Congenital X-linked Retinoschisis Research Articles

Генная терапия наследственных заболеваний сетчатки

This scientific literature review demonstrates high prospects of recent developments in gene therapy for the treatment of retinal diseases. First of all it concerns inherited pathologies such as retinitis pigmentosa and Leber congenital amaurosis. Nevertheless gene therapy is still quite far from its tangible application in clinical practice for other retinal diseases, although preliminary trial outcomes of its use for some of them (for example, achromatopsia, congenital X-linked retinoschisis) turn to be very promising. The data presented in this review inspire hope that gene therapy will be more accessible and widely-used in clinical practice. Key words:retinal diseases, inherited retinal diseases, gene therapy, voretigene neparvovec

Experience in managing patients with X-linked congenital retinoschisis

AIM: To describe the clinical manifestations and management experience of patients with X-linked congenital retinoschisis (XLRS).
 MATERIAL AND METHODS: The study was conducted in the ophthalmology department of the multidisciplinary clinical medical center Bonum (Yekaterinburg). Two brothers with XLRS were under observation. They underwent complete ophthalmological examinations, including electrophysiological examinations, optical coherence tomography (OCT), and fundus photoregistration. The mother refused genetic testing.
 RESULTS: Both siblings had early (up to 1 year) manifestations of central foveolamellar and peripheral bullous retinoschisis. The parents are phenotypically healthy, and the relatives have no hereditary eye diseases. The younger brother had a progressive peripheral retinoschisis and underwent barrier laser retinopexy; as a result, the progression stopped at the last examination. Acetazolamide 125 mg given orally daily for 4 weeks did not have a noticeable effect on the volume of bullous cavities. The older brother had been under observation for 4 years, and spontaneous closure of retinal cavities on the periphery in one eye and retinal detachment in the other after surgical treatment of retinoschisis were observed.
 CONCLUSION: Clinical cases of long-term follow-up of two brothers with XLRS are described. OCT is indicated to diagnose, assess the length and the state of the vitreoretinal interface, and monitor XLRS. Electroretignography is a specific and sensitive method for the complex diagnosis of XLRS. Barrier laser retinopexy is indicated for progressive peripheral retinoschisis. The efficacy and safety of carbonic anhydrase inhibitors in patients with XLRS require further study.

A Literary Pediatric Retina Fellowship With Michael T. Trese, MD.

Michael T. Trese, MD (1946-2022), a vitreoretinal surgeon, made significant contributions to the field of retina. Although most known for his work in pediatric retina surgery, he was a pioneer in areas such as medical retina, translational research, and telemedicine. This article reviews his major contributions to spread his knowledge more widely to vitreoretinal trainees and specialists. We discuss six areas where Trese made a lasting impact: lens-sparing vitrectomy, familial exudative vitreoretinopathy, congenital X-linked retinoschisis, autologous plasmin enzyme, regenerative medicine, and telemedicine. [Ophthalmic Surg Lasers Imaging Retina 2023;54:701-712.].

Optical coherence tomography findings of the peripheral retina in patients with congenital X-linked retinoschisis.

Congenital X-linked retinoschisis (XLRS) presents as macular retinoschisis/degeneration in almost all patients and as peripheral retinoschisis in half the patients. Although the optical coherence tomography (OCT) findings of macular retinoschisis have been well investigated, those of peripheral retinoschisis have rarely been reported. This study aimed to report the ultra-widefield OCT findings of the peripheral retina in patients with XLRS. Medical records of 10 Japanese patients (19 eyes) with clinically and/or genetically diagnosed XLRS were retrospectively reviewed. Funduscopic, electroretinographic, and OCT findings were reviewed and evaluated. Some were also genetically evaluated for the RS1 gene. OCT of the macula revealed schises and/or cystoid changes in the inner nuclear layer (INL) and outer nuclear layer. In contrast, OCT of the peripheral retina revealed schises and/or cystoid changes in the INL in eight eyes (44%), and/or splitting in the ganglion cell layer (GCL) in 10 (56%) of the 18 eyes with clear OCT images. No schisis or cystoid changes were found in the peripheral OCT images of eight eyes (44%). A 16-year-old boy presented with retinal splitting of the GCL and INL of the inferior retina, although he had no ophthalmoscopic peripheral retinoschisis. Genetic examinations were performed on three patients, all of whom had reported missense mutations in the RS1 gene. In XLRS, peripheral bullous retinoschisis results from GCL splitting in the retina. One of the 10 patients with XLRS showed intraretinal retinoschisis in the GCL in the inferior periphery, which was unremarkable on ophthalmoscopy (occult retinoschisis). Although both peripheral bullous retinoschisis and occult retinoschisis showed splitting/cystic changes in the GCL, further studies are needed to determine whether occult retinoschisis progresses to bullous retinoschisis.

Congenital X-linked Retinoschisis and Familial Exudative Vitreoretinopathy: Pathogenesis, Diagnosis, and Treatment

Congenital X-linked retinoschisis (CXLRS) is characterized by symmetric bilateral macular involvement, usually beginning in the first decade of life and affecting males. In the fundus examination, a wheel pattern developing due to schisis areas is observed in the macula. Fundus examination and optical coherence tomography (OCT) are essential for diagnosis in the early stages of the disease and exhibit characteristic findings. Peripheral retinoschisis occurs in approximately 50% of cases, usually in the inferior temporal quadrant. Visual acuity usually deteriorates in the first and second decades of life, but then remains relatively stable until the fifth or sixth decade. There is no proven treatment for CXLRS so far, gene therapy studies are ongoing. Familial exudative vitreoretinopathy (FEVR) is a rare inherited vitreoretinal disorder characterized by abnormal or incomplete vascularization of the peripheral retina. The disease is frequently inherited as autosomal dominant and less frequently autosomal recessive or X-linked recessive. FEVR is manifested by bilateral involvement, which may be asymmetrical. Its distinctive features include the avascular peripheral retina and peripheral ischemia, retinal neovascularization, and subretinal exudation. Epiretinal membrane and tractional retinal detachment may also develop in some patients. Laser photocoagulation therapy is effective in patients with peripheral retinal ischemia and neovascularization. In this review, the pathogenesis, clinical features, and treatment methods in CXLRS and FEVR disease will be discussed.

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Iwahashi, Chiharu MD1; Matsushita, Itsuka MD2; Kuniyoshi, Kazuki MD1; Kondo, Hiroyuki MD2; Kusaka, Shunji MD1 Author Information

A Spontaneous Nonhuman Primate Model of Myopic Foveoschisis.

Foveoschisis involves the pathologic splitting of retinal layers at the fovea, which may occur congenitally in X-linked retinoschisis (XLRS) or as an acquired complication of myopia. XLRS is attributed to functional loss of the retinal adhesion protein retinoschisin 1 (RS1), but the pathophysiology of myopic foveoschisis is unclear due to the lack of animal models. Here, we characterized a novel nonhuman primate model of myopic foveoschisis through clinical examination and multimodal imaging followed by morphologic, cellular, and transcriptional profiling of retinal tissues and genetic analysis. We identified a rhesus macaque with behavioral and anatomic features of myopic foveoschisis, and monitored disease progression over 14 months by fundus photography, fluorescein angiography, and optical coherence tomography (OCT). After necropsy, we evaluated anatomic and cellular changes by immunohistochemistry and transcriptomic changes using single-nuclei RNA-sequencing (snRNA-seq). Finally, we performed Sanger and whole exome sequencing with focus on the RS1 gene. Affected eyes demonstrated posterior hyaloid traction and progressive splitting of the outer plexiform layer on OCT. Immunohistochemistry showed increased GFAP expression in Müller glia and loss of ramified Iba-1+ microglia, suggesting macro- and microglial activation with minimal photoreceptor alterations. SnRNA-seq revealed gene expression changes predominantly in cones and retinal ganglion cells involving chromatin modification, suggestive of cellular stress at the fovea. No defects in the RS1 gene or its expression were detected. This nonhuman primate model of foveoschisis reveals insights into how acquired myopic traction leads to phenotypically similar morphologic and cellular changes as congenital XLRS without alterations in RS1.

EFFICACY OF INNER WALL RETINECTOMY FOR BULLOUS SCHISIS CAVITY HANGING OVER OR THREATENING THE MACULA IN PATIENTS WITH CONGENITAL X-LINKED RETINOSCHISIS.

To present the clinical characteristics, surgical outcomes, and surgical complications of patients with congenital X-linked retinoschisis who underwent vitrectomy for bullous schisis cavity hanging over or threatening the macula. Nine patients with congenital X-linked retinoschisis (12 eyes) who underwent vitrectomy at three tertiary hospitals and completed ≥3 years of postoperative follow-up were retrospectively investigated. Data were collected from patients' charts, including age at vitrectomy, surgical procedures, and postoperative complications. The age at vitrectomy ranged 4 months to 103 months (median: 14 months). Inner wall retinectomy was performed during the initial vitrectomy in eight eyes. Among the eight eyes that initially underwent inner wall retinectomy, one (12.5%) required subsequent retinal surgery for postoperative complication. Furthermore, four eyes did not undergo initial inner wall retinectomy but required subsequent retinal surgeries for postoperative complications. Three of five eyes (60.0%) treated with silicone oil tamponade and two of seven eyes (28.6%) that were not treated with silicone oil tamponade during the initial vitrectomy required subsequent retinal surgeries for postoperative complications. All eyes maintained a clear central visual axis at the last examination. Inner wall retinectomy seems beneficial in achieving a clear visual axis in eyes with bullous schisis cavity hanging over or threatening the macula in patients with congenital X-linked retinoschisis.

Identification of Interphotoreceptor retinoid-binding protein in the Schisis cavity fluid of a patient with congenital X-linked Retinoschisis

BackgroundThis case report describes the surgical outcome in a patient with congenital X-linked retinoschisis (CXLRS) and the results of proteomic analysis of surgically extracted samples from both vitreous and intraschisis cavities by mass spectrometry.Case presentationA 3-month-old boy presented with extensive retinoschisis involving macula and retinal periphery in both eyes. Genetic analysis confirmed retinoschisin 1 mutation (c.554C > T), and an electroretinogram showed significant reduction of b-wave and decreased cone and rod responses, which led to a diagnosis of CXLRS. By performing pars plana vitrectomy, including inner wall retinectomy, clear visual axes with stable retinal conditions and functional vision in both eyes were obtained during the 4 years of follow-up. Proteomic analysis of surgically retrieved fluid from the intraschisis cavity revealed a higher expression of interphotoreceptor retinoid-binding protein (IRBP) than that from the vitreous humor. However, both samples showed equal levels of albumin, transferrin, and pigment epithelium-derived factor.ConclusionsCellular adhesive imperfection in CXLRS may cause IRBP diffusion from the interphotoreceptor matrix, resulting in the strong expression of IRBP in the intraschisis cavity. An impaired retinoid cycle caused by an absence of IRBP in the retina may potentially underlie the pathology of CXLRS.

Анализ эффективности эндовитреального вмешательства с удалением внутренней пограничной мембраны у пациентов с Х-сцепленным врожденным ретиношизисом

Purpose of this article is to analyze the effectiveness of endovitreal surgery with removal of the internal limiting membrane in patients with X-linked congenital retinoschisis. Material and methods. Three male patients underwent a standard 25 G vitrectomy with staining and removal of the internal limiting membrane in the macular zone and pneumoretinopexy. Results. All operations were uneventful. Stabilization of the pathological process was noted during the study period. Conclusion. Endovitreal surgery with the removal of the inner limiting membrane in the macular zone stabilizes the progression of X-linked congenital retinoschisis. Key words: retinoschisis, internal limiting membrane, endovitreal surgery.

Pediatric Retinal Detachment: Risk Factors, Pathogenesis, Clinical Presentation, and Management

Pediatric retinal detachment is an uncommon and challenging disease; it differs from adult detachments in etiology, anatomic characteristics, management, and prognosis. The anatomic success, when achieved is frequently not related to functional recovery. To operate, the pediatric vitreoretinal surgeon must understand the characteristics that define diseases, such as retinopathy of prematurity (ROP), familial exudative vitreoretinopathy (FEVR), persistent fetal vasculature syndrome (PFVS), congenital x-linked retinoschisis (CXLRS) and Coats disease. Here we discuss key features of the surgical approach to complicated pediatric retinal detachments.

The Natural History of Congenital X-Linked Retinoschisis and Conversion between Phenotypes over Time

To evaluate the natural history of congenital X-linked retinoschisis (CXLRS) and to assess disease stability or progression over time. Retrospective case series at a single-center, tertiary care, pediatric retina practice. One hundred two eyes of 51 patients with CXLRS. The clinical examinations, fundus photographs, and OCT images of all patients with CXLRS were assessed. Eyes that initially demonstrated combined retinoschisis-retinal detachments and those with large, centrally overhanging schisis cavities were excluded from the analysis (n= 49) because they underwent surgery, which precluded observation of the natural disease course. Stability or conversion of CXLRS phenotype over time. Fifty-three eyes met inclusion criteria for observation of natural disease history over time. At the time of diagnosis, 7.5% of eyes showed type 1 disease (n= 4), 17% showed type 2 disease (n= 9), 66% showed type 3 disease (n= 35), and 9.5% showed type 4 disease (n= 5). Mean length of follow-up was 7.4 years. A total of 7.5% of eyes demonstrated a combined retinoschisis-retinal detachment requiring surgery (n= 4), whereas 1.8% demonstrated a large, centrally overhanging schisis cavity requiring surgery (n= 1). Overall, 83% of eyes (n= 44) remained the same type without conversion or development of a complication requiring surgery. The remaining 17% of eyes (n= 9) experienced some type of change from their baseline diagnosis, with 7.5% (n= 4) converting between phenotypes and 9.5% (n= 5) demonstrating a complication requiring surgery; 3.75% of eyes (n= 2) converted from type 2 to 3 and 7.5% of eyes (n= 4) converted from type 3 to a combined retinoschisis-retinal detachment with mean time to conversion of 4.07 years. This longitudinal study conveyed the natural history of CXLRS. Congenital X-linked retinoschisis displayed long-term stability in 83% of eyes with conversion or progression of the disease to a more severe phenotype in the remaining cases. Type 3 CXLRS was a risk factor for the development of a combined retinoschisis-retinal detachment and may benefit from closer follow-up.

Clinical observations of vitreoretinal surgery for four different phenotypes of X-linked congenital retinoschisis.

To evaluate the outcomes of vitreoretinal surgery for four different phenotypes of X-linked retinoschisis (XLRS). This study included thirty-one eyes of 25 patients who developed XLRS with severe complications. Among the 31 eyes, there were 7 eyes with vitreous hemorrhage, 8 eyes with retinal detachment and vitreous hemorrhage, and 16 eyes with rhegmatogenous retinal detachment. All of the patients underwent standard three-port pars plana vitrectomy. All of the eyes were divided into 4 groups before surgery according to a modified classification scheme, with the first three groups as follows: group A, with foveal cystic schisis; group B with macular lamellar schisis; and group C with foveolamellar changes. Peripheral schisis was not present in these 3 groups; however, group D was a complex group with both macular and peripheral changes. One year after surgery, we analyzed the best corrected visual acuity and postoperative anatomical and functional outcomes of these 4 groups. There were 7 eyes in group A (22.6%), 1 eye in group B (3.2%), 15 eyes in group C (48.4%) and 8 eyes in group D (25.8%). Postoperative anatomical and functional outcomes were satisfactory at the last visit, while the mean visual acuity was increased to 0.27±0.11, with a significant difference (t=-1.049, P=0.000) compared with the results before surgery (0.1±0.08). Visual acuity was improved in 23 eyes (74.2%). Complications were found in three eyes: two eyes with proliferative vitreoretinopathy and traction retinal detachment 10 and 12mo after surgery, respectively; and one eye with vitreous hemorrhage 15mo after surgery. These eyes were in groups C and D. The retinas remained attached in these 3 eyes after reoperation. We should pay greater attention to XLRS with foveolamellar changes because it is the most changeable phenotype. Once complications occur, vitreoretinal surgery can significantly improve visual acuity and restore the anatomic structure of the retina.

Congenital X-Linked Retinoschisis: An Updated Clinical 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.

Congenital X-Linked Retinoschisis: An Updated Clinical ReviewPrethy

Congenital X-Linked Retinoschisis: An Updated Clinical ReviewPrethy

Частота внутриглазных кровоизлияний при наследственных витреоретинальных дистрофиях

Hereditary vitreoretinal degenerations are a heterogeneous group of diseases, which are based on the degenerative changes of the retina and the vitreous. The occurrence of intrahemorrhages is different for different hereditary vitreoretinal degenerations. In some diseases (Wagner's disease, Jensen syndrome, Kniest dysplasia, Marfan's, Ehlers -Danlos syndrome, Alport, Bloch -Sulzberger, Walker -Warburg) intraocular hemorrhages almost never occur. In other vitreoretinopathies (X-linked congenital retinoschisis, familial exudative vitreoretinopathy, Norrie disease, Stickler syndrome), intraocular hemorrhages occur more often. The review describes the genetic aspects of the diseases and their clinical pictures. Special attention is given to the incidence and clinical manifestations of intraocular hemorrhage in the above mentioned vitreoretinopathies // Russian Ophthalmological Journal, 2017; 1: 104-10. doi: 10.21516/2072-0076-2017-10-1-104-110.

Molecular genetics and gene therapy of X-linked congenital retinoschisis

X-linked retinoschisis (XLRS) is a rare X-linked inherited retinal disorder, caused by mutations in retinoschisin 1 (RS1) gene. Three XLRS mice were established, providing ideal systems to study the mechanism and treatment methods for XLRS. RS1 gene mutations can induce abnormal secretion or adhesion function of RS1 protein. In the past year, phase I clinical trials for XLRS has begun in USA, using adeno associated virus (AAV, AAV8 or AAV2)-mediated gene delivery. With the rapid development of new generation of AAV vector that can transduce more retinal cells through intravitreous delivery, gene therapy for XLRS will have a brighter future. Key words: Retinoschisis/genetics; Gene Therapy; Review

WIDE-FIELD IMAGING OF NONEXUDATIVE AND EXUDATIVE CONGENITAL X-LINKED RETINOSCHISIS.

To describe wide-field imaging features of patients with congenital X-linked retinoschisis. This is a retrospective nonconsecutive series of 36 eyes from 18 patients with congenital X-linked retinoschisis from 2008 to 2014. Wide-field color fundus photographs, optical coherence tomography images, and wide-field fluorescein angiography images were reviewed. Patients were classified to have either exudative or nonexudative retinoschisis based on the presence or absence of lipid exudates. Eleven eyes exhibited exudative retinoschisis (30%), whereas the remaining were nonexudative. Exudative disease occurred more commonly in older patients (14.4 vs. 4.0 years; P < 0.001). The most frequent location of exudation was the macula. Subretinal hemorrhage was present in 4 eyes (11%). Macular findings included an atypical foveal avascular zone in 7 eyes (19%) and submacular fibrosis or retinal folds in 6 eyes (17%). Peripheral characteristics included fibrosis or folds (11%), bridging vessels (8%), and vascular sheathing (8%). Thirteen of the 22 eyes (59%) demonstrated leakage on fluorescein angiography. Exudation may be more common in congenital X-linked retinoschisis than previously recognized. The presence of exudates with concurrent angiographic leakage suggests that exudation may be due to chronic vascular permeability and not solely caused by intraschisis hemorrhage, which has been classically described.

Immediate Sequential Bilateral Pediatric Vitreoretinal Surgery: An International Multicenter Study

To determine the feasibility and safety of bilateral simultaneous vitreoretinal surgery in pediatric patients. International, multicenter, interventional, retrospective case series. Patients 17 years of age or younger from 24 centers worldwide who underwent immediate sequential bilateral vitreoretinal surgery (ISBVS)-defined as vitrectomy, scleral buckle, or lensectomy using the vitreous cutter-performed in both eyes sequentially during the same anesthesia session. Clinical history, surgical details and indications, time under anesthesia, and intraoperative and postoperative ophthalmic and systemic adverse events were reviewed. Ocular and systemic adverse events. A total of 344 surgeries from 172 ISBVS procedures in 167 patients were included in the study. The mean age of the cohort was 1.3±2.6 years. Nonexclusive indications for ISBVS were rapidly progressive disease (74.6%), systemic morbidity placing the child at high anesthesia risk (76.0%), and residence remote from surgery location (30.2%). The most common diagnoses were retinopathy of prematurity (ROP; 72.7% [P < 0.01]; stage 3, 4.8%; stage 4A, 44.4%; stage 4B, 22.4%; stage 5, 26.4%), familial exudative vitreoretinopathy (7.0%), abusive head trauma (4.1%), persistent fetal vasculature (3.5%), congenital cataract (1.7%), posterior capsular opacification (1.7%), rhegmatogenous retinal detachment (1.7%), congenital X-linked retinoschisis (1.2%), Norrie disease (2.3%), and viral retinitis (1.2%). Mean surgical time was 143±59 minutes for both eyes. Higher ROP stage correlated with longer surgical time (P= 0.02). There were no reported intraoperative ocular complications. During the immediate postoperative period, 2 eyes from different patients demonstrated unilateral vitreous hemorrhage (0.6%). No cases of endophthalmitis, choroidal hemorrhage, or hypotony occurred. Mean total anesthesia time was 203±87 minutes. There were no cases of anesthesia-related death, malignant hyperthermia, anaphylaxis, or cardiac event. There was 1 case of reintubation (0.6%) and 1 case of prolonged oxygen desaturation (0.6%). Mean follow-up after surgery was 103 weeks, and anatomic success and globe salvage rates were 89.8% and 98.0%, respectively. This study found ISBVS to be a feasible and safe treatment paradigm for pediatric patients with bilateral vitreoretinal pathologic features when repeated general anesthesia is undesirable or impractical.

Hereditäre Vitreoretinopathien und Netzhautablösung im Kindesalter

The number of retinal detachments in children is very low in comparison to the number in adults. One predisposing factor for development of paediatric retinal detachment is suffering from hereditary vitreoretinal degeneration (e.g., Stickler syndrome, Wagner syndrome, Kniest dysplasia, familial exudative vitreoretinopathy, congenital X-linked retinoschisis, Knobloch syndrome, incontinentia pigmenti, Norrie disease). Hereditary vitreoretinopathies are characterised by an abnormal-appearing vitreous gel with associated retinal changes. In most of these eyes further ocular abnormalities can be diagnosed. A group of hereditary disorders is associated with characteristic systemic abnormalities. Allied conditions should be considered in the clinical diagnosis. Vitreoretinopathies are the most common cause of inherited retinal detachment. In most eyes primary vitrectomy is necessary, and disease-specific surgical treatment is discussed.