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1.
Genes (Basel) ; 15(6)2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38927702

RESUMO

Inherited retinal diseases (IRDs) represent a frequent cause of blindness in children and adults. As a consequence of the phenotype and genotype heterogeneity of the disease, it is difficult to have a specific diagnosis without molecular testing. To date, over 340 genes and loci have been associated with IRDs. We present the molecular finding of 191 individuals with IRD, analyzed by targeted next-generation sequencing (NGS). For 67 of them, we performed a family segregation study, considering a total of 126 relatives. A total of 359 variants were identified, 44 of which were novel. Genetic diagnostic yield was 41%. However, after stratifying the patients according to their clinical suspicion, diagnostic yield was higher for well-characterized diseases such as Stargardt disease (STGD), at 65%, and for congenital stationary night blindness 2 (CSNB2), at 64%. Diagnostic yield was higher in the patient group where family segregation analysis was possible (68%) and it was higher in younger (55%) than in older patients (33%). The results of this analysis demonstrated that targeted NGS is an effective method for establishing a molecular genetic diagnosis of IRDs. Furthermore, this study underlines the importance of segregation studies to understand the role of genetic variants with unknow pathogenic role.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Distrofias Retinianas , Doença de Stargardt , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Masculino , Feminino , Distrofias Retinianas/genética , Distrofias Retinianas/diagnóstico , Adulto , Doença de Stargardt/genética , Linhagem , Criança , Pessoa de Meia-Idade , Cegueira Noturna/genética , Oftalmopatias Hereditárias/genética , Adolescente , Mutação , Degeneração Macular/genética , Miopia/genética , Pré-Escolar , Fenótipo , Adulto Jovem , Idoso , Doenças Genéticas Ligadas ao Cromossomo X
2.
Stem Cell Res ; 78: 103458, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38870564

RESUMO

The Stargardt's Disease, Type 1 (STGD1) is associated with the loss of function mutations in ABCA4. This gene codes for a retina-specific, ATP-binding cassette (ABC) family transporter, involved in the transport of the key visual cycle intermediate, all-trans-retinaldehyde (atRAL), across the photoreceptor cell membranes. Here, we report the establishment of a patient-specific, iPSC line (LVPEIi008-A), that carries a homozygous nonsense mutation at (c.6088C > T) position, within exon 44 of ABCA4. The patient-specific skin fibroblasts were reprogrammed using episomal plasmids and the stably expanding iPSC line expressed the key stemness and pluripotency markers, maintained its chromosomal integrity and tested negative for mycoplasma.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Códon sem Sentido , Éxons , Células-Tronco Pluripotentes Induzidas , Doença de Stargardt , Células-Tronco Pluripotentes Induzidas/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Doença de Stargardt/patologia , Humanos , Homozigoto , Linhagem Celular , Degeneração Macular/genética , Degeneração Macular/patologia , Degeneração Macular/metabolismo
3.
FASEB J ; 38(11): e23720, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38837708

RESUMO

Recessive Stargardt disease (STGD1) is an inherited juvenile maculopathy caused by mutations in the ABCA4 gene, for which there is no suitable treatment. Loss of functional ABCA4 in the retinal pigment epithelium (RPE) alone, without contribution from photoreceptor cells, was shown to induce STGD1 pathology. Here, we identified cathepsin D (CatD), the primary RPE lysosomal protease, as a key molecular player contributing to endo-lysosomal dysfunction in STGD1 using a newly developed "disease-in-a-dish" RPE model from confirmed STGD1 patients. Induced pluripotent stem cell (iPSC)-derived RPE originating from three STGD1 patients exhibited elevated lysosomal pH, as previously reported in Abca4-/- mice. CatD protein maturation and activity were impaired in RPE from STGD1 patients and Abca4-/- mice. Consequently, STGD1 RPE cells have reduced photoreceptor outer segment degradation and abnormal accumulation of α-synuclein, the natural substrate of CatD. Furthermore, dysfunctional ABCA4 in STGD1 RPE cells results in intracellular accumulation of autofluorescent material and phosphatidylethanolamine (PE). The altered distribution of PE associated with the internal membranes of STGD1 RPE cells presumably compromises LC3-associated phagocytosis, contributing to delayed endo-lysosomal degradation activity. Drug-mediated re-acidification of lysosomes in the RPE of STGD1 restores CatD functional activity and reduces the accumulation of immature CatD protein loads. This preclinical study validates the contribution of CatD deficiencies to STGD1 pathology and provides evidence for an efficacious therapeutic approach targeting RPE cells. Our findings support a cell-autonomous RPE-driven pathology, informing future research aimed at targeting RPE cells to treat ABCA4-mediated retinopathies.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Catepsina D , Lisossomos , Epitélio Pigmentado da Retina , Doença de Stargardt , Catepsina D/metabolismo , Catepsina D/genética , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Doença de Stargardt/metabolismo , Doença de Stargardt/patologia , Doença de Stargardt/genética , Animais , Humanos , Camundongos , Lisossomos/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos Knockout , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Degeneração Macular/genética
4.
Nucleic Acid Ther ; 34(3): 125-133, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38800942

RESUMO

The ABCA4 gene, involved in Stargardt disease, has a high percentage of splice-altering pathogenic variants, some of which cause complex RNA defects. Although antisense oligonucleotides (AONs) have shown promising results in splicing modulation, they have not yet been used to target complex splicing defects. Here, we performed AON-based rescue studies on ABCA4 complex splicing defects. Intron 13 variants c.1938-724A>G, c.1938-621G>A, c.1938-619A>G, and c.1938-514A>G all lead to the inclusion of different pseudo-exons (PEs) with and without an upstream PE (PE1). Intron 44 variant c.6148-84A>T results in multiple PE inclusions and/or exon skipping events. Five novel AONs were designed to target these defects. AON efficacy was assessed by in vitro splice assays using midigenes containing the variants of interest. All screened complex splicing defects were effectively rescued by the AONs. Although varying levels of efficacy were observed between AONs targeting the same PEs, for all variants at least one AON restored splicing to levels comparable or better than wildtype. In conclusion, AONs are a promising approach to target complex splicing defects in ABCA4.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Éxons , Íntrons , Oligonucleotídeos Antissenso , Splicing de RNA , Doença de Stargardt , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos Antissenso/farmacologia , Transportadores de Cassetes de Ligação de ATP/genética , Humanos , Íntrons/genética , Splicing de RNA/genética , Éxons/genética , Doença de Stargardt/genética , Doença de Stargardt/patologia , Mutação
5.
Cells ; 13(7)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38607040

RESUMO

Precision medicine is rapidly gaining recognition in the field of (ultra)rare conditions, where only a few individuals in the world are affected. Clinical trial design for a small number of patients is extremely challenging, and for this reason, the development of N-of-1 strategies is explored to accelerate customized therapy design for rare cases. A strong candidate for this approach is Stargardt disease (STGD1), an autosomal recessive macular degeneration characterized by high genetic and phenotypic heterogeneity. STGD1 is caused by pathogenic variants in ABCA4, and amongst them, several deep-intronic variants alter the pre-mRNA splicing process, generally resulting in the insertion of pseudoexons (PEs) into the final transcript. In this study, we describe a 10-year-old girl harboring the unique deep-intronic ABCA4 variant c.6817-713A>G. Clinically, she presents with typical early-onset STGD1 with a high disease symmetry between her two eyes. Molecularly, we designed antisense oligonucleotides (AONs) to block the produced PE insertion. Splicing rescue was assessed in three different in vitro models: HEK293T cells, fibroblasts, and photoreceptor precursor cells, the last two being derived from the patient. Overall, our research is intended to serve as the basis for a personalized N-of-1 AON-based treatment to stop early vision loss in this patient.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Oligonucleotídeos Antissenso , Humanos , Feminino , Criança , Doença de Stargardt/genética , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Células HEK293 , Íntrons , Transportadores de Cassetes de Ligação de ATP/genética
6.
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
7.
Nucleic Acid Ther ; 34(2): 73-82, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38466963

RESUMO

Pathogenic variants in ABCA4 are the underlying molecular cause of Stargardt disease (STGD1), an autosomal recessive macular dystrophy characterized by a progressive loss of central vision. Among intronic ABCA4 variants, c.4253+43G>A is frequently detected in STGD1 cases and is classified as a hypomorphic allele, generally associated with late-onset cases. This variant was previously reported to alter splicing regulatory sequences, but the splicing outcome is not fully understood yet. In this study, we attempted to better understand its effect on splicing and to rescue the aberrant splicing via antisense oligonucleotides (AONs). Wild-type and c.4253+43G>A variant-harboring maxigene vectors revealed additional skipping events, which were not previously detected upon transfection in HEK293T cells. To restore exon inclusion, we designed a set of 27 AONs targeting either splicing silencer motifs or the variant region and screened these in maxigene-transfected HEK293T cells. Candidate AONs able to promote exon inclusion were selected for further testing in patient-derived photoreceptor precursor cells. Surprisingly, no robust splicing modulation was observed in this model system. Overall, this research helped to adequately characterize the splicing alteration caused by the c.4253+43G>A variant, although future development of AON-mediated exon inclusion therapy for ABCA4 is needed.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Degeneração Macular , Humanos , Doença de Stargardt/genética , Células HEK293 , Íntrons/genética , Transportadores de Cassetes de Ligação de ATP/genética , Degeneração Macular/genética , Degeneração Macular/terapia , Mutação
8.
Pharm Res ; 41(4): 807-817, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38443629

RESUMO

OBJECTIVE: Current gene therapy of inherited retinal diseases is achieved mainly by subretinal injection, which is invasive with severe adverse effects. Intravitreal injection is a minimally invasive alternative for gene therapy of inherited retinal diseases. This work explores the efficacy of intravitreal delivery of PEGylated ECO (a multifunctional pH-sensitive amphiphilic amino lipid) plasmid DNA (pGRK1-ABCA4-S/MAR) nanoparticles (PEG-ELNP) for gene therapy of Stargardt disease. METHODS: Pigmented Abca4-/- knockout mice received 1 µL of PEG-ELNP solution (200 ng/uL, pDNA concentration) by intravitreal injections at an interval of 1.5 months. The expression of ABCA4 in the retina was determined by RT-PCR and immunohistochemistry at 6 months after the second injection. A2E levels in the treated eyes and untreated controls were determined by HPLC. The safety of treatment was monitored by scanning laser ophthalmoscopy and electroretinogram (ERG). RESULTS: PEG-ELNP resulted in significant ABCA4 expression at both mRNA level and protein level at]6 months after 2 intravitreal injections, and a 40% A2E accumulation reduction compared with non-treated controls. The PEG-ELNP also demonstrated excellent safety as shown by scanning laser ophthalmoscopy, and the eye function evaluation from electroretinogram. CONCLUSIONS: Intravitreal delivery of the PEG-ELNP of pGRK1-ABCA4-S/MAR is a promising approach for gene therapy of Stargardt Disease, which can also be a delivery platform for gene therapy of other inherited retinal diseases.


Assuntos
Nanopartículas , Retina , Camundongos , Animais , Doença de Stargardt/genética , Doença de Stargardt/metabolismo , Doença de Stargardt/terapia , Retina/metabolismo , Terapia Genética/métodos , Plasmídeos/genética , DNA/metabolismo , Camundongos Knockout , Polietilenoglicóis/metabolismo , Injeções Intravítreas , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo
9.
Ophthalmic Genet ; 45(2): 133-139, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38369462

RESUMO

PURPOSE: This study aims to evaluate the ABCA4 variants in patients diagnosed with Stargardt disease. METHODS: This is a retrospective study designed to investigate variants in the ABCA4 in Stargardt disease and the clinical findings of the cases. Sex, age, age of onset of symptoms, best-corrected visual acuity, color fundus photography, optical coherence tomography, and visual field test of the patients were recorded. Genetic analyses were screened, and patients with at least two variants in the ABCA4 were included in this study. RESULTS: Twenty-seven patients diagnosed with Stargardt disease with the ABCA4 variants were included in this study. Twelve of them (44.4%) were female and fifteen (55.5%) were male. The mean age of the cases was 27.44 years (ranging from 8 to 56 years). Thirty different variants were detected in 54 ABCA4 alleles of 27 patients. The two most common pathogenic variants were c.5882 G>A p.(Gly1961Glu) and c.52C>T p.(Arg18Trp) in this cohort. Two novel variants were identified (c.3855_3856dup, c.1554 + 3_1554 + 4del) and the patient with the c.1554 + 3_1554 + 4del variant additionally had a different ABCA4 variant in trans. The other novel variant was homozygous. CONCLUSIONS: In this study, two novel variants were described in a Turkish cohort with Stargardt disease. The variant c.52C>T p.(Arg18Trp) was the most common disease-causing variant besides the c.5882 G>A p.(Gly1961Glu) which was identified frequently in the previous studies. A larger sample size is necessary for describing different pathogenic variants and understanding the phenotype-genotype correlations.


Identifying variants and their pathogenicity in inherited diseases is important for widening the disease-causing mutations and future treatment options.Two novel variants (c.3855_3856dup, c.5910_5912dup) were described in a cohort with Stargardt disease.The most common variants could be different in ethnic groups.The variant c.52C>T p.(Arg18Trp) was the most common variant besides the c.5882G>A p.(Gly1961Glu) which was frequently identified in the previous studies.Describing different pathogenic variants and clinical findings of the patients is important for understanding the phenotype-genotype correlations.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Doença de Stargardt , Adulto , Feminino , Humanos , Masculino , Transportadores de Cassetes de Ligação de ATP/genética , Mutação , Estudos Retrospectivos , Criança , Adolescente , Adulto Jovem , Pessoa de Meia-Idade
10.
Clin Exp Optom ; 107(3): 255-266, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38252959

RESUMO

Recent advances have led to therapeutic options becoming available for people with inherited retinal disease. In particular, gene therapy has been shown to hold great promise for slowing vision loss from inherited retinal disease. Recent studies suggest that gene therapy is likely to be most effective when implemented early in the disease process, making consideration of paediatric populations important. It is therefore necessary to have a comprehensive understanding of retinal imaging in children with inherited retinal diseases, in order to monitor disease progression and to determine which early retinal biomarkers may be used as outcome measures in future clinical trials. In addition, as many optometrists will review children with an inherited retinal disease, an understanding of the expected imaging outcomes can improve clinical care. This review focuses on the most common imaging modality used in research assessment of paediatric inherited retinal diseases: optical coherence tomography. Optical coherence tomography findings can be used in both the clinical and research setting. In particular, the review discusses current knowledge of optical coherence tomography findings in eight paediatric inherited retinal diseases - Stargardt disease, Bests disease, Leber's congenital amaurosis, choroideremia, RPGR related retinitis pigmentosa, Usher syndrome, X-linked retinoschisis and, Batten disease.


Assuntos
Doenças Retinianas , Tomografia de Coerência Óptica , Humanos , Criança , Doenças Retinianas/diagnóstico por imagem , Doenças Retinianas/genética , Retina/diagnóstico por imagem , Doença de Stargardt , Proteínas do Olho
11.
Sci Rep ; 14(1): 684, 2024 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-38182646

RESUMO

Stargardt disease type 1 (STGD1), the most common form of hereditary macular dystrophy, can be caused by biallelic combinations of over 2200 variants in the ABCA4 gene. This leads to reduced or absent ABCA4 protein activity, resulting in toxic metabolite accumulation in the retina and damage of the retinal pigment epithelium and photoreceptors. Approximately 21% of all ABCA4 variants that contribute to disease influence ABCA4 pre-mRNA splicing. This emphasizes the need for therapies to restore disrupted ABCA4 splicing and halt STGD1 progression. Previously, QR-1011, an antisense oligonucleotide (AON), successfully corrected splicing abnormalities and restored normal ABCA4 protein translation in human retinal organoids carrying the prevalent disease-causing variant c.5461-10T>C in ABCA4. Here, we investigated whether QR-1011 could also correct splicing in four less common non-canonical splice site (NCSS) variants flanking ABCA4 exon 39: c.5461-8T>G, c.5461-6T>C, c.5584+5G>A and c.5584+6T>C. We administered QR-1011 and three other AONs to midigene-transfected cells and demonstrate that QR-1011 had the most pronounced effect on splicing compared to the others. Moreover, QR-1011 significantly increased full-length ABCA4 transcript levels for c.5461-8T>G and c.5584+6T>C. Splicing restoration could not be achieved in the other two variants, suggesting their more severe effect on splicing. Overall, QR-1011, initially developed for a single ABCA4 variant, exhibited potent splice correction capabilities for two additional severe NCSS variants nearby. This suggests the possibility of a broader therapeutic impact of QR-1011 extending beyond its original target and highlights the potential for treating a larger population of STGD1 patients affected by multiple severe ABCA4 variants with a single AON.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Oligodesoxirribonucleotídeos Antissenso , Organoides , Doença de Stargardt , Humanos , Transportadores de Cassetes de Ligação de ATP/genética , Éxons , Retina/citologia , Splicing de RNA/efeitos dos fármacos , Doença de Stargardt/tratamento farmacológico , Doença de Stargardt/genética , Oligodesoxirribonucleotídeos Antissenso/farmacologia , Organoides/efeitos dos fármacos
12.
Mol Ther ; 32(3): 837-851, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38243599

RESUMO

The high allelic heterogeneity in Stargardt disease (STGD1) complicates the design of intervention strategies. A significant proportion of pathogenic intronic ABCA4 variants alters the pre-mRNA splicing process. Antisense oligonucleotides (AONs) are an attractive yet mutation-specific therapeutic strategy to restore these splicing defects. In this study, we experimentally assessed the potential of a splicing modulation therapy to target multiple intronic ABCA4 variants. AONs were inserted into U7snRNA gene cassettes and tested in midigene-based splice assays. Five potent antisense sequences were selected to generate a multiple U7snRNA cassette construct, and this combination vector showed substantial rescue of all of the splicing defects. Therefore, the combination cassette was used for viral synthesis and assessment in patient-derived photoreceptor precursor cells (PPCs). Simultaneous delivery of several modified U7snRNAs through a single AAV, however, did not show substantial splicing correction, probably due to suboptimal transduction efficiency in PPCs and/or a heterogeneous viral population containing incomplete AAV genomes. Overall, these data demonstrate the potential of the U7snRNA system to rescue multiple splicing defects, but also suggest that AAV-associated challenges are still a limiting step, underscoring the need for further optimization before implementing this strategy as a potential treatment for STGD1.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Splicing de RNA , Humanos , Transportadores de Cassetes de Ligação de ATP/genética , Doença de Stargardt/genética , Mutação , Células Fotorreceptoras
13.
Ophthalmology ; 131(1): 87-97, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37598860

RESUMO

PURPOSE: Late-onset Stargardt disease is a subtype of Stargardt disease type 1 (STGD1), defined by an age of onset of 45 years or older. We describe the disease characteristics, underlying genetics, and disease progression of late-onset STGD1 and highlight the differences from geographic atrophy. DESIGN: Retrospective cohort study. PARTICIPANTS: Seventy-one patients with late-onset STGD1. METHODS: Medical files were reviewed for clinical data including age at onset, initial symptoms, and best-corrected visual acuity. A quantitative and qualitative assessment of retinal pigment epithelium (RPE) atrophy was performed on fundus autofluorescence images and OCT scans. MAIN OUTCOME MEASURES: Age at onset, genotype, visual acuity, atrophy growth rates, and loss of external limiting membrane, ellipsoid zone, and RPE. RESULTS: Median age at onset was 55.0 years (range, 45-82 years). A combination of a mild and severe variant in ATP-binding cassette subfamily A member 4 (ABCA4) was the most common genotype (n = 49 [69.0%]). The most frequent allele, c.5603A→T (p.Asn1868Ile), was present in 43 of 71 patients (60.6%). No combination of 2 severe variants was found. At first presentation, all patients have flecks. Foveal-sparing atrophy was present in 33.3% of eyes, whereas 21.1% had atrophy with foveal involvement. Extrafoveal atrophy was present in 38.9% of eyes, and no atrophy was evident in 6.7% of eyes. Time-to-event curves showed a median duration of 15.4 years (95% confidence interval, 11.1-19.6 years) from onset to foveal involvement. The median visual acuity decline was -0.03 Snellen decimal per year (interquartile range [IQR], -0.07 to 0.00 Snellen decimal; 0.03 logarithm of the minimum angle of resolution). Median atrophy growth was 0.590 mm2/year (IQR, 0.046-1.641 mm2/year) for definitely decreased autofluorescence and 0.650 mm2/year (IQR, 0.299-1.729 mm2/year) for total decreased autofluorescence. CONCLUSIONS: Late-onset STGD1 is a subtype of STGD1 with most commonly 1 severe and 1 mild ABCA4 variant. The general patient presents with typical fundus flecks and retinal atrophy in a foveal-sparing pattern with preserved central vision. Misdiagnosis as age-related macular degeneration should be avoided to prevent futile invasive treatments with potential complications. In addition, correct diagnosis lends patients with late-onset STGD1 the opportunity to participate in potentially beneficial therapeutic trials for STGD1. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Degeneração Retiniana , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Doença de Stargardt , Estudos Retrospectivos , Transportadores de Cassetes de Ligação de ATP/genética , Eletrorretinografia , Tomografia de Coerência Óptica , Atrofia , Progressão da Doença , Angiofluoresceinografia
14.
Eur J Ophthalmol ; 34(2): 524-528, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37649340

RESUMO

OBJECTIVE: To analyze the progression of macular atrophy in Fundus Flavimaculatus (FFM) versus Extensive Macular Atrophy with Pseudo-drusen (EMAP), using Spectralis® RegionFinder™ tool. METHODS: Retrospective review of patients diagnosed with FFM and EMAP. Ophthalmic imaging features were reviewed by retina specialists for each patient in both eyes. The atrophic zones were measured on fundus autofluorescence acquisitions using the RegionFinder™ tool. RESULTS: FFM group included 16 eyes of 8 patients, whose mean age was 61.42 ± 10.76 years, with a mean 4.54 ± 2.73 years of follow-up. EMAP group contained 16 eyes of 8 patients, whose mean age was 67.81 ± 3.03 years (p = 0.12), with a mean 3.62 ± 2.49 years of follow-up (P = 0.63). The atrophy progression rates were 3.73 ± 6.75 and 0.70 ± 0.98 mm2/year, for EMAP and FFM respectively. The yearly rate of progression of the atrophic areas in EMAP was 5.3 times higher than in FFM (mm2/year) (p = 0.03). CONCLUSION: The progression of the atrophy in eyes with Extensive Macular Atrophy with Pseudo-drusen (EMAP) is significantly more rapid than in eyes with Fundus Flavimaculatus (FFM).


Assuntos
Atrofia Geográfica , Degeneração Macular , Degeneração Retiniana , Drusas Retinianas , Humanos , Pessoa de Meia-Idade , Idoso , Doença de Stargardt , Atrofia Geográfica/diagnóstico , Degeneração Macular/diagnóstico , Retina/diagnóstico por imagem , Retina/patologia , Drusas Retinianas/diagnóstico , Fundo de Olho , Atrofia/patologia , Angiofluoresceinografia/métodos , Tomografia de Coerência Óptica/métodos
17.
Br J Ophthalmol ; 108(4): 495-505, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-37940365

RESUMO

Stargardt macular dystrophy (Stargardt disease; STGD1; OMIM 248200) is the most prevalent inherited macular dystrophy. STGD1 is an autosomal recessive disorder caused by multiple pathogenic sequence variants in the large ABCA4 gene (OMIM 601691). Major advances in understanding both the clinical and molecular features, as well as the underlying pathophysiology, have culminated in many completed, ongoing and planned human clinical trials of novel therapies.The aims of this concise review are to describe (1) the detailed phenotypic and genotypic characteristics of the disease, multimodal imaging findings, natural history of the disease, and pathogenesis, (2) the multiple avenues of research and therapeutic intervention, including pharmacological, cellular therapies and diverse types of genetic therapies that have either been investigated or are under investigation and (3) the exciting novel therapeutic approaches on the translational horizon that aim to treat STGD1 by replacing the entire 6.8 kb ABCA4 open reading frame.


Assuntos
Degeneração Macular , Humanos , Doença de Stargardt , Fenótipo , Mutação , Degeneração Macular/diagnóstico , Degeneração Macular/genética , Degeneração Macular/terapia , Genótipo , Transportadores de Cassetes de Ligação de ATP/genética
18.
Proc Natl Acad Sci U S A ; 120(50): e2314698120, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38064509

RESUMO

Mutations in many visual cycle enzymes in photoreceptors and retinal pigment epithelium (RPE) cells can lead to the chronic accumulation of toxic retinoid byproducts, which poison photoreceptors and the underlying RPE if left unchecked. Without a functional ATP-binding cassette, sub-family A, member 4 (ABCA4), there is an elevation of all-trans-retinal and prolonged buildup of all-trans-retinal adducts, resulting in a retinal degenerative disease known as Stargardt-1 disease. Even in this monogenic disorder, there is significant heterogeneity in the time to onset of symptoms among patients. Using a combination of molecular techniques, we studied Abca4 knockout (simulating human noncoding disease variants) and Abca4 knock-in mice (simulating human misfolded, catalytically inactive protein variants), which serve as models for Stargardt-1 disease. We compared the two strains to ascertain whether they exhibit differential responses to agents that affect cytokine signaling and/or ceramide metabolism, as alterations in either of these pathways can exacerbate retinal degenerative phenotypes. We found different degrees of responsiveness to maraviroc, a known immunomodulatory CCR5 antagonist, and to the ceramide-lowering agent AdipoRon, an agonist of the ADIPOR1 and ADIPOR2 receptors. The two strains also display different degrees of transcriptional deviation from matched WT controls. Our phenotypic comparison of the two distinct Abca4 mutant-mouse models sheds light on potential therapeutic avenues previously unexplored in the treatment of Stargardt disease and provides a surrogate assay for assessing the effectiveness for genome editing.


Assuntos
Degeneração Macular , Degeneração Retiniana , Humanos , Camundongos , Animais , Doença de Stargardt/metabolismo , Degeneração Macular/tratamento farmacológico , Degeneração Macular/genética , Degeneração Macular/metabolismo , Retinaldeído/metabolismo , Retina/metabolismo , Degeneração Retiniana/tratamento farmacológico , Degeneração Retiniana/genética , Degeneração Retiniana/metabolismo , Modelos Animais de Doenças , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo
19.
Stem Cell Res ; 73: 103252, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37979432

RESUMO

Pathogenic variants in ABCA4 are associated with Stargardt disease (STGD1), an autosomal recessive macular dystrophy characterized by bilateral central vision loss due to a progressive degeneration of retinal cells. An induced pluripotent stem cell (iPSC) line was generated from late-onset STGD1 patient-derived fibroblasts harboring bi-allelic ABCA4 variants by lentivirus-induced reprogramming. The obtained iPSC line (RMCGENi020-A) showed pluripotent features after the reprogramming process. The generation of this iPSC line facilitates its use to differentiate it into relevant retinal-like cell models, with the aim to adequately evaluate the effects of the ABCA4 variants.


Assuntos
Células-Tronco Pluripotentes Induzidas , Doença de Stargardt , Humanos , Transportadores de Cassetes de Ligação de ATP/genética , Células-Tronco Pluripotentes Induzidas/patologia , Degeneração Macular/genética , Degeneração Macular/patologia , Mutação , Doença de Stargardt/patologia
20.
BMC Ophthalmol ; 23(1): 422, 2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37864132

RESUMO

BACKGROUND: Inherited retinal diseases form a rare, highly heterogeneous group of genetic disorders characterized by retinal degeneration. It is considered one of the leading causes of debilitating visual loss and blindness in children and young adults. Despite this few population-based data studies on prevalence of inherited retinal diseases exist. Moreover, prevalence can vary widely depending on geographical area, population ethnicity and cultural habits. PURPOSE: To report the prevalence of different subtypes of Inherited retinal diseases in a large Egyptian cohort in a retrospective, hospital-based, cross-sectional study. METHODS: We conducted an extensive electronic medical record search for all the patients attending the outpatient clinic and investigation unit of Ain Shams University Hospital and the two branches of Watany Eye Hospital in the period between January 2015 and October 2022 aiming to identify the prevalence rate of different types of IRDs, patient demographics and stratify them according to their phenotype. RESULTS: We examined the electronic medical records of 478 222 patients, 971 patients were diagnosed with IRD by clinical examination with or without any of the following investigations: color fundus photography, fundus autofluorescence, fundus fluorescein angiography, optical coherence tomography and/or electrophysiological studies as electroretinogram, visual evoked potential and electrooculogram. The overall prevalence was 0.2%. The most common IRD encountered was isolated retinitis pigmentosa with a percentage of 78.9% followed by Stargardt disease at 6.3%, cone-rod dystrophy at 2.0%, autosomal recessive bestrophinopathy at 1.9% and unspecified IRD at 1.5%. CONCLUSION: Retinitis pigmentosa was the most common IRD encountered followed by Stargardt disease. Many of the dystrophies are the subject of clinical intervention trials, and population-based epidemiological data can guide phenotype-based genetic testing and help assess the future need for treatment.


Assuntos
Potenciais Evocados Visuais , Retinose Pigmentar , Criança , Adulto Jovem , Humanos , Doença de Stargardt , Estudos Retrospectivos , Estudos Transversais , Egito/epidemiologia , Prevalência , Retinose Pigmentar/diagnóstico
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