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Fundus photography and macular appearance of all patients At the macula of the first patient dystrophic changes, pigment mottling, marked cystic changes can be seen (A1, B1), for the second patient clear spoke-wheel pattern foveal schisis, cystic edema, star-shaped pigment mottling (A2, B2) could be seen, third patient showed foveal schisis and cystic changes (A3, B3).
Source publication
Juvenile X-linked retinoschisis (XLRS, MIM#312700) belongs to a group of the vitreoretinal dystrophies. We aimed to describe the phenotype-genotype correlation of three XLRS cases in juveniles with different novel mutations from the Lithuanian population. The patients demonstrated macular retinoschisis and typical cyst-like cavities on spectral-dom...
Contexts in source publication
Context 1
... eye movements for all patients were full, no squint, anterior segment was unremarkable. In fundus photography ( Figure 1) the macular reflex was lacking bilaterally for all patients, in fundus examination binocular optic papilla was oval, with clear boundaries, pink in color, cup/disc ratio (C/D) was physiological. SD-OCT scans ( Figure 2) of all patients revealed macular schisis with large intraretinal separation mainly in the inner nuclear layer (INL), less in the outer plexiform, outer nuclear layer and ganglion cell layer, extending beyond the foveal area and a certain amount and size of cavities formation. ...
Context 2
... J Ophthalmol, Vol. 11, No. 11, Nov.18, 2018 www.ijo.cn Tel:8629-82245172 8629-82210956 Email:ijopress@163.com or absence of the b-wave as compared to the a-wave (negative ERG). The multifocal ERG was performed for the second and third patients and showed a great reduction of central responses in both eyes. Second and third patients were treated with Nepafenaci 0.1% eye drops ...
Context 3
... eye movements for all patients were full, no squint, anterior segment was unremarkable. In fundus photography ( Figure 1) the macular reflex was lacking bilaterally for all patients, in fundus examination binocular optic papilla was oval, with clear boundaries, pink in color, cup/disc ratio (C/D) was physiological. SD-OCT scans ( Figure 2) of all patients revealed macular schisis with large intraretinal separation mainly in the inner nuclear layer (INL), less in the outer plexiform, outer nuclear layer and ganglion cell layer, extending beyond the foveal area and a certain amount and size of cavities formation. ...
Context 4
... J Ophthalmol, Vol. 11, No. 11, Nov.18, 2018 www.ijo.cn Tel:8629-82245172 8629-82210956 Email:ijopress@163.com or absence of the b-wave as compared to the a-wave (negative ERG). The multifocal ERG was performed for the second and third patients and showed a great reduction of central responses in both eyes. Second and third patients were treated with Nepafenaci 0.1% eye drops ...
Citations
... On the contrary, a Lithuanian study detailed a mutation in a 17-year-old boy with p.R141H, resulting in macular schisis characterized by substantial intraretinal separation primarily within INL, with a lesser degree of involvement in the outer plexiform layer, ONL, and GCL. [33] This discrepancy indicates varying degrees of disease severity across different age groups within various ethnicities. [34] Yet, confirming the associated pathogenicity with XLRS requires larger cohort studies. ...
Purpose:
Retinoschisis is a distinctive condition characterized by intraretinal layer clefts, primarily associated with X-linked recessive inheritance due to RS1 gene mutations. This study aims to uncover the RS1 mutation spectrum in a cohort of 22 X-linked retinoschisis cases from South India and emphasizes the genotypic and phenotypic associations within patients harboring only RS1 mutations.
Methods:
A total of 22 probands were suspected of having X-linked retinoschisis. All study subjects underwent ophthalmic investigations, including assessments of visual acuity, fundus examination, optical coherence tomography (OCT), and electroretinogram (ERG). RS1 gene screening was conducted using Sanger sequencing, and the pathogenicity of the variants was assessed through Sorting Intolerant from Tolerant (SIFT) and PolyPhen-2 in silico tools.
Results:
The study found that the probands had an average visual acuity of 0.79 ± 0.39 log of minimum angle of resolution (logMAR), ranging from 0.17 to 1.77. During fundus examination, the probands exhibited a characteristic spoke wheel-like pattern in the macular region. Furthermore, OCT analysis revealed distinct alterations in the inner retinal microstructure, and ERG results consistently showed a reduction in b-wave amplitude. Eventually, Sanger sequencing results showed hemizygous mutations in the RS1 gene in only 12 probands, including a novel missense mutation in the RS1 gene's signal sequence.
Conclusion:
This study provides valuable insights into the spectrum of RS1 mutations in X-linked retinoschisis probands from South India. It reveals distinct genotypic-phenotypic associations and highlights the clinical manifestations associated with the disease pathogenesis.
... 89 Patients present with a reduction in the b-wave amplitude, known as an 'electronegative response' on full field electroretinography. 90 The presence of pathology in the fovea of all affected patients leads to vision loss, with visual acuity generally stabilising at 6/15 to 6/36. 91,92 There is an association between X-linked retinoschisis and high hyperopia. 93 Diagnosis for X-linked retinoschisis is often delayed until school age, 91 as this is when visual dysfunction is usually noticed. ...
... However, inner nuclear layer schisis has been observed in children (aged 1-17 years) in several studies which have used OCT to analyse X-linked retinoschisis patients. 92,[96][97][98][99][100][101][102] The vast majority of these schisis are located primarily in the macula, with additional schitic pathology in the periphery. However, it has also been shown that RS1 mutations can cause a X-linked retinoschisis phenotype which spares the macula. ...
... 98,105 This reduction in central foveal thickness is likely due to the reduction in the typical schisis type lesion and the formation of atrophic lesions. 106 Strupaite et al. 92 measured central foveal thickness in three patients which showed a similar trend with age. The oldest patient (17 years) had a central foveal thickness in the right eye of 373 μm, which was 197 μm less than any other patient. ...
Recent advances have led to therapeutic options becoming available for people with inherited retinal disease. In particular, gene therapy has been shown to hold great promise for slowing vision loss from inherited retinal disease. Recent studies suggest that gene therapy is likely to be most effective when implemented early in the disease process, making consideration of paediatric populations important. It is therefore necessary to have a comprehensive understanding of retinal imaging in children with inherited retinal diseases, in order to monitor disease progression and to determine which early retinal biomarkers may be used as outcome measures in future clinical trials. In addition, as many optometrists will review children with an inherited retinal disease, an understanding of the expected imaging outcomes can improve clinical care. This review focuses on the most common imaging modality used in research assessment of paediatric inherited retinal diseases: optical coherence tomography. Optical coherence tomography findings can be used in both the clinical and research setting. In particular, the review discusses current knowledge of optical coherence tomography findings in eight paediatric inherited retinal diseases - Stargardt disease, Bests disease, Leber's congenital amaurosis, choroideremia, RPGR related retinitis pigmentosa, Usher syndrome, X-linked retinoschisis and, Batten disease.
... Moreover, the relationship between visual phenotype and genotype in XLRS patients is not transparent. Authors suggested lower ERG amplitudes in patients with variants of severe XLRS compared to variants of mild XLRS [3,20,21], while other authors mention patients with different genotypes and similar phenotypic characterization [22][23][24]. ...
Purpose
In this study, we report a case of a young adult with X-linked juvenile retinoschisis (XLRS) with a rare pathogenic variant in the RS1 gene (c.522 + 2 T > A).
Methods
Ophthalmological evaluation, optical coherence tomography, full-field and multifocal electroretinograms and extensive genetic screening of genes related to visual loss were carried out in the participant.
Results
Clinical ophthalmological exams revealed a mild to moderate impairment of visual acuity. Retinal imaging showed bilateral foveal schisis, as well as normal a-wave, reduction in the b-wave amplitudes in dark- and light- adapted full-field electroretinograms, and abnormal oscillatory potentials. We found also diffuse amplitude reduction in multifocal electroretinogram arrays. A canonical splice variant was identified in the RS1 gene (c.522 + 2 T > A).
Conclusion
A rare pathogenic variant of the RS1 gene was associated with diffuse retinal involvement (central and peripheral retina), probably in inner retina, and mild to moderate visual acuity impairment. The phenotypical characterization of rare mutations is relevant to provide information about the disease.
... 4 The retinoschisin 1 (RS1) gene on chromosome Xp22 is responsible for coding for the retinoschisin protein, which is implicated in cellular adhesion and cell-cell interactions. 5 Mutations in the RS1 gene have been identified as the underlying cause for XLRS. 5 The diagnosis of XLRS is often clinically obtained based on the hallmark of an intraretinal cystoid macular space and foveal schisis. Approximately half of affected patients are also affected by peripheral retinoschisis. ...
... 5 Mutations in the RS1 gene have been identified as the underlying cause for XLRS. 5 The diagnosis of XLRS is often clinically obtained based on the hallmark of an intraretinal cystoid macular space and foveal schisis. Approximately half of affected patients are also affected by peripheral retinoschisis. ...
This case report describes the detailed electrophysiological features and the corresponding relationship with the structural changes in a case of X-linked juvenile retinoschisis (XLRS). A 25-year-old male presented with a history of several years of decreased visual acuity in both eyes. The best corrected visual acuity was 20/200 in oculus dexter (OD) and 20/80 in oculus sinister. Retinoschisis was found in the macula by optical coherence tomography, which was more severe in OD. Electroretinogram revealed a similar electronegative waveform in both eyes. Visual evoked potential detected a reduced amplitude and delayed phase in P100-wave, which was worse in OD. The patient was diagnosed as XLRS and advised to undergo continuous medical observation. He was followed up for the next year, with no significant change in retinal function and structure being observed. These current findings suggest that electrophysiology permits the detailed analysis of the clinical picture of XLRS and helps to gain a deeper understanding of the pathogenesis.
... The hotspot variants of RS1 in European and USA were c.214G>A (p.E72K), c.304C>T (p.R102W), c.421C>T (p.R141C) and c.574G>A (p.P192S). 20 In the present study, the hotspot variants were c.214G>A (p.E72K), c.305G>A (p.R102Q) and c.625C>T (p.R209C). ...
... OCT is effective in the detection of splitting of retinal layers. 20 However, the atypical fundus changes, including macular hole, macular pigmentation, non-cystic atrophy, retinal dragging and exudative maculopathy, make clinical diagnosis difficult. 21 Therefore, genetic testing is necessary to verify the diagnosis. ...
Background/aims
X-linked retinoschisis (XLRS), associated with RS1 , is the most common type of X-linked retinopathy in children. This study aimed to identify clinical and genetic features of retinoschisis in 120 families with RS1 variants in China.
Methods
RS1 variants were collected from our in-house exome data and were predicted by multiple-step bioinformatics analysis. Clinical data of 122 patients from 120 families with potential pathogenic RS1 variants were analysed and summarised, respectively.
Result
Totally, 79 hemizygous variants (53 missense, 25 truncation and 1 indel), were detected. All except one (78/79, 98.7%), including 22 novels, were classified as potential pathogenic and detected exclusively in 120 families with retinoschisis. Clinical data demonstrated an average age of presentation at 5 years (1 month–41 years). Macular changes were classified as macular schisis (87.5%), macular atrophy (10.7%), normal (0.9%) and unclassified (0.9%). Patients with macular atrophy had older age but similar visual acuity compared with macular schisis. Peripheral retinal changes included flat retinoschisis (52.4%), bullous retinoschisis (BRS) (10.7%) and normal-like (36.9%) patients. Spontaneous regression was observed in two patients with BRS on follow-up examination. Visual acuity in the peripheral retinoschisis group was worse than that without peripheral retinoschisis.
Conclusion
Almost all rare RS1 variants were potential pathogenic. All patients with RS1 pathogenic variants showed detectable characteristics in the macula and/or peripheral retina. Our data on RS1 variants and associated clinical phenotypes may be of value for clinical diagnosis and genetic test of retinoschisis.
... A clinical perspective on human XLRS disease serves as a reference point to understand the murine XLRS models. XLRS is also known as Xlinked juvenile retinoschisis and is a bilateral recessively inherited juvenile retinal and macular degeneration with a prevalence estimated between 1/5,000-1/25,000 males worldwide (Chen et al., 2020;Eksandh et al., 2000;George et al., 1995b;Huopaniemi et al., 1999;Neriyanuri et al., 2016;Ores et al., 2018;Shinoda et al., 2000;Sikkink et al., 2007;Simonelli et al., 2003;Stepanova et al., 2021;Strupaite et al., 2018). XLRS was first described by the Austrian ophthalmologist Josef Haas in 1898 who noted many cystic cavities within the retina of two brothers ages 7 and 11 years old. ...
X-linked Retinoschisis (XLRS) is an early-onset transretinal dystrophy, often with a prominent macular component, that affects males and generally spares heterozygous females because of X-linked recessive inheritance. It results from loss-of-function RS1 gene mutations on the X-chromosome. XLRS causes bilateral reduced acuities from young age, and on clinical exam and by ocular coherence tomography (OCT) the neurosensory retina shows foveo-macular cystic schisis cavities in the outer plexiform (OPL) and inner nuclear layers (INL). XLRS manifests between infancy and school-age with variable phenotypic presentation and without reliable genotype-phenotype correlations. INL disorganization disrupts synaptic signal transmission from photoreceptors to ON-bipolar cells, and this reduces the electroretinogram (ERG) bipolar b-wave disproportionately to photoreceptor a-wave changes. RS1 gene expression is localized mainly to photoreceptors and INL bipolar neurons, and RS1 protein is thought to play a critical cell adhesion role during normal retinal development and later for maintenance of retinal structure. Several independent XLRS mouse models with mutant RS1 were created that recapitulate features of human XLRS disease, with OPL-INL schisis cavities, early onset and variable phenotype across mutant models, and reduced ERG b-wave to a-wave amplitude ratio. The faithful phenotype of the XLRS mouse has assisted in delineating the disease pathophysiology. Delivery to XLRS mouse retina of an AAV8-RS1 construct under control of the RS1 promoter restores the retinal structure and synaptic function (with increase of b-wave amplitude). It also ameliorates the schisis-induced inflammatory microglia phenotype toward a state of immune quiescence. The results imply that XLRS gene therapy could yield therapeutic benefit to preserve morphological and functional retina particularly when intervention is conducted at earlier ages before retinal degeneration becomes irreversible. A phase I/IIa single-center, open-label, three-dose-escalation clinical trial reported a suitable safety and tolerability profile of intravitreally administered AAV8-RS1 gene replacement therapy for XLRS participants. Dose-related ocular inflammation occurred after dosing, but this resolved with topical and oral corticosteroids. Systemic antibodies against AAV8 increased in dose-dependent fashion, but no antibodies were observed against the RS1 protein. Retinal cavities closed transiently in one participant. Technological innovations in methods of gene delivery and strategies to further reduce immune responses are expected to enhance the therapeutic efficacy of the vector and ultimate success of a gene therapy approach.
... X-linked retinoschisis (XLRS) is a retinal dystrophy caused by the mutation in the RS1 gene and results in schisis or splitting of the inner layers of the retina. [1] This is in contrast to retinal detachment in which the separation is between the neurosensory retina and retinal pigment epithelium (RPE). This entity has been described in the literature as early as the nineteenth century and with various names, such as "congenital vascular veils," "Juvenile retinoschisis" or "X-linked retinoschisis." ...
Although X-linked retinoschisis is a common retinal degeneration condition, the presence of a large retinal cyst obscuring the visual axis in an infant is a rare presentation. Herein, we describe such a case of a child who presented to us with the diagnosis of retinal detachment in both the eyes. However, following multimodal imaging and electrophysiology, the child was found to have bilateral juvenile retinoschisis with a large retinoschisis cyst involving the visual axis seen intraoperatively in the left eye. A limbal approach followed by lensectomy was used to excise the inner retinal layer of the cyst. The intracystic fluid was then drained and the stretched retinal vessels were endocauterized and severed without causing any iatrogenic outer retinal breaks and retinal detachment. The correct diagnosis and meticulous preoperative planning of the surgical procedure helped us manage this challenging case with a favorable anatomical and functional outcome.
Purpose
X-linked retinoschisis (XLRS), due to loss-of-function mutations in the retinoschisin ( RS1 ) gene, is characterized by a modest to severe decrease in visual acuity. Clinical trials for XLRS utilizing intravitreal (IVT) gene therapy showed ocular inflammation. We conducted a subretinal dose–response preclinical study using rAAV2tYF-CB-h RS1 utilizing the Rs1 knockout ( Rs1 -KO) mouse to investigate short- and long-term retinal rescue after subretinal gene delivery.
Methods
Rs1 -KO mice were subretinally injected with 2 μL of rAAV2tYF-CB-h RS1 vector with 8E9 viral genomes (vg)/eye, 8E8 vg/eye, 8E7 vg/eye, or sham injection, and compared to untreated eyes. Reconstitution of human RS1 protein was detected using western blotting. Analysis of retinal function by electroretinography (ERG) and structural analysis by optical coherence tomography (OCT) were performed at 1, 2, 3, 5, 7, and 12 months post injection (MPI). Immunohistochemistry (IHC) was performed to evaluate cone rescue on the cellular level. Functional vision was evaluated using a visually guided swim assay (VGSA).
Results
Western blotting analysis showed human RS1 protein expression in a dose-dependent manner. Quantification of western blotting showed that the RS1 protein expression in mice treated with the 8E8 vg dose was near the wild-type (WT) expression levels. ERG demonstrated dose-dependent effects: At 1 MPI the 8E8 vg dose treated eyes had higher light-adapted (LA) ERG amplitudes in 3.0 flash and 5 Hz flicker compared to untreated ( p < 0.0001) and sham-treated eyes ( p < 0.0001) which persisted until the 12 MPI endpoint, consistent with improved cone function. ERG b-wave amplitudes were higher in response to dark-adapted (DA) 0.01 dim flash and 3.0 standard combined response (SCR) compared to sham-treated ( p < 0.01) and untreated eyes ( p < 0.001) which persisted until 3 MPI, suggesting short-term improvement of the rod photoreceptors. All injections, including sham-treated, resulted in a cyst severity score of 1 (no cavities), with significant reductions compared to untreated eyes up to 3 MPI ( p < 0.05). The high and low dose groups showed inconsistent ERG improvements, despite reduced cyst severity, emphasizing the dose-dependent nature of gene augmentation’s efficacy and the tenuous connection between cyst reduction and ERG improvement. IHC data showed a significant cone rescue in eyes treated with the 8E8 vg dose compared to sham-treated and untreated eyes. VGSA showed better functional vision in 8E8 vg dose treated mice. Eyes treated with the highest dose showed occasional localized degeneration in the outer nuclear layer.
Conclusion
Our data suggest that a dose of 8E8 vg/eye subretinally improves retinal function and structure in the Rs1 -KO mouse. It improves cone function, rod function, and reduces cyst severity. Sham treatment resolves schisis cysts, but 8E8 vg/eye is needed for optimal retinal electrical function rescue. These findings offer a promising path for clinical translation to human trials.
Introduction
X-linked retinoschisis (XLRS) is a vitreoretinal dystrophy caused by RS1 gene mutations which disrupt retinoschisin protein function. A vital protein for maintaining retinal architecture, the absence of functional retinoschisin leads to the development of intraretinal cysts. The preliminary goal of this study was to investigate a low dose gene therapy in Rs1 knockout (Rs1-KO) mice; however, our experiments revealed an unexpected therapeutic effect of a hypertonic buffer, which led to further exploration of this effect.
Methods
10 Rs1-KO mice were subretinally injected with an AAV2/4 vector containing the RS1 gene driven by an Ef1a promoter. 16 Rs1-KO mice were subretinally injected with a hypertonic buffer (180 mM NaCl 0.001% F68/PBS (pH 7.4)) or an isotonic buffer (155.2 mM NaCl 0.001% F68/PBS, pH 7.0) as a sham control. Endpoints included electroretinogram (ERG), optical coherence tomography (OCT), and a visually guided swim assay (VGSA). An immunohistochemistry assay was used to quantify cone density in buffer injected and treatment-naive eyes.
Results
Unexpectedly, hypertonic buffer-injected eyes had significantly reduced cyst severity at 1 month post-injection (MPI) (p=<0.0001), significantly higher amplitudes in cone-dominant ERGs persisting to 5 months post-injection (5 Hz flicker; p=0.0018; 3.0 Flash; p=0.0060) and demonstrated improved navigational vision in the light compared to untreated Rs1-KO eyes (p<0.0001). To investigate the role of tonicity on this effect, an isotonic buffer-injected cohort was created (155.2 mM NaCl 0.001% F68/PBS, pH 7.0) (n=6). Surprisingly, hypertonic buffer-injected eyes exhibited a greater reduction in cyst severity and demonstrated improved cone-dominant ERG metrics over isotonic buffer-injected eyes. Using an immunohistochemistry assay, we demonstrated greater cone density in hypertonic buffer-injected eyes than untreated controls (p=0.0147), suggesting a possible cone preservation mechanism. Moreover, our findings reveal a negative correlation between the peak severity of cysts and long-term cone-dominant ERG metrics, implying that effectively managing cysts could yield enduring benefits for cone function.
Discussion/Conclusion
This study presents evidence that cyst resolution can be triggered through an osmosis-dependent pathway, and cyst resolution can have long term effects on cone signaling and survival, offering potential insights for the development of novel treatments for patients with XLRS.
Congenital X-linked retinoschisis is a common degenerative retinopathy characterized by bilateral mild to severe visual loss in males with splitting of retinal layers. Onset of the disease is usually during the first decade of life. The most common type is the complex type, and it is also the type in which complications are most common. Visual acuity remains stable in most of the patients however it may deteriorate during the first and second decades of life because of the sight-threatening complications like vitreous hemorrhage, rhegmatogenous retinal detachment, tractional retinal detachment, bullous retinoschisis involving the macula in some of the cases. These complications should be managed appropriately with advanced vitreoretinal surgical techniques. This chapter aimed to cover all aspects of the disease and provide information on the management of complications requiring surgery.KeywordsCongenital X-linked retinoschisisCXLRPediatric retinal detachmentFoveal cystVitreous hemorrhageRhegmatogenous retinal detachmentTractional retinal detachmentExudative retinal detachmentBullous retinoschisisInherited retinal diseasesVitrectomyInner layer retinectomyExternal drainageGene therapy
