Genotype-Phenotype of CRB1-Associated Early-Onset Retinal Dystrophy: Novel Insights on Retinal Architecture and Therapeutic Window for Clinical Trials.

Purpose: The purpose of this study was to investigate the genotypic and phenotypic characteristics of CRB1-associated early onset retinal dystrophy (CRB1-eoRD) and retinal architecture by swept-source optical coherence tomography (SS-OCT). Methods: Eleven probands with CRB1-eoRD were recruited. Clinical information, genetic analysis, and comprehensive ophthalmic examinations including SS-OCT and SS-OCT angiography (SS-OCTA) were conducted. Results: A total of 81.8% (9/11) of CRB1-eoRD presented as Leber congenital amaurosis (LCA). Common clinical manifestations included coin-like yellow-white retinal spots (20/22, 90.9%) and para-arteriolar retinal pigment epithelial retention (12/22, 54.5%). Nineteen different CRB1 variants were detected in our case series, including 12 missense, 3 frameshifts, 3 nonsense, and 1 splicing. Of them, 12 variants had been reported, and 7 were novel. SS-OCT showed thinner central macula (the LCA group, P < 0.0001), thicker total retina (P < 0.0001), thinner outer retina (P < 0.05), and thicker inner retina (P < 0.0001) compared with the healthy control. The inner/outer (I/O) retina thickness ratio of CRB1-eoRD was 3.0, higher than the healthy control of 1.2 and other inherited retinal diseases (IRDs) of 2.2 (P < 0.0001 and P = 0.0027, respectively). SS-OCTA revealed an increased vascular density and perfusion area of the superficial vascular complex and deep vascular complex in CRB1-eoRD. Conclusions: LCA emerges as a frequently occurring phenotype in CRB1-eoRD. The unique features of SS-OCT and SS-OCTA are illustrated, and the novel biomarker, I/O ratio, may facilitate early diagnosis. The insights gained from this study hold significant value in determining the treatment window for potential forthcoming CRB1 gene therapy.

Safety and effectiveness of intravitreal dexamethasone implant in patients with ocular toxocariasis.

AIMS: To evaluate the safety and effectiveness of intravitreal dexamethasone (DEX) implant in patients with active uveitis due to ocular toxocariasis (OT). METHODS: Seventy-eight patients with OT were recruited in this retrospective study, including 51 patients in DEX group treated with intravitreal DEX implant and 27 patients in control group without intervention. The reduction of vitreous haze scores (VHS), the best-corrected visual acuity (BCVA) changes, intraocular pressure (IOP) and cataract progression and formation were recorded at baseline (V0), 1 (V1), 3 (V3) and 6 months (V6) after treatment in DEX group, and V0 and V6 in control group. RESULTS: There was no change in VHS and BCVA in control group between V0 and V6. Better VHS (p=0.001) and BCVA (p=0.022) was achieved in DEX group; the rate of VHS=0 was 0%, 67.4%, 42.9% and 44.9% at V0, V1, V3 and V6, respectively (p＜0.001), and the mean BCVA was improved from logMAR 1.5±0.9 to 1.2±0.9 at V1, 1.4±1.0 at V3 and 1.4±1.2 at V6. A favourable BCVA at V1 was associated with older age (p=0.038) and uninvolved macula (p=0.000) in DEX group. No significant difference in IOP elevation ≥10 mm Hg, cataract progression and formation between groups. More eyes needed retinal surgery in control group (p<0.001). CONCLUSIONS: This was the first study to investigate use of intravitreal DEX implant in OT patients, which can efficiently reduce ocular inflammation and improve BCVA in macular uninvolved patients.

HIGH MYOPIA IS COMMON IN PATIENTS WITH X-LINKED RETINOPATHIES: Myopic Maculopathy Analysis.

PURPOSE: High myopia can occur as a single or syndromic condition. The aim of this study was to evaluate the refractive error and myopic maculopathy in patients with X-linked retinopathies. METHODS: Whole exome sequencing, Sanger sequencing, and comprehensive ocular examinations were performed in patients with X-linked retinopathies. RESULTS: A total of 17 patients were recruited, including six with CACNA1F, seven with RPGR, three with NYX, and one with OPN1MW mutations. The diagnoses were congenital stationary night blindness (6), cone-rod dystrophy (4), retinitis pigmentosa (4), achromatopsia (1), Leber congenital amaurosis (1), and myopia (1). Myopia was present in 88.2% patients, and 64.7% patients had high myopia. Gene analysis showed that high myopia was present in 80% patients with CACNA1F, 100% patients with NYX, and 57.1% patients with RPGR mutations. In the ATN classification, 64.7% of the patients were A1T0N0 and 35.3% were A0T0N0. The refractive errors progressed over time, even in patients with congenital stationary night blindness. Two females with heterozygous de novo RPGR mutations presented with retinitis pigmentosa or cone rod dystrophy combined with high myopia. CONCLUSION: High myopia is common in patients with X-linked retinopathies, and myopic maculopathy was only mild atrophy without traction and neovascularization.

Five novel dysfunctional variants in the TSPAN12 gene in familial exudative vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is an inheritable vitreoretinal disease characterized by incomplete retinal vascular development, which often leads to multiple retinal complications and causes severe vision loss in children. We reported the TSPAN12 variants' frequency in a cohort of FEVR and five novel TSPAN12 variants and related clinical features in six Chinese families. Seven hundred thirty-four families' genetic in-house data were reviewed. Whole-exome sequencing (WES) was performed in all probands; Sanger sequencing was conducted in the family members. Five novel variants from six families were noted, and clinical data were collected. Luciferase assays were applied to test the activity of the Norrin/ß-catenin signal caused by the mutant TSPAN12 genes. The frequency of TSPAN12 variants in FEVR is 8.79% (50/569). Five novel variants in TSPAN12 were identified in six families, including two missense variants, c.476G > A(p.Cys159Tyr) and c.81T > G(p.Ser27Arg), two frameshift variants, c.628_629insA(p.Met210Asnfs*42) and c.251delG(p.Gly84Glufs*3) and one nonsense, c.352G > T(p.Glu118*). Low vision, high myopia, nystagmus, and leukocoria are the common symptom at the first presentation. All variants were also predicted as pathogenic in silico. Moreover, the luciferase assay demonstrated that all variants caused severely compromised Norrin/ß-catenin signaling activity. In conclusion, the frequency of TSPAN12 variants in FEVR was 8.79% in our cohort. Five novel variants of TSPAN12 were identified. Moreover, we demonstrated the dysfunction of mutant variants via the downregulation of Norrin/ß-catenin signaling. These findings expanded the genetic and clinical spectrum of FEVR with TSPAN12 variants.

Identification of Five Novel Variants in the TSPAN12 Gene in Chinese Families With Familial Exudative Vitreoretinopathy.

Purpose: To report the novel causative variants in five Chinese families with familial exudative vitreoretinopathy (FEVR). Methods: Five unrelated Chinese families diagnosed with FEVR were enrolled in this study. Ocular examinations and genetic analysis were performed on the probands and family members. Luciferase assay was performed to evaluate the variants' impacts on Norrin/ß-catenin signaling activity. Results: Five novel variants, including two frameshifts, c.518delA (p.Glu173Glyfs*42) and c.719delT (p.Leu240Profs*21), two missenses, c.482G>T (p.Gly161Val) and c. 614G>C (p. Gly205Ala), and one nonsense, c.375G>A (p.Trp125*), were identified in the TSPAN12 gene in this study. All the variants were co-segregated within each family and were predicted as pathogenic in silico. The luciferase assay showed all variants lead to various degrees of compromised Norrin/ß-catenin signaling activity. Conclusions: Our study expanded the variant spectrum and provided information for the genetic testing of FEVR by showing five novel FEVR-associated pathogenic variants in TSPAN12. Translational Relevance: Our study expanded the spectrum of FEVR-associated TSPAN12 variants and further supported the inclusion of TSPAN12 gene in the evaluation of cases concerning for FEVR.

A potential anti-HIV-1 compound, Q308, inhibits HSV-2 infection and replication in vitro and in vivo.

HSV-2 is a common human pathogen worldwide that causes genital herpes. Due to the lack of an effective HSV-2 vaccine in the foreseeable future, there is an urgent need to develop effective, safe and affordable anti-HSV-2 agents. Our previous studies confirmed that a small-molecule compound, Q308, effectively inhibits the reactivation of latent HIV and might be developed as an anti-HIV-1 agent. Patients infected with HSV-2 are generally more susceptible to HIV-1 infection than normal humans. In this study, we found that Q308 treatment had strong inhibitory activity against both HSV-2 and acyclovir-resistant HSV-2 strains in vitro and reduced the viral titers in tissue. And this treatment effectively ameliorated the cytokine storm and pathohistological changes caused by HSV-2 infection in HSV-2-infected mice. Unlike nucleoside analogs such as acyclovir, Q308 inhibited post-viral entry events by attenuating the synthesis of viral proteins. Furthermore, Q308 treatment blocked HSV-2-induced PI3K/AKT phosphorylation due to its inhibition on viral infection and replication. Overall, Q308 treatment exhibits potent anti-HSV-2 activity by inhibiting viral replication both in vitro and in vivo. Q308 is a promising lead compound for the development of new anti-HSV-2/HIV-1 therapies, particularly against acyclovir-resistant HSV-2 strains.

ULTRA-WIDEFIELD OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN MILD FAMILIAL EXUDATIVE VITREORETINOPATHY.

PURPOSE: To investigate ultra-widefield optical coherence tomography angiography (UWF-OCTA) to detect and evaluate mild familial exudative vitreoretinopathy and compare the detective ratio of UWF-OCTA with ultra-widefield scanning laser ophthalmoscopy and ultra-widefield fluorescein angiography. METHODS: The patients with familial exudative vitreoretinopathy were included in this study. UWF-OCTA, using a 24- × 20-mm montage, was performed for all patients. All images were independently tested for the presence of familial exudative vitreoretinopathy-associated lesions. Statistical analysis was performed with SPSS V.24.0. RESULTS: Forty-six eyes of 26 participants were included in the study. Ultra-widefield optical coherence tomography angiography was found to be greatly superior to ultra-widefield scanning laser ophthalmoscopy in detecting peripheral retinal vascular abnormality ( P < 0.001) and peripheral retinal avascular zone ( P < 0.001). The detection rates of peripheral retinal vascular abnormality, peripheral retinal avascular zone, retinal neovascularization, macular ectopia, and temporal midperipheral vitreoretinal interface abnormality were comparable with ultra-widefield fluorescein angiography images ( P > 0.05). Furthermore, vitreoretinal traction (17/46, 37%) and small foveal avascular zone (17/46, 37%) were detected effectively on UWF-OCTA. CONCLUSION: Ultra-widefield optical coherence tomography angiography is a reliable noninvasive tool to detect familial exudative vitreoretinopathy lesions, especially in mild patients or asymptomatic family members. The unique manifestation of UWF-OCTA offers an alternative to ultra-widefield fluorescein angiography for the screening and diagnosis of FEVR.

NDP-related retinopathies: clinical phenotype of female carriers.

BACKGROUND/AIMS: Norrin cysteine knot growth factor (NDP) located on the X chromosome, was previously reported to cause Norrie disease and familial exudative vitreoretinopathy (FEVR), which are blindness-causing ocular disorders, in males. In this study, we aimed to explore the clinical characteristics of female carriers with NDP mutations. METHODS: Twelve female carriers from 11 unrelated families with pathogenic NDP mutations were recruited. Clinical data were collected from the NDP carriers. Comprehensive ocular examinations, including best corrected visual acuity, slit lamp examination, fundus photography and fundus fluorescein angiography (FFA) were evaluated. Targeted gene or whole exome sequencing was performed in the probands, and Sanger sequencing was performed to confirm NDP mutations in female carriers. RESULTS: Of the 12 females, 1 (1/12, 8.3%) presented with decreased visual acuity and 11 (11/12, 91.7%) were asymptomatic. Based on the FFA, peripheral vascular changes were noted in 66.7% (16/24) of the eyes of 75.0% (9/12) of the carriers. A total of 33.3% (8/24) had typical FEVR phenotype, 33.3% (8/24) had mild vascular abnormalities and 33.3% (8/24) was unremarkable. In addition, predominant changes such as telangiectatic endings (66.7%), anomalous circumferential vessel (37.5%), supernumerary vascular branching (33.3%), fluorescein leakage (29.2%), avascular area (8.3%), retina fold (8.3%) and peripheral straightening of retinal vessels (33.3%) were noted. CONCLUSION: Although NDP-related retinopathy is an X-linked recessive disorder, most of the female carriers of NDP exhibited clinical features of FEVR. Thus, timely examinations and lifelong monitoring should be conducted in the NDP female carriers.

Skills assessment after a grape-based microsurgical course for ophthalmology residents: randomised controlled trial.

AIMS: To introduce and assess a course using grapes as training models for ophthalmology residents to acquire basic microsurgical skills. METHODS: Ophthalmology residents who were novices at microsurgery were included. Participants were randomised into a 1:1 ratio to a 4-hour training programme based on fruit models (group A) or virtual reality (VR) modulator and silicone suture pads (group B), respectively. Before and after training, questionnaires were designed to measure their self-confidence with ophthalmic operations and with their coming role as surgical assistants. After training, each participant provided their interest in further studying microsurgery and was assessed for their general competence of ophthalmic microsurgery on porcine eyes. RESULTS: Eighty-three participants were included, with 42 ones in group A and 41 ones in group B. After training, participants in group A performed better in the uniformities of the suture span (p<0.05), suture thickness (p<0.05) and tissue protection (p<0.05) during the corneal suturing assessment. The overall scores of corneal suturing and circular capsulorhexis in the porcine eye in group A were comparable to those in group B (p=0.26 and 0.87, respectively). Group A showed a more positive attitude to withstand the training for more than 4 hours (p<0.001), as well as a higher willingness to receive more times of the training in the future (p<0.001). CONCLUSIONS: Training models based on grapes are equal to VR simulators and silicon suture pads to provide solid training tasks for ophthalmology residents to master basic microsurgical skills, and might have advantages in lower economic cost, and easy availability. TRIAL REGISTRATION NUMBER: ChiCTR2000040439.

TRPV4 channel is involved in HSV-2 infection in human vaginal epithelial cells through triggering Ca2+ oscillation.

Herpes simplex virus (HSV) infection induces a rapid and transient increase in intracellular calcium concentration ([Ca2+]i), which plays a critical role in facilitating viral entry. T-type calcium channel blockers and EGTA, a chelate of extracellular Ca2+, suppress HSV-2 infection. But the cellular mechanisms mediating HSV infection-activated Ca2+ signaling have not been completely defined. In this study we investigated whether the TRPV4 channel was involved in HSV-2 infection in human vaginal epithelial cells. We showed that the TRPV4 channel was expressed in human vaginal epithelial cells (VK2/E6E7). Using distinct pharmacological tools, we demonstrated that activation of the TRPV4 channel induced Ca2+ influx, and the TRPV4 channel worked as a Ca2+-permeable channel in VK2/E6E7 cells. We detected a direct interaction between the TRPV4 channel protein and HSV-2 glycoprotein D in the plasma membrane of VK2/E6E7 cells and the vaginal tissues of HSV-2-infected mice as well as in phallic biopsies from genital herpes patients. Pretreatment with specific TRPV4 channel inhibitors, GSK2193874 (1-4 µM) and HC067047 (100 nM), or gene silence of the TRPV4 channel not only suppressed HSV-2 infectivity but also reduced HSV-2-induced cytokine and chemokine generation in VK2/E6E7 cells by blocking Ca2+ influx through TRPV4 channel. These results reveal that the TRPV4 channel works as a Ca2+-permeable channel to facilitate HSV-2 infection in host epithelial cells and suggest that the design and development of novel TRPV4 channel inhibitors may help to treat HSV-2 infections.

ERK/MEK Pathway Regulates Th17 Cell Differentiation in Patients with Pemphigus Vulgaris.

Background: T helper (Th) cells are involved in the pathogenesis of pemphigus vulgaris (PV). However, the mechanism still needs more exploration. Aims: This study aimed to evaluate the molecular mechanism of the dysregulation of Th17 cells in the peripheral blood of patients with PV. Materials and Methods: Serum levels of IL-17 and anti-Dsg3 titres in patients with PV were analysed using ELISA. The mRNA expression of retinoic acid orphan receptor γt (RORγt) in CD4+ T cells was detected using reverse transcription-quantitative PCR (qPCR). The number of Th17 cells was examined using flow cytometry. Western blot analysis and immunofluorescent staining were also performed to investigate the expression levels of ERK/MAPK signalling proteins and Th17 lineage-associated proteins. Results: The proportion of Th17 cells and Th17 spectrum-associated proteins (p-STAT3, RORγt and IL-17) were upregulated in CD4+ cells in PV patients. The increased transcriptional levels of RORγt and IL-17 correlated positively with the severity of PV. Elevated phosphorylation of the ERK signalling factors was found in the collected CD4+ T cells in PV patients. The inhibition of the ERK signalling pathway significantly reduced the differentiation of Th17 cells in PV patients in vitro. Conclusion: Th17 cells are essential in the dysregulation of PV, and ERK signalling is involved in Th17-type immunity and promotes the development of PV. The study here provides us with a potential therapeutic target for PV.

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.

Ocular findings and genetic test in Alström syndrome in childhood.

This study aimed to investigate the mutation spectrums and ocular features of Alström syndrome (AS) patients. Six AS patients from five unrelated families were included. Ocular and systemic examinations were performed in all subjects. Whole-exome sequencing (WES) was performed in the probands, and Sanger sequencing was performed for mutation validation and segregation analysis. Among the six patients, the first symptoms included nystagmus, poor fixation, and photophobia. Five patients had high hyperopia, four of whom (80%) were initially diagnosed with amblyopia before referral with prescribed corrective lenses and amblyopia treatment, but no improvement was obtained. Optical coherence tomography (OCT) revealed progressive damage to the photoreceptor layer, including blurred ellipsoid zone (EZ) and lack of interdigitation zone (IZ) within the macula, and thorough loss of photoreceptor layer in the peripheral retina. Electroretinograms (ERG) demonstrated severely diminished cone and rod responses. WES identified biallelic variants of ALMS1 in all the six patients, including two novels, c.3892C > T (p.Gln1298*) and c.2888_2897del (p.Ser963Thrfs*15) and five knowns, c.10819C > T (p.Arg3607Trp), c.2090C > A (p.Ser697*), c.4891C > T (p.Gln1631*), c.10825C > T (p.Arg3069*) and c.6430C > T (Arg2146*). In conclusion, this study expanded the ocular features and genotypic spectrum of AS. High hyperopia is a significant and common feature of AS. OCT and ERG are essential accessory techniques for the diagnosis of AS. If a patient had high hyperopia with a noneffective response to amblyopic treatment, the diagnosis of AS should be suspected, and detailed ocular examination, systemic evaluation, and genetic testing recommended.

ROP-like retinopathy in full/near-term newborns: A etiology, risk factors, clinical and genetic characteristics, prognosis and management.

Purpose: Retinopathy of prematurity (ROP) like retinopathy (ROPLR) could occur in full/near-term newborns. The causes and clinical features are still largely elusive. This study focused on the risk factors, clinical and genetic characteristics, treatment and outcome, and prognosis of ROPLR. Methods: A total of 47 consecutive full/near-term newborns during 2016-2017 with ROPLR were included. The clinical and genetic characteristics, treatment and outcome, prognosis, and potential underlying etiology of ROPLR were were analyzed. Results: 91 eyes of 47 infants were found to have ROPLR. The ROPLR regressed completely in 65.9% and partially in 20.9% of eyes without any interventions. Retinal changes of family exudative vitreoretinopathy (FEVR) were allocated in 12 neonates (group A), perinatal hypoxia-ischemia were categorized in 17 neonates (group B), and the other 18 neonates were categorized in group C. Compared to those in group B/C, infants in group A had significantly more severe retinopathy (stage 4/5, p < 0.001) and more treatments (p < 0.00 risk factor 1). Conclusions: Perinatal hypoxia-ischemia might be a major risk factor for ROPLR, in which spontaneous regression was common. FEVR, confirmed by positive family findings and genetic testing, might be the second risk factor of ROPLR, in which retinopathy is more severe and treatment is needed.

Cytokine Profile in Aqueous Humor of Patients With Ocular Toxocariasis.

Purpose: Ocular toxocariasis (OT) is a vision-threatening disease with a largely unknown intraocular pathogenesis. Herein, we determined the cytokine expression profile in aqueous humor (AH) of patients with OT. Methods: This is a retrospective case-control study of cytokine levels in AH of patients with OT and uveitis and control subjects. Thirty samples from eyes with OT, 23 from eyes with non-OT uveitis, and 25 from eyes with age-related cataract were analyzed using a multiplexed magnetic bead immunoassay. Thirty-one cytokines were detected and classified into 5 categories: T-helper type 1 (Th1) -associated cytokines, Th2-associated cytokines, Th17 cytokine, proinflammatory mediators, and growth factors. Results: In the 31 cytokines, 9 cytokines were undetectable, including IL-1a, IL-1b, IL-2, IL-3, IL-12p70, IL-17A, TGF-a, TNF-ß, and IFN-g. From the 22 cytokines, 13 exhibited significantly increased expression in the OT group than in the control group, including TNF-a, IFN-a2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, sCD40L, PDGF-AA, PDGF-AB/BB, FLT3l, and EGF. There were 5 cytokines exhibited significantly increased expression in the OT group than in non-OT group, including IL-5, IL-9, IL-10, IL-13, and PDGF-AA. There was no significantly decreased expression in any cytokines in the OT group when compared with control or non-OT groups. To the 5 cytokines that showed significant difference in OT group alone, IL-10 and IL-13 exhibited more than 13-fold increase, and IL-5 showed the most obvious as 27-fold increase in OT patients, when compared with that in control group. Conclusion: The cytokine profile expression in aqueous humor from patients with ocular toxocariasis was investigated, and our findings suggest that Th1 and Th17 cytokine responses are not enhanced, whereas the cytokine status was polarized toward a Th2 response. Our findings also suggest the involvement of IL-5, IL-10, and IL-13 in the immunopathogenesis of ocular toxocariasis.

FZD4 in a Large Chinese Population With Familial Exudative Vitreoretinopathy: Molecular Characteristics and Clinical Manifestations.

Purpose: The purpose of this study was to establish a genotype-phenotype correlation of familial exudative vitreoretinopathy (FEVR) caused by FZD4 gene mutations. Methods: Six hundred fifty-one probands and their family members were recruited based on a clinical diagnosis of FEVR between 2015 and 2021 at Zhongshan Ophthalmic Center. Ocular examinations were performed in all participants. Targeted gene panel sequencing and whole-exome sequencing were performed in the probands, and Sanger sequencing was used to verify the mutations and segregation analysis was performed in the family members. Results: Fifty-one FZD4 mutations (24 novels and 27 known) were detected in 84 families. Of these 168 eyes with FEVR, the eyes at stages 1, 2, 3, 4, and 5 were 29 (17.3%), 15 (8.9%), 19 (11.3%), 55 (32.7%), and 12 (7.1%), respectively. Exact stage of 38 (22.6%) eyes could not be determined. The FEVR phenotypes were more severe in the probands than the phenotypes in the family members (P < 0.001). The families were divided into two groups, probands that inherited the variant from the mother, and probands that inherited the variant from the father. In addition, the FEVR stage differences between these two groups were different (P < 0.05). Despite the mutations being located in different domains of FZD4, no significant differences were identified among the domains in terms of FEVR staging, retinal folds, retinal detachment, temporal midperipheral vitreoretinal interface abnormality, and foveal hypoplasia. Conclusions: The FZD4 probands had severer phenotype than the family members, and the FEVR stage difference was greater between the probands and mothers than that between the probands and fathers.

Update on the Phenotypic and Genotypic Spectrum of KIF11-Related Retinopathy.

Background: This study aimed to report the frequency of KIF11-mutations in a large familial exudative vitreoretinopathy (FEVR) population, extend the clinical spectrum of KIF11-associated retinopathy and compare KIF11-associated retinopathy to FEVR with mutations in other genes. Methods: Genetic data collected from 696 FEVR families were reviewed. The ocular phenotypes in patients with KIF11 mutations were analyzed and compared with those of FEVR patients with mutations in other genes (FZD4, TSPAN12, LRP5, NDP and JAG1). Results: In a cohort of 696 FEVR families, disease-causing KIF11 mutations were identified in 3.6% of families (25/696). Among 25 KIF11 mutations, 80% (20/25) carried variants of loss of function and 48% (12/25) of variants were de novo. The phenotypes were variable. Compared with FEVR with disease-causing mutations in other genes, chorioretinal dysplasia was observed in 44.2% (31/70) of eyes with KIF11-associated retinopathy and in only 1.3% (1/70) of eyes with FEVR with mutations in other genes (p < 0.01). Increase and straightening of peripheral vessels (ISPV) was observed in 17.1% (12/70) of eyes with KIF11-associated retinopathy, and in 50% (39/78) of eyes with FEVR with mutations in other genes (p < 0.01). Conclusions: The frequency of the KIF11 mutation in FEVR was 3.6% in our database. The manifestation of KIF11-associated retinopathy was variable and different from the phenotype in FEVR caused by other genes. Chorioretinal dysplasia, instead of retinal folds, was the dominant phenotype in KIF11-associated retinopathy. ISPV was rare in KIF11-associated retinopathy. Moreover, our study revealed that most pathogenic KIF11 mutations were de novo.

CHARACTERISTICS OF THE FOVEAL MICROVASCULATURE IN CHILDREN WITH MARFAN SYNDROME: An Optical Coherence Tomography Angiography Study.

PURPOSE: To investigate the characteristics of foveal microvasculature in children with Marfan syndrome (MFS). METHODS: Ninety eyes from 45 MFS patients and 76 eyes from 38 healthy individuals of age-matched, sex-matched, and axial length-matched were enrolled. Characteristics of the superficial capillary plexus including the vessel density, perfusion density, and foveal avascular zone were analyzed by optical coherence tomography angiography. RESULTS: The vessel density and the circularity index of the foveal avascular zone were significantly decreased in the MFS group compared with the controls (P = 0.017 and P = 0.004 respectively). In MFS group, the central vessel density (P = 0.003) and perfusion density (P = 0.001) were negatively correlated with the best-corrected visual acuity. The foveal avascular zone area was correlated with the aortic diameters (P = 0.001) and the paratemporal perfusion density was correlated with the ejection fraction (P = 0.003). Moreover, the paratemporal perfusion density and the circularity index of foveal avascular zone were found to be correlated with the aortic Z-score (P < 0.001 and P = 0.003 respectively). CONCLUSION: Retinal microvascular decrease and its correlation with best-corrected visual acuity and cardiac functions were observed in the MFS group. The optical coherence tomography angiography may help to characterize the underlying pathophysiology features of MFS and enable early detection and prevention of vascular changes in MFS.

NONINVASIVE DIAGNOSTIC STRATEGY OF OCULAR TOXOCARIASIS BASED ON CLINICAL FEATURES.

PURPOSE: To develop a noninvasive diagnostic strategy based on the clinical manifestations of ocular toxocariasis (OT) and evaluate its sensitivity and specificity. METHODS: Patients with unilateral OT-like lesions were enrolled retrospectively and classified into OT and non-OT groups according to the immunologic diagnosis criterion of anti-OT immunoglobulin G. Nine clinical manifestations were recorded and compared between the groups. Among them, the retrolental membrane, branch-like vitreous strands, and retinal granulomas were the most common, which were further classified into three categories, including at least 1 of three signs, at least two of three signs, and all three signs positive. Diagnostic sensitivity and specificity were calculated for each strategy. RESULTS: There were 105 immunologically confirmed patients with OT and 70 patients with non-OT uveitis/vitreoretinopathy. Retinal granulomas, retrolental membrane, and branch-like vitreous strands were significantly more frequent in OT patients than in non-OT patients. At least 1 of 3 signs positive strategy showed the highest sensitivity (100.0%) but the lowest specificity (62.0%). At least 2 of 3 signs positive strategies showed 80.0% sensitivity and 94.3% specificity. All 3 signs positive strategies had the lowest sensitivity (46.7%) and the highest specificity (100.0%). The cutoff point of this revealed an area under the curve of 0.85 and a 95% confidence interval of 0.79 to 0.91. CONCLUSION: A comprehensive strategy based on at least two out of three positive signs showed excellent sensitivity and specificity and could serve as a noninvasive and fast screening strategy for the clinical diagnosis of OT.