X-linked Juvenile Retinoschisis Research Articles

Early Developmental Characteristics and Features of a Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis

X-linked juvenile retinoschisis (XLRS) is a hereditary retinal degeneration affecting young males caused by mutations in the retinoschisin (RS1) gene. We generated human induced pluripotent stem cells (hiPSCs) from XLRS patients and established three-dimensional retinal organoids (ROs) for disease investigation. This disease model recapitulates the characteristics of XLRS, exhibiting defects in RS1 protein production and photoreceptor cell development. XLRS ROs also revealed dysregulation of Na/K-ATPase due to RS1 deficiency and increased ERK signaling pathway activity. Transcriptomic analyses of XLRS ROs showed decreased expression of retinal cells, particularly photoreceptor cells. Furthermore, relevant recovery of the XLRS phenotype was observed when co-cultured with control ROs derived from healthy subject during the early stages of differentiation. In conclusion, our in vitro XLRS RO model presents a valuable tool for elucidating the pathophysiological mechanisms underlying XLRS, offering insights into disease progression. Additionally, this model serves as a robust platform for the development and optimization of targeted therapeutic strategies, potentially improving treatment outcomes for patients with XLRS.

Investigating the role of Caspase-1 in a mouse model of Juvenile X-linked Retinoschisis

Investigating the role of Caspase-1 in a mouse model of Juvenile X-linked Retinoschisis

Deep Learning with Automatic Data Augmentation for Segmenting Schisis Cavities in the Optical Coherence Tomography Images of X-Linked Juvenile Retinoschisis Patients.

X-linked juvenile retinoschisis (XLRS) is an inherited disorder characterized by retinal schisis cavities, which can be observed in optical coherence tomography (OCT) images. Monitoring disease progression necessitates the accurate segmentation and quantification of these cavities; yet, current manual methods are time consuming and result in subjective interpretations, highlighting the need for automated and precise solutions. We employed five state-of-the-art deep learning models-U-Net, U-Net++, Attention U-Net, Residual U-Net, and TransUNet-for the task, leveraging a dataset of 1500 OCT images from 30 patients. To enhance the models' performance, we utilized data augmentation strategies that were optimized via deep reinforcement learning. The deep learning models achieved a human-equivalent accuracy level in the segmentation of schisis cavities, with U-Net++ surpassing others by attaining an accuracy of 0.9927 and a Dice coefficient of 0.8568. By utilizing reinforcement-learning-based automatic data augmentation, deep learning segmentation models demonstrate a robust and precise method for the automated segmentation of schisis cavities in OCT images. These findings are a promising step toward enhancing clinical evaluation and treatment planning for XLRS.

X-linked juvenile retinoschisis associated with an RS1 in-frame deletion and bilateral central serous chorioretinopathy.

To report the case of a patient with X-linked juvenile retinoschisis (XLRS), caused by an in-frame deletion of the RS1 gene, who presented visual loss due to bilateral central serous chorioretinopathy (CSC).Methods: Observational case report. A 34-year-old man, with type-A personality, presented with a one-month history of decreased visual acuity and metamorphopsia in his right eye. Funduscopic examination showed a dome-like foveal elevation in both eyes (OU), as well as subtle pigmentary changes of the retinal pigment epithelium with a tapetal reflex in the fovea. Spectral-domain optical coherence tomography revealed intraretinal cystic foveal changes and serous retinal detachment in OU. Fundus fluorescein angiography of OU showed a focal area of intense hyperfluorescence with leakage in late phases. Electroretinogram revealed a markedly attenuated b-wave and a diminished a-wave in photopic and scotopic phases. Genetic testing revealed a hemizygous c.282_284delCTT deletion in the RS1 gene, predicting a p.Ser95del change at the protein level. The patient was diagnosed with XLRS and central serous chorioretinopathy as a coexisting condition. Patient was observed during a 3-month period but showed no improvement. Therefore, subthreshold micropulse laser was applied, achieving complete resolution of signs and symptoms of CSC. CSC can be a cause of acute or subacute visual loss in patients with XLRS when other complications such as vitreous hemorrhage and retinal detachment have been excluded.

Do the retinal abnormalities in X-linked juvenile retinoschisis include impaired phototransduction?

X-linked juvenile retinoschisis (XLRS), a hereditary retinal disorder primarily affecting males, is characterized by the formation of cystic spaces between the outer plexiform layer and outer nuclear layer of the retina. Mutations in the RS1 gene, which encodes the extracellular binding protein retinoschisin, are responsible for XLRS pathogenesis. While the role of retinoschisin in maintaining retinal integrity is well established, there is growing evidence suggesting compromised photoreceptor function in XLRS. To investigate the molecular pathways affected by RS1 deficiency, particularly in phototransduction, we performed electroretinographic (ERG) and proteomic analyses on retinae from Rs1 knockout mice, a model of human XLRS. The Rs1 knockout mice had reduced ERG a-wave amplitudes. Correspondingly, differential expression analysis revealed downregulation of proteins crucial for phototransduction, with Ingenuity Pathway Analysis (IPA) highlighting “phototransduction” as the most significantly downregulated biological theme. Compensatory mechanisms were also observed in the IPA, including upregulation of synaptic remodeling, inflammation, cell adhesion, and G-protein signaling. These findings strongly implicate an underrecognized role of photoreceptor dysfunction in XLRS pathology. We speculate that entrapment of mutant retinoschisin protein within photoreceptor inner segments as well as disrupted reciprocal regulation between L-type voltage-gated calcium channels and retinoschisin contribute to the dysfunction in photoreceptors.

Hyaluronic acid-based nanoparticles to deliver drugs to the ocular posterior segment

Ocular posterior segment diseases such as uveitis, X-linked juvenile retinoschisis, or age-related macular degeneration usually result in progressive and irreversible vision loss. Although intravitreal injection is the main way to deliver drugs to the posterior eye, it still has shortcomings as an invasive operation. Nanocontrolled drug delivery technology is a promising option to avoid frequent injections. Due to the particularity of the human intraocular structure, drugs have unique pharmacokinetic characteristics in the eye. Various nanoparticles have been successfully investigated in experimental studies for vitreous injection, with advantages and drawbacks. Here, we introduce an ideal nanopolymer modifier to build nanodelivery systems in vitreous cavities. Hyaluronic acid (HA) is a natural polysaccharide with a broad molecular weight range, negatively charged surface, ligand–receptor binding capabilities, and hyaluronidase breakdown capability. Advances in CD44 receptor targeting for HA-based nanoparticles can improve mobility and penetration in the vitreous and retina, stabilize the nanoparticles, and regulate drug release. This review summarizes the intravitreal administration of nanoplatforms based on HA and the benefits of HA in drug delivery systems.

TOPICAL CARBONIC ANHYDRASE INHIBITORS IN THE LONG-TERM TREATMENT OF JUVENILE X-LINKED RETINOSCHISIS.

To describe the response to long-term topical dorzolamide treatment in patients with juvenile X-linked retinoschisis and cystic-like foveal lesions. This was a retrospective interventional case series that included 18 eyes of 10 patients with genetically confirmed juvenile X-linked retinoschisis examined at the Cleveland Clinic Cole Eye Institute, a tertiary referral center, between 2005 and 2021. Patients were treated with topical 2% dorzolamide two to three times daily in both eyes. Two eyes were excluded because of retinal detachment. Primary outcome measures were logarithm of minimum angle of resolution visual acuity and optical coherence tomography based central subfield thickness. The mean follow-up was 8.38 years (SD, 3.41 years). The mean baseline and final central subfield thickness was 429.88 µ m (SD, 143.36 µ m) and 372.28 µ m, respectively (SD, 147.13 µ m, P = 0.10). The mean baseline and final logarithm of minimum angle of resolution visual acuity was 0.45 (SD, 0.17) and 0.34, respectively (SD, 0.22, P < 0.01). None of the patients experienced any side effects from topical dorzolamide. The study data support previous reports of improved visual acuity in X-linked retinoschisis patients on topical dorzolamide treatment. This is the longest follow-up for a series of juvenile X-linked retinoschisis patients treated with a topical carbonic anhydrase inhibitor to date. A large, prospective, randomized clinical trial is needed to provide stronger evidence regarding the efficacy of topical carbonic anhydrase inhibitors in juvenile X-linked retinoschisis.

X-linked retinoschisis: OCT-angiography in two brothers from a four-generation family with a p.Arg197Cys pathogenic variant in the RS1 gene.

X-linked juvenile retinoschisis (XLRS) is a rare genetic disease causing retinal splitting. The aim of this work is to describe the optical coherence tomography angiography (OCTA) features in two brothers affected by an hemizygous c.589C>T (p.Arg197Cys) pathogenic variant in exon 6 of the RS1 gene. Each patient underwent a complete ophthalmological examination, including measurement of best corrected visual acuity, slit-lamp biomicroscopy, fundus color photographs, fundus autofluorescence and infrared imaging, fluorescein angiography, spectral-domain optical coherence tomography (SD-OCT) and optical coherence tomography angiography (OCTA). En Face SD-OCT and OCTA revealed the presence of two different pattern of cystic lesions, fusiform and oval, disposed on a petaloid or irregular manner in the perifoveolar area. A widening of the foveal avascular zone with interruption of the vascular arcades was clearly evident. Furthermore, a capillary drop-out was observed in the superficial plexus of the central retina, other than capillary ectasia in the deep capillary plexus. Straight gray lines were visible among the cysts. OCTA data herein described allow a detailed morphological evaluation of XLRS other than a quantitative assessment of retinal capillary flow in this disease. The retinal alterations that we have reported may be helpful to better understand this rare condition with OCTA being a sensitive technique to monitor the evolution of the disease and the response to potential future therapeutic approaches aimed to restore vision.

Generation of a X-linked juvenile retinoschisis patient-derived induced pluripotent stem cell line ZOCi004-A

X-linked juvenile retinoschisis (XLRS), caused by the mutation of RS1 gene, is one of the most common causes of macular degeneration for male adolescents. The mutations and clinical manifestations of the disease are diverse. Neither the relationship between the genotypes and phenotypes, nor the radical treatment like gene therapy has been found by now. Retrospective studies have shown that carbonic anhydrase inhibitors can help reduce cysts. However, the specifically pharmacological mechanism remains unknown. Here, we culture induced pluripotent stem cells by drawing peripheral blood from a patient with XLRS, which are supposed to facilitate related researches.

Spatial and Temporal Integration Abnormalities in X-Linked Retinoschisis.

PurposeTo evaluate spatial and temporal integration across the visual field in individuals with juvenile X-linked retinoschisis (XLRS).MethodsNine subjects with XLRS and 10 visually normal individuals participated. Luminance thresholds were measured at 15 locations along the horizontal visual field meridian. Locations were grouped into four regions for analysis: foveal, parafoveal (2°), perifoveal (5°–10°), and peripheral (10°–60°). For spatial integration measurements, stimulus duration was 100 ms, and size ranged from 0.01 to 2.32 deg2 (Goldmann I–V). For temporal integration measurements, stimulus size was 0.15 deg2 (Goldmann III), and duration ranged from 12 to 800 ms. The effect of stimulus size and duration on the subjects' threshold was described using integration models.ResultsLuminance thresholds for the XLRS group were more elevated for small targets (2.0×–12.6×) than for large targets (1.25×–3.2×) compared to controls for all locations. Likewise, thresholds for the XLRS group were more elevated for short durations (6.3×) than for long durations (4.0×) in the fovea and parafovea but were similarly elevated at all durations (2.0×–2.5×) in the perifovea and periphery. For both the size and duration experiments, thresholds measured in the fovea, parafovea, and perifovea of XLRS subjects were highly similar to those measured from the peripheral field of the controls.ConclusionsSpatial and temporal integration characteristics of the XLRS fovea, parafovea, and perifovea are similar to those of the normal periphery. The results also indicate that scaling stimulus size equates thresholds for the XLRS and control subjects throughout the visual field, but scaling duration does not.

Retinoschisin Deficiency Induces Persistent Aberrant Waves of Activity Affecting Neuroglial Signaling in the Retina.

Genetic disorders that present during development make treatment strategies particularly challenging because there is a need to disentangle primary pathophysiology from downstream dysfunction caused at key developmental stages. To provide a deeper insight into this question, we studied a mouse model of X-linked juvenile retinoschisis, an early-onset inherited condition caused by mutations in the Rs1 gene encoding retinoschisin (RS1) and characterized by cystic retinal lesions and early visual deficits. Using an unbiased approach in expressing the fast intracellular calcium indicator GCaMP6f in neuronal, glial, and vascular cells of the retina of RS1-deficient male mice, we found that initial cyst formation is paralleled by the appearance of aberrant spontaneous neuroglial signals as early as postnatal day 15, when eyes normally open. These presented as glutamate-driven wavelets of neuronal activity and sporadic radial bursts of activity by Müller glia, spanning all retinal layers and disrupting light-induced signaling. This study confers a role to RS1 beyond its function as an adhesion molecule, identifies an early onset for dysfunction in the course of disease, establishing a potential window for disease diagnosis and therapeutic intervention.SIGNIFICANCE STATEMENT Developmental disorders make it difficult to distinguish pathophysiology due to ongoing disease from pathophysiology due to disrupted development. Here, we investigated a mouse model for X-linked retinoschisis, a well defined monogenic degenerative disease caused by mutations in the Rs1 gene, which codes for the protein retinoschisin. We evaluated the spontaneous activity of explanted retinas lacking retinoschisin at key stages of development using the unbiased approach of ubiquitously expressing GCaMP6f in all retinal neurons, vasculature, and glia. In mice lacking RS1, we found that an array of novel phenotypes, which present around eye opening, are linked to glutamatergic neurotransmission and affect visual processing. These data identify a novel pathophysiology linked to RS1, and define a window where treatments might be best targeted.

Retinoschisin and novel Na/K-ATPase interaction partners Kv2.1 and Kv8.2 define a growing protein complex at the inner segments of mammalian photoreceptors

The RS1 gene on Xp 22.13 encodes retinoschisin which is known to directly interact with the retinal Na/K-ATPase at the photoreceptor inner segments. Pathologic mutations in RS1 cause X-linked juvenile retinoschisis (XLRS), a hereditary retinal dystrophy in young males. To further delineate the retinoschisin-Na/K-ATPase complex, co-immunoprecipitation was performed with porcine and murine retinal lysates targeting the ATP1A3 subunit. This identified the voltage-gated potassium (Kv) channel subunits Kv2.1 and Kv8.2 as direct interaction partners of the retinal Na/K-ATPase. Colocalization of the individual components of the complex was demonstrated at the membrane of photoreceptor inner segments. We further show that retinoschisin-deficiency, a frequent consequence of molecular pathology in XLRS, causes mislocalization of the macromolecular complex during postnatal retinal development with a simultaneous reduction of Kv2.1 and Kv8.2 protein expression, while the level of retinal Na/K-ATPase expression remains unaffected. Patch-clamp analysis revealed no effect of retinoschisin-deficiency on Kv channel mediated potassium ion currents in vitro. Together, our data suggest that Kv2.1 and Kv8.2 together with retinoschisin and the retinal Na/K-ATPase are integral parts of a macromolecular complex at the photoreceptor inner segments. Defective compartmentalization of this complex due to retinoschisin-deficiency may be a crucial step in initial XLRS pathogenesis.

X-linked Juvenile Retinoschisis in a Young Female.

X-linked juvenile retinoschisis has recessive inheritance which occurs due to RS1 gene mutation. We report an instance in a female managed with systemic and topical carbonic-anhydrase inhibitors. 18-year female presented with bilateral blurred vision for two years. Best corrected vision was 6/24 right eye and 6/12 left eye. Fundus examination, ocular coherence tomography and fundus fluorescein angiography supported the diagnosis. Systemic and topical carbonic-anhydrase inhibitors were advised and followed for six months with scrutinization of possible adverse drug reaction. Juvenile retinoschisis being rare among females, prompt diagnosis and management helps for the restoration of the vision and foveal anatomy. Keywords: Carbonic anhydrase inhibitors; female; retinoschisin ; X linked juvenile retinoschisis.

X-linked juvenile retinoschisis on swept source OCT, OCT-angiography and “en face” OCT

X-linked juvenile retinoschisis on swept source OCT, OCT-angiography and “en face” OCT

Optical Coherence Tomography Angiography in Pediatric Retinal Disorders.

The rapid and noninvasive nature of optical coherence tomography angiography (OCTA) makes it a potentially valuable tool for imaging the retina in children. With the optimization of tabletop systems and the development of experimental handheld OCTA devices, there is expanded potential for OCTA in the clinic and the operating room. This article reviews the utility of OCTA in some of the most common pediatric retinal disorders. A thorough computerized PubMed search was performed to review relevant published journal articles to contextualize and identify the role of OCTA in common retinal disorders with vascular involvement affecting children. Pertinent results and findings from original investigations and case reports were summarized. The ability to quickly collect both qualitative and quantitative information about retinal microvasculature, in both the clinic and operating room settings, with OCTA, has led to the uncovering of microvascular features and morphologic changes in many pediatric retinal disorders such as Coats Disease, familial exudative vitreoretinopathy, incontinentia pigmenti, sickle cell retinopathy, Stargardt Disease, X-linked juvenile retinoschisis, retinopathy of prematurity, diabetic retinopathy in type 1 diabetes, pediatric retinal tumors, and choroidal neovascularization. OCTA is a relevant tool to aid early detection, guide intervention, monitor treatment response, and understand pathogenesis in a number of pediatric retinal disorders.

Phenotype Heterogeneity and the Association Between Visual Acuity and Outer Retinal Structure in a Cohort of Chinese X-Linked Juvenile Retinoschisis Patients

Purpose: X-linked juvenile retinoschisis (XLRS), caused by mutations in the RS1 gene, is an X-linked recessive inherited disease that typically involves both eyes in the first 2 decades of life. Recently, the phenotype heterogeneity of this condition has drawn increasing attention. We reported various phenotypes caused by RS1 gene mutations in eleven patients from ten Chinese families. Methods: Data on the medical history of the patients from ten Han families of central China were collected. Ophthalmic examinations including best-corrected visual acuity (BCVA), fundus photography, ultra-wide-angle sweep source optical coherence tomography (SS-OCT), and electroretinography (ERG) were performed. Adaptive optics (AO) images were acquired to evaluate the cone photoreceptor mosaic when applicable. Venous blood of the probands and their family members was collected, and DNA was subjected to sequencing based on next-generation sequencing with a custom-designed targeted gene panel PS400 for inherited retinal diseases. Validation was performed by Sanger sequencing and cosegregation. Pathogenicity was determined in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Ten RS1 mutations, including eight missense mutations and two terminator mutations, were identified in 10 XLRS families. c.657C > A (p.C219X) was a novel mutation in this cohort. These patients showed a variety of clinical phenotypes, including fovea schisis, bullous retinoschisis, and macular or peripheral atrophy. Fifteen eyes of eight patients exhibited macular retinoschisis, and twelve eyes of seven patients exhibited peripheral retinoschisis. In addition, three patients showed asymmetrical fundus manifestations. Of importance, three patients without macular retinoschisis were misdiagnosed until genetic testing results were obtained. AO showed a decrease in cone density and loss of regularity in the cystic schisis macular of XLRS. Furthermore, the BCVA was associated with the photoreceptor inner segment and outer segment (IS/OS) thickness. Conclusion: With complicated clinical manifestations, a considerable portion of XLRS patients may present various phenotypes. It should be noted that asymmetry in fundus appearance in both eyes could lead to misdiagnosis easily. Thus, genetic testing is crucial for making a final diagnosis in those patients who are suspected of having amblyopia, bilateral or unilateral macular atrophy, or conditions presenting an asymmetric fundus appearance. In addition, the residual cone photoreceptor structure was critical for the maintenance of useful vision.

Clinical manifestation and current therapeutics in X-juvenile retinoschisis.

X-linked juvenile retinoschisis (XLRS) is one of the common early-onset hereditary retinal degenerative diseases in men. The common symptoms of XLRS range from mild to severe central vision loss and radial stripes created by the fovea, the division of the inner layer of the retina in the peripheral retina and the significant decrease in b-wave amplitude (ERG). Retinoschisin, the 224-amino-acid protein product of the retinoschisis 1 (RS1) gene, contains a discoid domain as the primary structural unit, an N-terminal cleavable signal sequence, and an oligomerization-area component. Retinoschisin is a homo-octamer complex with disulfide links that are released by retinal cells. It helps preserve the retina's integrity by binding to the surface of photoreceptors and bipolar cells. As a recessive genetic disease, XLRS was usually treated by prescribing low vision aids in most clinical cases. A gene replacement therapy based on adeno-associated virus vectors was initiated and showed a breakthrough in treating XLRS in 2014. Understanding the revolution of gene therapy for treating XLRS may accelerate its development and make this gene therapy the template for developing therapeutics against other inherited retinal diseases.

Macular cysts in bietti crystalline dystrophy

Bietti crystalline dystrophy (BCD) is a rare autosomal disorder characterized by the presence of intraretinal crystalline deposits and later chorioretinal degeneration. We describe a case of BCD with macular cysts. Macular cysts have been reported in many retinal dystrophies such as Juvenile X-linked retinoschisis, Goldmann-Favre Syndrome, and fenetrated sheen dystrophy. BCD with macular cysts is rarely reported in the literature.

Analysis of microstructural changes in an X-linked juvenile retinoschisis patient harboring RS1 G668A mutation by en-face optical coherence tomography imaging

<br>Juvenile X-linked retinoschisis (JXLR) is an X-linked recessive retinal dystrophy caused by retinoschisin (<i>RS1</i>) gene mutations. The current study reports and describes the cumulative findings of en-face OCT for a 7-year-old JXLR patient harboring a hemizygous pathogenic <i>RS1</i> mutation (c.G668A; p.Cys223Tyr), where residue 223 is vital for cellular adhesion. Fundoscopy showed cart-wheel appearance at macula. Further, en-face OCT revealed characteristic schitic lesions in the ganglion cell layer, inner plexiform layer, inner nuclear layer, and outer plexiform layer. Our report adds to the Indian <i>RS1</i> mutation spectrum and casts insights into the schisis microstructure using en-face imaging.<br>

Clinical and Genetic Study of X-Linked Juvenile Retinoschisis in the Czech Population.

The aim of this study was to identify RS1 pathogenic variants in Czech patients with X-linked retinoschisis (XLRS) and to describe the associated phenotypes, including natural history, in some cases. Twenty-one affected males from 17 families were included. The coding region of RS1 was directly sequenced and segregation of the identified mutations was performed in available family members. In total, 12 disease-causing variants within RS1 were identified; of these c.20del, c.275G>A, c.[375_379del; 386A>T], c.539C>A and c.575_576insT were novel, all predicted to be null alleles. The c.539C>A mutation occurred de novo. Three patients (aged 8, 11 and 19 years) were misdiagnosed as having intermediate uveitis and treated with systemic steroids. Repeat spectral domain optical coherence tomography examinations in four eyes documented the transition from cystoid macular lesions to macular atrophy in the fourth decade of life. Four individuals were treated with topical dorzolamide and in two of them, complete resolution of the cystic macular lesions bilaterally was achieved, while one patient was noncompliant. Rebound phenomenon after discontinuation of dorzolamide for 7 days was documented in one case. Misdiagnosis of XLRS for uveitis is not uncommon; therefore, identification of disease-causing variants is of considerable benefit to the affected individuals.