Abstract Purpose To present the clinical findings of patients diagnosed with syphilitic outer retinopathy. Study design A retrospective clinical study. Patients and Methods The study involved four Japanese men whose medical charts were reviewed and analyzed retrospectively. Results All patients declined decimal visual acuity to 0.1, 0.2, 0.4, 0.6, and 0.8. Their fundus appearances were generally normal, except for one patient who displayed faint white dots in the upper macular region. Two patients showed dye leakage from retinal vessels during fluorescein angiography. Optical coherence tomography (OCT) results revealed abnormalities in all patients: three had a disrupted ellipsoid zone (EZ) and hyper-reflective nodules at the retinal pigment epithelium line, while one patient presented with a blurred EZ. The patients had myopia ranging from –4.5 to –7.5 diopters. They were diagnosed with syphilitic outer retinopathy based on the findings from the fundus examination, OCT, and serologic tests and were treated with oral amoxicillin, resulting in improved vision. Conclusions The OCT findings are typical for diagnosing syphilitic outer retinopathy. Myopia was prevalent in the four patients, indicating a need for further research on refractive errors in patients with syphilitic outer retinopathy.

Introduction: Macular hole is a rare complication in patients with retinitis pigmentosa that significantly reduces visual acuity. Although vitreous surgery for macular holes generally yields favorable outcomes, postoperative macular atrophy has been reported. We report the second case of retinitis pigmentosa in a patient who developed a 13-year progressive macular atrophy after macular hole surgery. Case Presentation: A 64-year-old Japanese woman, who had been diagnosed with retinitis pigmentosa at 52 years of age, presented to our hospital with blurred vision in her left eye. Phacovitrectomy of the left eye was performed after a full-thickness macular hole was revealed by optical coherence tomography. We stained the internal limiting membrane during surgery using 0.05% indocyanine green and peeled it around the macular hole. Nevertheless, slight atrophy of the retinal pigment epithelium appeared in the left macula 17 days after surgery. The macular hole closed 1 year after surgery, and the macular atrophy gradually became more apparent and enlarged. Thirteen years later, atrophy had expanded to 2.5-disc diameters, and the left decimal best-corrected visual acuity was 0.1; no macular degeneration appeared in the right eye. Genetic examination revealed compound heterozygous variants in the EYS gene. Conclusion: Macular atrophy can develop after dye-assisted macular hole surgery for patients with retinitis pigmentosa. Potential risk factors for the development of postoperative macular atrophy include dye toxicity, light toxicity, surgical intervention in the macula, postoperative inflammation, and genotype. However, the exact cause of atrophy remains uncertain.

PURPOSE: To ascertain the characteristics of achromatopsia (ACHM) in Japan by analyzing the genetic and phenotypic features of patients with ACHM. METHODS: The medical records of 52 patients from 47 Japanese families who were clinically diagnosed with ACHM were reviewed in this retrospective observational study. RESULTS: Thirty-six causative variants of ACHM were identified in 26 families via whole-exome sequencing: PDE6C (12 families), CNGA3 (10 families), CNGB3 (two families), and GNAT2 (two families). However, none of the 6 causative variants that are known to cause ACHM, or the 275 other genes listed in RetNet, were observed in 19 families. A significant trend toward older age and worsening of ellipsoid zone disruption on optical coherence tomography images was observed (P < 0.01). Progressive ellipsoid zone disruptions were observed in 13 eyes of seven patients during the follow-up visits. These patients harbored one or more variants in PDE6C. CONCLUSION: The ACHM phenotype observed in this study was similar to those observed in previous reports; however, the causative gene variants differed from those in Europe. The low identification ratio of causative genes in whole-exome sequencing suggests the presence of unique hotspots in Japanese patients with ACHM that were not detectable via ordinal whole-exome sequencing.

Introduction In Japan, inherited retinal dystrophy caused by biallelic variants of the RPE65 gene is exceedingly rare. The purpose of this study was to describe a Japanese male patient with a novel variant in RPE65 associated with Leber congenital amaurosis (LCA). Case report The patient, diagnosed with LCA, exhibited infantile nystagmus and reported experiencing night blindness since early childhood. At 27 years of age, the patient underwent an ophthalmologically evaluation. Corrected visual acuity was Snellen equivalent 20/133 in the right eye and Snellen equivalent 20/100 in the left eye. Fundus examination revealed alterations in the retinal pigment epithelium characterized by hypopigmentation and narrowing of retinal vessels. Fundus autofluorescence imaging demonstrated a generally diminished autofluorescent signal. Full-field electroretinography identified a generalized dysfunction of both rod and cone systems in each eye. Whole exome sequencing identified a novel missense variant in RPE65 (NM_000329.3): c.1172C &gt; A p.(Ala391Asp), which was classified as pathogenic, as well as a recurrent variant p.(Arg515Trp). Conclusion This study provides valuable insights into the genotype–phenotype correlation of RPE65-associated LCA in Japanese patients, with critical implications for enhanced diagnostic accuracy and informed therapeutic decisions.

In vertebrates, retinal neural circuitry for visual perception is organized in specific layers. The outer plexiform layer is the first synaptic region in the visual pathway, where photoreceptor synaptic terminals connect with bipolar and horizontal cell processes. However, molecular mechanisms underlying cone synapse formation to mediate OFF pathways remain unknown. This study reveals that Necl-1/CADM3 is localized at S- and S/M-opsin-containing cones and dendrites of type 4 OFF cone bipolar cells (CBCs). In Necl-1-/- mouse retina, synapses between cones and type 4 OFF CBCs were dislocated, horizontal cell distribution became abnormal, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were dislocated. Necl-1-/- mice exhibited aberrant short-wavelength-light-elicited signal transmission from cones to OFF CBCs, which was rescued by AMPA receptor potentiator. Additionally, Necl-1-/- mice showed impaired optokinetic responses. These findings suggest that Necl-1 regulates cone synapse formation to mediate OFF cone pathways elicited by short-wavelength light in mouse retina.

BACKGROUND: KCNV2-associated retinopathy causes a phenotype reported as "cone dystrophy with nyctalopia and supernormal rod responses (CDSRR; OMIM# 610356)," featuring pathognomonic findings on electroretinography (ERG). Here, we report the clinical courses of two siblings with CDSRR. CASE REPORTS: Patient 1: A 3-year-old boy with intermittent exophoria was referred to our hospital. The patient's decimal best-corrected visual acuity (BCVA) at age 6 was 0.7 and 0.7 in the right and left eyes, respectively. Photophobia and night blindness were also observed. Because the ERG showed a delayed and supernormal b-wave with a "squaring (trough-flattened)" a-wave in the DA-30 ERG, and CDSRR was diagnosed. The patient's vision gradually worsened, and faint bilateral bull's eye maculopathy was observed at the age of 27 years, although the fundi were initially unremarkable. Genetic examination revealed a homozygous missense variant, c.529T > C (p.Cys177Arg), in the KCNV2 gene. Patient 2: The second patient was Patient 1's younger sister, who was brought to our hospital at 3 years of age. The patient presented with exotropia, mild nystagmus, photophobia, night blindness, and color vision abnormalities. The patients' decimal BCVA at age 13 was 0.6 and 0.4 in the right and left eyes, respectively, and BCVA gradually decreased until the age of 24 years. The fundi were unremarkable. The siblings had similar ERG findings and the same homozygous missense variant in the KCNV2 gene. CONCLUSIONS: The siblings had clinical findings typical of CDSRR. High-intense flash ERG is recommended for identifying pathognomonic "squaring" a-waves in patients with CDSRR.

Purpose: This study aimed to determine the incidence of the Amalric triangular sign (ATS) in patients with central retinal artery occlusion (CRAO) and investigate its association with visual function and carotid Doppler ultrasonography findings. Methods: A retrospective chart review was conducted on 21 eyes from 21 cases with complete CRAO. Best-corrected visual acuity (BCVA) and carotid Doppler ultrasonography findings [peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistance index (RI) = (PSV-EDV)/PSV] were investigated. Results: Three patients (14%) exhibited the ATS. BCVA at first visit was significantly worse in ATS-positive than in ATS-negative (P = 0.024). Doppler waveform analysis of the common carotid artery (CCA) showed that ATS-positive patients had a significantly lower EDV [P = 0.009, median 10 (range 9–10) vs. 17 (13–24) m/s] and significantly higher RI [P = 0.021, median 0.80 (range 0.79–0.83) vs. 0.72 (0.66–0.82)] than did ATS-negative. Conclusions: The ATS was observed in three patients with CRAO, who showed worse BCVA at the first visit than did those without the ATS. Carotid Doppler ultrasonography revealed that ATS-positive patients had a significantly higher RI and lower EDV at the CCA than did ATS-negative, indicating steno-occlusive changes in the internal carotid artery.

PURPOSE: To clarify the genetic and clinical features of Japanese patients with ABCA4-associated retinopathy. DESIGN: Retrospective, multicenter cohort study METHODS: Patients with retinal degeneration and biallelic ABCA4 variants were recruited from 13 different hospitals. Whole exome sequencing analysis was used for genetic testing. Comprehensive ophthalmic examinations were performed on matched patients. The primary outcome measure was identifying multimodal retinal imaging findings associated with disease progression. RESULTS: This study included 63 patients: 19 with missense/missense, 23 with missense/truncation, and 21 with truncation/truncation genotypes. In total, 62 variants were identified, including 29 novel variants. Six patients had a mild phenotype characterized by foveal-sparing or preserved foveal structure, including four with missense/missense and two with missense/truncation genotypes. The p.Arg212His variant was the most frequent in patients with mild phenotypes (4/12 alleles). Clinical findings showed a disease duration-dependent worsening of the phenotypic stage. Patients with the truncation/truncation genotype exhibited rapid retinal degeneration within a few years and definite fundus autofluorescence imaging patterns, including hyper autofluorescence at the macula and few or no flecks. CONCLUSIONS: Our results indicate that missense/missense or missense/truncation genotypes, including the p.Arg212His variant, are associated with a relatively mild phenotype. In contrast, the truncation/truncation genotype causes rapid and severe retinal degeneration in Japanese patients with ABCA4-associated retinopathy. These data are vital in predicting patient prognosis, guiding genetic counseling, and stratifying patients for future clinical trials.

This study evaluated the long-term visual outcomes of patients in whom at least one eye underwent successful lens-sparing vitrectomy (LSV) for stage 4A retinopathy of prematurity (ROP). A retrospective chart review was conducted using the data of 61 eyes of 42 patients with a minimum 4-year follow-up after successful LSV, with or without anti-vascular endothelial growth factor (VEGF) therapy, and whose best-corrected visual acuity (BCVA) was measurable using Landolt rings at the final visit. The mean age at the final follow-up was 10.1 ± 3.3 years. Before LSV, all eyes underwent laser ablation therapy. Twenty eyes (32.8%) with high vascular activity received anti-VEGF therapy before LSV. The mean decimal BCVA at the final follow-up was 0.23 ± 0.26 (range: hand motion to 1.2). Twenty-three eyes (54.1%) had a decimal BCVA of ≥0.4. Among 49 phakic eyes at the final examination, the mean refractive error was -10.1 ± 5.0 D, with 37 eyes (75.5%) having high myopia (>-6.0 D). No significant differences were observed in terms of decimal BCVA and refractive errors between eyes with and without anti-VEGF therapy. Approximately half of the patients had a decimal BCVA of ≥0.4, despite myopic refraction after successful LSV for stage 4A ROP. LSV for stage 4A ROP seemed to be associated with good visual function, despite myopic refraction.

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 RS1 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 RS1 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 (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.

Inherited retinal diseases (IRDs) comprise a phenotypically and genetically heterogeneous group of ocular disorders that cause visual loss via progressive retinal degeneration. Here, we report the genetic characterization of 1210 IRD pedigrees enrolled through the Japan Eye Genetic Consortium and analyzed by whole exome sequencing. The most common phenotype was retinitis pigmentosa (RP, 43%), followed by macular dystrophy/cone- or cone-rod dystrophy (MD/CORD, 13%). In total, 67 causal genes were identified in 37% (448/1210) of the pedigrees. The first and second most frequently mutated genes were EYS and RP1, associated primarily with autosomal recessive (ar) RP, and RP and arMD/CORD, respectively. Examinations of variant frequency in total and by phenotype showed high accountability of a frequent EYS missense variant (c.2528G>A). In addition to the two known EYS founder mutations (c.4957dupA and c.8805C>G) of arRP, we observed a frequent RP1 variant (c.5797C>T) in patients with arMD/CORD.

Background: We investigated the incidence and clinical characteristics of eyes showing retinal detachment (RD) after anti-vascular endothelial growth factor (VEGF) for retinopathy of prematurity (ROP). Methods: A retrospective chart review of 76 consecutive eyes of 45 patients (18 girls and 27 boys) with stage 3 ROP who received anti-VEGF therapy between January 2012 and August 2020 with a minimum follow-up of 6 months was conducted. Eyes were divided into two groups: the vitrectomy (V) group that required vitrectomy for RD after anti-VEGF therapy and the non-vitrectomy (non-V) group that did not require vitrectomy. Data were collected from patient charts, including sex, postmenstrual age (PMA) at birth, birth weight, PMA at anti-VEGF therapy, comorbidities, reactivation, examination interval, and subsequent vitrectomies. Results: The median PMA at birth was 24.7 (range, 22.1-29.3) weeks. Twenty-seven eyes (35.1%) exhibited ROP reactivation at 6.4 ± 3.1 weeks after anti-VEGF therapy. The V group included six eyes of five patients, all of whom exhibited reactivation and developed RD 10.1 ± 6.5 weeks after anti-VEGF therapy. The types of RD were conventional (classic) in two eyes and circumferential (unique to RD after anti-VEGF) in four eyes. Three eyes required repeated vitrectomy. All eyes, except one eye in the V group, achieved retinal attachment at the last examination. The non-V group included 70 eyes of 40 patients, of which 21 exhibited reactivation and were treated successfully with laser (17 eyes) or second anti-VEGF (4 eyes). The proportion of eyes with plus disease was significantly higher in the V group (50.0%) than in the non-V group (10.0%) (P = 0.035). V group included 3 of 22 eyes (13.6%) in which the interval between the last examination and the diagnosis of reactivation was <1 week and 3 of 5 eyes (60.0%) in which the interval was more than 1 week (P = 0.024). The two groups showed no significant differences in the other factors. Conclusion: Approximately 8% of eyes developed RD about 10 weeks after anti-VEGF therapy for ROP. Eyes with history of plus disease should be carefully monitored at appropriate intervals after anti-VEGF therapy for ROP.

PURPOSE: To report the outcomes of two only seeing eyes of two cases with retinoblastoma in which vitrectomy was performed to treat vitreous hemorrhage or rhegmatogenous retinal detachment after treatment for retinoblastoma. OBSERVATIONS: Case 1 was an 8-month-old girl whose bilateral retinoblastoma (group D, OU) was treated by chemotherapy and focal ablation therapy. As the tumor size increased, enucleation was required in the right eye. At 4 years of age, about 1 year after the last treatment for retinoblastoma, lens-sparing vitrectomy was performed for dense, nonclearing vitreous hemorrhage, which had occurred 6 months previously. No recurrence of the tumor was found, and the patient's visual acuity improved to 0.9 postoperatively. Case 2 was a 4-month-old boy who was diagnosed with bilateral retinoblastoma (group D, OD; group C, OS) and underwent treatment, including systemic and local chemotherapy and proton beam therapy. Because large, regressed tumor masses were present in the posterior pole of the right eye, the left eye was the only seeing eye. At the age of 1 year 7 months, retinal detachment developed in the left eye 1 month after cryotherapy was performed for tumor recurrence. Although a scleral buckling procedure without drainage was performed, the retina was not reattached. The retina was reattached after vitrectomy with melphalan irrigation and silicone oil tamponade. However, recurrence was noted 6 months after the operation, and enucleation was required. CONCLUSION AND IMPORTANCE: Vitrectomy appears to be beneficial for the treatment of vision-threatening complications after retinoblastoma treatment. However, vitrectomy may be associated with the potential spread of tumor cells and/or tumor recurrence and therefore should be reserved as the last treatment modality for only seeing eyes. Careful postoperative follow-up is mandatory.

BACKGROUND: This 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 PRESENTATION: A 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. CONCLUSIONS: Cellular 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.

Peripherin-2 (PRPH2) is one of the causative genes of inherited retinal dystrophy. While the gene is relatively common in Caucasians, reports from Asian ethnicities are limited. In the present study, we report 40 Japanese patients from 30 families with PRPH2-associated retinal dystrophy. We identified 17 distinct pathogenic or likely pathogenic variants using next-generation sequencing. Variants p.R142W and p.V200E were relatively common in the cohort. The age of onset was generally in the 40’s; however, some patients had earlier onset (age: 5 years). Visual acuity of the patients ranged from hand motion to 1.5 (Snellen equivalent 20/13). The patients showed variable phenotypes such as retinitis pigmentosa, cone-rod dystrophy, and macular dystrophy. Additionally, intrafamilial phenotypic variability was observed. Choroidal neovascularization was observed in three eyes of two patients with retinitis pigmentosa. The results demonstrate the genotypic and phenotypic variations of the disease in the Asian cohort.

BACKGROUND: To report a case of severe acute bilateral outer retinitis after tonsillitis and rapid morphologic and functional recovery after steroid treatment. METHODS: Observational case report. RESULTS: A 26-year-old woman with acute bilateral blurred vision that developed after tonsillitis underwent spectral-domain optical coherence tomography (SD-OCT) that showed photoreceptor outer segment damage. Full-field electroretinography (ERG) and multifocal ERG were nonrecordable. The patient had a remarkable anatomic and functional recovery in response to steroid treatment; however, partial damage remained around the macula on SD-OCT, and an adaptive optics imaging system showed damaged cone photoreceptors. CONCLUSIONS: Prednisolone is an effective treatment for a disease that is believed to be due to suspicious involvement of the autoimmune system. Even severe outer retinitis can recover completely with rapid diagnosis and treatment.

PURPOSE: To determine the characteristics of fundus autofluorescence (FAF) images and visual functions in eyes with Stickler syndrome using ultra-widefield FAF images. METHODS: Forty-six eyes of 26 patients with mutations in the COL2A1 gene underwent ultra-widefield FAF imaging. The eyes were categorized into three types; no signs of abnormal AF, predominantly hyperfluorescent AF (hyper-AF), and predominantly hypofluorescent AF (hypo-AF). Goldmann perimetry was performed on 34 eyes, and line-scan images of the abnormal AF lesions were obtained by swept-source optical coherence tomography in 4 eyes. RESULTS: Abnormal AF lesions were found in 37 eyes of 21 (80.7%) of the 26 patients. Hyper-AF was found in 15 eyes and hypo-AF was found in 22 eyes. The FAF changes corresponded with the funduscopically observed radial paravascular retinal degeneration. The average age at the examination was significantly younger in patients who had eyes with hyper-AF or no abnormal AF than in those with hypo-AF (12.8 vs. 28.4 years; P = 0.009). Abnormal AF-associated visual field defects were found in 5/10 (50%) eyes with hyper-AF and 17/18 (94%) eyes with hypo-AF. Hyper-AF changes tended to appear before retinal changes were detectable by fluorescein angiography. An absence of the ellipsoid zone and the outer nuclear layer and a thinning of the overall retinal thickness were found corresponding to the hypo-AF lesions in the swept source optical coherence tomography images. CONCLUSION: Abnormal FAF is characteristic of eyes with Stickler syndrome. Age-related alterations of the FAF was associated with visual field defects and disruption of the photoreceptors and retinal pigment epithelial cells.

Purpose: To determine the clinical and genetic characteristics of patients with GUCY2D-associated retinal disorder (GUCY2D-RD). Methods: Fifteen patients from 12 families with inherited retinal disorder (IRD) and harboring GUCY2D variants were ascertained from 730 Japanese families with IRD. Comprehensive ophthalmological examinations, including visual acuity (VA) measurement, retinal imaging, and electrophysiological assessment were performed to classify patients into three phenotype subgroups; macular dystrophy (MD), cone-rod dystrophy (CORD), and Leber congenital amaurosis (LCA). In silico analysis was performed for the detected variants, and the molecularly confirmed inheritance pattern was determined (autosomal dominant/recessive [AD/AR]). Results: The median age of onset/examination was 22.0/38.0 years (ranges, 0-55 and 1-73) with a median VA of 0.80/0.70 LogMAR units (ranges, 0.00-1.52 and 0.10-1.52) in the right/left eye, respectively. Macular atrophy was identified in seven patients (46.7%), and two had diffuse fundus disturbance (13.3%), and six had an essentially normal fundus (40.0%). There were 11 patients with generalized cone-rod dysfunction (78.6%), two with entire functional loss (14.3%), and one with confined macular dysfunction (7.1%). There were nine families with ADCORD, one with ARCORD, one with ADMD, and one with ARLCA. Ten GUCY2D variants were identified, including four novel variants (p.Val56GlyfsTer262, p.Met246Ile, p.Arg761Trp, p.Glu874Lys). Conclusions: This large cohort study delineates the disease spectrum of GUCY2D-RD. Diverse clinical presentations with various severities of ADCORD and the early-onset severe phenotype of ARLCA are illustrated. A relatively lower prevalence of GUCY2D-RD for ADCORD and ARLCA in the Japanese population was revealed. Translational Relevance: The obtained data help to monitor and counsel patients, especially in East Asia, as well as to design future therapeutic approaches.

Biallelic variants in the EYS gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic EYS variants, to determine the clinical/genetic spectrum of EYS-associated retinal disease (EYS-RD), and to discover disease-associated variants with relatively high allele frequency (1%-10%) in a nationwide Japanese cohort. Sixty-six affected subjects from 61 families with biallelic or multiple pathogenic/disease-associated EYS variants were ascertained by whole-exome sequencing. Three phenotype groups were identified in EYS-RD: retinitis pigmentosa (RP; 85.94%), cone-rod dystrophy (CORD; 10.94%), and Leber congenital amaurosis (LCA; 3.12%). Twenty-six pathogenic/disease-associated EYS variants were identified, including seven novel variants. The two most prevalent variants, p.(Gly843Glu) and p.(Thr2465Ser) were found in 26 and twelve families (42.6%, 19.7%), respectively, for which the allele frequency (AF) in the Japanese population was 2.2% and 3.0%, respectively. These results expand the phenotypic and genotypic spectrum of EYS-RD, accounting for a high proportion of EYS-RD both in autosomal recessive RP (23.4%) and autosomal recessive CORD (9.9%) in the Japanese population. The presence of EYS variants with relatively high AF highlights the importance of considering the pathogenicity of non-rare variants in relatively prevalent Mendelian disorders.

DRAM2-associated retinopathy is a rare inherited retinal dystrophy, and its outcome has not been determined. A single retinal involvement by a mutation of the DRAM2 gene is unexplained. We found three unrelated patients with a disease-causing DRAM2 variant in a biallelic state from 1555 Japanese individuals of 1314 families with inherited retinal dystrophy. We reviewed their medical records and examined their peripheral lymphocytes by transmission electron microscopy (TEM). Patient 1 was a 38-year-old woman who complained of night blindness and reduced vision. She developed macular degeneration at age 43 years. Patients 2 and 3 were a man and a woman both of whom noticed night blindness in their 30s. Both had a degeneration in the macula and midperiphery in their 40s, which progressed to a diffuse retinal degeneration in their 60s when their vision was reduced to hand motions. Three novel DRAM2 variants were identified. TEM of the lymphocytes of Patients 1 and 2 showed abnormal structures in 40.6% and 0.3% of the peripheral lymphocytes, respectively. We concluded that the DRAM2-associated retinopathy of our patients was a progressive rod-cone dystrophy, and the visual outcome was poor. The systemic effect of DRAM2 mutations may be compensable and have variations.

GUCA1A gene variants are associated with autosomal dominant (AD) cone dystrophy (COD) and cone-rod dystrophy (CORD). GUCA1A-associated AD-COD/CORD has never been reported in the Japanese population. The purpose of this study was to investigate clinical and genetic features of GUCA1A-associated AD-COD/CORD from a large Japanese cohort. We identified 8 variants [c.C50_80del (p.E17VfsX22), c.T124A (p.F42I), c.C204G (p.D68E), c.C238A (p.L80I), c.T295A (p.Y99N), c.A296C (p.Y99S), c.C451T (p.L151F), and c.A551G (p.Q184R)] in 14 families from our whole exome sequencing database composed of 1385 patients with inherited retinal diseases (IRDs) from 1192 families. Three variants (p.Y99N, p.Y99S, and p.L151F), which are located on/around EF-hand domains 3 and 4, were confirmed as "pathogenic", whereas the other five variants, which did not co-segregate with IRDs, were considered "non-pathogenic". Ophthalmic findings of 9 patients from 3 families with the pathogenic variants showed central visual impairment from early to middle-age onset and progressive macular atrophy. Electroretinography revealed severely decreased or non-recordable cone responses, whereas rod responses were highly variable, ranging from nearly normal to non-recordable. Our results indicate that the three pathogenic variants, two of which were novel, underlie AD-COD/CORD with progressive retinal atrophy, and the prevalence (0.25%, 3/1192 families) of GUCA1A-associated IRDs may be low among Japanese patients.

Purpose: To determine the course of occult macular dystrophy (OMD, Miyake's disease) and to propose stages of OMD based on the optical coherence tomographic (OCT) findings. Methods: Sixty-one patients from 33 families with OMD who carried one of the proven variants of the RP1L1 gene were studied at seven centers in Japan. Ophthalmological examinations including the best-corrected visual acuity (BVCA) and OCT were performed. Results: The median age at the last visit was 50 years with a range of 10 to 88 years, and the median age at the symptom onset was 30 years with a range of 3 to 60 years. There were significant negative correlations between the duration of OMD and BCVA, the central retinal thickness (CRT) and the thickness between external limiting membrane and retinal pigment epithelium (ERT). The BCVA gradually decreased for 10 years after symptom onset and was stable thereafter. Kaplan-Meier survival curves of the BCVA and retinal thickness showed that all of the patients had retained a vision of 1.0 logMAR, and over 80% of the patients had retained 50% thickness of the normal CRT and ERT for at least 60 years after symptom onset. The stages of OMD based on the visual symptoms and OCT findings are proposed. Conclusions: The photoreceptors do not become completely atrophic even at the late stage, which may account for the good retinal pigment epithelium (RPE) structure and normal-appearing fundus. The proposed stages facilitate the investigation of the pathogenicity of OMD and provide information to determine the effectiveness of therapeutic procedures.

Purpose: Cone/cone-rod dystrophy is a large group of retinal disorders with both phonotypic and genetic heterogeneity. The purpose of this study was to characterize the phenotype of eight patients from seven families harboring POC1B mutations in a cohort of the Japan Eye Genetics Consortium (JEGC). Methods: Whole-exome sequencing with targeted analyses identified homozygous or compound heterozygous mutations of the POC1B gene in 7 of 548 families in the JEGC database. Ophthalmologic examinations including the best-corrected visual acuity, perimetry, fundus photography, fundus autofluorescence imaging, optical coherence tomography, and full-field and multifocal electroretinography (ERGs) were performed. Results: There were four men and four women whose median age at the onset of symptoms was 15.6 years (range, 6-23 years) and that at the time of examination was 40.3 years (range, 22-67 years). The best-corrected visual acuity ranged from -0.08 to 1.52 logMAR units. The funduscopic appearance was normal in all the cases except in one case with faint mottling in the fovea. Optical coherence tomography revealed an absence of the interdigitation zone and blurred ellipsoid zone in the posterior pole, but the foveal structures were preserved in three cases. The full-field photopic ERGs were reduced or extinguished with normal scotopic responses. The central responses of the multifocal ERGs were preserved in two cases. The diagnosis was either generalized cone dystrophy in five cases or cone dystrophy with foveal sparing in three cases. Conclusions: Generalized or peripheral cone dystrophy with normal funduscopic appearance is the representative phenotype of POC1B-associated retinopathy in our cohort.

PURPOSE: To determine the contribution of the ON and OFF cone bipolar cell pathways to the electroretinograms (ERGs) elicited by ultraviolet (UV) and middle wavelength light in mice. MATERIALS AND METHODS: The experiments were performed on 8- to 10-week-old C57BL/6J mice. The ERGs elicited by single-flash and flickering UV light stimuli were compared to those elicited by green light stimuli under photopic conditions. Pharmacological agents were used to selectively block the ON and OFF pathways contributing to the ERGs. Saline was used as a control. The flicker ERGs elicited by UV light were compared to the ERGs elicited by green light after the injection of the pharmacological agents to determine the contribution of the cone ON and OFF pathways to the ERGs. RESULTS: The photopic single-flash and flicker ERGs were more sensitive to the UV light stimuli than to those elicited by green light stimuli. The flicker ERG responses elicited by both UV and green light stimuli at stimulus frequencies lower than 15-Hz decreased after L-2-amino-4-phosphobutyric acid was injected. The ERGs elicited by UV light at 30-Hz and by green light at frequencies lower than 15-Hz decreased significantly after the intravitreal injection of cis-2, 3-piperidine-dicarboxylic acid. An analysis of the ON and OFF components of the flicker ERGs showed that there might be pharmacological differences between the UV light-sensitive responses and the green light-sensitive responses. CONCLUSIONS: These results suggest that the UV light-sensitive cones connect to both the ON and OFF bipolar cells differently than that of the green light-sensitive cones.

Purpose: To report clinical and genetic features of a Japanese patient with end-stage retinitis pigmentosa (RP) caused by a homozygous PDE6A variant. Methods: We performed comprehensive ophthalmic examinations. Whole exome sequencing analysis was used to investigate the RP patient with parental consanguinity. The pedigree included 4 RP patients in the two generations, which suggests presumed pseudo-autosomal dominant inheritance. Results: A PDE6A variant (p.R653X) was identified to be homozygous and disease-causing in the patient. Homozygosity mapping revealed the homozygous region including the variant and confirmation of autosomal recessive inheritance. The patient reported night blindness at 4 years of age and exhibited typical RP fundus appearance with macula involvement during the follow-up period from at the age of 52-69 years. At the age of 52, the patient exhibited a loss of visual acuity and had severely constricted visual fields, with a further gradual deterioration of her vision until she was 69 years old. At the age of 69, funduscopy showed severe chorioretinal degeneration in the area from the posterior pole to the peripheral retina. Conclusions and Importance: This is the first report that the PDE6A variant (p.R653X) has been identified as one of the causes of autosomal recessive RP in the Japanese population. Longitudinal natural history/end-stage findings demonstrated early-onset and a severe RP phenotype with macula involvement when the patient was in her 50s and severe chorioretinal degenerations in her late 60s.

X-linked congenital retinoschisis (XLRS) is an inherited retinal disorder characterized by reduced central vision and schisis of the macula and peripheral retina. XLRS is caused by mutations in the RS1 gene. We have identified 37 different mutations in the RS1 gene, including 12 novel mutations, in 67 Japanese patients from 56 XLRS families. We present clinical features of these patients in relation to the associated mutations.

Variants in the retinitis pigmentosa GTPase regulator (RPGR) gene are a major cause of X-linked inherited retinal disorder (IRD). We herein describe the clinical and genetic features of 14 patients from 13 Japanese families harboring RPGR variants in a nationwide cohort. Comprehensive ophthalmological examinations were performed to classify the patients into one of the phenotype subgroups: retinitis pigmentosa (RP) and cone rod dystrophy (CORD). The mean age of onset/at examination was 13.8/38.1 years (range, 0–50/11–72), respectively. The mean visual acuity in the right/left eye was 0.43/0.43 (range, 0.1–1.7/−0.08–1.52) LogMAR unit. Eight patients had RP, and six had CORD. Whole-exome sequencing with target analyses identified 13 RPGR variants in 730 families with IRD, including 8 novel variants. An association between the phenotype subgroup and the position of variants (cutoff of amino acid 950) was revealed. To conclude, the clinical and genetic spectrum of RPGR-associated retinal disorder was first illustrated in a Japanese population, with a high proportion of novel variants. These results suggest the distinct genetic background of RPGR in the Japanese population, in which the genotype–phenotype association was affirmed. This evidence should be helpful monitoring and counseling patients and in selecting patients for future therapeutic trials.

Blue cone monochromacy (BCM) is characterized by loss of function of both OPN1LW (the first) and OPN1MW (the downstream) genes on the X chromosome. The purpose of this study was to investigate the first and downstream genes in the OPN1LW/OPN1MW array in four unrelated Japanese males with BCM. In Case 1, only one gene was present. Abnormalities were found in the promoter, which had a mixed unique profile of first and downstream gene promoters and a -71A > C substitution. As the promoter was active in the reporter assay, the cause of BCM remains unclear. In Case 2, the same novel mutation, M273K, was present in exon 5 of both genes in a two-gene array. The mutant pigments showed no absorbance at any of the wavelengths tested, suggesting that the mutation causes pigment dysfunction. Case 3 had a large deletion including the locus control region and entire first gene. Case 4 also had a large deletion involving exons 2-6 of the first gene. As an intact LCR was present upstream and one apparently normal downstream gene was present, BCM in Case 4 was not ascribed solely to the deletion. The deletions in Cases 3 and 4 were considered to have been caused by non-homologous recombination.

[抄録] 本研究の目的は, 網膜の杆体と錐体の部位別の感度を測定するために, 市販の視野計を改造し, それを臨床応用しようとするものである. 対象は, 正常眼と網膜疾患（杆体１色覚, オカルト黄斑ジストロフィ, 急性帯状潜在性網膜外層症, 錐体ジストロフィ, 網膜色素変性, 糖尿病網膜症）であった. 方法は, 視力検査や眼底検査等の眼科一般検査に加えて, 蛍光眼底造影, 光干渉断層計, 全視野網膜電図, 多局所網膜電図の諸検査を行った. 一部の網膜疾患に対しては遺伝子解析を行った. 視野検査は, まず市販の自動視野計を改造して, 暗順応および明順応下の両方の条件で検査を行えるようにした. また, 視標に用いる色フィルターを波長500nm と波長650nm のものに交換して視野検査を行った. 検査はまず白色視標を用いて, つぎに色視標を用いて暗順応・明順応下の両方の条件で視野検査を行った. その結果, 正常眼，病眼ともに改造した自動視野計を用いて検査が可能であった. オカルト黄斑ジストロフィと急性帯状潜在性網膜外層症では, 白視標を用いた明順応下での視野検査では局所的な感度低下を認め, 色視標を用いた検査では同部位において錐体機能障害を示唆する結果が得られた. 結論として, 市販の自動視野計を改造することにより, 今まで困難であった杆体・錐体の網膜局所の感度測定を可能とした. 本検査は, 今後, 臨床の現場で応用できると考えられた.

動的視野検査の概念、測定、検査結果に影響する因子、正常視野、網膜疾患と視野異常（動的視野検査が有用な網膜疾患）、網膜疾患以外に動的視野検査が有効な症例、自動動的視野検査について述べた。

背景：先天網膜分離症とその類縁疾患の自験例についてその臨床像を報告する。
症例：症例は、（伴性劣性）若年網膜分離症が13例26眼、青錐体強調症候群（enhanced S-cone syndrome）が2例4眼、Goldmann-Favre症候群の可能性があると考えられた症例が2例4眼であった。若年網膜分離症は9例17眼(65%)に黄斑部網膜分離を、5例8眼(31%)に周辺部網膜分離をみとめた。網膜電図(electroretinogram, ERG)では、flash ERGのb波は全症例で減弱しており、7例14眼(54%)でnegative型であった。2例2眼(8%)に網膜剥離があり、1例に硝子体手術を行った。硝子体手術後は黄斑部の網膜分離は消失した。青錐体強調症候群の2例4眼では、scotopic ERGはnon-recordableで、flash ERGはa波頂点潜時が延長した特徴ある波形を示した。Goldmann-Favre症候群の可能性があると考えられた2例4眼はいずれも女性で、硝子体混濁を伴う網膜変性を両眼にみとめ、scotopic ERGは消失または減弱し、flash ERGはnegative型を示した。
結論：先天網膜分離症とその類縁

未熟児網膜症は小児の失明原因第一を占める重要な疾患である。2019年11月に本疾患に対する抗血管内皮増殖因子治療薬としてranibizumab（ルセンティス）が承認され、重症未熟児網膜症の治療予後改善が期待されている。しかし、抗血管内皮増殖因子治療後に増殖膜線維化が進行し、牽引性網膜剥離の発生、増悪を生じる症例があり、今後の問題になると予想されている。 そこで今回の研究では未熟児網膜症における増殖膜の線維化、およびそれに伴う病態悪化に着目し、それに関与する種々のサイトカインや抗血管内皮増殖因子治療による影響を明らかにしたいと考えている。2020年度は臨床例からの検体採取を行った。具体的にはご両親に研究計画の説明、検体採取のリスク等を説明した上で、書面による同意を得て、未熟児網膜症に対して硝子体手術を行った５例８眼から硝子体液を採取した。採取した硝子体液は急速冷凍し、deep freezerで保存している。なお、当該年度の症例では増殖膜を採取できる症例がなく、これに関しては2021年度以降で適切な症例があれば検体採取を行う予定である。今後も症例を積み重ね、10例程度の検体が出そろった段階で、硝子体内の種々のサイトカイン量測定をELISAキットにて行う予定である。また、それらの症例の術時の線維化の程度や術前の処置としてranibizumab（抗血管内皮増殖因子）が硝子体内に投与された症例があるので、術前ranibizumab投与の有無と種々の差サイトカインの関連も検討する予定である。

本研究は網膜内リモデリングを利用した再生医療の実現と新たな創薬基盤を目指した。網膜内層には、OFF層とON層があるが、緑内障の初期にOFF層が障害を受けることが知られ、我々は緑内障モデルマウスにて網膜内層のシナプス形成（シナプトジェネシス）がOFF層で起こる可能性を見出した。そこで、OFF層を分離するマーカーを探索し、網膜内の細胞接着分子Necl-1が、OFF層の経路を分離することを見出した。次いで、Necl-1が網膜内発現と機能について解析した。シナプトジェネシスにおけるNecl-1の機能を解析するため、レポータマウスと多光子顕微鏡観察による網膜内リモデリング観察の基盤を完成した。

重症未熟児網膜症に対しranibizumab投与を行った22例43眼では20.9%で再燃がみられた。bevacizumab投与を行った21例37眼では13.5%の再燃率で、前者でやや再燃率がやや高い傾向がみられた（P=0.556）。多重ロジスティック解析で修正35週以下での抗VEGF治療 (OR, 7.524; 95% CI, 1.494–37.89; p = 0.014) と病型として aggressive posterior ROPであったこと (OR, 5.532; 95% CI, 1.049–29.17; p = 0.044)の2つが有意な要因であった。

重症未熟児網膜症に対してranibizumab（0.25mg）を硝子体内投与し、その効果、再燃割合、血清中血管内皮増殖因子（VEGF）への影響を14例27眼で検討した。投与後2、3日以内に全例で網膜血管の拡張蛇行の改善、水晶体血管膜の退縮、増殖膜白鞘化が認められ、治療効果があったと判定された。7眼に治療後平均7.3週で再燃が認められた。投与前の血清VEGF濃度に比し、投与翌日のそれのみ有意に減少したが、投与１、２、４週後では有意差を認めず、ranibizumabの血清VEGF濃度抑制効果は一過性であると思われた。

重症未熟児網膜症11例に対して抗血管内皮細胞増殖因子(VEGF)治療（アバスチン投与）を行った症例について、投与翌日、1週後、2週後に血清を採取、血清中のアバスチン濃度、VEGF濃度を測定した。その結果、アバスチン投与後に血清アバスチン濃度は経時的に上昇し、逆に血清VEGF濃度は経時的に減少し、両者は負の相関を示した。これらの結果から眼内に投与したアバスチンは血清中に移行し、血清中のVEGF濃度を低下させる可能性があることが示された。今後、抗VEGF治療を考える上で、薬剤選択の際の判断材料になるものと思われる。