Search Results (41)

Adeno-associated virus (AAV) vectors have emerged as the leading platform for retinal gene therapy due to their favorable safety profile, low immunogenicity, and ability to mediate long-term transgene expression within the immune-privileged ocular environment. By integrating diverse strategies such as gene augmentation and gene editing, AAV-based therapies have demonstrated considerable promise in treating both inherited and acquired retinal disorders. However, their clinical translation remains limited by several key challenges, including restricted packaging capacity, suboptimal transduction efficiency, the risk of gene therapy-associated uveitis, and broader societal concerns such as disease burden and ethical oversight. This review summarizes recent advances aimed at overcoming these barriers, with a particular focus on delivery route-specific disease applicability, multi-vector systems, and capsid engineering approaches to enhance payload capacity, targeting specificity, and biosafety. By synthesizing these developments, we propose a conceptual and technical framework for a more efficient, safer, and broadly applicable AAV platform to accelerate clinical adoption in retinal gene therapy. Full article

Background/Objectives: Inherited retinal diseases (IRDs) are a heterogeneous group of rare eye disorders characterized by progressive photoreceptor degeneration, leading to severe visual impairment or even blindness. This study aims to investigate the prevalence, types, and clinical significance of ophthalmic comorbidities in Portuguese patients with IRDs. Methods: This nationwide Portuguese population-based retrospective study was based on the IRD-PT registry (retina.com.pt). Statistical analysis was conducted using Microsoft^® Excel^® for Microsoft 365 and IBM SPSS Statistics version 29.0.2.0. Informed consent was obtained from all participants. Results: A total of 1531 patients (1254 families) from six centers were enrolled. The cohort consisted of 51% males, with a mean age of 45.8 ± 19.3 years and a mean age at diagnosis of 39.4 ± 19.5 years. Overall, ocular comorbidities were reported in 644 patients (42.1%). In 176 individuals (11.5%), multiple concurrent comorbidities were found. Cataract was the most common comorbidity (21.3%), followed by amblyopia (6.3%) and high myopia (5.9%). Statistically significant associations with ocular comorbidities were observed in isolated progressive IRDs. Specifically, AR RP was associated with cataract (p < 0.001), and gene analysis revealed several significant associations. CRB1 was statistically linked to epiretinal membrane (ERM) (p = 0.003), EYS with cataract (p = 0.001), PROM1 with choroidal neovascularization (CNV) (p = 0.0026), and USH2A with macular hole (p = 0.01). Patients with the RPE65 mutation in Leber congenital amaurosis were associated with ERM (p = 0.019). There was also a significant association between X-linked RP and high myopia (p < 0.001) and CNV in Best disease (p < 0.001); in syndromic IRDs, cataract, cystoid macular edema, and ERM were observed in Usher syndrome, p = 0.002, p = 0.002, and p = 0.005, respectively, and the MYO7A gene was linked to cataract (p = 0.041) and strabismus (p = 0.013); pseudoxanthoma elasticum was significantly associated with CNV (p = 0.002); and foveal hypoplasia was associated with anterior segment dysgenesis (p < 0.001). Conclusions: This study enhances the current understanding of ocular comorbidities in IRDs in Portuguese patients. Common findings were cataract, refractive error, and CME. Stationary IRDs and pattern dystrophies showed fewer concomitant comorbidities, supporting their classification as non-progressive or benign conditions. The significance of registries like IRD-PT cannot be overstated, particularly in the context of rare diseases. These databases serve multiple crucial functions in enabling detailed documentation of disease characteristics and long-term monitoring of disease progression. Full article

Retinal degeneration, characterized by the progressive loss of photoreceptors, retinal pigment epithelium cells, and/or ganglion cells, is a leading cause of vision impairment. These diseases are generally classified as inherited (e.g., retinitis pigmentosa, Stargardt disease) or acquired (e.g., age-related macular degeneration, diabetic retinopathy, glaucoma) ocular disorders that can lead to blindness. Available treatment options focus on managing symptoms or slowing disease progression and do not address the underlying causes of these diseases. However, recent advancements in regenerative medicine offer alternative solutions for repairing or protecting degenerated retinal tissue. Stem and progenitor cell therapies have shown great potential to differentiate into various retinal cell types and can be combined with gene editing, extracellular vesicles and exosomes, and bioactive molecules to modulate degenerative cellular pathways. Additionally, gene therapy and neuroprotective molecules play a crucial role in enhancing the efficacy of regenerative approaches. These innovative strategies hold the potential to halt the progression of retinal degenerative disorders, repair or replace damaged cells, and improve visual function, ultimately leading to a better quality of life for those affected. Full article

Background and Objectives: Pathogenic variants in the PAX2 gene have been associated with a spectrum of eye and kidney disorders, ranging from papillorenal syndrome (known as renal coloboma syndrome) to isolated nephrosis without kidney morphological anomalies (focal segmental glomerulosclerosis), inherited in an autosomal dominant manner. However, due to the growing number of reports of pathogenic variants in the PAX2 gene, it is observed that genotype–phenotype correlation is not always consistent. We present patients from two unrelated families with PAX2 pathogenic variants c.685C>T and c.250G>A, highlighting the diverse phenotypic expression of PAX2-related disorders. Materials and Methods: We analyzed clinical and genetic data from two families who were tested for genomic abnormalities using targeted next-generation sequencing and Sanger sequencing for segregation analysis. Results: In Family A, a 27-year-old male presented with chronic kidney disease stage 3, proteinuria, and multicystic kidney dysplasia diagnosed at 11 years old. An ophthalmologic examination revealed bilateral optic nerve dysplasia. In Family B, a 6-year-old female and her 4-year-old sister were clinically diagnosed with renal hypoplasia, while their 36-year-old father presented with chronic kidney disease stage 3, focal segmental glomerulosclerosis, and optic disc pits. Genetic analysis identified a heterozygous PAX2 pathogenic variant c.685C>T, p.(Arg229*), in Family A and a heterozygous PAX2 pathogenic variant c.250G>A, p.(Gly84Ser) in Family B. Conclusions: The literature and our data further support that the same PAX2 variants may cause diverse kidney and ocular phenotypes among unrelated families and within the same family. Due to variable expressivity, a wide range of clinical manifestations of rare hereditary kidney diseases are still underdiagnosed, and a multidisciplinary approach is required to detect extrarenal signs of PAX2-related disorder. Full article

Degenerative and developmental eye disorders, including inherited retinal dystrophies (IRDs), anophthalmia, and congenital cataracts arise from genetic mutations, causing progressive vision loss or congenital structural abnormalities. IRDs include a group of rare, genetically, and clinically heterogeneous retinal diseases. It is caused by variations in at least 324 genes, affecting numerous retinal regions. In addition to IRDs, other developmental eye disorders such as anophthalmia and congenital cataracts also have a strong genetic basis. Autosomal recessive IRDs, anophthalmia, and congenital cataracts are common in consanguineous populations. In many endogamous populations, including those in Pakistan, a significant proportion of IRD and anophthalmia cases remain genetically undiagnosed. The present study investigated the variations in IRDs, anophthalmia, and congenital cataracts genes in 50 affected families. These unrelated consanguineous families were recruited from the different provinces of Pakistan including Punjab, Khyber Pakhtoon Khwa, Sindh, Gilgit Baltistan, and Azad Kashmir. Whole exome sequencing (WES) was conducted for the proband of each family. An in-house customized pipeline examined the data, and bioinformatics analysis predicted the pathogenic effects of identified variants. The relevant identified DNA variants of selected families were assessed in parents and healthy siblings via Sanger sequencing. WES identified 12 novel variants across 10 known IRD-associated genes. The four most frequently implicated genes were CRB1 (14.3%), GUCY2D (9.5%), AIPL1 (9.5%), and CERKL (7.1%) that together accounted for 40.4% of all molecularly diagnosed cases. Additionally, 25 reported variants in 19 known IRDs, anophthalmia, and congenital cataracts-associated genes were found. Among the identified variants, p. Trp278X, a stop–gain mutation in the AIPL1 (NM_014336) gene, was the most common causative variant detected. The most frequently observed phenotype was retinitis pigmentosa (46.5%) followed by Leber congenital amaurosis (18.6%). Furthermore, 98% of pedigrees (49 out of 50) were affected by autosomal recessive IRDs, anophthalmia and congenital cataracts. The discovery of 12 novel likely pathogenic variants in 10 IRD genes, 25 reported variants in 19 known IRDs, anophthalmia and congenital cataracts genes, atypical phenotypes, and inter and intra-familial variability underscores the genetic and phenotypic heterogeneity of developmental and degenerative eye disorders in the Pakistani population and further expands the mutational spectrum of genes associated with these ocular disorders. Full article

Background: Chronic granulomatous disease (CGD) is a rare genetic disorder that causes primary immunodeficiency. In addition to increasing infection susceptibility in various bodily systems, several ocular manifestations have been described in males. This condition is well described in males, due to its X-linked recessive inheritance. However, here we present, to our knowledge, the first cases of X-linked CGD chorioretinitis in female carriers, possibly due to skewed X-inactivation (lyonization). Methods: Comprehensive multimodal imaging, including color fundus photography, short-wavelength autofluorescence, and spectral domain optical coherence tomography (OCT), was conducted. Functional assessment was completed with full-field electroretinogram (ff-ERG). Results: This report details two sisters with X-linked CGD carrier status, both presenting chorioretinal lesions on fundoscopy. Observed features included punched-out chorioretinal lesions, perivascular atrophy, and peripheral pigment changes. Autofluorescence imaging confirmed hypoautofluorescent areas correlating with chorioretinal atrophy, and OCT revealed retinal collapse and ellipsoid zone loss in one sibling. Despite these structural changes, visual function remained stable with minimal progression over time. Subsequent serial ERGs did not show progression. Conclusions: The findings highlight that skewed X-inactivation may contribute to retinal changes in asymptomatic CGD carriers, underscoring the need for awareness of potential ocular manifestations in X-linked genetic disorders in female carriers. Full article

Visual electrophysiology is a valuable tool for evaluating the visual system in various systemic syndromes. This review highlights its clinical application in a selection of syndromes associated with hearing loss, mitochondrial dysfunction, obesity, and other multisystem disorders. Techniques such as full-field electroretinography (ffERG), multifocal electroretinography (mfERG), pattern electroretinography (PERG), visual evoked potentials (VEP), and electrooculography (EOG) offer insights into retinal and optic nerve function, often detecting abnormalities before clinical symptoms manifest. In hearing loss syndromes like Refsum disease, Usher syndrome (USH), and Wolfram syndrome (WS), electrophysiology facilitates the detection of early retinal changes that precede the onset of visual symptoms. For mitochondrial disorders such as maternally-inherited diabetes and deafness (MIDD), Kearns–Sayre syndrome (KSS), and neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome, these tests can be useful in characterizing retinal degeneration and optic neuropathy. In obesity syndromes, including Bardet-Biedl syndrome (BBS), Alström syndrome, and Cohen syndrome, progressive retinal degeneration is a hallmark feature. Electrophysiological techniques aid in pinpointing retinal dysfunction and tracking disease progression. Other syndromes, such as Alagille syndrome (AGS), abetalipoproteinemia (ABL), Cockayne syndrome (CS), Joubert syndrome (JS), mucopolysaccharidosis (MPS), Neuronal ceroid lipofuscinoses (NCLs), and Senior–Løken syndrome (SLS), exhibit significant ocular involvement that can be evaluated using these methods. This review underscores the role of visual electrophysiology in diagnosing and monitoring visual system abnormalities across a range of syndromes, potentially offering valuable insights for early diagnosis, monitoring of progression, and management. Full article

Background: Disruption of HCCS results in microphthalmia with linear skin lesions (MLS) characterized by microphthalmia/anophthalmia, corneal opacity, aplastic skin lesions, variable central nervous system and cardiac anomalies, intellectual disability, and poor growth in heterozygous females. Structural variants consisting of chromosomal rearrangements or deletions are the most common variant type, but a small number of intragenic variants have been reported. Methods: Exome sequencing identified variants affecting HCCS. Results: Three novel intragenic variants and two genomic deletions of HCCS were found in individuals with primarily ocular features of MLS. X-inactivation was highly skewed in affected individuals with all three intragenic variants. Corneal opacity was the most penetrant feature (100%). In addition, a duplication of uncertain significance including both HCCS and AMELX was identified in a male with corneal anomalies, glaucoma, an atrial septal defect, and enamel hypoplasia along with a family history of developmental ocular disorders consistent with X-linked inheritance. Conclusion: Although variable expressivity is a known feature of MLS, our findings provide additional support for including HCCS in testing for individuals with isolated ocular anomalies and provide further evidence for its association with congenital aphakia, aniridia/other iris defects, and corneal staphyloma/ectasia. Full article

Marfan syndrome is an inherited connective tissue disorder that affects the cardiovascular, musculoskeletal, and ocular systems. It is caused by pathogenic variants in the fibrillin-1 gene (FBN1). Fibrillin is a primary component of microfibrils, which are found throughout the extracellular matrix (ECM) and provide elasticity and resilience to connective tissue. Microfibrils also play a role in signaling by sequestering growth factors and interacting with cell surface receptors. In many tissues, microfibrils are interwoven with elastin, collagens, and other elements of the ECM. However, uniquely in the ciliary zonule of the eye, microfibrils exist in cell-free bundles largely devoid of other components. This structure offers a rare opportunity to study a pure population of fibrillin microfibrils in a relatively native state. Here, we briefly review the organization of the zonule and describe recent experiments in which we measure zonular biomechanics, providing insights into microfibril dynamics that would be challenging to obtain in other contexts. Full article

Background: Alport syndrome (AS) is a genetic disorder characterized by progressive renal disease, ocular abnormalities, and sensorineural hearing loss. However, the audiological profile of patients with AS remains elusive. Thus, this study aims to evaluate the natural history of auditory function in patients with AS. Methods: Exome or targeted sequencing for deafness genes was performed to confirm the pathogenic variants in patients with AS. Results: We identified fifteen individuals with AS who carried pathogenic variants of COL4A3, COL4A4, or COL4A5. Among fifteen, twelve (80%) showed hematuria, and six (40%) showed proteinuria. The patients exhibited bilateral sensorineural hearing loss, which was progressive and symmetric. The hearing thresholds increased according to age and plateaued at the level of 53 dB HL, indicating the hearing loss did not reach the severe-to-moderate level. The auditory dysfunction showed a distinct natural history depending on the inheritance pattern, but there was no remarkable difference between males and females among X-linked AS. Conclusions: Auditory dysfunction in AS is progressive up to the level of moderate hearing loss. Precise auditory rehabilitation for patients with AS is warranted depending on the inheritance pattern and genetic predisposition. Full article

Inherited retinal degenerations (IRDs) are a group of genetic disorders characterized by the progressive degeneration of retinal cells, leading to irreversible vision loss. SLC4A7 has emerged as a candidate gene associated with IRDs, yet its mechanisms remain largely unknown. This study aims to investigate the role of slc4a7 in retinal development and its associated molecular pathogenesis in zebrafish. Morpholino oligonucleotide knockdown, CRISPR/Cas9 genome editing, quantitative RT-PCR, eye morphometric measurements, immunofluorescent staining, TUNEL assays, visual motor responses, optokinetic responses, rescue experiments, and bulk RNA sequencing were used to assess the impact of slc4a7 deficiency on retinal development. Our results demonstrated that the knockdown of slc4a7 resulted in a dose-dependent reduction in eye axial length, ocular area, and eye-to-body-length ratio. The fluorescence observations showed a significant decrease in immunofluorescence signals from photoreceptors and in mCherry fluorescence from RPE in slc4a7-silenced morphants. TUNEL staining uncovered the extensive apoptosis of retinal cells induced by slc4a7 knockdown. Visual behaviors were significantly impaired in the slc4a7-deficient larvae. GO and KEGG pathway analyses reveal that differentially expressed genes are predominantly linked to aspects of vision, ion channels, and phototransduction. This study demonstrates that the loss of slc4a7 in larvae led to profound visual impairments, providing additional insights into the genetic mechanisms predisposing individuals to IRDs caused by SLC4A7 deficiency. Full article

Congenital stationary night blindness (CSNB) is a genetically heterogeneous inherited retinal disorder, caused by over 300 mutations in 17 different genes. While there are numerous fly models available for simulating ocular diseases, most are focused on mimicking retinitis pigmentosa (RP), with animal models specifically addressing CSNB limited to mammals. Here, we present a CSNB fly model associated with the mtt gene, utilizing RNA interference (RNAi) to silence the mtt gene in fly eyes (homologous to the mammalian GRM6 gene) and construct a CSNB model. Through this approach, we observed significant defects in the eye structure and function upon reducing mtt expression in fly eyes. This manifested as disruptions in the compound eye lens structure and reduced sensitivity to light responses. These results suggest a critical role for mtt in the function of fly adult eyes. Interestingly, we found that the mtt gene is not expressed in the photoreceptor neurons of adult flies but is localized to the inner lamina neurons. In summary, these results underscore the crucial involvement of mtt in fly retinal function, providing a framework for understanding the pathogenic mechanisms of CSNB and facilitating research into potential therapeutic interventions. Full article

Inherited retinal diseases (IRDs) constitute a prevalent group of inherited ocular disorders characterized by marked genetic diversity alongside moderate clinical variability. Among these, ABCA4-related eye pathology stands as a prominent form affecting the retina. In this study, we conducted an in-depth analysis of 96 patients harboring ABCA4 variants in the European part of Russia. Notably, the complex allele c.[1622T>C;3113C>T] (p.Leu541Pro;Ala1038Val, or L541P;A1038V) and the variant c.5882G>A (p.Gly1961Glu or G1961E) emerged as primary contributors to this ocular pathology within this population. Additionally, we elucidated distinct disease progression characteristics associated with the G1961E variant. Furthermore, our investigation revealed that patients with loss-of-function variants in ABCA4 were more inclined to develop phenotypes distinct from Stargardt disease. These findings provide crucial insights into the genetic and clinical landscape of ABCA4-related retinal dystrophies in this specific population. Full article

Neurofibromatosis type 1 (NF1) is a rare inherited neurocutaneous disorder with a major impact on the skin, nervous system and eyes. The ocular diagnostic hallmarks of this disease include iris Lisch nodules, ocular and eyelid neurofibromas, eyelid café-au-lait spots and optic pathway gliomas (OPGs). In the last years, new manifestations have been identified in the ocular district in NF1 including choroidal abnormalities (CAs), hyperpigmented spots (HSs) and retinal vascular abnormalities (RVAs). Recent advances in multi-modality imaging in ophthalmology have allowed for the improved characterization of these clinical signs. Accordingly, CAs, easily detectable as bright patchy nodules on near-infrared imaging, have recently been added to the revised diagnostic criteria for NF1 due to their high specificity and sensitivity. Furthermore, subclinical alterations of the visual pathways, regardless of the presence of OPGs, have been recently described in NF1, with a primary role of neurofibromin in the myelination process. In this paper, we reviewed the latest progress in the understanding of choroidal and retinal abnormalities in NF1 patients. The clinical significance of the recently revised diagnostic criteria for NF1 is discussed along with new updates in molecular diagnosis. New insights into NF1-related neuro-ophthalmic manifestations are also provided based on electrophysiological and optical coherence tomography (OCT) studies. Full article

Microcephaly and chorioretinopathy are genetic disorders that are inherited in an autosomal recessive manner. The most frequent ocular manifestation is the presence of lacunar atrophy in the retina and choroid. The diagnosis of this condition can be challenging as several potential causes and related syndromes need to be ruled out. We present two cases of microcephaly and chorioretinopathy in Mexican patients, their clinical characterization, and discuss the differential diagnoses that should be considered. An 8-year-old girl was examined due to a history of decreased vision in both eyes. Fundus examination showed excavated, well-defined, sectorial, bilateral, and symmetrical areas of chorioretinal atrophy. An 18-year-old male had a history of poor vision since childhood. Previous ophthalmological examinations reported bilateral symmetric chorioretinal atrophy with pigment accumulation. Both patients had a prior diagnosis of microcephaly and language delay. Blood tests and a comprehensive systemic evaluation ruled out intrauterine infections. The electroretinogram showed decreased amplitude and increased implicit time in the photopic and scotopic responses. Genetic tests revealed mutations in the TUBGCP4 gene, leading to a diagnosis of microcephaly and chorioretinopathy. As observed in these cases, there was variability in retinal lesions. The presence of chorioretinal lacunae and genetic testing can help to correctly diagnose this disorder. Full article