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Journal of Clinical Medicine Feb 2023Macular dystrophies are a heterogeneous group of genetic disorders that often severely threatens the bilateral central vision of the affected patient. While advances in... (Review)
Review
Macular dystrophies are a heterogeneous group of genetic disorders that often severely threatens the bilateral central vision of the affected patient. While advances in molecular genetics have been instrumental in the understanding and diagnosis of these disorders, there remains significant phenotypical variation among patients within any particular subset of macular dystrophies. Electrophysiological testing remains a vital tool not only to characterize vision loss for differential diagnosis but also to understand the pathophysiology of these disorders and to monitor the treatment effect, potentially leading to therapeutic advances. This review summarizes the application of electrophysiological testing in macular dystrophies, including Stargardt disease, bestrophinopathies, X-linked retinoschisis, Sorsby fundus dystrophy, Doyne honeycomb retina dystrophy, autosomal dominant drusen, occult macular dystrophy, North Carolina macular dystrophy, pattern dystrophy, and central areolar choroidal dystrophy.
PubMed: 36835965
DOI: 10.3390/jcm12041430 -
Indian Journal of Ophthalmology Oct 2019
Topics: Humans; Male; Middle Aged; Ophthalmoscopy; Retina; Retinoschisis; Visual Acuity
PubMed: 31546543
DOI: 10.4103/ijo.IJO_193_19 -
Annals of Translational Medicine Aug 2021Inherited retinal diseases (IRDs) are a genetically variable collection of devastating disorders that lead to significant visual impairment. Advances in genetic... (Review)
Review
Inherited retinal diseases (IRDs) are a genetically variable collection of devastating disorders that lead to significant visual impairment. Advances in genetic characterization over the past two decades have allowed identification of over 260 causative mutations associated with inherited retinal disorders. Thought to be incurable, gene supplementation therapy offers great promise in treating various forms of these blinding conditions. In gene replacement therapy, a disease-causing gene is replaced with a functional copy of the gene. These therapies are designed to slow disease progression and hopefully restore visual function. Gene therapies are typically delivered to target retinal cells by subretinal (SR) or intravitreal (IVT) injection. The historic Food and Drug Administration (FDA) approval of voretigene neparvovec for RPE65-associated Leber's congenital amaurosis (LCA) spurred tremendous optimism surrounding retinal gene therapy for various other monogenic IRDs. Novel disease-causing mutations continue to be discovered annually, and targeted genetic therapy is now under development in clinical and preclinical models for many IRDs. Numerous clinical trials for other IRDs are ongoing or have recently completed. Disorders being targeted for genetic therapy include retinitis pigmentosa (RP), choroideremia (CHM), achromatopsia (ACHM), Leber's hereditary optic neuropathy, usher syndrome (USH), X-linked retinoschisis, and Stargardt disease. Here, we provide an update of completed, ongoing, and planned clinical trials using gene supplementation strategies for retinal degenerative disorders.
PubMed: 34532415
DOI: 10.21037/atm-20-4726 -
Asia-Pacific Journal of Ophthalmology... 2018We present an updated clinical review of the pathophysiology, progression, and current treatments in pediatric patients with congenital X-linked retinoschisis (CXLRS).... (Review)
Review
We present an updated clinical review of the pathophysiology, progression, and current treatments in pediatric patients with congenital X-linked retinoschisis (CXLRS). CXLRS is an X-linked inherited retinal degeneration characterized by splitting of the superficial layers of the retina. Most recent classification divides CXLRS into 4 distinct clinical phenotypes: type 1, foveal; type 2, foveolamellar; type 3, complex; and type 4, foveoperipheral. The majority of retinoschisis cavities remain stable throughout life and may spontaneously collapse. However, a select number of patients progress to macula-involving peripheral retinoschisis, rhegmatogenous, and combined tractional-rhegmatogenous detachments that require further intervention. Although several advances have been made over the past several decades, medical therapy remains limited to case series‒based carbonic anhydrase therapy and prophylactic laser retinopexy. Recent advances in genetic-based clinical trials with the retinoschisis gene are promising. Vitreoretinal surgical approaches remain complex, case-based, and require careful planning depending on the configuration and location of the retinoschisis cavity.
Topics: Diagnostic Imaging; Disease Management; Genetic Testing; Genetic Therapy; Humans; Retinoschisis
PubMed: 29633586
DOI: 10.22608/APO.201803 -
BMC Research Notes May 2021Retinoschisis and Norrie disease are X-linked recessive retinal disorders caused by mutations in RS1 and NDP genes respectively. Both are likely to be monogenic and no...
OBJECTIVE
Retinoschisis and Norrie disease are X-linked recessive retinal disorders caused by mutations in RS1 and NDP genes respectively. Both are likely to be monogenic and no locus heterogeneity has been reported. However, there are reports showing overlapping features of Norrie disease and retinoschisis in a NDP knock-out mouse model and also the involvement of both the genes in retinoschisis patients. Yet, the exact molecular relationships between the two disorders have still not been understood. The study investigated the association between retinoschisin (RS1) and norrin (NDP) using in vitro and in silico approaches. Specific protein-protein interaction between RS1 and NDP was analyzed in human retina by co-immunoprecipitation assay and MALDI-TOF mass spectrometry. STRING database was used to explore the functional relationship.
RESULT
Co-immunoprecipitation demonstrated lack of a direct interaction between RS1 and NDP and was further substantiated by mass spectrometry. However, STRING revealed a potential indirect functional association between the two proteins. Progressively, our analyses indicate that FZD4 protein interactome via PLIN2 as well as the MAP kinase signaling pathway to be a likely link bridging the functional relationship between retinoschisis and Norrie disease.
Topics: Animals; Blindness; Eye Proteins; Genetic Diseases, X-Linked; Humans; Mice; Mutation; Nervous System Diseases; Retina; Retinal Degeneration; Retinoschisis; Spasms, Infantile
PubMed: 34039417
DOI: 10.1186/s13104-021-05617-5 -
Journal of Clinical Medicine Jul 2023Peripapillary intrachoroidal cavitation (PICC) is a yellow-orange lesion, located at the outer border of the myopic conus. First described as a localized detachment of... (Review)
Review
Peripapillary intrachoroidal cavitation (PICC) is a yellow-orange lesion, located at the outer border of the myopic conus. First described as a localized detachment of the retinal pigment epithelium, its intrachoroidal location was later revealed, justifying its current name. PICC is related to other myopic complications such as posterior staphyloma, but its pathogenesis is not clear to date. Although it has been considered a benign condition, most eyes with PICC show visual field defects, which leads to diagnostic uncertainty as these deficits resemble those seen in glaucoma. Furthermore, eyes with PICC may develop macular detachment with retinoschisis. Finally, misdiagnosis of PICC as a metastatic choroidal tumor may lead to unnecessary and anxiety-inducing investigations. Advances in optical coherence tomography (OCT) imaging have improved the visualization of ocular structures, contributing to the understanding of PICC. Recently, high optic nerve sheath traction forces during eye movements in highly myopic eyes have been suggested as promoters of PICC, renewing interest around this condition. However, a review of PICC is still lacking. Therefore, we aimed to provide a concise yet comprehensive overview of the current state of the art, focusing on OCT illustrations, pathophysiology and potential future perspectives based on the biomechanics of the optic nerve.
PubMed: 37510829
DOI: 10.3390/jcm12144712 -
Ophthalmology May 2022To examine the genetic and clinical features in children and adults with X-linked retinoschisis (XLRS). (Observational Study)
Observational Study
PURPOSE
To examine the genetic and clinical features in children and adults with X-linked retinoschisis (XLRS).
DESIGN
Single-center consecutive, retrospective, observational study.
PARTICIPANTS
Adults and children with molecularly confirmed XLRS followed up between 1999 and 2020.
METHODS
Analysis of genetic, clinical, and retinal imaging findings, including OCT and fundus autofluorescence (FAF), cross-sectionally and longitudinally, was performed.
MAIN OUTCOMES MEASURES
RS1, variants, type of variants and phenotype correlations, age of onset, complications rates and types, fundoscopy findings, OCT metrics, FAF patterns, correlations including between best corrected visual acuity (BCVA) and age, and OCT characteristics.
RESULTS
One hundred thirty-two male patients were identified harboring 66 retinoschisin 1 variants, with 7 being novel. The mean age at onset was 16.5 years (range, 0-58 years). Seventy-one patients (71/75 [94.7%]) were symptomatic at presentation; all had decreased best-corrected visual acuity (BCVA). Funduscopy findings were symmetric in 104 patients (104/108 [96.3%]), with the most common finding being macular schisis (82.4%), whereas peripheral retinoschisis was present in 38.9% and macular atrophy was present in 11.1%. Twenty patients (18.5%) demonstrated complications (vitreous hemorrhage, retinal detachment, or both). Mean BCVA was 0.65 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/89) in the right eye and 0.64 logMAR (Snellen equivalent, 20/87) in the left eye. Mean BCVA change over a mean interval of 6.7 years was 0.04 and 0.01 logMAR for right and left eyes, respectively. A normal FAF pattern was identified in 16 of 106 eyes (15.1%); 45 eyes (42.5%) showed a spoke-wheel pattern, 13 eyes (12.3%) showed foveal hyperautofluorescence, and 18 eyes (17.0%) showed a central reduction in signal. In total, 14 patients demonstrated evidence of progression on FAF over time. On OCT, foveoschisis was observed in 172 eyes (172/215 [80%]), parafoveal schisis was observed in 171 eyes (171/215 [79.5%]), and foveal atrophy was observed in 44 eyes (44/215 [20.5%]). Cystoid changes were localized to the inner nuclear layer (172/181 eyes [95%]), the outer nuclear layer (97/181 [53.6%]), and the ganglion cell layer (92/181 [50.8%]). Null variants were associated with worse final BCVA and aforementioned complications.
CONCLUSIONS
X-linked retinoschisis is highly phenotypically variable, but with relative foveal and BCVA preservation until late adulthood, allowing more accurate prognostication. The slowly (often minimally) progressive disease course may pose a challenge in identification of early end points for therapeutic trials aimed at altering the kinetics of degeneration.
Topics: Adult; Atrophy; Electroretinography; Eye Proteins; Humans; Male; Retina; Retinoschisis; Retrospective Studies; Tomography, Optical Coherence; Vision Disorders
PubMed: 34822951
DOI: 10.1016/j.ophtha.2021.11.019 -
Journal of Clinical Medicine May 2023X-linked retinoschisis (XLRS) shows features also seen in patients with uveitis and is recognized as an uveitis masquerade syndrome. This retrospective study aimed to...
X-linked retinoschisis (XLRS) shows features also seen in patients with uveitis and is recognized as an uveitis masquerade syndrome. This retrospective study aimed to describe characteristics of XLRS patients with an initial uveitis diagnosis and to contrast these to patients with an initial XLRS diagnosis. Patients referred to a uveitis clinic, which turned out to have XLRS ( = 4), and patients referred to a clinic for inherited retinal diseases ( = 18) were included. All patients underwent comprehensive ophthalmic examinations, including retinal imaging with fundus photography, ultra-widefield fundus imaging, and optical coherence tomography (OCT). In patients with an initial diagnosis of uveitis, a macular cystoid schisis was always interpreted as an inflammatory macular edema; vitreous hemorrhages were commonly interpreted as intraocular inflammation. Patients with an initial diagnosis of XLRS rarely (2/18; = 0.02) showed vitreous hemorrhages. No additional demographic, anamnestic, and anatomical differences were found. An increased awareness of XLRS as a uveitis masquerade syndrome may facilitate early diagnosis and may prevent unnecessary therapies.
PubMed: 37297924
DOI: 10.3390/jcm12113729 -
Frontiers in Medicine 2023X-linked retinoschisis (XLRS) is an inherited retinal disease (IRD) caused by pathogenic mutations in the retinoschisin gene, . Affected individuals develop retinal...
INTRODUCTION
X-linked retinoschisis (XLRS) is an inherited retinal disease (IRD) caused by pathogenic mutations in the retinoschisin gene, . Affected individuals develop retinal layer separation, leading to loss of visual acuity (VA). Several XLRS gene therapy trials have been attempted but none have met their primary endpoints. An improved understanding of XLRS natural history and clinical outcomes may better inform future trials. Here, we report the long-term functional and structural outcomes of XLRS and the relevance of genotypes to the visual prognosis of affected individuals.
METHODS
A retrospective chart review of patients with molecularly confirmed X-linked retinoschisis was performed. Functional and structural outcomes, and RS1 genotype data, were included for analysis.
RESULTS
Fifty-two patients with XLRS from 33 families were included in the study. Median age at symptom onset was 5 years (range 0-49) and median follow-up was 5.7 years (range 0.1-56.8). Macular retinoschisis occurred in 103 of 104 eyes (99.0%), while peripheral retinoschisis occurred in 48 of 104 eyes (46.2%), most often in the inferotemporal quadrant (40.4%). Initial and final VA were similar (logMAR 0.498 vs. 0.521; = 0.203). Fifty of 54 eyes (92.6%) developed detectable outer retinal loss by age 20, and 29 of 66 eyes (43.9%) had focal or diffuse outer retinal atrophy (ORA) by age 40. ORA but not central subfield thickness (CST) was associated with reduced VA. Inter-eye correlation was modest for VA (-squared = 0.03; = 0.08) and CST (-squared = 0.15; = 0.001). Carbonic anhydrase inhibitors (CAIs) improved CST ( = 0.026), but not VA ( = 0.380). Eight of 104 eyes (7.7%) had XLRS-related retinal detachment (RD), which was associated with poorer outcomes compared to eyes without RD (median final VA 0.875 vs. 0.487; <0.0001). null genotypes had greater odds of at least moderate visual impairment at final follow-up (OR 7.81; 95% CI 2.17, 28.10; = 0.002) which was independent of age at onset, initial CST, initial ORA, or previous RD.
DISCUSSION
Overall, long-term follow-up of XLRS patients demonstrated relatively stable VA, with presenting CST, development of ORA, and null mutations associated with poorer long-term visual outcomes, indicating a clinically relevant genotype-phenotype correlation in XLRS.
PubMed: 37396901
DOI: 10.3389/fmed.2023.1204095 -
Clinical Ophthalmology (Auckland, N.Z.) 2020Pathologic myopia (PM) is an ocular disorder characterized by a spherical equivalent (SE) of more than - 6.0 diopters (D) or by an axial length (AL) of more than 26.5... (Review)
Review
Pathologic myopia (PM) is an ocular disorder characterized by a spherical equivalent (SE) of more than - 6.0 diopters (D) or by an axial length (AL) of more than 26.5 millimeters (mm). PM is associated with myopic maculopathy (MM). The ATN classification describes all the aspects of MM which regroups atrophic, tractional and neovascular consequences to the sclera, choroid and retina of highly myopic eyes. The advent of OCT allowed to define the ultrastructural characteristics of the tractional changes in MM, described by the term myopic traction maculopathy (MTM). They include foveoschisis/maculoschisis/retinoschisis (FS/MS/RS), retinal/foveal detachment (RD/FD), lamellar macular holes (LMH) and full-thickness macular holes (FTMH) with or without RD (MHRD). The MTM staging system (MSS) describes all foveal and retinal changes related to MTM and their natural history interpreting them as different stages of a single progressive disorder. The management of MTM can be just observation for the earliest cases with good vision or surgery for the severe stages with vision loss. There are two possible surgical approaches: ab externo, that acts on the alteration of the scleral shape and includes posterior scleral reinforcement and macular buckle. Ab interno, that targets the alteration of the foveal profile and consists in pars plana vitrectomy with removal of all the epiretinal tractions, maneuvers on the internal limiting membrane, and the use of intravitreal tamponade and laser. As they target two different sides of the same pathology, the two techniques have to be selected on the base of the MTM stage, single or combined.
PubMed: 33173268
DOI: 10.2147/OPTH.S237483