Search Results (268)

Nephrotic syndrome (NS) is characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Apart from the traditional causes of NS, such as minimal change disease, focal segmental glomerulosclerosis, diabetes, infections, malignancies, autoimmune conditions, and nephrotoxic agents, there are also rare causes of NS, whose knowledge is of the utmost importance. The aim of this article was to highlight the less well-known causes that have a significant impact on diagnosis and treatment. Genetic syndromes such as Schimke immuno-osseous dysplasia, familial lecithin-cholesterol acyltransferase deficiency with two clinical variants (fish-eye Disease and the p.Leu364Pro mutation), lead to NS through mechanisms involving podocyte and lipid metabolism dysfunction. Congenital disorders of glycosylation and Nail–Patella Syndrome emphasize the role of deranged protein processing and transcriptional regulation in glomerular injury. The link of NS with type 1 diabetes, though rare, suggests an etiology on the basis of common HLA loci and immune dysregulation. Histopathological analysis, particularly electron microscopy, shows mainly podocyte damage, mesangial sclerosis, and alteration of the basement membrane, which aids in differentiating rare forms. Prompt recognition of these novel etiologies by genetic analysis, renal biopsy, and an interdisciplinary panel is essential to avoid delays in diagnosis and tailored treatment. Full article

The cornea, the transparent anterior window of the eye, critically refracts light and protects intraocular structures. Corneal pathologies, including trauma, infection, chemical injury, metabolic diseases, genetic conditions, and age-related degeneration, can lead to significant visual impairment. While penetrating keratoplasty or full-thickness corneal transplantation remains a standard and effective intervention for severe corneal dysfunction, limitations in donor tissue availability and the risk of immunogenic graft rejection necessitate alternative therapeutic strategies. Furthermore, for cases of isolated epithelial disfunction, a full-thickness cornea graft may not be required or effective. This review examines the potential of corneal epithelial constructs derived from autologous stem cells with functional barrier properties for corneal reconstruction and in vitro pharmacotoxicity testing. In this review, we delineate the current limitations of corneal transplantation, the advantages of stem cell-based approaches, and recent advances in generating engineered corneal epithelium. Finally, we address remaining technical challenges and propose future research directions aimed at clinical translation. Full article

Recent findings highlight that Reelin, a glycoprotein involved in neural development, synaptic plasticity, and neuroinflammation, plays some specific roles in neurodegenerative disorders associated with aging, such as age-related macular degeneration (AMD) and Alzheimer’s disease (AD). Reelin modulates synaptic function and guarantees homeostasis in neuronal-associated organs/tissues (brain and retina). The expression of Reelin is dysregulated in these neurological disorders, showing common pathways depending on chronic neurogenic inflammation and/or dysregulation of the extracellular matrix in which Reelin plays outstanding roles. Recently, the relationship between AMD and AD has gained increasing attention as they share many common risk factors (aging, genetic/epigenetic background, smoking, and malnutrition) and histopathological lesions, supporting certain pathophysiological crosstalk between these two diseases, especially regarding neuroinflammation, oxidative stress, and vascular complications. Outside the nervous system, Reelin is largely produced at the gastrointestinal epithelial level, in close association with innervated regions. The expression of Reelin receptors inside the gut suggests interesting aspects in the field of the gut–brain–eye axis, as dysregulation of the intestinal microbiota has been frequently described in neurodegenerative and behavioral disorders (AD, autism, and anxiety and/or depression), most probably linked to inflammatory, neurogenic mediators, including Reelin. Herein we examined previous and recent findings on Reelin and neurodegenerative disorders, offering findings on Reelin’s potential relation with the gut–brain and gut–brain–eye axes and providing novel attractive hypotheses on the gut–brain–eye link through neuromodulator and microbiota interplay. Neurodegenerative disorders will represent the ground for a future starting point for linking the common neurodegenerative biomarkers (β-amyloid and tau) and the new proteins probably engaged in counteracting neurodegeneration and synaptic loss. Full article

Background: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare genetic disorder, often leading to injuries and serious infections. In 2018, we established a multidisciplinary clinic (MDC) to provide structured, proactive care. We assessed the MDC’s impact on hospitalizations, surgeries, and infection rates. Methods: A retrospective study of genetically confirmed CIPA patients, treated from 2014 to 2024. Data from electronic medical records were compared between the pre-MDC (2014–2017) and post-MDC (2018–2024) periods. The core MDC team includes an infectious disease specialist, orthopedic surgeon, and nurses. The patients are stratified according to their carriage of resistant organisms and are managed using strict infection control measures. Follow-ups are scheduled routinely or as needed. Treatment is guided by clinical findings and culture results. Results: A total of 59 patients were included in the study. The baseline age did not differ significantly between the two periods. Hospitalization rates declined by 30.7% (from 57.7 to 40.0 per 1000 days), and clinic visits decreased by 42.9% (25.5 to 14.6). Overall surgical rates remained stable (2.8 to 2.7), with a 61.9% decrease in eye surgeries and a 130.5% increase in elective tooth extractions. Infection rates increased by 52% (from 6.6 to 10.1 per 1000 days). Conclusions: The implementation of the MDC bundle led to reduced hospitalizations, clinic visits, and eye surgeries, alongside the increased use of elective tooth extractions and culture testing. Closer monitoring and early infection management contributed to fewer severe complications. These findings support the value of structured, proactive multidisciplinary care in improving outcomes for children with CIPA. Full article

Gene therapy has emerged as a promising treatment for several eye diseases since it may restore vision and stop blindness. Many eye diseases, including retinitis pigmentosa and macular degeneration, have historically been rather difficult to treat and usually cause permanent vision loss. However, thanks to advances in gene therapy, many disorders can now be effectively targeted and genetically changed, providing a safer, more direct, maybe even curative approach. By introducing, altering, or repairing specific genes inside the eye, gene therapy seeks to fix the defective genes causing these disorders, thereby improving general eye health and visual ability. Voretigene neparvovec is one FDA- and EMA-approved treatment for RPE65 mutations. Retinitis pigmentosa, age-related macular degeneration, X-linked retinoschisis, choroideremia, and Stargardt disease are among the several eye disorders still under clinical trials, and experimental treatment is in progress. As research on gene therapy develops, it opens the path for groundbreaking treatments that could fundamentally change the ophthalmic care scene. Full article

To compare the clinical characteristics of inherited retinal diseases (IRDs) caused by biallelic versus monoallelic variants in the RP1, BEST1, and PROM1 genes. A total of 52 patients (26 female) with genetically confirmed IRDs were retrospectively selected from the records of the Harkness Eye Institute Clinical Coordinating Center at Columbia University Irving Medical Center. In RP1, 3 individuals with biallelic variants and 22 patients with monoallelic variants classified as pathogenic or likely pathogenic were selected. In BEST1, eight individuals with biallelic variants and nine individuals with monoallelic variants classified as either pathogenic or likely pathogenic were included. In PROM1, four individuals with biallelic variants and six patients with monoallelic variants classified as pathogenic or likely pathogenic were selected. All patients underwent multimodal retinal imaging and, when available, full-field electroretinography (ffERG). In all three genes, individuals with biallelic variants had markedly earlier disease onset and more severe phenotypes. In RP1, on SD-OCT, foveal involvement was observed in all biallelic cases (3/3, 100%) and in 4/22 (18%) monoallelic cases. In BEST1, the average age of onset in the biallelic cohort was 7.12 years, and the average age was 32.7 years in the monoallelic cohort. Four of eight (50%) patients in the biallelic group were additionally found to have widespread serous lesions outside of the central macula. This finding was not observed in the monoallelic group. Three of eight (38%) biallelic BEST1 patients had moderate reductions in their photopic flicker. All monoallelic BEST1 patients had photopic responses within the normal range. PROM1 biallelic cases showed severe functional impairment on ffERG, while most monoallelic cases retained normal responses. In the biallelic cohort, four of four (100%) of patients had severely attenuated or extinguished photopic responses. In the monoallelic PROM1 group, four of five (80%) monoallelic PROM1 patients had normal photopic responses, and P2-2 had mildly attenuated photopic responses. Individuals with biallelic variants exhibited earlier disease onset, more severe retinal degeneration, and significantly reduced retinal function compared with those with monoallelic variants. These observations highlight the role of loss-of-function mechanisms in more aggressive disease courses and underscore the importance of considering zygosity when determining prognosis and planning gene-based therapies. Full article

Objectives: This study aims to describe the clinical features and genetic findings of nine Vietnamese patients with autosomal recessive bestrophinopathy. Methods: This retrospective and cross-sectional study included individuals diagnosed with autosomal recessive bestrophinopathy at the Eye Clinic, Vietnam National Geriatric Hospital between May 2024 and April 2025. The patients underwent a visual acuity assessment, retinal multimodal imaging, and molecular testing through BEST1 gene sequencing. Results: Nine patients from seven unrelated families were included. The mean age was 38.6 years (range: 14.1–79.6). Visual acuity ranged from 20/20 to 20/125. All patients showed vitelliform lesions, subretinal deposits, and both intraretinal and subretinal fluid. Other main features included diffuse macular hyperfluorescence and hyperopia. Less common clinical features encompassed glaucoma, retinoschisis, outer retinal thinning, serous retinal detachment, retinal thickening, and thinning of the retinal pigment epithelium. Compound heterozygous or homozygous variants were detected in all patients. Among the five identified BEST1 variants, the most frequent were p.(A195V) and p.(R200*). One novel variant, p.(K289*), was detected. Conclusions: The main clinical retinal features of nine Vietnamese patients with autosomal recessive bestrophinopathy included vitelliform lesions, subretinal deposits, retinal fluid, and diffuse macular hyperfluorescence. The most common variants were p.(A195V) and p.(R200*). Additionally, the identification of various compound heterozygotes and a novel BEST1 variant expands the mutation spectrum of the disease. Full article

Keratoconus (KC) is the most common ectatic corneal disease. In this review, the systemic aspects of the disease are discussed, including patient age, genetics, systemic inflammatory status and immune system dysregulation, atopy and eye rubbing, systemic metabolism, the metabolism of micronutrients (including vitamin D), and hormonal balance. The association between KC and metabolic diseases, collagen diseases, and psychiatric conditions is also considered. The evidence that is currently available strongly suggests a systemic predisposition toward KC. The understanding that KC may be the local manifestation of a systemic disease could allow earlier detection/prevention and pave the way for research into new treatments addressing the pathogenetic foundations of KC, rather than limiting intervention to the corneal disease. Full article

ABCC6, a key regulator in ectopic calcification, plays a crucial role in mineralization through the modulation of extracellular purinergic pathways and production of inorganic pyrophosphate (PPi), which inhibits calcification. Inherited deficiencies in ABCC6 lead to pseudoxanthoma elasticum (PXE) and related conditions, characterized by calcification in various tissues, particularly affecting the skin, eyes, and cardiovascular system. Although PXE does not directly impact the nervous system, secondary neurological issues arise from cerebrovascular complications, increasing the risk of strokes linked to arterial blockages resembling atherosclerosis. This review investigates the connection between ABCC6 mutations and cerebral small vessel disease (SVD), expanding the understanding of PXE and related phenotypes. Mutations in ABCC6, identified as causing PXE, contribute to systemic metabolic dysfunction, with significant implications for cerebrovascular health. An association between ABCC6 mutations and cerebral SVD has been suggested in various studies, particularly in populations with distinct genetic backgrounds. Emerging evidence indicates that pathogenic mutations increase the risk of ischemic strokes, with both homozygous and heterozygous carriers showing susceptibility. Mechanistically, ABCC6 deficiency is implicated in dyslipidemia and atherosclerosis, further exacerbating cerebrovascular risks. Increased arterial pulsatility, linked to carotid siphon calcification, may also contribute to microvascular damage and subsequent brain injury. Understanding these mechanisms is vital for developing targeted diagnostic and therapeutic strategies for managing cerebrovascular risks in PXE patients. This review emphasizes the need for comprehensive genetic screening and the consideration of traditional vascular risk factors in patient management, highlighting the complex interplay between genetic mutations and environmental influences affecting cerebrovascular health. Future research should focus on longitudinal studies to elucidate the causal pathways linking arterial calcification, pulsatility, and brain damage in PXE. Full article

Background/Objectives: Joubert syndrome (JS, MIM 213300) is a rare genetic condition characterized by respiratory control disturbances, abnormal eye movements, ataxia, cognitive impairment, and the notable agenesis of the cerebellar vermis. The molar tooth sign visible in magnetic resonance imaging of the brain serves as a diagnostic tool for JS. Variants in the TCTN3 gene can lead to the development of several diseases, including JS type 18, Orofaciodigital syndrome IV, and Meckel–Gruber syndrome. Methods: We performed whole-exome sequencing (WES) in a 49-year-old woman with JS characterized by severe intellectual disability, ataxic gait, agenesis of the cerebellar vermis leading to the molar tooth sign, dystonic movements, strabismus, and nystagmus. Moreover, the patient also showed a thickened corpus callosum. Results: Molecular analysis through WES revealed the heterozygous variants c.182dup (p.G62Wfs*18) and c.1452+4del in the TCTN3 gene, expanding our understanding of the genetic diversity and potential phenotypic implications associated with TCTN3 variations. Conclusions: To our knowledge, this is the first patient with JS and a thickened corpus callosum. Moreover, a thickened corpus callosum has never been identified in patients with pathogenic variants of the TCTN3 gene. Full article

Hypertensive retinopathy (HR) is a serious eye disease that can lead to permanent vision loss if not diagnosed early. The conventional diagnostic methods are subjective and time-consuming, so there is a need for an automated and reliable system. In this study, a three-stage method that provides high accuracy in HR diagnosis is proposed. In the first stage, 14 well-known Convolutional Neural Network (CNN) models were evaluated, and the top three models were identified. Among these models, DenseNet169 achieved the highest accuracy rate of 87.73%. In the second stage, the deep features obtained from these three models were combined and classified using machine learning (ML) algorithms including Support Vector Machine (SVM), Random Forest (RF), and Extreme Gradient Boosting (XGBoost). The SVM with a sigmoid kernel achieved the best performance (92% accuracy). In the third stage, feature selection was performed using metaheuristic optimization techniques including Genetic Algorithm (GA), Artificial Bee Colony (ABC), Particle Swarm Optimization (PSO), and Harris Hawk Optimization (HHO). The HHO algorithm increased the classification accuracy to 94.66%, enhancing the model’s generalization ability and reducing misclassifications. The proposed method provides superior accuracy in the diagnosis of HR at different severity levels compared to single-model CNN approaches. These results demonstrate that the integration of Deep Learning (DL), ML, and optimization techniques holds significant potential in automated HR diagnosis. Full article

Background: Methylmalonic acidemia combined with homocystinuria (cblC) can lead to infantile maculopathy. Although significant visual deterioration is commonly reported in early-onset cblC, we found poor awareness regarding formal assessments of ocular complications, especially in newborns, and of how these complications relate to the timing of therapy initiation. In this work, we present our experience and perform a literature review. Methods: We performed sequential fundus examinations, optical coherence tomography (OCT) and full-field electroretinography (ERG) under sedation following detection of signs of retinal degeneration. We also assessed visual fields using kinetic attraction perimetry. Results: We report a newborn who was referred on the eighth day of life, following a diagnosis of cblC through newborn screening (NBS), and who began treatment that same day. Close monitoring of retinal changes through fundus examinations allowed the detection of signs of retinal degeneration at 3 months, which progressed when checked at 5 months. At 7 months, OCT showed retinal thinning with the appearance of bull’s eye maculopathy in the corresponding region on fundoscopy; ERG revealed a reduction in the amplitude of both scotopic and photopic components, whereas kinetic attraction perimetry showed no abnormalities. Genetic investigation confirmed the disease, compound heterozygous for a nonsense variant in MMACHC and a splicing one in PRDX1. Conclusions: In cblC, retinal degeneration occurs in the first months of life despite timely treatment and adequate biochemical control, and it may manifest before any signs of visual deprivation appear. However, there is an early, narrow window during which therapy may slow down retinal degeneration enough to prevent sensory nystagmus. We recommend initiating therapy immediately after biochemical diagnosis, along with close ophthalmological monitoring, before the appearance of any signs. Full article

Sjögren’s disease (SjD) is a systemic autoimmune disorder primarily causing dry eyes and mouth. It frequently overlaps with other autoimmune diseases (AIDs), including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the genetic basis of SjD remains underexplored, limiting our understanding of its connections to other immune-mediated conditions. In this study, we aimed to identify gene networks associated with SjD through the integration of genetic, transcriptomic, and epigenomic data. We further compared the genetic factors of SjD with other immune-mediated diseases. We analyzed genome-wide association studies (GWAS) summary statistics, DNA methylation, and transcriptomic data using our in-house network-based methods, dmGWAS and EW_dmGWAS, to identify key gene modules associated with SjD. In dmGWAS analysis, discovery and evaluation datasets were used to identify consensus results. We conducted gene-set, cell-type, and disease-enrichment analyses on significant gene modules and explored potential drug targets. Genetic correlations and Mendelian randomization were applied to assess SjD’s link with 17 other AIDs and 16 cancer types. dmGWAS identified 207 and 211 gene modules in the discovery and evaluation phases, respectively, while EW_dmGWAS detected 886 modules. Key modules highlighted 55 genes (discovery), 52 genes (evaluation), and 59 genes (EW_dmGWAS), with at least 50 genes from each analysis linked to AIDs and cancer. Enrichment analyses confirmed their relevance to immune and oncogenic pathways. We pinpointed four candidate drug targets associated with AIDs. We developed a novel integrative omics approach to identify potential genetic markers of SjD and compared them with AIDs and cancers. Our approach can be similarly applied to other disease studies. Full article

Senior–Loken syndrome (SLSN) is a group of rare autosomal recessive disorders caused by dysfunction of the primary cilium, primarily affecting the kidneys (typically leading to nephronophthisis) and eyes (typically leading to retinal degeneration). Moreover, patients with SLSN may experience additional multisystemic symptoms, such as developmental delay, intellectual disability, ataxia, and nystagmus. To date, eight genes have been demonstrated to cause SLSN, all encoding for proteins involved in the structure and functions of the primary cilium. This places SLSN within an expanding category of diseases known as “ciliopathies”. Due to the genetic heterogeneity and significant phenotypic overlap with other ciliopathies, establishing a definitive diagnosis during the initial consultation remains a challenge for clinicians. Furthermore, current research on SLSN-related ciliopathies predominantly focuses on renal involvement, while the ocular manifestations remain insufficiently explored and lack a comprehensive review. Therefore, with the goal of offering practical guidance for clinical practice, this review aims to provide a comprehensive overview of the clinical features, along with an ocular perspective on the molecular mechanisms, genetic underpinnings, and advances in the treatment of SLSN. Full article

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by loss of muscle atonia and abnormal behaviors occurring during REM sleep. Idiopathic RBD (iRBD) is recognized as the strongest prodromal hallmark of α-synucleinopathies, with an established conversion rate to a neurodegenerative condition that reaches up to 96.6% at 15 years of follow-up. Moreover, RBD-converters display a more severe clinical trajectory compared to those that do not present with RBD. However, the extent to which iRBD represents a distinct genetic entity or an early manifestation of neurodegeneration remains unclear. To address this, we applied Genomic Structural Equation Modeling (GenomicSEM) using a GWAS-by-subtraction approach to disentangle the genetic architecture of iRBD from the shared genomic liability across α-synucleinopathies. Our findings highlight the SNCA locus as a key genetic regulator of iRBD susceptibility. While iRBD exhibits a partially distinct genetic signature, residual genomic overlap with neurodegenerative traits suggests that its genetic architecture exists along a continuum of α-synucleinopathy risk. In this scenario, the associations with neuroanatomical correlates may serve as early indicators of a trajectory toward future neurodegeneration. These findings provide a framework for identifying biomarkers that could aid in disease stratification and risk prediction, potentially improving early intervention strategies. Full article