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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.

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.

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., (© 2022. The Author(s).)

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.

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., Competing Interests: Declaration of Competing Interest All authors declare that they have no competing interests., (Published by Elsevier B.V.)

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.

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., (Published [2020]. This article is a U.S. Government work and is in the public domain in the USA.)

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., (© 2020 Wiley Periodicals LLC.)

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., (© 2020 Wiley Periodicals LLC.)

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., (© 2020 Wiley Periodicals LLC.)

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., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., (Copyright © 2020 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.)

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.

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.

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., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

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.

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 (β = -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.

Voretigene neparvovec-rzyl was recently approved for the treatment of Leber congenital amaurosis, and the use of gene therapy for eye disease is attracting even greater interest. The eye has immune privileged status, is easily accessible, requires a reduced dosage of therapy due to its size and is highly compartmentalized, significantly reducing systemic spread. Adeno-associated virus (AAV), with its low pathogenicity, prolonged expression profile and ability to transduce multiple cell types, has become the leading gene therapy vector. Target diseases have moved beyond currently untreatable inherited dystrophies to common, partially treatable acquired conditions such as exudative age-related macular degeneration and glaucoma, but use of the technology in these conditions imposes added obligations for caution in vector design. This review discusses the current status of AAV gene therapy trials in genetic and acquired ocular diseases, and explores new scientific developments, which could help ensure effective and safe use of the therapy in the future., (© 2018 Royal Australian and New Zealand College of Ophthalmologists.)

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.

Inherited retinal disease (IRD) affects about 1 in 3000 to 1 in 5000 individuals and is now believed to be the most common cause of blindness registration in developed countries. Until recently, the management of such conditions had been exclusively supportive. However, advances in molecular biology and medical engineering have now seen the rise of a variety of approaches to restore vision in patients with IRDs. Optogenetic approaches are primarily aimed at rendering secondary and tertiary neurons of the retina light-sensitive in order to replace degenerate or dysfunctional photoreceptors. Such approaches are attractive because they provide a "causative gene-independent" strategy, which may prove suitable for a variety of patients with IRD. We discuss theoretical and practical considerations in the selection of optogenetic molecules, vectors, surgical approaches and review previous trials of optogenetics for vision restoration. Optogenetic approaches to vision restoration have yielded promising results in pre-clinical trials and a phase I/II clinical trial is currently underway (ClinicalTrials.gov NCT02556736). Despite the significant inroads made in recent years, the ideal optogenetic molecule, vector and surgical approach have yet to be established., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. The pathophysiology of the interaction between RPE and PR cells preceding the formation of retinal detachment remains not well-understood. Our studies of molecular pathology in the canine BEST1 disease model revealed retina-wide abnormalities at the RPE-PR interface associated with defects in the RPE microvillar ensheathment and a cone PR-associated insoluble interphotoreceptor matrix. In vivo imaging demonstrated a retina-wide RPE-PR microdetachment, which contracted with dark adaptation and expanded upon exposure to a moderate intensity of light. Subretinal BEST1 gene augmentation therapy using adeno-associated virus 2 reversed not only clinically detectable subretinal lesions but also the diffuse microdetachments. Immunohistochemical analyses showed correction of the structural alterations at the RPE-PR interface in areas with BEST1 transgene expression. Successful treatment effects were demonstrated in three different canine BEST1 genotypes with vector titers in the 0.1-to-5E11 vector genomes per mL range. Patients with biallelic BEST1 mutations exhibited large regions of retinal lamination defects, severe PR sensitivity loss, and slowing of the retinoid cycle. Human translation of canine BEST1 gene therapy success in reversal of macro- and microdetachments through restoration of cytoarchitecture at the RPE-PR interface has promise to result in improved visual function and prevent disease progression in patients affected with bestrophinopathies., Competing Interests: Conflict of interest statement: W.W.H. and the University of Florida have a financial interest in the use of AAV therapies, and own equity in a company (AGTC, Inc.) that might, in the future, commercialize some aspects of this work., (Copyright © 2018 the Author(s). Published by PNAS.)

Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous group of non-progressive retinal disorder with largely normal fundus appearance. The mode of inheritance can be autosomal dominant (adCSNB), autosomal recessive (arCSNB) or X-chromosomal (XLCSNB). Additional ocular signs can be myopia, hyperopia, strabismus, nystagmus and reduced visual acuity. The Riggs and Schubert-Bornschein form of CSNB can be discriminated by electroretinography. While the Riggs form represents a dysfunction of the rods, a signal transmission defect from photoreceptors to bipolar cell is described in patients with the more frequently occurring Schubert-Bornschein form. The Schubert-Bornschein form can be further divided into incomplete (icCSNB) and complete (cCSNB) showing different electroretinograms (ERGs). While patients with cCSNB show a dysfunction of the ON-signaling pathway, patients with icCSNB show a dysfunction of the ON- and OFF-signaling pathways, affecting visual acuity as well. Using classical linkage, candidate gene analyses and more recent next-generation sequencing approaches, to date, mutations in 13 different genes have been associated with this disease. In vitro and in vivo models showed a correlation of the phenotype of patients with the expression, protein localization and function of the respective molecules: genes, mutated in patients with the Riggs form of CSNB have an important role in the rod phototransduction cascade. Genes mutated in patients with icCSNB, code for proteins important for glutamate neurotransmitter release at the synaptic cleft of the photoreceptors. Genes mutated in patients with cCSNB, code for proteins important for glutamate uptake and further signal transmission to the ON-bipolar cells. Preliminary in vivo studies showed that CSNB may be cured by gene therapy. These studies concerning CSNB are important for the precise diagnosis of patients with this disease, but are also helpful in deciphering key molecules essential for signal transmission from photoreceptors to bipolar cells. So far, it is a poorly understood field., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

We report two cases of bilateral severe familial exudative vitreoretinopathy (FEVR) presenting with bilateral angle closure glaucoma, with evidence of neovascularization in one eye of each case. Both cases displayed bilateral disc dragging with evidence of avascular retinae on fundus fluorescein angiography. Retinal laser photocoagulation and antivascular endothelial growth factor injections provided satisfactory regression of the neovascularization. Medical management of glaucoma was administered to both patients. Lens aspiration with posterior chamber intraocular lens implantation was performed for one eye of each patient. It helped in clearing media as well as in increasing anterior chamber depth, helping in indirect control of intraocular pressure. Although the primary pathology of FEVR lies in the retina, a comprehensive glaucoma screening is essential. We conclude that neovascular glaucoma albeit uncommon in FEVR, may be the presenting feature in advanced unlasered cases, and should be specifically looked for.

The most common iris lesions are iris nevi, iris melanomas and iris pigment epithelium cysts. However, there is an abundance of rare differential diagnoses that have to be considered, including other melanocytic and non-melanocytic lesions. Diagnostic tools include the slit lamp examination, gonioscopy, tonometry, transillumination, ultrasound biomicroscopy (UBM), optical coherence tomography, fluorescein angiography and standardized photography-assisted documentation. The timely identification of malignant lesions (i.e. iris melanoma) is paramount. To assess malignancy criteria of iris nevi, the ABCDEF rule (age young, blood, clock hour inferior, diffuse growth, ektropion uveae, feathery margins) can be applied. Statistically, up to 11% of iris nevi may develop into iris melanomas within 20 years. TNM Staging follows the 2010 AJCC cancer staging manual and helps determine the optimal treatment strategy. Treatment options include radiotherapy, such as plaque brachytherapy and proton beam radiation therapy, as well as surgical excision. Both the surgical and the radiotherapeutic approaches show comparable local tumor control rates. However, the spectrum of therapy-related side effects and complications may differ amongst treatment modalities. After initial treatment, patients should be followed up every 3 - 6 months. Tumor-related mortality ranges between 0 - 11% and is significantly lower than in other uveal melanomas. A prognostic value of common genetic alterations, which have been identified as significant prognostic factors in posterior uveal melanoma, could not be shown for iris melanoma., Competing Interests: Interessenkonflikt: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: To analyse the visual quality achieved by fitting corneo-scleral contact lenses (CScL) in an uncommon case of bilateral keratoconus, high hyperopia and astigmatism., Methods: A 45-year-old man presented for eye examination due to the unsatisfactory quality of his vision wearing soft toric contact lenses. He presented high hyperopia and astigmatism with bilateral keratoconus. He was fitted with CScL to correct his irregular astigmatism and ocular aberrations. A diagnostic trial set was used in the fitting process and he was assessed according to standardised fitting methodology. Visual acuity, corneal topography, biometry and ocular aberrations were evaluated. The follow-up period was 1year., Results: The best spectacle-corrected visual acuity was 20/32 with +8.00/-4.50×30° for the right eye (RE) and 20/25 with +7.75/-2.25×120° for the left eye (LE). After CScL fitting, visual acuity was improved to 20/20 and 20/16 for the RE and LE, respectively. The patient wore these contact lenses an average of 13h a day. The total high order aberrations decreased by approximately 79% in the RE (2.37-0.50μm) and 47% in the LE (1.04-0.55μm) after CScL fitting. Visual quality and wearing time were maintained after 1year wearing CScL. In addition, no adverse ocular effects were found during this period., Conclusion: The present case report describes how the patient had CScL fitted successfully for management of keratoconus with high hyperopia and astigmatism. They provided optimal visual quality, along with prolonged use times and no adverse effects to the cornea., (Copyright © 2017 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by severe congenital/early infancy visual loss, nystagmus, amaurotic pupils and markedly reduced/absent full-field electroretinograms. The vast genetic heterogeneity of inherited retinal disease has been established over the last 10 - 20 years, with disease-causing variants identified in 25 genes to date associated with LCA/EOSRD, accounting for 70-80% of cases, with thereby more genes yet to be identified. There is now far greater understanding of the structural and functional associations seen in the various LCA/EOSRD genotypes. Subsequent development/characterisation of LCA/EOSRD animal models has shed light on the underlying pathogenesis and allowed the demonstration of successful rescue with gene replacement therapy and pharmacological intervention in multiple models. These advancements have culminated in more than 12 completed, ongoing and anticipated phase I/II and phase III gene therapy and pharmacological human clinical trials. This review describes the clinical and genetic characteristics of LCA/EOSRD and the differential diagnoses to be considered. We discuss in further detail the diagnostic clinical features, pathophysiology, animal models and human treatment studies and trials, in the more common genetic subtypes and/or those closest to intervention., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Idiopathic intracranial hypertension, otherwise known as primary pseudotumor cerebri syndrome (PTCS), most frequently occurs in obese women of childbearing age. However, children may be affected as well. This review will address recent findings regarding demographics, diagnosis, and treatment of pediatric PTCS. Prepubertal children with primary PTCS have an equal sex distribution and less frequent obesity compared with adult patients. However, female gender and obesity are risk factors for primary PTCS in postpubertal children. Compared with adults, children with PTCS more frequently present with ocular motility deficits and more often have associated medical conditions that increase the risk of developing PTCS. Visual field testing may be unreliable, and the optimal modality to monitor visual function is unknown. MRI shows signs of elevated intracranial pressure (ICP) in children with PTCS similar to that of adults. It has now been established that elevated ICP in children ≤18 years old is greater than 25 cm H20 in nonobese, nonsedated children, and greater than 28 cm H2O in the remainder. Optical coherence tomography (OCT) may be used to distinguish pseudopapilledema from papilledema, monitor response to treatment in preverbal children, and identify patients with PTCS at risk for permanent visual loss. However, the precise role of OCT in the management of pediatric PTCS remains to be determined.

Familial exudative vitreoretinopathy is a hereditary insufficiency of retinal vascularture, which manifests a variety of vitreoretinal abnormalities, including nonvascularlized retina, abnormality of retinal vessel growing, dragged retina, retinal folds and total retinal detachment. While causative genes have been identified, cases are often sporadic. Periodic examination is necessary to find recurrence of the disease and late complications, including rhegmatogenous retinal detachment, cataract and glaucoma.

Genome editing is a cutting-edge technology that generates DNA double strand breaks at the specific genomic DNA sequence through nuclease recognition and cleavage, and then achieves insertion, replacement, or deletion of the target gene via endogenous DNA repair mechanisms, such as non-homologous end joining, homology directed repair, and homologous recombination. So far, more than 600 human hereditary eye diseases and systemic hereditary diseases with ocular phenotypes have been found. However, most of these diseases are of incompletely elucidated pathogenesis and without effective therapies. Genome editing technology can precisely target and alter the genomes of animals, establish animal models of the hereditary diseases, and elucidate the relationship between the target gene and the disease phenotype, thereby providing a powerful approach to studying the pathogenic mechanisms underlying the hereditary eye diseases. In addition, correction of gene mutations by the genome editing brings a new hope to gene therapy for the hereditary eye diseases. This review introduces the molecular characteristics of 4 major enzymes used in the genome editing, including homing endonucleases, zinc finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein 9 (Cas9), and summarizes the current applications of this technology in investigating the pathogenic mechanisms underlying the hereditary eye diseases. (Chin J Ophthalmol, 2017, 53: 386-371 ) .

Bestrophinopathies, one of the most common forms of inherited macular degenerations, are caused by mutations in the BEST1 gene expressed in the retinal pigment epithelium (RPE). Both human and canine BEST1-linked maculopathies are characterized by abnormal accumulation of autofluorescent material within RPE cells and bilateral macular or multifocal lesions; however, the specific mechanism leading to the formation of these lesions remains unclear. We now provide an overview of the current state of knowledge on the molecular pathology of bestrophinopathies, and explore factors promoting formation of RPE-neuroretinal separations, using the first spontaneous animal model of BEST1-associated retinopathies, canine Best (cBest). Here, we characterize the nature of the autofluorescent RPE cell inclusions and report matching spectral signatures of RPE-associated fluorophores between human and canine retinae, indicating an analogous composition of endogenous RPE deposits in Best Vitelliform Macular Dystrophy (BVMD) patients and its canine disease model. This study also exposes a range of biochemical and structural abnormalities at the RPE-photoreceptor interface related to the impaired cone-associated microvillar ensheathment and compromised insoluble interphotoreceptor matrix (IPM), the major pathological culprits responsible for weakening of the RPE-neuroretina interactions, and consequently, formation of vitelliform lesions. These salient alterations detected at the RPE apical domain in cBest as well as in BVMD- and ARB-hiPSC-RPE model systems provide novel insights into the pathological mechanism of BEST1-linked disorders that will allow for development of critical outcome measures guiding therapeutic strategies for bestrophinopathies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Characteristics of inherited retinal dystrophies include deficiencies in light perception and nervous conduction within the retina, leading to reduced vision or even blindness. In this context, the loss of function of photoreceptor-specific genes causes a variety of clinically and aetiologically distinct syndromes - each of them belonging to the group of rare diseases. With a prevalence of 1 in 2500, however, inherited retinal diseases are clinically significant and important - especially since these diseases lead to restrictions of a patient's fitness for work and overall quality of life. More than 250 genetic mutations causing the various types of inherited retinal dystrophies have been identified by now (https://sph.uth.tmc.edu/Retnet). In recent years, preclinical research on suitable animal models has yielded important progress in the understanding of the mutations underlying the pathological and molecular biological processes of these diseases. These findings have led to the development of novel and innovative therapeutic strategies for the treatment of inherited retinal dysfunctions, which are still incurable. Meanwhile, many of the successful preclinical studies have led to translational research projects aiming to find treatment options for human patients. However, some preliminary results of these human translational studies indicate the need to optimise and refine the underlying therapeutic concepts., (Georg Thieme Verlag KG Stuttgart · New York.)

The knowledge of the genetic basis of many eye diseases is constantly increasing. Besides retinal degeneration, developmental defects of the anterior segment, cataracts, and the development of the basic structure are often associated with genetic defects. Moreover, a lot of genetic syndromes involve eye abnormalities. The impact of genetics has become more and more evident in ophthalmological practice. Although genetic counselling is usually carried out by human geneticists, the increasing availability of therapeutic options requires ophthalmologists to have some basic knowledge of the genetic causes and how to identify them. The first step in this regard is to recognise potential genetic eye disorders and to initiate an adequate genetic analysis to confirm the diagnosis. This review discusses possible and necessary investigations within the patient's family facing ophthalmologists after the genetic cause of an eye disease has been identified., (Georg Thieme Verlag KG Stuttgart · New York.)

New genome editing tools in molecular biology are revolutionising precise genome surgery and have greatly influenced experimental ophthalmology too. Aside from the commonly used nuclease-based platforms, such as the zinc-finger nucleases (ZFN) and transcription activator-like effector nucleases (TALEN), CRISPR/Cas systems, clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) genes, perform very efficiently in site-specific DNA cleavage within living cells. DNA double strand breaks (DSB) are repaired through two different conserved repair pathways: NHEJ (non-homologous end joining) and HDR (homology directed repair). By using the correct DNA templates, these repair pathways can be used to knock out defective genes or to repair mutations. Genome editing technology lays the ground for new strategies in basic science, biotechnology, and biomedical science, as well as clinical studies with genome editing. Therapeutic gene editing strategies are now concentrating on diseases in the retina, due to the comparatively easy accessibility of the eye and with local application in vivo., (Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies. This review serves to analyze clinical progress in genetic diagnostic testing and implications for retinal gene therapy., Methods: A literature search of PubMed and OMIM was conducted to relevant articles in inherited retinal dystrophies., Results: Next-generation genetic sequencing allows the simultaneous analysis of all the approximately 250 genes that cause inherited retinal dystrophies. Reported diagnostic rates range are high and range from 51% to 57%. These new sequencing tools are highly accurate with sensitivities of 97.9% and specificities of 100%. Retinal gene therapy clinical trials are underway for multiple genes including RPE65, ABCA4, CHM, RS1, MYO7A, CNGA3, CNGB3, ND4, and MERTK for which a molecular diagnosis may be beneficial for patients., Conclusion: Comprehensive next-generation genetic sequencing of all retinal dystrophy genes is changing the paradigm for how retinal specialists perform genetic testing for inherited retinal degenerations. Not only are high diagnostic yields obtained, but mutations in genes with novel clinical phenotypes are also identified. In the era of retinal gene therapy clinical trials, identifying specific genetic defects will increasingly be of use to identify patients who may enroll in clinical studies and benefit from novel therapies.

Rare genetic diseases affect about 7% of the general population and over 7000 distinct clinical syndromes have been described with the majority being due to single gene defects. This review will provide a critical overview of genetic strategies that are being pioneered to halt or reverse disease progression in inherited neurodegenerative diseases. This field of research covers a vast area and only the most promising treatment paradigms will be discussed with a particular focus on inherited eye diseases, which have paved the way for innovative gene therapy paradigms, and mitochondrial diseases, which are currently generating a lot of debate centred on the bioethics of germline manipulation., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The aim of this review is to provide a comprehensive summary of current gene therapy clinical trials for monogenic and optic nerve disorders.The number of genes for which gene-based therapies are being developed is growing. At the time of writing this review gene-based clinical trials have been registered for Leber congenital amaurosis 2 (LCA2), retinitis pigmentosa 38, Usher syndrome 1B, Stargardt disease, choroideremia, achromatopsia, Leber hereditary optic neuropathy (LHON) and X-linked retinoschisis. Apart from RPE65 gene therapy for LCA2 and MT-ND4 for LHON which has reached phase III, all other trials are in investigation phase I and II, i.e. testing the efficacy and safety.Because of the relatively easy accessibility of the retina and its ease of visualization which allows monitoring of efficacy, gene-based therapies for inherited retinal disorders represent a very promising treatment option. With the development of novel therapeutic approaches, the importance of establishing not only clinical but also molecular genetic diagnosis is obvious.Key words: gene therapy, monogenic retinal diseases, optic nerve atrophy, mitochondrial disease.

Hereditary vitreous degeneration muddy is rare in clinic. Here we report ten cases (thirteen eyes) of hereditary vitreous degeneration muddy from two families. All patients presented with vitreous opacity, and the textures appeared tough and tensile. Two cases had concurrent detachment of rhegmatogenous retina. HE staining showed red changeableness, and methyl violet staining appeared purple. All patients received vitrectomy with traditional Chinese medicine treatment, and got satisfactory efficacy.

The G90D mutation in the rhodopsin gene leads to autosomal dominant congenital stationary night blindness (CSNB) in patients. This occurs because the G90D mutant protein cannot efficiently bind chromophore and is constitutively active. To combat this mutation, we designed and characterized two different hammerhead ribozymes to cleave G90D transcript. In vitro testing showed that the G90D1 ribozyme efficiently and specifically cleaved the mutant transcript while G90D2 cleaved both WT and mutant transcript. AAV-mediated delivery of G90D1 under the control of the mouse opsin promoter (MOP500) to G90D transgenic eyes showed that the ribozyme partially retarded the functional degeneration (as measured by electroretinography [ERG]) associated with this mutation. These results suggest that with additional optimization, ribozymes may be a useful part of the gene therapy knockdown strategy for dominant retinal disease.

A retinal pigmented epithelial (RPE) disorder, bestrophinopathy has recently been proven to be amenable to gene and cell-based therapies in preclinical models. RPE disorders and allied retinal degenerations exhibit significant genetic heterogeneity, and diverse mutations can result in similar disease phenotypes. Several RPE disorders have recently become targets for gene therapies in humans. The year 2011 brought a new advance in cell-based therapies, with the Food and Drug Administration approving clinical trials using embryonic stem cells for an RPE disorder known as age-related macular degeneration. Recent studies on induced pluripotent stem (iPS)-RPE generation indicate strong potential for developing patient-specific disease models in vitro, which could eventually enable personalized treatment. This mini-review will briefly highlight the suitability of the retina for gene and cell therapies, the pathophysiology of bestrophinopathy, and the research and treatment opportunities afforded by stem cell and genetic therapies.

A previously healthy, immunocompetent 67-year-old female presented with a one-month history of general symptoms, weight loss, night fevers, and bilateral lower extremity edema. On admission she had severe anemia, acute kidney injury, and multiple lymphadenopathies. An excisional biopsy of one of the axillary lymphadenopathies confirmed hyaline-vascular Castleman's disease. This rare disease is a polyclonal lymphoproliferative disorder that affects the normal lymph node architecture. According to its location it can be divided in unicentric (localized) or multicentric disease; it can be further divided according to histopathology in hyaline-vascular or plasmatic cells variety. Clinical presentation relates more to histopathological variety than to centricity. Human herpes virus 8 is ubiquitous in this disease and, along with interleukin 6, plays an important role in pathogenesis and symptoms presentation. Surgery is the go-to treatment of localized disease, while systemic chemotherapy is the option in multicentric disease. Communication between the clinical and anatomopathological teams is crucial; lag in diagnosis can lead to futile investigations in search of other diseases and delay in treatment.

Background: Genetic eye pathology represents a significant percentage of the causes of blindness in industrialized countries. This study explores the level of understanding and perceptions of genetics and inherited eye diseases and the attitudes to genetic testing and gene therapy., Methods: The study was conducted in two parts. Participant groups included were: undergraduate students of optometry, primary eye care professionals and members of the general public. A preliminary study aimed to understand perceptions and to explore the level of knowledge about genetics in general, eye genetics and gene therapy. A second survey was designed to explore attitudes to genetic testing and gene therapy., Results: The majority of participants (82%) perceived genetics as an important science. However, none of them showed a high level of understanding of genetics and inherited eye diseases. Undergraduate students and primary eye care professionals were better informed about inherited eye diseases than the general public (p = 0.001). The majority (80%) across all three groups had a positive attitude to genetic testing and gene therapy. There was a lack of knowledge about the genetic services available among all groups of participants., Conclusion: This calls for serious thinking about the level of dissemination of information about genetics and inherited eye diseases. It shows a broadly supportive attitude to genomic medicine among the public. Improving public awareness and education in inherited eye diseases can improve the utility of genetic testing and therapy.

Congenital stationary night blindness (CSNB) refers to a group of genetically and clinically heterogeneous retinal disorders. Seventeen different genes with more than 360 different mutations and more than 670 affected alleles have been associated with CSNB, including genes coding for proteins of the phototransduction cascade, those important for signal transmission from the photoreceptors to the bipolar cells or genes involved in retinoid recycling in the retinal pigment epithelium. This article describes the phenotypic characteristics of different forms of CSNB that are necessary for accurate diagnosis and to direct and improve genetic testing. An overview of classical and recent methods used to identify specific CSNB genotypes is provided and a meta-analysis of all previously published and novel data is performed to determine the prevalence of disease-causing mutations. Studies of the underlying molecular pathogenic mechanisms based on cell culture techniques and animal studies are outlined. The article highlights how the study of CSNB has increased understanding of the mechanisms of visual signalling in the retina, likely to prove important in developing future treatments for CSNB and other retinal disorders., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Abnormalities in the BEST1 gene have recently been recognised as causing autosomal recessive bestrophinopathy (ARB). ARB has been noted to have a variable phenotypic presentation, distinct from that of autosomal dominant Best vitelliform macular dystrophy (BVMD). Both conditions are associated with deposits in the retina, a reduced or absent electro-oculography (EOG) light rise, and the risk of developing angle-closure glaucoma. Herein, we describe the clinical and genetic characteristics of a young male diagnosed with ARB associated with angle-closure glaucoma resulting from a novel homozygous mutation in BEST1., Methods: All research involved in this case adhered to the tenets of the Declaration of Helsinki. The proband underwent slitlamp examination, retinal autofluorescence imaging and optical coherence tomography after presenting with deteriorating vision. The findings prompted genetic testing with bi-directional DNA sequencing of coding and flanking intronic regions of BEST1. The proband's family members were subsequently screened., Results: A provisional diagnosis of ARB was made based on the findings of subretinal and schitic lesions on fundoscopy and retinal imaging, together with abnormal EOG and electroretinography. Genetic testing identified a novel homozygous mutation in BEST1, c.636+1 G>A. Family members were found to carry one copy of the mutation and had no clinical or electrophysiological evidence of disease. The proband was additionally diagnosed with angle-closure glaucoma requiring topical therapy, peripheral iridotomies and phacoemulsification., Conclusions: Phenotypic overlap, reduced penetrance, variable expressivity and the ongoing discovery of new forms of bestrophinopathies add to the difficulty in distinguishing these retinal diseases. All patients diagnosed with ARB or BVMD should be examined for narrow angles and glaucoma, given their frequent association with these conditions.

Nuclear hormone receptors play a major role in many important biological processes. Most nuclear hormone receptors are ubiquitously expressed and regulate processes such as metabolism, circadian function, and development. They function in these processes to maintain homeostasis through modulation of transcriptional gene networks. In this study we evaluate the effectiveness of a nuclear hormone receptor gene to modulate retinal degeneration and restore the integrity of the retina. Currently, there are no effective treatment options for retinal degenerative diseases leading to progressive and irreversible blindness. In this study we demonstrate that the nuclear hormone receptor gene Nr1d1 (Rev-Erbα) rescues Nr2e3-associated retinal degeneration in the rd7 mouse, which lacks a functional Nr2e3 gene. Mutations in human NR2E3 are associated with several retinal degenerations including enhanced S cone syndrome and retinitis pigmentosa. The rd7 mouse, lacking Nr2e3, exhibits an increase in S cones and slow, progressive retinal degeneration. A traditional genetic mapping approach previously identified candidate modifier loci. Here, we demonstrate that in vivo delivery of the candidate modifier gene, Nr1d1 rescues Nr2e3 associated retinal degeneration. We observed clinical, histological, functional, and molecular restoration of the rd7 retina. Furthermore, we demonstrate that the mechanism of rescue at the molecular and functional level is through the re-regulation of key genes within the Nr2e3-directed transcriptional network. Together, these findings reveal the potency of nuclear receptors as modulators of disease and specifically of NR1D1 as a novel therapeutic for retinal degenerations.

Degenerative lesions of the peripheral retina are present from teenage years onwards and increase with age. These abnormabilities are frequent, some of them being benign while others predispose to retinal tears and detachment. In the latter case, the lesions are rhegmatogenous and may justify prophylactic treatment by laser photocoagulation. We distinguish congenital lesions of the peripheral retina and intraretinal, chorioretinal and vitreoretinal degenerations. The holes and tears observed in 2% of the population consist of round atrophic holes, "horseshoe" tears, oral dialyses and giant tears., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Genetic testing is of increasing clinical utility for diagnosing inherited eye disease. Clarifying a clinical diagnosis is important for accurate estimation of prognosis, facilitating genetic counselling and management of families, and in the future will direct gene-specific therapeutic strategies. Often, precise diagnosis of genetic ophthalmic conditions is complicated by genetic heterogeneity, a difficulty that the so-called 'next-generation sequencing' technologies promise to overcome. Despite considerable counselling and ethical complexities, next-generation sequencing offers to revolutionize clinical practice. This will necessitate considerable adjustment to standard practice but has the power to deliver a personalized approach to genomic medicine for many more patients and enhance the potential for preventing vision loss., (© 2013 Royal Australian and New Zealand College of Ophthalmologists.)

Ongoing clinical trials are targeting several previously intractable hereditary causes of blindness of congenital, childhood or early adulthood onset, mainly in the optic nerve and retina. The intended stage of initiation of the new therapeutic approaches ranges from neonatal life and a structurally intact retinal tissue to adult life with a complete loss of photoreceptors. It must be assumed that some of the trials will succeed in producing new therapies and action must be taken to refine and accelerate diagnostics and to preserve therapeutic potential in blind people.