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Indian Journal of Ophthalmology Jun 2024Retinoschisis is a distinctive condition characterized by intraretinal layer clefts, primarily associated with X-linked recessive inheritance due to RS1 gene mutations....
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.
Topics: Humans; Retinoschisis; Male; India; Tomography, Optical Coherence; Electroretinography; Eye Proteins; Adult; Phenotype; Genotype; Visual Acuity; Mutation; Adolescent; DNA Mutational Analysis; Child; Young Adult; Pedigree; Female; Middle Aged; DNA; Retina
PubMed: 38317323
DOI: 10.4103/IJO.IJO_2525_23 -
International Journal of Molecular... Jan 2024X-linked juvenile retinoschisis (XLRS) is an early-onset progressive inherited retinopathy affecting males. It is characterized by abnormalities in the macula, with... (Review)
Review
X-linked juvenile retinoschisis (XLRS) is an early-onset progressive inherited retinopathy affecting males. It is characterized by abnormalities in the macula, with formation of cystoid retinal cavities, frequently accompanied by splitting of the retinal layers, impaired synaptic transmission of visual signals, and associated loss of visual acuity. XLRS is caused by loss-of-function mutations in the retinoschisin gene located on the X chromosome (, MIM 30083). While proof-of-concept studies for gene augmentation therapy have been promising in in vitro and rodent models, clinical trials in XLRS patients have not been successful thus far. We performed a systematic literature investigation using search strings related to XLRS and gene therapy in in vivo and in vitro models. Three rounds of screening (title/abstract, full text and qualitative) were performed by two independent reviewers until consensus was reached. Characteristics related to study design and intervention were extracted from all studies. Results were divided into studies using (1) viral and (2) non-viral therapies. All in vivo rodent studies that used viral vectors were assessed for quality and risk of bias using the SYRCLE's risk-of-bias tool. Studies using alternative and non-viral delivery techniques, either in vivo or in vitro, were extracted and reviewed qualitatively, given the diverse and dispersed nature of the information. For in-depth analysis of in vivo studies using viral vectors, outcome data for optical coherence tomography (OCT), immunohistopathology and electroretinography (ERG) were extracted. Meta-analyses were performed on the effect of recombinant adeno-associated viral vector (AAV)-mediated gene augmentation therapies on a- and b-wave amplitude as well as the ratio between b- and a-wave amplitudes (b/a-ratio) extracted from ERG data. Subgroup analyses and meta-regression were performed for model, dose, age at injection, follow-up time point and delivery method. Between-study heterogeneity was assessed with a Chi-square test of homogeneity (I). We identified 25 studies that target RS1 and met our search string. A total of 19 of these studies reported rodent viral methods in vivo. Six of the 25 studies used non-viral or alternative delivery methods, either in vitro or in vivo. Of these, five studies described non-viral methods and one study described an alternative delivery method. The 19 aforementioned in vivo studies were assessed for risk of bias and quality assessments and showed inconsistency in reporting. This resulted in an unclear risk of bias in most included studies. All 19 studies used AAVs to deliver intact human or murine in rodent models for XLRS. Meta-analyses of a-wave amplitude, b-wave amplitude, and b/a-ratio showed that, overall, AAV-mediated gene augmentation therapy significantly ameliorated the disease phenotype on these parameters. Subgroup analyses and meta-regression showed significant correlations between b-wave amplitude effect size and dose, although between-study heterogeneity was high. This systematic review reiterates the high potential for gene therapy in XLRS, while highlighting the importance of careful preclinical study design and reporting. The establishment of a systematic approach in these studies is essential to effectively translate this knowledge into novel and improved treatment alternatives.
Topics: Male; Humans; Animals; Mice; Retinoschisis; Retina; Electroretinography; Genetic Therapy; Mutation; Eye Proteins
PubMed: 38279267
DOI: 10.3390/ijms25021267 -
Indian Journal of Ophthalmology Feb 2024Double optic disc pit maculopathy is a rare entity. It can be difficult to manage because of excessive leakage and chronic maculopathy.
BACKGROUND
Double optic disc pit maculopathy is a rare entity. It can be difficult to manage because of excessive leakage and chronic maculopathy.
PURPOSE
To describe surgical management in a case of double optic disc pits with maculopathy.
SYNOPSIS
A 42-year-old male presented with double optic disc pits with macular detachment in the left eye. The best-corrected visual acuity (BCVA) was 20/60, N12. Preoperative OCT showed the presence of two disc pits. The macular region had large retinoschisis and subretinal fluid (SRF) with a central foveal thickness of 879 microns and loss of the ellipsoid zone. A shallow communication from the temporal aspect of the disc to the submacular area was also noted. Among the options of observation, laser photocoagulation, and surgery, the patient opted for surgical management.
SURGICAL TECHNIQUE
A standard-3 port 23-gauge pars plana vitrectomy was done. After staining the ILM with brilliant blue, ILM peeling was done with the help of forceps and Finesse loop. ILM flaps were inverted over to cover the optic disc pits and sealed with a drop of fibrin glue. Next, 20% SF6 gas was used for tamponade. Pre- and post-surgery parameters such as visual acuity and OCT were evaluated.
POSTOPERATIVE EVALUATION
After 6 weeks, left eye BCVA was 20/40 with OCT showing reduced SRF and reduced intraretinal schisis with a foveal thickness of 546 microns. At 3 months of follow-up, the vision in the left eye had improved to 20/30 with further reduction in the retinoschisis and foveal thickness of 482 microns.
HIGHLIGHTS
In this interesting case, we demonstrate a unique way of sealing the defect surgically by vitrectomy and inverted ILM flap with fibrin glue over the disc pits. Despite sealing the maculopathy is slow to resolve.
VIDEO LINK
https://youtu.be/s9nY5UPe1s4.
Topics: Male; Humans; Adult; Retinoschisis; Retinal Detachment; Optic Disk; Fibrin Tissue Adhesive; Tomography, Optical Coherence; Endotamponade; Retinal Diseases; Eye Abnormalities; Macular Degeneration; Vitrectomy; Laser Coagulation
PubMed: 38273697
DOI: 10.4103/IJO.IJO_2205_23 -
Ophthalmic Research 2024The aim of this study was to evaluate the clinical characteristics and surgical outcomes of the epiretinal membrane foveoschisis (ERM-FS) with different morphological... (Observational Study)
Observational Study
INTRODUCTION
The aim of this study was to evaluate the clinical characteristics and surgical outcomes of the epiretinal membrane foveoschisis (ERM-FS) with different morphological types.
METHODS
This retrospective observational study reviewed 44 consecutive ERM-FS patients who underwent ERM surgery. According to the optical coherence tomography images, ERM-FS was classified into three groups: group A, FS crossed the fovea with the foveola elevated; group B, FS located at the foveal edges with a near-normal central foveal point thickness; and group C, FS with undermined foveal edges with a near-normal central foveal point thickness.
RESULTS
There were 10 eyes in group A, 20 eyes in group B, and 14 eyes in group C. Preoperatively, eyes in group A had the best best-corrected visual acuity (BCVA), the thickest central foveal point thickness, and the highest ellipsoid zone (EZ) intact rate among the three groups. After surgery, a resolution of foveoschisis was observed in 40.0%, 45.0%, and 50.0% of the eyes in group A, group B, and group C (p = 0.928), respectively. BCVA was significantly improved postoperatively. Although there was no significant difference in BCVA among the three groups at 1 month postoperatively, BCVA of group A was the best at 4 and 10 months. Correlation analysis indicated that the type of ERM-FS, baseline BCVA, central foveal point thickness, and postoperative EZ continuity (all p < 0.05) were important factors for the final BCVA.
CONCLUSIONS
The damage to the retinal structure and visual function was milder in group A ERM-FS. Our study emphasized the necessity of OCT-based subtyping in patients with ERM-FS.
Topics: Humans; Retrospective Studies; Vitrectomy; Visual Acuity; Epiretinal Membrane; Female; Male; Fovea Centralis; Tomography, Optical Coherence; Aged; Retinoschisis; Middle Aged; Follow-Up Studies
PubMed: 38246146
DOI: 10.1159/000536206 -
Saudi Journal of Ophthalmology :... 2023The purpose of this study was to develop a visually guided swim assay (VGSA) for measuring vision in mouse retinal disease models comparable to the multi-luminance...
PURPOSE
The purpose of this study was to develop a visually guided swim assay (VGSA) for measuring vision in mouse retinal disease models comparable to the multi-luminance mobility test (MLMT) utilized in human clinical trials.
METHODS
Three mouse retinal disease models were studied: Bardet-Biedl syndrome type 1 (), = 5; Bardet-Biedl syndrome type 10 (), = 11; and X linked retinoschisis (retinoschisin knockout; KO), = 5. Controls were normally-sighted mice, = 10. Eyeless mice, n = 4, were used to determine the performance of animals without vision in VGSA.
RESULTS
Eyeless mice had a VGSA time-to-platform (TTP) 7X longer than normally-sighted controls ( < 0.0001). Controls demonstrated no difference in their TTP in both lighting conditions; the same was true for . At 4-6 M, KO and had longer TTP in the dark than controls ( = 0.0156 and = 1.23 × 10, respectively). At 9-11 M, both BBS models had longer TTP than controls in light and dark with times similar to ( < 0.0001), demonstrating progressive vision loss in BBS models, but not in controls nor in KO. At 1 M, ERG light-adapted (cone) amplitudes were nonrecordable, resulting in a floor effect. VGSA did not reach a floor until 9-11 M. ERG combined rod/cone b-wave amplitudes were nonrecordable in all three mutant groups at 9-11 M, but VGSA still showed differences in visual function. ERG values correlate non-linearly with VGSA, and VGSA measured the continual decline of vision.
CONCLUSION
ERG is no longer a useful endpoint once the nonrecordable level is reached. VGSA differentiates between different levels of vision, different ages, and different disease models even after ERG is nonrecordable, similar to the MLMT in humans.
PubMed: 38155679
DOI: 10.4103/sjopt.sjopt_155_23 -
International Journal of Ophthalmology 2023To characterize the ophthalmic clinical phenotype of a family with retinitis pigmentosa (RP) and closed-angle glaucoma and to detect pathogenic genes and mutation sites...
AIM
To characterize the ophthalmic clinical phenotype of a family with retinitis pigmentosa (RP) and closed-angle glaucoma and to detect pathogenic genes and mutation sites causing RP in this family.
METHODS
Ophthalmic clinic performance was examined in detail in 8 enrolled family members. Genomic DNA was extracted from the peripheral blood of 4 family members for whole-exome sequencing (WES) to select potential genetic mutations whose structures were identified by bioinformatics analysis. Then, Sanger sequencing was used in 12 family members and control group members to validate and confirm the disease-causing mutation loci, and we analyzed the genotype-phenotype relationships.
RESULTS
The known c.512C>T (p.P171L) mutation in the () gene was only found in afflicted family members and was confirmed by WES and Sanger sequencing as the pathogenic mutation in this family. In addition to being diagnosed with RP, family member III:4 was found to have bilateral closed-angle glaucoma, high myopia, and concurrent cataracts, and family members II:2 and II:4 had pathological changes of anterior chamber angle narrowing. Family members IV:3 and IV:4 were found to have retinoschisis.
CONCLUSION
Glaucoma and related pathological changes, such as retinoschisis, in family members are preliminarily considered RP complications caused by mutation.
PubMed: 38111930
DOI: 10.18240/ijo.2023.12.07 -
Ophthalmology. Retina Jun 2024To date, there is no standard treatment regimen for carbonic anhydrase inhibitors (CAIs) in X-linked retinoschisis (XLRS) patients. This retrospective study aims to...
PURPOSE
To date, there is no standard treatment regimen for carbonic anhydrase inhibitors (CAIs) in X-linked retinoschisis (XLRS) patients. This retrospective study aims to evaluate the efficacy of CAIs on visual acuity and cystoid fluid collections (CFC) in XRLS patients in Dutch and Belgian tertiary referral centers.
DESIGN
Retrospective cohort study.
PARTICIPANTS
Forty-two patients with XLRS.
METHODS
In total, 42 patients were enrolled. To be included, patients had to have previous treatment with an oral CAI (acetazolamide), a topical CAI (brinzolamide/dorzolamide), or a combination of an oral and a topical CAI for at least 4 consecutive weeks. We evaluated the effect of the CAI on best-corrected visual acuity (BCVA) and central foveal thickness (CFT) on OCT.
MAIN OUTCOME MEASURES
Central foveal thickness and BCVA.
RESULTS
The median age at the baseline visit of the patients in this cohort study was 14.7 (range, 43.6) years, with a median (interquartile range [IQR]) follow-up period of 4.0 (2.2-5.2) years. During the follow-up period, 25 patients were treated once with an oral CAI (60%), 24 patients were treated once with a topical CAI (57%), and 11 patients were treated once with a combination of both topical and oral CAI (26%). We observed a significant reduction of CFT for oral CAI by 14.37 μm per 100 mg per day (P < 0.001; 95% confidence interval [CI], -19.62 to -9.10 μm) and for topical CAI by 7.52 μm per drop per day (P = 0.017; 95% CI, -13.67 to -1.32 μm). The visual acuity changed significantly while on treatment with oral CAI by -0.0059 logMAR per 100 mg (P = 0.008; 95% CI, -0.010 to -0.0013 logMAR). Seven patients (17%) had side effects leading to treatment discontinuation.
CONCLUSIONS
Our data indicate that treatment with (oral) CAI may be beneficial for short-term management of CFC in patients with XLRS. Despite a significant reduction in CFT, the change in visual acuity was modest and not of clinical significance. Nonetheless, the anatomic improvement of the central retina in these patients may be of value to create an optimal retinal condition for future potential treatment options such as gene therapy.
FINANCIAL DISCLOSURE(S)
The authors have no proprietary or commercial interest in any materials discussed in this article.
Topics: Humans; Carbonic Anhydrase Inhibitors; Retinoschisis; Retrospective Studies; Visual Acuity; Male; Tomography, Optical Coherence; Adult; Adolescent; Female; Follow-Up Studies; Young Adult; Treatment Outcome; Child; Subretinal Fluid; Middle Aged; Sulfonamides; Administration, Oral
PubMed: 38104928
DOI: 10.1016/j.oret.2023.12.003 -
Translational Vision Science &... Dec 2023To assess the quantitative differences in vessel density and retinal thickness of X-linked retinoschisis (XLRS) patients and RS1 mutation carriers, and the correlation...
PURPOSE
To assess the quantitative differences in vessel density and retinal thickness of X-linked retinoschisis (XLRS) patients and RS1 mutation carriers, and the correlation with best-corrected visual acuity (BCVA) with swept source optical coherence tomography (SS-OCT) and OCT angiography (OCTA).
METHODS
We analyzed the correlation between the BCVA of XLRS patients and the SS-OCT and OCTA findings including the detailed structural characteristics of XLRS patients.
RESULTS
Besides the schitic changes in various retinal layers, the structural disturbance of outer retina was universally found. In 29 eyes included in the quantitative analysis, XLRS patients showed lower vessel density of the superficial capillary plexus, deep capillary plexus and lower thickness of the outer nuclear layer. BCVA was correlated with the thickness of the outer plexiform layer and outer nuclear layer and the thickness from the outer limiting membrane to the retinal pigment epithelium. Carriers showed higher thickness of outer plexiform layer and smaller foveal avascular zone area.
CONCLUSIONS
SS-OCT and OCTA could identify the pathological alterations of the individual retinal layers and capillaries, which could pinpoint the exact location of the damages related to visual impairment. In the carriers, the subtle alterations that can be detected with SS-OCT, despite their normal visual acuity, may be caused by the lyonization.
TRANSLATIONAL RELEVANCE
Swept source optical coherence tomography can be used as an efficient technique to expose the retinal damage related to visual impairment for prognosis and follow-up.
Topics: Humans; Retinoschisis; Tomography, Optical Coherence; Retina; Angiography; Vision, Low; Visual Acuity
PubMed: 38054929
DOI: 10.1167/tvst.12.12.7 -
Frontiers in Medicine 2023Congenital X-linked retinoschisis (XLRS) presents as macular retinoschisis/degeneration in almost all patients and as peripheral retinoschisis in half the patients....
INTRODUCTION
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.
METHODS
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 gene.
RESULTS
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 gene.
CONCLUSION
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 (). 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.
PubMed: 38034549
DOI: 10.3389/fmed.2023.1280564 -
Frontiers in Medicine 2023Carbonic anhydrase inhibitors (CAIs) reduce macular schisis in patients with X-linked retinoschisis (XLRS). The purpose of this study was to determine if CAIs reduce the...
PURPOSE
Carbonic anhydrase inhibitors (CAIs) reduce macular schisis in patients with X-linked retinoschisis (XLRS). The purpose of this study was to determine if CAIs reduce the incidence of complications from XLRS, including macular atrophy, retinal tears, and retinal detachment (RD), the most common causes of vision loss in patients with XLRS.
METHODS
For this retrospective interventional case series, a chart review of patients examined at Cincinnati Children's Hospital Medical Center [CCHMC] and Cincinnati Eye Institute [CEI] between 1/1/2015 and 1/16/2023 was performed. Male patients were included based on genetically-confirmed or typical clinical presentation with known family history of XLRS with at least two follow-up visits.
RESULTS
Twenty-eight patients (56 eyes) with XLRS were included. There were 10 variants among the 21 genotyped patients. Median age at clinical diagnosis was 10.4 years old (range: 0.4-55.7 years) with median follow-up time of 4.7 years (range: 0.2-38.3 years). Median presenting Snellen visual acuity was 20/60 (logMAR 0.48, range: 0.18-3). In 26 eyes of 15 patients treated with CAIs, median CST pre-treatment was 416 microns (range: 198-701 microns), and median percentage decrease in CST on treatment was 21.8% (range: 0-74.5%) from highest pre-treatment CST. Reduction in CST with CAI use was statistically significant ( = 0.02), but not logMAR VA ( = 0.64). There was no significant difference in CST between patients treated with topical vs. oral CAI ( = 0.95) or between patients with partial or complete CAI adherence ( = 0.60). Ten eyes of seven patients had an RD requiring surgical intervention. No treated eyes developed new macular atrophy, peripheral retinoschisis, retinal tears, or RD; two eyes on topical CAIs had spontaneous resolution of bullous peripheral retinoschisis.
CONCLUSION
During the follow-up period, patients taking CAIs reduced macular schisis and did not experience new complications of macular atrophy, retinal tears, or RD. This is a relatively large cohort with long-term follow-up periods for patients with XLRS. Reduced macular schisis may not require perfect adherence with CAIs. A large, prospective, randomized, controlled clinical trial is needed to determine the potential of CAIs to improve visual function, reduce retinoschisis, and prevent RD.
PubMed: 38020097
DOI: 10.3389/fmed.2023.1281068