 (p.(Arg391His) or p.(Arg391Cys)) of the TUBB4B protein. Both had a distinct IRD phenotype with peripheral round yellowish lesions with pigmented spots and mild or moderate SNHL, respectively. Yet the phenotype was milder with a sectorial pattern of bone spicules in one patient, likely due to a genetically confirmed mosaicism for p.(Arg391His). Three patients were heterozygous for an amino acid exchange at position 390 (p.(Arg390Gln) or p.(Arg390Trp)) and presented with another distinct retinal phenotype with well demarcated pericentral retinitis pigmentosa. All showed SNHL ranging from mild to severe. One additional patient showed a variant distinct from codon 390 or 391 (p.(Tyr310His)), and presented with congenital profound hearing loss and reduced responses in ERG. Variants at codon positions 390 and 391 were predicted to decrease the structural stability of TUBB4B and its complex with α-tubulin, as well as the complex affinity. In conclusion, the twofold larger reduction in heterodimer affinity exhibited by Arg391 substitutions suggested an association with the more severe retinal phenotype, compared to the substitution at Arg390.


Assuntos
Códon , Perda Auditiva Neurossensorial , Fenótipo , Tubulina (Proteína) , Humanos , Feminino , Tubulina (Proteína)/genética , Tubulina (Proteína)/química , Masculino , Adulto , Perda Auditiva Neurossensorial/genética , Códon/genética , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Criança , Linhagem , Adolescente , Substituição de Aminoácidos , Adulto Jovem , Retinose Pigmentar/genética
11.
Elife ; 122024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38727583

RESUMO

Retinitis pigmentosa (RP) is an inherited retinal disease in which there is a loss of cone-mediated daylight vision. As there are >100 disease genes, our goal is to preserve cone vision in a disease gene-agnostic manner. Previously we showed that overexpressing TXNIP, an α-arrestin protein, prolonged cone vision in RP mouse models, using an AAV to express it only in cones. Here, we expressed different alleles of Txnip in the retinal pigmented epithelium (RPE), a support layer for cones. Our goal was to learn more of TXNIP's structure-function relationships for cone survival, as well as determine the optimal cell type expression pattern for cone survival. The C-terminal half of TXNIP was found to be sufficient to remove GLUT1 from the cell surface, and improved RP cone survival, when expressed in the RPE, but not in cones. Knock-down of HSP90AB1, a TXNIP-interactor which regulates metabolism, improved the survival of cones alone and was additive for cone survival when combined with TXNIP. From these and other results, it is likely that TXNIP interacts with several proteins in the RPE to indirectly support cone survival, with some of these interactions different from those that lead to cone survival when expressed only in cones.


Assuntos
Células Fotorreceptoras Retinianas Cones , Retinose Pigmentar , Tiorredoxinas , Animais , Camundongos , Alelos , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Sobrevivência Celular , Modelos Animais de Doenças , Deleção de Genes , Mutação de Sentido Incorreto , Células Fotorreceptoras Retinianas Cones/metabolismo , Células Fotorreceptoras Retinianas Cones/patologia , Epitélio Pigmentado da Retina/metabolismo , Retinose Pigmentar/genética , Retinose Pigmentar/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
12.
Ophthalmic Res ; 67(1): 301-310, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38705136

RESUMO

INTRODUCTION: Retinitis pigmentosa (RP), a heterogeneous inherited retinal disorder causing gradual vision loss, affects over 1 million people worldwide. Pathogenic variants in CNGA1 and CNGB1 genes, respectively, accounting for 1% and 4% of cases, impact the cyclic nucleotide-gated channel in rod photoreceptor cells. The aim of this study was to describe and compare genotypic and clinical characteristics of a cohort of patients with CNGA1- or CNGB1-related RP and to explore potential genotype-phenotype correlations. METHODS: The following data from patients with CNGA1- or CNGB1-related RP, followed in five Italian inherited retinal degenerations services, were retrospectively collected: genetic variants in CNGA1 and CNGB1, best-corrected visual acuity (BCVA), ellipsoid zone (EZ) width, fundus photographs, and short-wavelength fundus autofluorescence (SW-AF) images. Comparisons and correlation analyses were performed by first dividing the cohort in two groups according to the gene responsible for the disease (CNGA1 and CNGB1 groups). In parallel, the whole cohort of RP patients was divided into two other groups, according to the expected impact of the variants at protein level (low and high group). RESULTS: In total, 29 patients were recruited, 11 with CNGA1- and 18 with CNGB1-related RP. In both CNGA1 and CNGB1, 5 novel variants in CNGA1 and 5 in CNGB1 were found. BCVA was comparable between CNGA1 and CNGB1 groups, as well as between low and high groups. CNGA1 group had a larger mean EZ width compared to CNGB1 group, albeit not statistically significant, while EZ width did not differ between low and high groups A statistically significant correlation between EZ width and BCVA as well as between EZ width and age were observed in the whole cohort of RP patients. Fundus photographs of all patients in the cohort showed classic RP pattern, and in SW-AF images an hyperautofluorescent ring was observed in 14/21 patients. CONCLUSION: Rod CNG channel-associated RP was demonstrated to be a slowly progressive disease in both CNGA1- and CNGB1-related forms, making it an ideal candidate for gene augmentation therapies.


Assuntos
Canais de Cátion Regulados por Nucleotídeos Cíclicos , Genótipo , Fenótipo , Retinose Pigmentar , Acuidade Visual , Humanos , Retinose Pigmentar/genética , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/fisiopatologia , Masculino , Feminino , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Adulto Jovem , Adolescente , Eletrorretinografia , Tomografia de Coerência Óptica/métodos , Idoso , Mutação , Criança , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Angiofluoresceinografia/métodos , Estudos de Associação Genética , Análise Mutacional de DNA , Linhagem , DNA/genética
13.
Ophthalmic Res ; 67(1): 348-357, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38718781

RESUMO

INTRODUCTION: Retinitis pigmentosa (RP) is a chronic progressive disease causing loss of visual acuity and ultimately blindness. This visual impairment can contribute to psychiatric comorbidity and worse overall quality of life (QOL). Our goal was to assess the relationship between the severity of disease for people with RP and QOL as it pertains to mental health, social support, disability resources, and financial factors. METHODS: This was a survey study conducted from June 2021 to February 2022 including 38 people with RP. QOL was assessed through a survey questionnaire focusing specifically on demographics, visual function, family, employment, social support, and mental health/well-being. Statistical analysis was conducted using a χ2 test for significance. RESULTS: A best corrected visual acuity (BCVA) of less than 20/200 (p = 0.0285) and living alone (p = 0.0358) were both statistically significant independent risk factors for experiencing depressive symptoms. Highest education level attained and unemployment rate were not found to be related to the development of depressive symptoms. Subjects had a higher unemployment rate (64% vs. US rate of 3.6%) and a high likelihood of reporting depressive symptoms (47.4%). CONCLUSION: People with RP are more likely to be unemployed and to develop depressive symptoms when compared to the general population. Similar to previous studies' findings, those with a BCVA of less than 20/200 were statistically more likely to experience depressive symptoms; living alone is a novel risk factor that is also associated with the presence of depressive symptoms. Contrary to prior findings, highest education level and unemployment status were found not to be related to the development of depressive symptoms. These patients may benefit from regular depression screenings and optional establishment of care with a psychiatrist or psychologist if they live alone or their BCVA is 20/200 or worse.


Assuntos
Qualidade de Vida , Retinose Pigmentar , Acuidade Visual , Humanos , Retinose Pigmentar/psicologia , Retinose Pigmentar/epidemiologia , Retinose Pigmentar/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Inquéritos e Questionários , Idoso
14.
Stem Cell Res ; 78: 103448, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38810502

RESUMO

Mutations in the eyes shut homolog (EYS) gene are one of the common causes of autosomal recessive retinitis pigmentosa (RP). The lack of suitable animal models hampers progress understanding of the disease mechanism and drug development. This study reported the reprogramming of CD34+ hematopoietic stem/progenitor cells from a patient with compound heterozygous EYS mutations (c.6416 G > A and c.7228 + 1 G > A) into the induced pluripotent stem cell line, MUi038-A, using non-integrating vectors. The MUi038-A demonstrates pluripotency, tri-lineage differentiation potential, and a normal karyotype, offering a valuable model for studying the mechanism of EYS-related RP and new therapeutic development.


Assuntos
Proteínas do Olho , Células-Tronco Pluripotentes Induzidas , Retinose Pigmentar , Humanos , Retinose Pigmentar/patologia , Retinose Pigmentar/genética , Retinose Pigmentar/metabolismo , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Linhagem Celular , Diferenciação Celular , Mutação
16.
Invest Ophthalmol Vis Sci ; 65(5): 39, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38787546

RESUMO

Purpose: Post-saccadic oscillations (PSOs) reflect movements of gaze that result from motion of the pupil and lens relative to the eyeball rather than eyeball rotations. Here, we analyzed the characteristics of PSOs in subjects with age-related macular degeneration (AMD), retinitis pigmentosa (RP), and normal vision (NV). Our aim was to assess the differences in PSOs between people with vision loss and healthy controls because PSOs affect retinal image stability after each saccade. Methods: Participants completed a horizontal saccade task and their gaze was measured using a pupil-based eye tracker. Oscillations occurring in the 80 to 200 ms post-saccadic period were described with a damped oscillation model. We compared the amplitude, decay time constant, and frequency of the PSOs for the three different groups. We also examined the correlation between these PSO parameters and the amplitude, peak velocity, and final deceleration of the preceding saccades. Results: Subjects with vision loss (AMD, n = 6, and RP, n = 5) had larger oscillation amplitudes, longer decay constants, and lower frequencies than subjects with NV (n = 7). The oscillation amplitudes increased with increases in saccade deceleration in all three groups. The other PSO parameters, however, did not show consistent correlations with either saccade amplitude or peak velocity. Conclusions: Post-saccadic fixation stability in AMD and RP is reduced due to abnormal PSOs. The differences with respect to NV are not due to differences in saccade kinematics, suggesting that anatomic and neuronal variations affect the suspension of the iris and the lens in the patients' eyes.


Assuntos
Fixação Ocular , Degeneração Macular , Pupila , Retinose Pigmentar , Movimentos Sacádicos , Humanos , Movimentos Sacádicos/fisiologia , Retinose Pigmentar/fisiopatologia , Feminino , Masculino , Fixação Ocular/fisiologia , Pessoa de Meia-Idade , Degeneração Macular/fisiopatologia , Idoso , Pupila/fisiologia , Cristalino/fisiopatologia , Adulto , Acuidade Visual/fisiologia
17.
Nat Commun ; 15(1): 4316, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773095

RESUMO

As signalling organelles, cilia regulate their G protein-coupled receptor content by ectocytosis, a process requiring localised actin dynamics to alter membrane shape. Photoreceptor outer segments comprise an expanse of folded membranes (discs) at the tip of highly-specialised connecting cilia, into which photosensitive GPCRs are concentrated. Discs are shed and remade daily. Defects in this process, due to mutations, cause retinitis pigmentosa (RP). Whilst fundamental for vision, the mechanism of photoreceptor disc generation is poorly understood. Here, we show membrane deformation required for disc genesis is driven by dynamic actin changes in a process akin to ectocytosis. We show RPGR, a leading RP gene, regulates actin-binding protein activity central to this process. Actin dynamics, required for disc formation, are perturbed in Rpgr mouse models, leading to aborted membrane shedding as ectosome-like vesicles, photoreceptor death and visual loss. Actin manipulation partially rescues this, suggesting the pathway could be targeted therapeutically. These findings help define how actin-mediated dynamics control outer segment turnover.


Assuntos
Actinas , Proteínas do Olho , Retinose Pigmentar , Animais , Actinas/metabolismo , Camundongos , Retinose Pigmentar/metabolismo , Retinose Pigmentar/genética , Proteínas do Olho/metabolismo , Proteínas do Olho/genética , Cílios/metabolismo , Humanos , Segmento Externo das Células Fotorreceptoras da Retina/metabolismo , Camundongos Knockout , Camundongos Endogâmicos C57BL , Membrana Celular/metabolismo
18.
Medicina (Kaunas) ; 60(5)2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38792980

RESUMO

Purpose: To describe an atypical phenotypic pattern of late-onset retinitis pigmentosa (RP) due to the same specific c.425A>G (p.Tyr142Cys) heterozygous mutation in the cone-rod homeobox gene (CRX gene) in two unrelated Italian patients. Case 1: A 67-year-old woman (P.P.) was incidentally diagnosed with sector RP at the age of 50. The patient was initially asymptomatic and did not have any family history of retinal dystrophy. Fundus examination showed the presence of typical retinal pigmentary deposits with a peculiar pericentral/sector distribution. Genomic sequencing disclosed the missense mutation c.425A>G (p.Tyr142Cys) in the CRX gene. During the follow-up period of 7 years, the patient maintained good visual acuity and complained only of mild symptoms. Case 2: A 76-year-old man (P.E.) presented with nyctalopia and visual field constriction since the age of 50. Fundus examination showed the presence of retinal pigment deposits with a concentric pericentral and perimacular pattern. A full-field electroretinogram (ffERG) showed extinguished scotopic responses and reduced abnormal photopic and flicker cone responses. Genomic sequencing identified the same missense mutation, c.425A>G (p.Tyr142Cys), in the CRX gene. Similarly to the first case, during the whole follow-up of 7 years, the visual acuity remained stable, as did the visual field and the patient's symptoms. Conclusions: We report the first cases of late-onset retinitis pigmentosa related to a specific heterozygous CRX gene mutation in exon 4. We also report two atypical phenotypic RP patterns related to mutations in the CRX gene.


Assuntos
Proteínas de Homeodomínio , Retinose Pigmentar , Transativadores , Humanos , Retinose Pigmentar/genética , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/fisiopatologia , Feminino , Idoso , Itália , Masculino , Proteínas de Homeodomínio/genética , Transativadores/genética , Mutação de Sentido Incorreto , Mutação , Eletrorretinografia/métodos , Fenótipo
19.
Genes (Basel) ; 15(4)2024 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-38674450

RESUMO

Retinitis pigmentosa is a group of genetically determined retinal dystrophies characterized by primary photoreceptor apoptosis and can occur in isolated or syndromic conditions. This study reviewed the clinical data of 15 patients with syndromic retinitis pigmentosa from a Rare Disease Reference Center in Brazil and the results of their next-generation sequencing tests. Five males and ten females participated, with the mean ages for ocular disease onset, fundoscopic diagnosis, and molecular evaluation being 9, 19, and 29 years, respectively. Bardet-Biedl syndrome (n = 5) and Usher syndrome (n = 3) were the most frequent diagnoses, followed by other rare conditions. Among the patients, fourteen completed molecular studies, with three negative results and eleven revealing findings in known genes, including novel variants in MKKS (c.432_435del, p.Phe144Leufs*14), USH2A (c.(7301+1_7302-1)_(9369+1_9370-1)del), and CEP250 (c.5383dup, p.Glu1795Glyfs*13, and c.5050del, p.Asp1684Thrfs*9). Except for Kearn-Sayre, all presented an autosomal recessive inheritance pattern with 64% homozygosity results. The long gap between symptom onset and diagnosis highlights the diagnostic challenges faced by the patients. This study reaffirms the clinical heterogeneity of syndromic retinitis pigmentosa and underscores the pivotal role of molecular analysis in advancing our understanding of these diseases.


Assuntos
Retinose Pigmentar , Humanos , Retinose Pigmentar/genética , Retinose Pigmentar/patologia , Retinose Pigmentar/diagnóstico , Masculino , Feminino , Adulto , Adolescente , Criança , Adulto Jovem , Síndromes de Usher/genética , Síndromes de Usher/patologia , Síndromes de Usher/diagnóstico , Brasil/epidemiologia , Pessoa de Meia-Idade , Sequenciamento de Nucleotídeos em Larga Escala , Síndrome de Bardet-Biedl/genética , Mutação
20.
Indian J Ophthalmol ; 72(7): 956-961, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38622849

RESUMO

This study aims to investigate the relationship between pachychoroid spectrum disorders and retinitis pigmentosa (RP) or rod-cone dystrophy through a comprehensive literature review. The purpose is to explore the association between these disorders, understand their underlying mechanisms, and summarize the existing hypotheses and opinions. A thorough review of the literature was conducted using PubMed, focusing on articles related to central serous chorioretinopathy (CSC), RP, pachychoroid pigment epitheliopathy, pachychoroid neovasculopathy, polypoidal choroidal vasculopathy, focal choroidal excavation, peripapillary pachychoroid neovasculopathy, and peripheral exudative hemorrhagic chorioretinopathy. Relevant studies were selected for a detailed narrative review and analysis. Several studies have reported the coexistence of CSC and RP, indicating a potential association between the two conditions. The dysfunction of the retinal pigment epithelium is proposed as a common factor. Choroidal thinning is observed in RP, but conflicting results exist regarding choroidal thickness (CT). While some studies support choroidal thinning in RP, others suggest preserved or increased thickness. Additionally, cases of pachychoroid neovasculopathy and polypoidal choroidal vasculopathy in RP have been reported, suggesting an overlap between these conditions. The literature suggests conflicting reports on CT changes in RP. Future research should focus on large-scale studies using comprehensive imaging techniques, genetic analysis, and long-term follow-up to uncover the underlying mechanisms and determine the prevalence of pachychoroid spectrum disorders in RP patients.


Assuntos
Corioide , Angiofluoresceinografia , Fundo de Olho , Retinose Pigmentar , Tomografia de Coerência Óptica , Humanos , Retinose Pigmentar/diagnóstico , Tomografia de Coerência Óptica/métodos , Angiofluoresceinografia/métodos , Corioide/irrigação sanguínea , Corioide/patologia , Corioide/diagnóstico por imagem , Doenças da Coroide/diagnóstico , Epitélio Pigmentado da Retina/patologia , Coriorretinopatia Serosa Central/diagnóstico , Acuidade Visual
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