Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 257
Filtrar
1.
Genes (Basel) ; 15(6)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38927662

RESUMO

Inherited cone disorders (ICDs) are a heterogeneous sub-group of inherited retinal disorders (IRDs), the leading cause of sight loss in children and working-age adults. ICDs result from the dysfunction of the cone photoreceptors in the macula and manifest as the loss of colour vision and reduced visual acuity. Currently, 37 genes are associated with varying forms of ICD; however, almost half of all patients receive no molecular diagnosis. This review will discuss the known ICD genes, their molecular function, and the diseases they cause, with a focus on the most common forms of ICDs, including achromatopsia, progressive cone dystrophies (CODs), and cone-rod dystrophies (CORDs). It will discuss the gene-specific therapies that have emerged in recent years in order to treat patients with some of the more common ICDs.


Assuntos
Defeitos da Visão Cromática , Distrofias de Cones e Bastonetes , Células Fotorreceptoras Retinianas Cones , Humanos , Defeitos da Visão Cromática/genética , Distrofias de Cones e Bastonetes/genética , Células Fotorreceptoras Retinianas Cones/patologia , Células Fotorreceptoras Retinianas Cones/metabolismo , Distrofia de Cones/genética , Cegueira/genética , Animais , Terapia Genética/métodos
2.
Genes (Basel) ; 15(5)2024 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-38790254

RESUMO

Pathogenic variants in the Crumbs homolog 1 (CRB1) gene lead to severe, childhood-onset retinal degeneration leading to blindness in early adulthood. There are no approved therapies, and traditional adeno-associated viral vector-based gene therapy approaches are challenged by the existence of multiple CRB1 isoforms. Here, we describe three CRB1 variants, including a novel, previously unreported variant that led to retinal degeneration. We offer a CRISPR-Cas-mediated DNA base editing strategy as a potential future therapeutic approach. This study is a retrospective case series. Clinical and genetic assessments were performed, including deep phenotyping by retinal imaging. In silico analyses were used to predict the pathogenicity of the novel variant and to determine whether the variants are amenable to DNA base editing strategies. Case 1 was a 24-year-old male with cone-rod dystrophy and retinal thickening typical of CRB1 retinopathy. He had a relatively preserved central outer retinal structure and a best corrected visual acuity (BCVA) of 60 ETDRS letters in both eyes. Genetic testing revealed compound heterozygous variants in exon 9: c.2843G>A, p.(Cys948Tyr) and a novel variant, c.2833G>A, p.(Gly945Arg), which was predicted to likely be pathogenic by an in silico analysis. Cases 2 and 3 were two brothers, aged 20 and 24, who presented with severe cone-rod dystrophy and a significant disruption of the outer nuclear layers. The BCVA was reduced to hand movements in both eyes in Case 2 and to 42 ETDRS letters in both eyes in Case 3. Case 2 was also affected with marked cystoid macular lesions, which are common in CRB1 retinopathy, but responded well to treatment with oral acetazolamide. Genetic testing revealed two c.2234C>T, p.(Thr745Met) variants in both brothers. As G-to-A and C-to-T variants, all three variants are amenable to adenine base editors (ABEs) targeting the forward strand in the Case 1 variants and the reverse strand in Cases 2 and 3. Available PAM sites were detected for KKH-nSaCas9-ABE8e for the c.2843G>A variant, nSaCas9-ABE8e and KKH-nSaCas9-ABE8e for the c.2833G>A variant, and nSpCas9-ABE8e for the c.2234C>T variant. In this case series, we report three pathogenic CRB1 variants, including a novel c.2833G>A variant associated with early-onset cone-rod dystrophy. We highlight the severity and rapid progression of the disease and offer ABEs as a potential future therapeutic approach for this devastating blinding condition.


Assuntos
Sistemas CRISPR-Cas , Proteínas do Olho , Edição de Genes , Proteínas de Membrana , Proteínas do Tecido Nervoso , Humanos , Masculino , Edição de Genes/métodos , Proteínas de Membrana/genética , Adulto Jovem , Proteínas do Olho/genética , Proteínas do Tecido Nervoso/genética , Adulto , Distrofias de Cones e Bastonetes/genética , Distrofias de Cones e Bastonetes/patologia , Feminino , Simulação por Computador , Terapia Genética/métodos , Estudos Retrospectivos
3.
Nat Commun ; 15(1): 3562, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38670966

RESUMO

The diagnosis of inherited retinal degeneration (IRD) is challenging owing to its phenotypic and genotypic complexity. Clinical information is important before a genetic diagnosis is made. Metabolomics studies the entire picture of bioproducts, which are determined using genetic codes and biological reactions. We demonstrated that the common diagnoses of IRD, including retinitis pigmentosa (RP), cone-rod dystrophy (CRD), Stargardt disease (STGD), and Bietti's crystalline dystrophy (BCD), could be differentiated based on their metabolite heatmaps. Hundreds of metabolites were identified in the volcano plot compared with that of the control group in every IRD except BCD, considered as potential diagnosing markers. The phenotypes of CRD and STGD overlapped but could be differentiated by their metabolomic features with the assistance of a machine learning model with 100% accuracy. Moreover, EYS-, USH2A-associated, and other RP, sharing considerable similar characteristics in clinical findings, could also be diagnosed using the machine learning model with 85.7% accuracy. Further study would be needed to validate the results in an external dataset. By incorporating mass spectrometry and machine learning, a metabolomics-based diagnostic workflow for the clinical and molecular diagnoses of IRD was proposed in our study.


Assuntos
Aprendizado de Máquina , Metabolômica , Degeneração Retiniana , Retinose Pigmentar , Doença de Stargardt , Humanos , Metabolômica/métodos , Diagnóstico Diferencial , Degeneração Retiniana/diagnóstico , Degeneração Retiniana/sangue , Degeneração Retiniana/genética , Degeneração Retiniana/metabolismo , Masculino , Feminino , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Retinose Pigmentar/sangue , Retinose Pigmentar/metabolismo , Doença de Stargardt/genética , Adulto , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Biomarcadores/sangue , Metaboloma , Criança , Distrofias de Cones e Bastonetes/diagnóstico , Distrofias de Cones e Bastonetes/genética , Distrofias de Cones e Bastonetes/sangue , Distrofias de Cones e Bastonetes/metabolismo , Espectrometria de Massas , Degeneração Macular/sangue , Degeneração Macular/diagnóstico , Degeneração Macular/genética
4.
BMC Med Genomics ; 17(1): 100, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38649918

RESUMO

BACKGROUND: This report presents a clinical case of syndromic rod-cone dystrophy due to a splice site variant in the ARL2BP gene causing situs inversus, asthenozoospermia, unilateral renal agenesis and microcysts. The presence of renal agenesis and cryptorchidism expands the clinical manifestations due to ARL2BP variants. The detailed, long-term follow-up contributes valuable insights into disease progression, aiding clinical diagnosis and patient management. CASE PRESENTATION: The male patient complained of photophobia as the first symptom when he was 20 years old followed by nyctalopia, loss of central visual acuity and peripheral visual field ten years later. Genetic analysis identified a likely pathogenic homozygous variant (c.294-1G > C) involving the splicing acceptor site of intron 4. Reported symptoms together with full-field stimulus threshold testing, electroretinogram and advanced multimodal imaging allowed us to recognize the typical characteristics of a mixed retinal dystrophy. Despite the end-stage retinal disease, this patient still retained a useful residual vision at 63 years and had a slow disease progression during the last 5 years of evaluation. DISCUSSION AND CONCLUSIONS: Our findings underscore the variable clinical presentation of ARL2BP variants, emphasizing the importance of a nuanced approach in diagnosing and managing patients. The presence of renal cysts warrants consideration of a differential diagnosis, particularly with Senior-Loken (SLS), Bardet-Biedl (BBS) and Joubert syndromes (JS) but also with Short Rib Thoracic Dysplasia 9, highlighting the need for careful phenotypic evaluation in these cases.


Assuntos
Homozigoto , Nefropatias , Rim , Situs Inversus , Humanos , Masculino , Distrofias de Cones e Bastonetes/genética , Anormalidades Congênitas/genética , Rim/anormalidades , Rim/diagnóstico por imagem , Nefropatias/genética , Nefropatias/congênito , Sítios de Splice de RNA/genética , Situs Inversus/genética , Situs Inversus/complicações , Síndrome , Pessoa de Meia-Idade
5.
Int J Mol Sci ; 25(7)2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38612704

RESUMO

This study investigates the toxic effect of harmful materials, unfiltered by the placenta, on neonatal umbilical cord (UC) vessels, focusing on stress-induced adaptations in transcriptional and translational processes. It aims to analyze changes in pathways related to mRNA condensate formation, transcriptional regulation, and DNA damage response under maternal smoking-induced stress. UC vessels from neonates born to smoking (Sm) and nonsmoking mothers (Ctr) were examined. Immunofluorescence staining and confocal microscopy assessed the localization of key markers, including Transcription Complex Subunit 1 (CNOT1) and the largest subunit of RNA polymerase II enzyme (RPB1). Additionally, markers of DNA damage response, such as Poly(ADP-ribose) polymerase-1, were evaluated. In Sm samples, dissolution of CNOT1 granules in UC vessels was observed, potentially aiding stalled translation and enhancing transcription via RPB1 assembly and translocation. Control vessels showed predominant cytoplasmic RPB1 localization. Despite adaptive responses, Sm endothelial cells exhibited significant damage, indicated by markers like Poly(ADP-ribose) polymerase-1. Ex vivo metal treatment on control vessels mirrored Sm sample alterations, emphasizing marker roles in cell survival under toxic exposure. Maternal smoking induces specific molecular adaptations in UC vessels, affecting mRNA condensate formation, transcriptional regulation, and DNA damage response pathways. Understanding these intricate molecular mechanisms could inform interventions to improve neonatal health outcomes and mitigate adverse effects of toxic exposure during pregnancy.


Assuntos
Distrofias de Cones e Bastonetes , Células Endoteliais , Recém-Nascido , Humanos , Feminino , Gravidez , Regulação da Expressão Gênica , Transcrição Gênica , Poli(ADP-Ribose) Polimerases , RNA Mensageiro/genética , Fatores de Transcrição
7.
J Med Genet ; 61(7): 613-620, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38499336

RESUMO

BACKGROUND: As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases. METHODS: We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines. RESULTS: A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases. CONCLUSION: A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.


Assuntos
Retinose Pigmentar , Feminino , Humanos , Masculino , Distrofias de Cones e Bastonetes/genética , Distrofias de Cones e Bastonetes/patologia , População do Leste Asiático/genética , Predisposição Genética para Doença , Variação Genética , Japão , Amaurose Congênita de Leber/genética , Amaurose Congênita de Leber/patologia , Mutação , Retinose Pigmentar/genética , Retinose Pigmentar/patologia , Síndromes de Usher/genética
8.
JAMA Ophthalmol ; 142(4): 301-308, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38421662

RESUMO

Importance: Reliable biomarkers with diagnostic and prognostic values are needed for upcoming gene therapy trials for spinocerebellar ataxias. Objective: To identify ophthalmological biomarkers in a sample of spinocerebellar ataxia type 7 (SCA7) carriers. Design, Setting, and Participants: This article presents baseline data from a cross-sectional natural history study conducted in Paris, France, reference centers for rare diseases from May 2020 to April 2021. Data were analyzed from September to December 2022. Fifteen adult ATXN7 pathogenic expansion carriers (9 with preataxia and 6 with ataxia) were included, all with a Scale for the Assessment and Rating of Ataxia (SARA) score of 15 of 40 or lower. Patients were recruited at the Paris Brain Institute, and all contacted patients accepted to participate in the study. Main Outcomes and Measures: Three visits (baseline, 6 months, and 12 months) were planned, including neurological examination (SARA and Composite Cerebellar Functional Severity Score), ophthalmological examination (best-corrected visual acuity, microperimetry, full-field electroretinogram, optical coherence tomography, and fundus autofluorescence imaging), and neurofilament light chain (NfL) measurements. Here we report the baseline ophthalmic data from the cohort and determine whether there is a correlation between disease scores and ophthalmic results. Results: Among the 15 included SCA7 carriers (median [range] age, 38 [18-60] years; 8 women and 7 men), 12 displayed cone or cone-rod dystrophy, with the number of CAG repeats correlating with disease severity (ρ, 0.73, 95% CI, 0.34 to 0.90; P < .001). Two patients with cone-rod dystrophy exhibited higher repeat numbers and greater ataxia scores (median [range] SARA score, 9 [7-15]) compared to those with only cone dystrophy (median [range] SARA score, 2 [0-5]). A correlation emerged for outer nuclear layer thickness with SARA score (ρ, -0.88; 95% CI, -0.96 to -0.59; P < .001) and NfL levels (ρ, -0.87; 95% CI, -0.86 to 0.96; P < .001). Moreover, ataxia severity was correlated with visual acuity (ρ: 0.89; 95% CI, 0.68 to 0.96; P < .001) and retinal sensitivity (ρ, -0.88; 95% CI, -0.96 to 0.59; P < .001). Conclusions and Relevance: In this cross-sectional study, retinal abnormalities were found at preataxic stages of the disease. Most of the carriers presented with cone dystrophy and preserved rod function. The outer nuclear layer thickness correlated with SARA score and plasma NfL levels suggesting nuclear layer thickness to be a biomarker of disease severity. These findings contribute to understanding the dynamics of SCA7-related retinal dystrophy and may help lay the groundwork for future therapeutic intervention monitoring and clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04288128.


Assuntos
Distrofia de Cones , Distrofias de Cones e Bastonetes , Ataxias Espinocerebelares , Adulto , Masculino , Humanos , Feminino , Estudos Transversais , Ataxias Espinocerebelares/diagnóstico , Cerebelo , Biomarcadores
9.
Hum Mol Genet ; 33(9): 802-817, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38297980

RESUMO

Mutations in Cytosolic Carboxypeptidase-like Protein 5 (CCP5) are associated with vision loss in humans. To decipher the mechanisms behind CCP5-associated blindness, we generated a novel mouse model lacking CCP5. In this model, we found that increased tubulin glutamylation led to progressive cone-rod dystrophy, with cones showing a more pronounced and earlier functional loss than rod photoreceptors. The observed functional reduction was not due to cell death, levels, or the mislocalization of major phototransduction proteins. Instead, the increased tubulin glutamylation caused shortened photoreceptor axonemes and the formation of numerous abnormal membranous whorls that disrupted the integrity of photoreceptor outer segments (OS). Ultimately, excessive tubulin glutamylation led to the progressive loss of photoreceptors, affecting cones more severely than rods. Our results highlight the importance of maintaining tubulin glutamylation for normal photoreceptor function. Furthermore, we demonstrate that murine cone photoreceptors are more sensitive to disrupted tubulin glutamylation levels than rods, suggesting an essential role for axoneme in the structural integrity of the cone outer segment. This study provides valuable insights into the mechanisms of photoreceptor diseases linked to excessive tubulin glutamylation.


Assuntos
Distrofias de Cones e Bastonetes , Tubulina (Proteína) , Humanos , Camundongos , Animais , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Distrofias de Cones e Bastonetes/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Células Fotorreceptoras Retinianas Cones/metabolismo , Mutação
10.
Genet Med ; 26(6): 101106, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38420906

RESUMO

PURPOSE: Inherited retinal diseases (IRDs) are a group of monogenic conditions that can lead to progressive blindness. Their missing heritability is still considerable, due in part to the presence of disease genes that await molecular identification. The purpose of this work was to identify novel genetic associations with IRDs. METHODS: Patients underwent a comprehensive ophthalmological evaluation using standard-of-care tests, such as detailed retinal imaging (macular optical coherence tomography and short-wavelength fundus autofluorescence) and electrophysiological testing. Exome and genome sequencing, as well as computer-assisted data analysis were used for genotyping and detection of DNA variants. A minigene-driven splicing assay was performed to validate the deleterious effects of 1 of such variants. RESULTS: We identified 8 unrelated families from Hungary, the United States, Israel, and The Netherlands with members presenting with a form of autosomal recessive and nonsyndromic retinal degeneration, predominantly described as rod-cone dystrophy but also including cases of cone/cone-rod dystrophy. Age of disease onset was very variable, with some patients experiencing first symptoms during their fourth decade of life or later. Myopia greater than 5 diopters was present in 5 of 7 cases with available refractive data, and retinal detachment was reported in 2 cases. All ascertained patients carried biallelic loss-of-function variants in UBAP1L (HGNC: 40028), a gene with unknown function and with homologies to UBAP1, encoding a protein involved in ubiquitin metabolism. One of these pathogenic variants, the intronic NM_001163692.2:c.910-7G>A substitution, was identified in 5 unrelated families. Minigene-driven splicing assays in HEK293T cells confirmed that this DNA change is responsible for the creation of a new acceptor splice site, resulting in aberrant splicing. CONCLUSION: We identified UBAP1L as a novel IRD gene. Although its function is currently unknown, UBAP1L is almost exclusively expressed in photoreceptors and the retinal pigment epithelium, hence possibly explaining the link between pathogenic variants in this gene and an ocular phenotype.


Assuntos
Linhagem , Degeneração Retiniana , Humanos , Masculino , Feminino , Adulto , Degeneração Retiniana/genética , Pessoa de Meia-Idade , Mutação com Perda de Função , Genes Recessivos , Criança , Adolescente , Distrofias de Cones e Bastonetes/genética , Hungria , Adulto Jovem , Predisposição Genética para Doença
11.
Medicina (Kaunas) ; 60(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38399542

RESUMO

Background and Objectives. Retinitis pigmentosa (RP) is the most common inherited rod-cone dystrophy (RCD), resulting in nyctalopia, progressive visual field, and visual acuity decay in the late stages. The autosomal dominant form (ADRP) accounts for about 20% of RPs. Among the over 30 genes found to date related to ADRP, RP1 pathogenic variants have been identified in 5-10% of cases. In a cohort of RCD patients from the Palermo province on the island of Sicily, we identified a prevalent nonsense variant in RP1, which was associated with ADRP. The objective of our study was to analyse the clinical and molecular data of this patient cohort and to evaluate the potential presence of a founder effect. Materials and Methods. From 2005 to January 2023, 84 probands originating from Western Sicily (Italy) with a diagnosis of RCD or RP and their relatives underwent deep phenotyping, which was performed in various Italian clinical institutions. Molecular characterisation of patients and familial segregation of pathogenic variants were carried out in different laboratories using Sanger and/or next-generation sequencing (NGS). Results. Among 84 probands with RCD/RP, we found 28 heterozygotes for the RP1 variant c.2219C>G, p.Ser740* ((NM_006269.2)*, which was therefore significantly prevalent in this patient cohort. After a careful interview process, we ascertained that some of these patients shared the same pedigree. Therefore, we were ultimately able to define 20 independent family groups with no traceable consanguinity. Lastly, analysis of clinical data showed, in our patients, that the p.Ser740* nonsense variant was often associated with a late-onset and relatively mild phenotype. Conclusions. The high prevalence of the p.Ser740* variant in ADRP patients from Western Sicily suggests the presence of a founder effect, which has useful implications for the molecular diagnosis of RCD in patients coming from this Italian region. This variant can be primarily searched for in RP-affected subjects displaying compatible modes of transmission and phenotypes, with an advantage in terms of the required costs and time for analysis. Moreover, given its high prevalence, the RP1 p.Ser740* variant could represent a potential candidate for the development of therapeutic strategies based on gene editing or translational read-through therapy for suppression of nonsense variants.


Assuntos
Distrofias de Cones e Bastonetes , Retinose Pigmentar , Humanos , Distrofias de Cones e Bastonetes/genética , Sicília/epidemiologia , Efeito Fundador , Proteínas do Olho , Retinose Pigmentar/genética , Retinose Pigmentar/diagnóstico , Fenótipo , Linhagem , Mutação , Análise Mutacional de DNA , Proteínas Associadas aos Microtúbulos/genética
12.
JAMA Netw Open ; 7(1): e2352387, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38241046

RESUMO

Importance: COVID-19 vaccine-derived antibodies in pregnant people may protect infants from severe infection in the first 6 months of life via transplacental antibody transfer. Few data exist on maternally derived SARS-CoV-2 antibodies in preterm compared with full-term infants in association with vaccination timing. Objective: To compare SARS-CoV-2 anti-Spike (anti-S) antibody levels in preterm and full-term infants in the context of vaccine dose timing before delivery. Design, Setting, and Participants: This prospective cohort study enrolled pregnant individuals and collected paired maternal and cord blood samples at delivery at the University of Washington between February 1, 2021, and January 31, 2023. Participants who had received at least 2 doses of a messenger RNA COVID-19 vaccine before delivery and did not have a history of prior COVID-19 infection or detectable anti-SARS-CoV-2 nucleocapsid antibodies were included. Exposures: Timing of the last vaccine dose and preterm or full-term gestational age at delivery. Main Outcomes and Measures: Paired maternal and cord samples were tested for anti-S antibody, and linear regression was used to evaluate associations between preterm delivery and anti-S antibody levels. Covariates included timing of last dose, number of doses, insurance status, and immunosuppressing medications. Results: A total of 220 participants (median [IQR] age, 34 [32-37] years; 212 [96.4%] female) with 36 preterm and 184 full-term deliveries were studied. Before delivery, 121 persons received 2 vaccine doses and 99 persons received 3 or more vaccine doses. The geometric mean concentration of maternal anti-S antibodies was 674 (95% CI, 577-787) after 2 doses and 8159 (95% CI, 6636-10 032) after 3 or more doses (P < .001). The cord anti-S antibody geometric mean concentration was 1000 (95% CI, 874-1144) after 2 doses and 9992 (95% CI, 8381-11 914) after 3 or more doses (P < .001). After adjustment for vaccine timing and number of doses before delivery, no association was found between preterm delivery and cord anti-S antibody levels (ß = 0.44; 95% CI, -0.06 to 0.94). Conclusions and Relevance: In this prospective cohort study of pregnant individuals with preterm and full-term deliveries, receipt of 3 or more compared with 2 doses of COVID-19 vaccine before delivery resulted in 10-fold higher cord anti-S antibody levels. Maternal antibody concentration appeared more important than delivery gestational age in determining cord anti-S antibody levels. The number of doses and timing considerations for COVID-19 vaccine in pregnancy should include individuals at risk for preterm delivery.


Assuntos
COVID-19 , Distrofias de Cones e Bastonetes , Nascimento Prematuro , Lactente , Gravidez , Recém-Nascido , Feminino , Humanos , Adulto , Masculino , Vacinas contra COVID-19 , Estudos Prospectivos , COVID-19/prevenção & controle , SARS-CoV-2 , Anticorpos Antivirais
13.
Prog Retin Eye Res ; 100: 101244, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38278208

RESUMO

Inherited retinal diseases (IRD) are a leading cause of blindness in the working age population and in children. The scope of this review is to familiarise clinicians and scientists with the current landscape of molecular genetics, clinical phenotype, retinal imaging and therapeutic prospects/completed trials in IRD. Herein we present in a comprehensive and concise manner: (i) macular dystrophies (Stargardt disease (ABCA4), X-linked retinoschisis (RS1), Best disease (BEST1), PRPH2-associated pattern dystrophy, Sorsby fundus dystrophy (TIMP3), and autosomal dominant drusen (EFEMP1)), (ii) cone and cone-rod dystrophies (GUCA1A, PRPH2, ABCA4, KCNV2 and RPGR), (iii) predominant rod or rod-cone dystrophies (retinitis pigmentosa, enhanced S-Cone syndrome (NR2E3), Bietti crystalline corneoretinal dystrophy (CYP4V2)), (iv) Leber congenital amaurosis/early-onset severe retinal dystrophy (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1), (v) cone dysfunction syndromes (achromatopsia (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2, ATF6), X-linked cone dysfunction with myopia and dichromacy (Bornholm Eye disease; OPN1LW/OPN1MW array), oligocone trichromacy, and blue-cone monochromatism (OPN1LW/OPN1MW array)). Whilst we use the aforementioned classical phenotypic groupings, a key feature of IRD is that it is characterised by tremendous heterogeneity and variable expressivity, with several of the above genes associated with a range of phenotypes.


Assuntos
Oftalmopatias Hereditárias , Doenças Retinianas , Humanos , Distrofias de Cones e Bastonetes/genética , Distrofias de Cones e Bastonetes/fisiopatologia , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/fisiopatologia , Genótipo , Amaurose Congênita de Leber/genética , Amaurose Congênita de Leber/terapia , Amaurose Congênita de Leber/fisiopatologia , Biologia Molecular , Fenótipo , Doenças Retinianas/genética , Doenças Retinianas/fisiopatologia , Doenças Retinianas/terapia
14.
Genet Med ; 26(6): 101081, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38293907

RESUMO

PURPOSE: Progressive inherited retinal degenerations (IRDs) affecting rods and cones are clinically and genetically heterogeneous and can lead to blindness with limited therapeutic options. The major gene defects have been identified in subjects of European and Asian descent with only few reports of North African descent. METHODS: Genome, targeted next-generation, and Sanger sequencing was applied to cohort of ∼4000 IRDs cases. Expression analyses were performed including Chip-seq database analyses, on human-derived retinal organoids (ROs), retinal pigment epithelium cells, and zebrafish. Variants' pathogenicity was accessed using 3D-modeling and/or ROs. RESULTS: Here, we identified a novel gene defect with three distinct pathogenic variants in UBAP1L in 4 independent autosomal recessive IRD cases from Tunisia. UBAP1L is expressed in the retinal pigment epithelium and retina, specifically in rods and cones, in line with the phenotype. It encodes Ubiquitin-associated protein 1-like, containing a solenoid of overlapping ubiquitin-associated domain, predicted to interact with ubiquitin. In silico and in vitro studies, including 3D-modeling and ROs revealed that the solenoid of overlapping ubiquitin-associated domain is truncated and thus ubiquitin binding most likely abolished secondary to all variants identified herein. CONCLUSION: Biallelic UBAP1L variants are a novel cause of IRDs, most likely enriched in the North African population.


Assuntos
Distrofias de Cones e Bastonetes , Linhagem , Peixe-Zebra , Humanos , Distrofias de Cones e Bastonetes/genética , Distrofias de Cones e Bastonetes/patologia , Masculino , Feminino , Peixe-Zebra/genética , Animais , Genes Recessivos , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Mutação/genética , Células Fotorreceptoras Retinianas Cones/patologia , Células Fotorreceptoras Retinianas Cones/metabolismo , Retina/patologia , Retina/metabolismo , Adulto , Tunísia , Retinose Pigmentar/genética , Retinose Pigmentar/patologia , Fenótipo , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/patologia
15.
PLoS One ; 19(1): e0296167, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38285672

RESUMO

PURPOSE: To compared the vessel density (VD) around the optic nerve head (ONH) in eyes with cone-rod dystrophy (CORD) and healthy control eyes in a sector-wise manner and to investigate the relationship between VD around the ONH and visual function in CORD eyes. METHODS: Twenty-six eyes in 14 CORD patients and 25 eyes in 25 healthy control subjects were examined. Using OCT angiography images, the VDs in the superficial and deep capillary plexus at the macula (sVDm and dVDm) and those around the ONH in the superior, temporal, inferior and nasal region (VDnh_s, VDnh_t, VDnh_i, and VDnh_n, respectively) were measured for each eye. Patient age, visual acuity (VA) and VDs were then compared between two groups. Moreover, the relationships between VA and the VDs were analyzed using a linear mixed model and AICc model selection. RESULTS: No significant difference in age was seen between the CORD and control groups (p = 0.87, Wilcoxon rank sum test), but the VA was significantly lower in the CORD group (p<0.0001). Both sVDm and dVDm were significantly lower in the CORD eyes than in the control eyes (both p<0.0001). Among VDnh_s, VDnh_t, VDnh_i, and VDnh_n, however, only VDnh_t differed significantly between the CORD and control groups (p = 0.035). Among age, VDnh_t, dVDm, and sVDm, the optimal model for VA included only VDnh_t and dVDm. CONCLUSIONS: In addition to the VD in the deep capillary plexus at the macula, the measurement of temporal VD around the ONH might be useful for predicting visual function in eyes with CORD.


Assuntos
Distrofias de Cones e Bastonetes , Disco Óptico , Humanos , Angiofluoresceinografia/métodos , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Disco Óptico/diagnóstico por imagem , Disco Óptico/irrigação sanguínea
16.
Am J Ophthalmol ; 258: 43-54, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37437832

RESUMO

PURPOSE: To validate a novel mobility test (MOST, MObility Standardized Test) and performance outcomes in real (RL) and virtual (VR) environments to be used for interventional clinical studies in order to characterize vision impairment in rod-cone dystrophies, also known as retinitis pigmentosa (RP). DESIGN: Prospective, interventional, noninvasive, reliability and validity analysis. METHODS: We designed MOST to be used in both VR and RL and conducted 3 experimental studies with 89 participants to (1) validate the difficulty of the mobility courses (15 controls), (2) determine the optimal number of light levels and training trials (14 participants with RP), and (3) validate the reproducibility (test-retest), reliability (VR/RL), sensitivity, and construct/content validity of the test (30 participants with RP and 30 controls). A comprehensive ophthalmologic examination was performed in all subjects. Outcomes of interest included MOST performance score, visual acuity, contrast sensitivity, dark adaptation thresholds, visual field parameters, and correlation between the performance score and visual function. RESULTS: The mobility courses exhibited statistically similar difficulty, and 5 trials are sufficient to control for the learning effect. MOST is highly reproducible (test-retest correlations >0.98) and reliable (correlations VR/RL = 0.98). MOST achieved a discrimination between participants with RP and controls (accuracy >95%) and between early and late stages of the disease (82.3% accuracy). The performance score is correlated with visual function parameter (0.57-0.94). CONCLUSION: MOST is a validated mobility test, with the controlled learning effect, excellent reproducibility, and high agreement between RL and VR conditions, as well as sensitivity and specificity to measure disease progression and therapeutic benefit in rod-cone dystrophies.


Assuntos
Distrofias de Cones e Bastonetes , Retinose Pigmentar , Realidade Virtual , Humanos , Reprodutibilidade dos Testes , Estudos Prospectivos , Retinose Pigmentar/diagnóstico
17.
Ophthalmic Res ; 67(1): 9-22, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38091967

RESUMO

INTRODUCTION: The objective of this study was to investigate the clinical characteristics and genetic spectrum of adult-onset cone/cone-rod dystrophy (AOCD/AOCRD) in Korean individuals. METHODS: This is a single-center, retrospective cross-sectional study. We analyzed 22 individuals with genetically confirmed cone dystrophy, with symptoms beginning after 30 years of age. All patients underwent comprehensive ophthalmic and electrophysiological examinations. Exome sequencing of 296 genes associated with inherited retinal disease was performed. The clinical features of patients with AOCD/AOCRD and the causative genes and variants detected by exome sequencing were analyzed. RESULTS: The median age at the first visit was 52 years (range, 31-76 years), and the most common initial symptom was reduced visual acuity. In most cases, fundus photography showed a bull's eye pattern with foveal sparing, consistent with perifoveal photoreceptor loss on optical coherence tomography. We identified disease-causing variants in six genes: RP1, CRX, CDHR1, PROM1, CRB1, and GUCY2D. Pathogenic variants in RP1, CRX, and CDHR1 were identified in 77% of the AOCD/AOCRD cases, including p.Cys1399LeufsTer5, p.Arg1933Ter, and p.Ile2061SerfsTer12 in RP1; p.Ter300GlnextTer118 in CRX; and p.Glu201Lys in CDHR1. No characteristic imaging differences were observed for any of the causative genes. Most of the RP1-related AOCD/AOCRD cases showed a decreased amplitude only in the photopic electroretinogram (ERG), whereas CRX-related AOCD/AOCRD cases showed a slightly decreased amplitude in both the scotopic and photopic ERGs. CONCLUSION: In case of visual impairment with bull's eye pattern of RPE atrophy recognized after the middle age, a comprehensive ophthalmic examination and genetic test should be considered, with the possibility of AOCD/AOCRD in East Asians.


Assuntos
Distrofias de Cones e Bastonetes , Adulto , Pessoa de Meia-Idade , Humanos , Idoso , Distrofias de Cones e Bastonetes/diagnóstico , Distrofias de Cones e Bastonetes/genética , Distrofias de Cones e Bastonetes/patologia , Estudos Retrospectivos , Estudos Transversais , Linhagem , Mutação , Eletrorretinografia , Tomografia de Coerência Óptica , Fenótipo , Proteínas do Olho/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Proteínas Relacionadas a Caderinas
18.
Ophthalmic Genet ; 45(2): 201-206, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37728066

RESUMO

PURPOSE: Retinitis pigmentosa (RP) associated with biallelic variants in CDHR1 has rarely been reported, and detailed phenotyping data are not available. RP implies relative preservation of foveal cones, when compared to cone-rod dystrophy associated with biallelic null variants in CDHR1. We hypothesize that RP may occur in association with one or more hypomorphic CDHR1 alleles. MATERIALS AND METHODS: Retrospective report of a 48-year-old patient with CDHR1-associated RP with a hypomorphic missense variant c.562 G>A, p. (Gly188Ser) and a novel, unreported variant affecting a canonical splice acceptor site (c.784-1 G>C). Clinical examination, multimodal retinal imaging, electroretinography, visual field testing, and mesopic microperimetry were undertaken 8 years apart. Scotopic microperimetry was also performed. The DNA sequence context of the variants was examined to identify theoretical CRISPR-Cas9 base-editing strategies. RESULTS: The patient presented at 35 years with a 12-year history of nyctalopia. His best corrected visual acuity was 20/20. Clinical presentation, multimodal retinal imaging studies, electroretinography, and mesopic microperimetry were typical of a progressive rod-cone dystrophy (i.e. classic RP). There were no scotomas within the central field as would be expected at this age in CDHR1-associated cone-rod dystrophy. Scotopic microperimetry suggested some preservation of macular cone over rod function, although both were severely impaired. A suitable CRISPR adenine base editor was identified that could theoretically correct the missense variant c.562 G>A, p. (Gly188Ser). CONCLUSIONS: CDHR1-associated RP shows a relative preservation of cone function in the presence of a presumed hypomorphic allele and may be considered a hypomorphic disease phenotype. Further work is required to identify modifying factors that determine disease phenotype since macular dystrophy, with relative sparing of rods, may also occur with hypomorphic CDHR1 alleles.


Assuntos
Distrofias de Cones e Bastonetes , Retinose Pigmentar , Humanos , Proteínas Relacionadas a Caderinas , Distrofias de Cones e Bastonetes/genética , Eletrorretinografia , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Retina , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Estudos Retrospectivos , Adulto
20.
Spec Care Dentist ; 44(4): 1026-1035, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38151709

RESUMO

Jalili syndrome (JS) (MIM#217080) is a rare autosomal recessive disorder with oculo-dental malformations. The clinical phenotype is characterized by the presence of Cone-Rod Dystrophy (CRD) and Amelogenesis Imperfecta (AI). Genetic mechanism entails a mutation in the CNNM4, a metal transporter gene located on Chromosome 2q11.2. A high fluoride concentration in groundwater has also been identified as an epigenetic factor in this syndrome. JS draws the attention of dentists due to its distinct oral manifestations. To the best of our knowledge, this is the first genetically confirmed pediatric case report from the Indian subcontinent emphasizing the clinical and radiographic features of this condition and its management in a 6-year-old child.


Assuntos
Amelogênese Imperfeita , Humanos , Criança , Amelogênese Imperfeita/genética , Masculino , Distrofias de Cones e Bastonetes/genética , Retinose Pigmentar , Radiografia Panorâmica , Fenótipo , Proteínas de Transporte de Cátions
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...