ABSTRACT
Objetivo Evaluar la posibilidad de terapia génica en pacientes con enfermedades oculares hereditarias con diagnóstico genético establecido. Los objetivos secundarios son revisar la tasa de diagnóstico genético y hacer una actualización de los genes para los cuales hay estudios clínicos o preclínicos en curso que pudieran permitir la terapia génica. Métodos Estudio observacional, retrospectivo y multicéntrico de 177 pacientes con enfermedades oculares hereditarias a quienes se realizó estudio genético.Resultados De 177 pacientes con estudio genético, se incluyeron 146. Se identificaron variantes causantes de enfermedad en 117 pacientes con lo que se obtuvo una tasa de detección de variantes del 80,1%. Se encontraron variantes patogénicas en 47 genes, siendo ABCA4 el gen más común (17,9%), seguido por CRB1 (11,9%). De los pacientes con diagnóstico genético, el 64,1% tienen una variante en un gen para el cual se ha estudiado terapia génica y solo el 40,1% presentan una variante en genes con estudios para su terapia génica en fase clínica. Conclusiones El estudio genético ha abierto nuevos horizontes en el manejo de pacientes con enfermedades oculares hereditarias. Cerca de dos tercios de los pacientes presentó variantes patogénicas en genes para los cuales se ha evaluado la posibilidad de terapia génica. Sin embargo, muchos estudios se encuentran en fase preclínica. Se debe adecuar las expectativas de los pacientes sometidos a estudio genético y sus familias (AU)
Objective To evaluate the possibility of gene therapy in patients with inherited ocular conditions and established genetic diagnosis. The secondary objectives were to determine the genetic diagnostic rate and to update the list of genes for which there are ongoing clinical trials or preclinical studies that could allow for gene therapy. Methods Observational, retrospective, multicentric study of 177 patients with inherited ocular conditions that underwent genetic testing. Results Of 177 patients with genetic testing, 146 were enrolled for this study. Disease-causing variants were identified in 117 patients (variant detection rate of 80.1%). Pathogenic variants were found in 47 genes, with ABCA4 being the most common gene (17.9%), followed by CRB1 (11.9%). 64.1% of patients with a genetic diagnosis have a variant in genes for which gene therapy has been studied and only 40.1% have a variant in genes with studies for gene therapy in clinical phase. Conclusions Genetic testing has opened new horizons in the management of patients with hereditary ocular diseases. About two-thirds of the patients had pathogenic variants in genes for which gene therapy has been evaluated. However, many studies are in the pre-clinical phase. The expectations of patients undergoing genetic study and their families should be managed accordingly (AU)
Subject(s)
Humans , Genetic Therapy/methods , Retinal Diseases/therapy , Eye Diseases, Hereditary/therapy , Retrospective StudiesABSTRACT
Congenital stationary night blindness (CSNB) is an inherited retinal disease (IRD) that causes night blindness in childhood with heterogeneous genetic, electrophysical, and clinical characteristics. The development of sequencing technologies and gene therapy have increased the ease and urgency of diagnosing IRDs. This study describes seven Taiwanese patients from six unrelated families examined at a tertiary referral center, diagnosed with CSNB, and confirmed by genetic testing. Complete ophthalmic exams included best corrected visual acuity, retinal imaging, and an electroretinogram. The effects of identified novel variants were predicted using clinical details, protein prediction tools, and conservation scores. One patient had an autosomal dominant CSNB with a RHO variant; five patients had complete CSNB with variants in GRM6, TRPM1, and NYX; and one patient had incomplete CSNB with variants in CACNA1F. The patients had Riggs and Schubert-Bornschein types of CSNB with autosomal dominant, autosomal recessive, and X-linked inheritance patterns. This is the first report of CSNB patients in Taiwan with confirmed genetic testing, providing novel perspectives on molecular etiology and genotype-phenotype correlation of CSNB. Particularly, variants in TRPM1, NYX, and CACNA1F in our patient cohort have not previously been described, although their clinical significance needs further study. Additional study is needed for the genotype-phenotype correlation of different mutations causing CSNB. In addition to genetic etiology, the future of gene therapy for CSNB patients is reviewed and discussed.
Subject(s)
Eye Diseases, Hereditary , Genetic Diseases, X-Linked , Myopia , Night Blindness , Humans , Eye Diseases, Hereditary/genetics , Eye Diseases, Hereditary/therapy , Eye Diseases, Hereditary/diagnosis , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/therapy , Mutation , Myopia/diagnosis , Myopia/genetics , Myopia/therapy , Night Blindness/diagnosis , Night Blindness/genetics , Night Blindness/therapy , Pedigree , TRPM Cation Channels/geneticsABSTRACT
Inherited retinal disorders (IRD) are a common cause of severe visual impairment among children and young adults in Denmark. Gene therapy with voretigene neparvovec for a specific, and in Denmark common, cause of IRD (RPE65-related retinal dystrophy) was implemented as standard clinical practice in 2020 as the first of its kind. Twelve Danish patients have been treated with very positive outcomes. Genetically based therapies for other genetic causes of IRD are underway in clinical trials and are expected to change the outlooks for patients who would otherwise become blind early in life.
Subject(s)
Eye Diseases, Hereditary , Retinal Dystrophies , Child , Young Adult , Humans , Genetic Therapy , Retinal Dystrophies/genetics , Retinal Dystrophies/therapy , Eye Diseases, Hereditary/genetics , Eye Diseases, Hereditary/therapy , MutationABSTRACT
Axenfeld-Rieger Syndrome (ARS) is a rare autosomal dominant genetic disease with considerable expressive variability, characterized by ocular and non-ocular manifestations, cardiovascular, mild craniofacial abnormalities and dental malformations. Current data report an incidence of Xenfeld-Rieger syndrome in the population of 1: 200,000.The case described is that of a 14-year-old female patient whose ARS is suspected and investigated following a dental specialist visit for orthodontic reasons, acquired the patient's family and clinical data following a medical approach multidisciplinary, we proceed to the orthodontic involved the use of the Rapid Palatal Expander (RPE) and a fixed orthodontic treatment.The aim of this study is to report the case of the orthopaedic and orthodontic treatment in a patient affected by ARS and with facial dysmorphism and teeth anomalies associated to ocular anomalies.
Subject(s)
Eye Abnormalities , Eye Diseases, Hereditary , Orthopedics , Adolescent , Anterior Eye Segment/abnormalities , Child , Eye Abnormalities/genetics , Eye Diseases, Hereditary/genetics , Eye Diseases, Hereditary/therapy , Female , HumansABSTRACT
Inherited retinal diseases (IRDs) are a heterogeneous group of conditions that include retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EO[S]RD), which differ in severity and age of onset. IRDs are caused by mutations in >250 genes. Variants in the RPE65 gene account for 0.6-6% of RP and 3-16% of LCA/EORD cases. Voretigene neparvovec is a gene therapy approved for the treatment of patients with an autosomal recessive retinal dystrophy due to confirmed biallelic RPE65 variants (RPE65-IRDs). Therefore, the accurate molecular diagnosis of RPE65-IRDs is crucial to identify 'actionable' genotypes-i.e., genotypes that may benefit from the treatment-and is an integral part of patient management. To date, hundreds of RPE65 variants have been identified, some of which are classified as pathogenic or likely pathogenic, while the significance of others is yet to be established. In this review, we provide an overview of the genetic diagnostic workup needed to select patients that could be eligible for voretigene neparvovec treatment. Careful clinical characterization of patients by multidisciplinary teams of experts, combined with the availability of next-generation sequencing approaches, can accelerate patients' access to available therapeutic options.
Subject(s)
Eye Diseases, Hereditary/genetics , Retinal Diseases/genetics , cis-trans-Isomerases/genetics , Eye Diseases, Hereditary/diagnosis , Eye Diseases, Hereditary/therapy , Genetic Counseling , Genetic Testing/methods , Genetic Therapy , Genetic Variation , Genotype , Humans , Mutation , Retinal Diseases/diagnosis , Retinal Diseases/therapyABSTRACT
Ocular morphogenesis in vertebrates is a highly organized process, orchestrated largely by intrinsic genetic programs that exhibit stringent spatiotemporal control. Alternations in these genetic instructions can lead to hereditary or nonhereditary congenital disorders, a major cause of childhood visual impairment, and contribute to common late-onset blinding diseases. Currently, limited treatment options exist for clinical phenotypes involving eye development. This review summarizes recent advances in our understanding of early-onset ocular disorders and highlights genetic complexities in development and diseases, specifically focusing on coloboma, congenital glaucoma and Leber congenital amaurosis. We also discuss innovative paradigms for potential therapeutic modalities.
Subject(s)
Eye Diseases, Hereditary/genetics , Child , Eye/embryology , Eye/metabolism , Eye Diseases, Hereditary/pathology , Eye Diseases, Hereditary/therapy , Genetic Therapy/methods , Humans , Molecular Targeted Therapy/methods , Stem Cell Transplantation/methodsABSTRACT
Ion channels are membrane-spanning integral proteins expressed in multiple organs, including the eye. In the eye, ion channels are involved in various physiological processes, like signal transmission and visual processing. A wide range of mutations have been reported in the corresponding genes and their interacting subunit coding genes, which contribute significantly to an array of blindness, termed ocular channelopathies. These mutations result in either a loss- or gain-of channel functions affecting the structure, assembly, trafficking, and localization of channel proteins. A dominant-negative effect is caused in a few channels formed by the assembly of several subunits that exist as homo- or heteromeric proteins. Here, we review the role of different mutations in switching a "sensing" ion channel to "non-sensing," leading to ocular channelopathies like Leber's congenital amaurosis 16 (LCA16), cone dystrophy, congenital stationary night blindness (CSNB), achromatopsia, bestrophinopathies, retinitis pigmentosa, etc. We also discuss the various in vitro and in vivo disease models available to investigate the impact of mutations on channel properties, to dissect the disease mechanism, and understand the pathophysiology. Innovating the potential pharmacological and therapeutic approaches and their efficient delivery to the eye for reversing a "non-sensing" channel to "sensing" would be life-changing.
Subject(s)
Channelopathies , Eye Diseases, Hereditary , Genetic Diseases, X-Linked , Ion Channels , Leber Congenital Amaurosis , Myopia , Night Blindness , Retinitis Pigmentosa , Animals , Channelopathies/genetics , Channelopathies/metabolism , Channelopathies/pathology , Channelopathies/therapy , Disease Models, Animal , Eye Diseases, Hereditary/genetics , Eye Diseases, Hereditary/metabolism , Eye Diseases, Hereditary/pathology , Eye Diseases, Hereditary/therapy , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/metabolism , Genetic Diseases, X-Linked/pathology , Genetic Diseases, X-Linked/therapy , Humans , Ion Channels/genetics , Ion Channels/metabolism , Leber Congenital Amaurosis/genetics , Leber Congenital Amaurosis/metabolism , Leber Congenital Amaurosis/pathology , Leber Congenital Amaurosis/therapy , Myopia/genetics , Myopia/metabolism , Myopia/pathology , Myopia/therapy , Night Blindness/genetics , Night Blindness/metabolism , Night Blindness/pathology , Night Blindness/therapy , Retinitis Pigmentosa/genetics , Retinitis Pigmentosa/metabolism , Retinitis Pigmentosa/pathology , Retinitis Pigmentosa/therapyABSTRACT
Ophthalmic genetics is a much needed and growing area in India. Ethnic diversity, with a high degree of consanguinity, has led to a high prevalence of genetic disorders in the country. As the second most populous country in the world, this naturally results in a significant number of affected people overall. Practice involves coherent association between ophthalmologists, genetic counselor and pediatricians. Eye genetics in India in recent times has witnessed advanced research using cutting edge diagnostics, next generation sequencing (NGS) approaches, stem cell therapies, gene therapy and genomic editing. This article will highlight the studies reporting genetic variations in the country, challenges in practice, and the latest advances in ophthalmic genetic research in India.
Subject(s)
Eye Diseases, Hereditary/genetics , High-Throughput Nucleotide Sequencing , Ophthalmology/trends , Precision Medicine , Eye Diseases, Hereditary/diagnosis , Eye Diseases, Hereditary/pathology , Eye Diseases, Hereditary/therapy , Genetic Research , Genome, Human/genetics , Genomics/trends , Humans , India/epidemiologyABSTRACT
Current genetic screening methods for inherited eye diseases are concentrated on the coding exons of known disease genes (gene panels, clinical exome). These tests have a variable and often limited diagnostic rate depending on the clinical presentation, size of the gene panel and our understanding of the inheritance of the disorder (with examples described in this issue). There are numerous possible explanations for the missing heritability of these cases including undetected variants within the relevant gene (intronic, up/down-stream and structural variants), variants harbored in genes outside the targeted panel, intergenic variants, variants undetectable by the applied technology, complex/non-Mendelian inheritance, and nongenetic phenocopies. In this article we further explore and review methods to investigate these sources of missing heritability.
Subject(s)
Eye Diseases, Hereditary/diagnosis , Eye Diseases, Hereditary/genetics , Genome, Human/genetics , Genomics/methods , Eye Diseases, Hereditary/epidemiology , Eye Diseases, Hereditary/therapy , Humans , Ophthalmology/trendsABSTRACT
Genetic testing in a multisite clinical trial network for inherited eye conditions is described in this retrospective review of data collected through eyeGENE®, the National Ophthalmic Disease Genotyping and Phenotyping Network. Participants in eyeGENE were enrolled through a network of clinical providers throughout the United States and Canada. Blood samples and clinical data were collected to establish a phenotype:genotype database, biorepository, and patient registry. Data and samples are available for research use, and participants are provided results of clinical genetic testing. eyeGENE utilized a unique, distributed clinical trial design to enroll 6,403 participants from 5,385 families diagnosed with over 30 different inherited eye conditions. The most common diagnoses given for participants were retinitis pigmentosa (RP), Stargardt disease, and choroideremia. Pathogenic variants were most frequently reported in ABCA4 (37%), USH2A (7%), RPGR (6%), CHM (5%), and PRPH2 (3%). Among the 5,552 participants with genetic testing, at least one pathogenic or likely pathogenic variant was observed in 3,448 participants (62.1%), and variants of uncertain significance in 1,712 participants (30.8%). Ten genes represent 68% of all pathogenic and likely pathogenic variants in eyeGENE. Cross-referencing current gene therapy clinical trials, over a thousand participants may be eligible, based on pathogenic variants in genes targeted by those therapies. This article is the first summary of genetic testing from thousands of participants tested through eyeGENE, including reports from 5,552 individuals. eyeGENE provides a launching point for inherited eye research, connects researchers with potential future study participants, and provides a valuable resource to the vision community.
Subject(s)
Choroideremia/genetics , Eye Diseases, Hereditary/genetics , Retinitis Pigmentosa/genetics , Stargardt Disease/genetics , ATP-Binding Cassette Transporters/genetics , Adaptor Proteins, Signal Transducing/genetics , Choroideremia/diagnosis , Choroideremia/epidemiology , Choroideremia/therapy , Extracellular Matrix Proteins/genetics , Eye Diseases, Hereditary/diagnosis , Eye Diseases, Hereditary/epidemiology , Eye Diseases, Hereditary/therapy , Eye Proteins/genetics , Female , Genetic Testing/trends , Genetic Therapy/trends , Humans , Male , Peripherins/genetics , Retinitis Pigmentosa/diagnosis , Retinitis Pigmentosa/epidemiology , Retinitis Pigmentosa/therapy , Stargardt Disease/diagnosis , Stargardt Disease/epidemiology , Stargardt Disease/therapyABSTRACT
South America comprises of heterogeneous topographies, populations, and health care systems. Therefore, it is not surprising to see differences among the countries regarding expertise, education, and practices of ophthalmic genetics for patients with rare eye diseases. Nevertheless, common challenges such as limited genetics training in medical schools and among ophthalmologists, scarcity of diagnostic tools for phenotyping, and expensive genetic testing not covered by the public healthcare systems, are seen in all of them. Here, we provide a detailed report of the current status of ophthalmic genetics, described by the personal views of local ophthalmologists from Brazil, Colombia, Argentina, and Chile. By reporting our strengths and weaknesses as a region, we intend to highlight the need for guidelines on how to manage these patients aligned with public health policies. Our region contributes to research worldwide, with thousands of well diagnosed patients from a number of unique and genetically diverse populations. The constant expansion of ophthalmic genetics and molecular diagnostics requires us to join forces to collaborate across South America and with other countries to improve access to next-generation diagnostics and ultimately improve patient care.
Subject(s)
Eye Diseases, Hereditary/diagnosis , Eye Diseases, Hereditary/genetics , Ophthalmology/trends , Precision Medicine , Eye Diseases, Hereditary/epidemiology , Eye Diseases, Hereditary/therapy , Humans , South America/epidemiologyABSTRACT
El neonato tiene un diámetro horizontal de la córnea, generalmente de hasta 10 mm, con un crecimiento de hasta 2 mm en los primeros 2 años de vida. Presentamos un caso de megalocórnea, un trastorno raro, recesivo, ligado al cromosoma X, en un niño de 3 meses de edad, buscando revisar lo que la literatura médica aporta como información sobre la enfermedad, así como los parámetros diagnósticos y de seguimiento de sus principales diagnósticos diferenciales
The neonate has a horizontal diameter of the cornea, usually up to 10 mm with growth up to 2 mm in the first 2 years of life. We report a case of megalocornea, a rare, recessive, X-linked disorder in a 3-month-old child, seeking to review what the medical literature brings information about the condition, as well as diagnostic and follow-up parameters, of its main differential diagnoses
Subject(s)
Humans , Male , Child , Eye Diseases, Hereditary , Genetic Diseases, X-Linked , Cornea/anatomy & histology , Eye Diseases, Hereditary/diagnosis , Eye Diseases, Hereditary/etiology , Eye Diseases, Hereditary/therapy , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/etiology , Genetic Diseases, X-Linked/therapyABSTRACT
Retinal development is under the coordinated control of overlapping networks of signaling pathways and transcription factors. The paper was conceived as a review of the data and ideas that have been formed to date on homeobox genes mutations that lead to the disruption of eye organogenesis and result in inherited eye/retinal diseases. Many of these diseases are part of the same clinical spectrum and have high genetic heterogeneity with already identified associated genes. We summarize the known key regulators of eye development, with a focus on the homeobox genes associated with monogenic eye diseases showing retinal manifestations. Recent advances in the field of genetics and high-throughput next-generation sequencing technologies, including single-cell transcriptome analysis have allowed for deepening of knowledge of the genetic basis of inherited retinal diseases (IRDs), as well as improve their diagnostics. We highlight some promising avenues of research involving molecular-genetic and cell-technology approaches that can be effective for IRDs therapy. The most promising neuroprotective strategies are aimed at mobilizing the endogenous cellular reserve of the retina.
Subject(s)
Eye Diseases, Hereditary/genetics , Eye Diseases, Hereditary/metabolism , Genes, Homeobox , Retina/metabolism , Retinal Diseases/genetics , Retinal Diseases/metabolism , Animals , Cell- and Tissue-Based Therapy , Disease Models, Animal , Eye Diseases, Hereditary/diagnosis , Eye Diseases, Hereditary/therapy , Genetic Therapy , High-Throughput Nucleotide Sequencing , Humans , Mutation , Pathology, Molecular , Retinal Diseases/diagnosis , Retinal Diseases/therapy , Transcription Factors/metabolismABSTRACT
The neonate has a horizontal diameter of the cornea, usually up to 10mm with growth up to 2mm in the first 2 years of life. We report a case of megalocornea, a rare, recessive, X-linked disorder in a 3-month-old child, seeking to review what the medical literature brings information about the condition, as well as diagnostic and follow-up parameters, of its main differential diagnoses.
Subject(s)
Eye Diseases, Hereditary , Genetic Diseases, X-Linked , Cornea/anatomy & histology , Eye Diseases, Hereditary/diagnosis , Eye Diseases, Hereditary/etiology , Eye Diseases, Hereditary/therapy , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/etiology , Genetic Diseases, X-Linked/therapy , Humans , Infant , MaleABSTRACT
Due to improved phenotyping and genetic characterization, the field of 'incurable' and 'blinding' inherited retinal diseases (IRDs) has moved substantially forward. Decades of ascertainment of IRD patient data from Philadelphia and Toronto centers illustrate the progress from Mendelian genetic types to molecular diagnoses. Molecular genetics have been used not only to clarify diagnoses and to direct counseling but also to enable the first clinical trials of gene-based treatment in these diseases. An overview of the recent reports of gene augmentation clinical trials by subretinal injections is used to reflect on the reasons why there has been limited success in this early venture into therapy. These first-in human experiences have taught that there is a need for advancing the techniques of delivery of the gene products - not only for refining further subretinal trials, but also for evaluating intravitreal delivery. Candidate IRDs for intravitreal gene delivery are then suggested to illustrate some of the disorders that may be amenable to improvement of remaining central vision with the least photoreceptor trauma. A more detailed understanding of the human IRDs to be considered for therapy and the calculated potential for efficacy should be among the routine prerequisites for initiating a clinical trial.
Subject(s)
Clinical Trials as Topic , Eye Diseases, Hereditary/therapy , Genetic Therapy/methods , Gene Transfer Techniques , Humans , Leber Congenital Amaurosis/therapy , Retinal Degeneration/therapy , Retinitis Pigmentosa/therapyABSTRACT
The purpose of this study was to evaluate the retinal function by electroretinograms (ERGs) recorded with the RETeval system using skin electrodes after pars plana vitrectomy (PPV) with gas tamponade in eyes with a rhegmatogeneous retinal detachment (RRD). Flicker ERGs were recorded from 17 eyes with an RRD before (baseline), within 2 weeks after the PPV when the size of the tamponade gas was approximately one-half of the vitreous cavity (P1), and when the gas had been completely absorbed (P2). The amplitudes of the flicker ERGs at each phase were compared to that at the baseline. The median (25th, 75th percentile) of the amplitude was 10.0 µV (5.5, 13.0 µV) at the baseline, 11.7 µV at P1 (7.8, 14.8 µV; P = 0.003), and 17.1 µV at P2 (11.7 23.3 µV; P < 0.001). The ratio of the amplitudes in the affected eye to that in the fellow eye at the baseline and at each phase was calculated, and the ratio of the amplitudes at P1 and P2 were significantly and positively correlated (P = 0.723, P = 0.001; Spearman's rank correlation coefficient). We conclude that recordings the flicker ERGs with skin electrodes can be used to assess the physiology of eyes even with the vitreous cavity half-filled with the gas used to tamponade the retina.
Subject(s)
Electroretinography/methods , Eye Diseases, Hereditary/therapy , Retinal Detachment/therapy , Vitrectomy/methods , Aged , Aged, 80 and over , Electrodes , Female , Humans , Male , Middle Aged , Retina/physiopathology , Retinal Detachment/surgery , Retinal Perforations/surgery , Retrospective Studies , Visual Acuity/physiologyABSTRACT
INTRODUCTION: In published series, a large proportion of patients with craniosynostosis show impaired vision. MATERIALS AND METHODS: A literature review was performed, using the PubMed and Google Scholar databases, to identify original and review articles on the consequences of craniosynostosis on the eyes and visual pathways, and on the ophthalmological management of craniosynostosis. RESULTS AND DISCUSSION: Many ophthalmic, potentially sight-threatening, complications, can occur in patients with craniosynostosis, especially when syndromic. Optic neuropathy, mostly resulting from the papilledema-optic atrophy sequence, secondary to raised intracranial pressure (ICP), should be diagnosed early, in order to promptly lower the ICP. Cyclovertical and horizontal strabismus and refractive errors are frequent in unicoronal synostosis (anterior plagiocephaly) and syndromic craniosynostosis. Exorbitism, encountered in some cases of syndromic craniofacial synostosis, leads to exposure keratopathy, which requires aggressive management to avoid severe irremediable corneal complications. Amblyopia can result from optic neuropathy, corneal opacities, strabismus, or refractive errors. If undiagnosed and untreated at a young age, it results in permanent visual impairment. CONCLUSION: Children with craniosynostosis require a multidisciplinary care network including a pediatric ophthalmologist. Systematic ophthalmological follow-up enables papilledema to be diagnosed and amblyopia to be diagnosed and treated, in order to avoid visual impairment.
Subject(s)
Craniosynostoses/complications , Craniosynostoses/therapy , Eye Diseases, Hereditary/etiology , Eye Diseases, Hereditary/therapy , Vision Disorders/etiology , Vision Disorders/therapy , Adolescent , Child , Child, Preschool , Craniosynostoses/pathology , Humans , Infant , Visual Pathways/pathologyABSTRACT
Cataract, the clinical correlate of opacity or light scattering in the eye lens, is usually caused by the presence of high-molecular-weight (HMW) protein aggregates or disruption of the lens microarchitecture. In general, genes involved in inherited cataracts reflect important processes and pathways in the lens including lens crystallins, connexins, growth factors, membrane proteins, intermediate filament proteins, and chaperones. Usually, mutations causing severe damage to proteins cause congenital cataracts, while milder variants increasing susceptibility to environmental insults are associated with age-related cataracts. These may have different pathogenic mechanisms: Congenital cataracts induce the unfolded protein response and apoptosis. By contrast, denatured crystallins in age-related cataracts are bound by α-crystallin and form light-scattering HMW aggregates. New therapeutic approaches to age-related cataracts use chemical chaperones to solubilize HMW aggregates, while attempts are being made to regenerate lenses using endogenous stem cells to treat congenital cataracts.
Subject(s)
Cataract/genetics , Cataract/therapy , Eye Diseases, Hereditary/genetics , Eye Diseases, Hereditary/therapy , Stem Cell Transplantation , Apoptosis , Cataract/congenital , Crystallins/genetics , HumansABSTRACT
Purpose: Moderate to high hyperopia is associated with visual deficits. Currently, to our knowledge no study has reported its longitudinal refraction change in a large sample of schoolchildren. We investigated the longitudinal changes in spherical equivalent (SE) refractive error among schoolchildren with moderate to high hyperopia. Methods: Medical records of patients seeking refractions at Zhongshan Ophthalmic Center between 2009 and 2017 were reviewed retrospectively. Eligible criteria included hyperopia ≥+2.00 diopters (D) at an initial age of 6 to 8 years, at least three visits, and at least a 2-year follow-up. Individual pattern of refraction development was evaluated based on the mean rate of change in SE. Mixed-effect regression analysis was used to explore factors associated with the rate of change. Results: A total of 1769 cases were identified. Median initial age was 6.4 (interquartile range [IQR], 5.9 to 7.1) years and median age at the final visit was 10.1 (IQR, 8.9 to 11.5) years. Median initial SE was +3.13 (IQR, +2.38 to +5.25) D. On average, participants experienced a myopic shift of -0.35 ± 0.27 D/year. A considerable number of eyes (721, 40.8%) demonstrated a longitudinal change of less than ±0.25 D/year and approximately 1 of 3 (611/1769) eyes demonstrated a change of >-0.50 and ≤-0.25 D/year. Children with greater initial hyperopia (ß = -0.02, P < 0.001) experienced significantly faster reduction in hyperopic refraction. Age and sex had statistically significant but clinically insignificant impacts on the rate of hyperopia reduction. Conclusions: Variation exists in the refraction development of schoolchildren with moderate to high hyperopia. A considerable percentage of eyes demonstrates longitudinally stable refraction.
Subject(s)
Eye Diseases, Hereditary/physiopathology , Hyperopia/physiopathology , Refraction, Ocular/physiology , Visual Acuity , Child , Child, Preschool , Disease Progression , Eye Diseases, Hereditary/diagnosis , Eye Diseases, Hereditary/therapy , Eyeglasses , Female , Follow-Up Studies , Humans , Hyperopia/diagnosis , Hyperopia/therapy , Male , Prognosis , Retrospective Studies , Time Factors , Vision TestsABSTRACT
Enhanced S-cone syndrome (ESCS) is caused by recessive mutations in the photoreceptor cell transcription factor NR2E3. Loss of NR2E3 is characterized by repression of rod photoreceptor cell gene expression, over-expansion of the S-cone photoreceptor cell population, and varying degrees of M- and L-cone photoreceptor cell development. In this study, we developed a CRISPR-based homology-directed repair strategy and corrected two different disease-causing NR2E3 mutations in patient-derived induced pluripotent stem cells (iPSCs) generated from two affected individuals. In addition, one patient's iPSCs were differentiated into retinal cells and NR2E3 transcription was evaluated in CRISPR corrected and uncorrected clones. The patient's c.119-2A>C mutation caused the inclusion of a portion of intron 1, the creation of a frame shift, and generation of a premature stop codon. In summary, we used a single set of CRISPR reagents to correct different mutations in iPSCs generated from two individuals with ESCS. In doing so we demonstrate the advantage of using retinal cells derived from affected patients over artificial in vitro model systems when attempting to demonstrate pathophysiologic mechanisms of specific mutations.