Language：English   Publisher：Journal of Medical Genetics  

Background As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases. Methods We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines. Results A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases. Conclusion A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.

DOI： 10.1136/jmg-2023-109750

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Language：English  

DOI： 10.7759/cureus.60653

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Language：English   Publisher：Ophthalmic Genetics  

Background: Nanophthalmos (NNO) is a rare condition with significantly shorter axial length than normal. Several genes are known to cause NNO, among them the MFRP and PRSS56 genes have been reported to cause majority of NNOs. The purpose of this study was to determine the genetic basis of Japanese patients with NNO. Materials and Methods: We studied seven patients with NNO. Whole exome sequencing (WES) and Sanger sequencing were performed to determine the variants causing the NNO. We also reviewed the medical charts of the patients to determine the phenotype of these seven patients. Results: WES revealed that four patients from three families carried homozygous frameshift variants of the PRSS56 gene (c.1066dupC). Two novel variants of the MFRP gene were detected in the other two patients: one proband had a homozygous missense variant (c.1486 G>A) and the other had a compound heterozygous variant (c.1486 G>A and c.662_663insT). The axial length of the eight eyes with the PRSS56 variant was 15.69 ± 0.48 mm (mean ± SD) and that for the 4 eyes with the MFRP variant was 15.63 ± 0.69 mm. Three of the six cases with the PRSS56 or MFRP variant had the uveal effusion syndrome. Conclusions: NNOs in Japanese patients are caused by variants of the PRSS56 and MFRP genes as in other ethnic populations. In addition, two new variants of the MFRP gene were found in our cohort. The phenotypes and anomalies in Japanese patients with NNO were similar to those reported for other ethnic populations.

DOI： 10.1080/13816810.2023.2208220

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To determine the factors significantly associated with the amplitudes and implicit times of the flicker electroretinograms (ERGs) recorded with the RETeval system by analyzing the comprehensive data obtained during a health checkup screening. METHODS: Flicker ERGs were recorded with the RETeval system from 373 individuals who had a normal fundus and optical coherence tomography images. The sex, age, anthropometric, ophthalmologic, and hematologic data were collected from all participants who were 40- to 89-years-of-age. Univariable and multivariable linear mixed effects regression analyses were performed to identify factors that were significantly associated with the implicit times and amplitudes of the RETeval flicker ERGs. RESULTS: Univariable linear mixed effects regression analysis showed significant correlations between the implicit times and the best-corrected visual acuity, the age, the axial length, the blood sugar level, and the blood urea nitrogen level. Analyses by multivariable linear mixed effects regression identified that the axial length (β = 0.28), the age (β = 0.24), and the blood sugar level (β = 0.092) were three independent factors that were significantly correlated with the implicit times of the RETeval flicker ERGs. Univariable linear mixed effects regression analysis also showed significant correlations between the amplitudes of the RETeval flicker ERGs and the age, the platelet count, and the creatinine level. Multivariable linear mixed effects regression models identified the age (β = -0.092), the platelet count (β = 0.099), and the creatinine level (β = -0.12) as three independent factors that were significantly correlated with the amplitudes of the RETeval flicker ERGs. However, the smoking habits, body mass index, and the blood pressure were not significantly correlated with either the implicit times or amplitudes of the RETeval flicker ERGs. CONCLUSIONS: Our results indicate that the age and some ophthalmologic and hematologic findings but not the anthropometric findings were significantly associated with the implicit times and amplitudes of the RETeval flicker ERGs. Thus, clinicians should remember these factors when analyzing the RETeval flicker ERGs.

DOI： 10.1371/journal.pone.0284686

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410214679

CiNii Research

Publisher：Scientific Reports  

The purpose of this study was to investigate the effects of surgeon-related factors on the surgical outcome of pars plana vitrectomy (PPV) and scleral buckling (SB) surgery on eyes with a rhegmatogenous retinal detachment (RRD). This was a nationwide, multicenter, observational study of the data in the Japan-RD Registry. Registered cases that had undergone surgery for a RRD by 128 accredited surgeons in 26 institutions were studied. The surgeon-related factors that significantly affected surgical success and visual outcomes of simple RRD treated by PPV or SB at 6 months postoperatively were analyzed and compared. Among 3446 registered cases, 2533 cases met the inclusion criteria with 1896 in the PPV group and 637 cases in the SB group. The median total number of lifetime cases was 150 and the rate of surgeries/year was 22. Multivariate regression analyses showed that the number and rate of surgeries/year were not significantly associated with the surgical outcome in the PPV group. However, surgeons with a higher average annual number of surgeries had significantly better surgical outcomes in the SB group (P = 0.038). Analyses of a nationwide registry showed that SB but not PPV surgeries require sufficient experience and case numbers to acquire and maintain skills to treat RRDs successfully.

DOI： 10.1038/s41598-022-07838-5

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1002/humu.24492

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Language：English   Publisher：Retina  

Purpose:To assess the macular function by focal macular electroretinography and static perimetry in eyes with retinitis pigmentosa.Methods:Eighty-eight eyes of 88 retinitis pigmentosa patients were analyzed. The relationships between the focal macular electroretinography components and the mean deviations (MDs) of the Humphrey Field Analyzer 10-2 were determined. Spectral-domain optical coherence tomography was used to determine the integrity of the ellipsoid zone (EZ) and the interdigitation zone.Results:Forward-backward stepwise regression analyses showed that the amplitudes (r = 0.45, P < 0.01) and implicit times (r = -0.29, P < 0.01) of the b-waves were significantly correlated with the MDs. Some of the eyes had reduced b-wave amplitudes (<1.0 µV) and disrupted interdigitation zone, despite having a better MD (≥ -10.0 dB) and intact EZ. Subgroup analyses of eyes with better MD (≥ -10.0 dB) showed that the EZ width was correlated with the MDs but not with the b-wave amplitude. The thickness of the EZ-retinal pigment epithelium as an alternative indicator of interdigitation zone was correlated with the b-wave amplitude (r = 0.32, P = 0.04) but not with the MDs (r = -0.10, P = 0.53).Conclusion:The fact that the focal macular electroretinography amplitudes are reduced before the shortening of the EZ in the early stage of retinitis pigmentosa indicates that the focal macular electroretinography amplitudes are an earlier indicator of macular dysfunction than the Humphrey Field Analyzer 10-2 findings.

DOI： 10.1097/IAE.0000000000003589

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Language：Japanese   Publisher：眼科臨床紀要会  

Language：Japanese   Publisher：Scientific Reports  

It is known that social factors affect the choice of treatments, and special attention has been paid to sex differences. The purpose of this study was to determine whether regional and sex differences exist in the treatment of rhegmatogenous retinal detachment (RD). We used Japan-RD Registry database of 2523 patients aged ≥ 40 years between February 2016 and March 2017 in 5 Japanese regions. Regional differences of patients’ perioperative factors were analyzed. The factors affecting the proportion of patients who underwent surgery within one week of the onset, defined as early-surgery, were examined by logistic regression. We observed regional differences in perioperative factors, especially in the use of phacovitrectomy, general anesthesia, and air-tamponade, which was higher in certain regions. (Fisher’s exact test, all P = 0.012) The proportion of early-surgery was significantly higher among men in Kyushu region (Odds ratio (OR) 1.83; 95% confidence interval (CI) 1.08–3.12; P = 0.02), and it was also significantly higher after adjusting for covariates (OR 1.89; 95% CI 1.06–3.42; P = 0.02). Regional and sex differences exist in the treatment of RD in Japan. Although there was no significant differences in the anatomical outcomes, women in certain regions of Japan are less likely to receive early surgical intervention for RD.

DOI： 10.1038/s41598-021-00186-w

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To describe the intraoperative and postoperative morphological and functional outcomes after autologous neurosensory retinal flap transplantation (ART) for a high myopia-related refractory macular hole (MH). METHODS: This prospective interventional study enrolled five eyes of five patients (age range 54-84 years) with highly myopic refractory MHs who underwent ART. All cases were evaluated with intraoperative optical coherence tomography and postoperative optical coherence tomography, optical coherence tomography angiography, and microperimetry for at least 6 months postoperatively. RESULTS: Intraoperatively, the MH was covered by an ART flap with a persistent small subretinal space that was filled with the ART flap after 4 days to 6 days. Optical coherence tomography discriminated the original from the transplanted retina. The mean basal diameter of the original MH decreased from 1,504 ± 684 µm preoperatively to 1,111 ± 356 µm postoperatively. The best-corrected visual acuity improved in two cases, was stable in two cases, and deteriorated in one case. Microperimetry demonstrated no obvious postoperative changes in the fixation points and the absolute scotoma corresponding to the base of MHs with chorioretinal atrophy. In two eyes, choroidal neovascularization developed beneath the transplanted retinas. CONCLUSION: Transplanted tissue was in a fixed position by 1 week postoperatively with a decreased diameter of the original MH. Postoperative fixation points were on the original retina at the MH edge. Because choroidal neovascularization may develop, detailed monitoring is required.

DOI： 10.1097/IAE.0000000000003000

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PURPOSE: To report the clinical course and high resolution images of autosomal recessive retinitis pigmentosa (RP) associated with a variant of the RP1 gene (c.4052_4053ins328/p.Tyr1352Alafs*9; m1), a high frequency founder variant in Japanese RP patients. STUDY DESIGN: Retrospective case series. METHODS: Nine patients from 5 unrelated Japanese families were studied. Five patients had the m1 variant homozygously, and 4 patients had the m1 variant compound heterozygously with another frameshift variant (c.4196delG/p.Cys1399Leufs*5). Ophthalmic examinations including adaptive optics (AO) fundus imaging were performed periodically. RESULTS: The fundus photographs, fundus autofluorescence (FAF) images, and optical coherence tomographic (OCT) images indicated severe retinal degeneration in all the patients involving the macula even at a young age (20 s). The areas of surviving photoreceptors in the central macula were seen as hyper-autofluorescent regions in the FAF images and preserved outer retinal structure in the OCT images; they were identifiable in the AO fundus images in 8 eyes. The borders of the surviving photoreceptor areas were surrounded by hyporeflective clumps, presumably containing melanin, and the size of these areas decreased progressively during the 4-year follow-up period. The disappearance of the surviving photoreceptor areas was associated with complete blindness. CONCLUSION: Patients with RP associated with the m1 variant have a progressive and severe retinal degeneration that begins at an early age. Monitoring the surviving photoreceptor areas by AO fundus imaging can provide a more precise pathological record of retinal degeneration.

DOI： 10.1007/s10384-020-00752-1

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Language：English   Publishing type：Research paper (scientific journal)  

The retinitis pigmentosa 2 (RP2) gene is one of the causative genes for X-linked inherited retinal disorder. We characterized the clinical/genetic features of four patients with RP2-associated retinal disorder (RP2-RD) from four Japanese families in a nationwide cohort. A systematic review of RP2-RD in the Japanese population was also performed. All four patients were clinically diagnosed with retinitis pigmentosa (RP). The mean age at examination was 36.5 (10-47) years, and the mean visual acuity in the right/left eye was 1.40 (0.52-2.0)/1.10 (0.52-1.7) in the logarithm of the minimum angle of resolution unit, respectively. Three patients showed extensive retinal atrophy with macular involvement, and one had central retinal atrophy. Four RP2 variants were identified, including two novel missense (p.Ser6Phe, p.Leu189Pro) and two previously reported truncating variants (p.Arg120Ter, p.Glu269CysfsTer3). The phenotypes of two patients with truncating variants were more severe than the phenotypes of two patients with missense variants. A systematic review revealed additional 11 variants, including three missense and eight deleterious (null) variants, and a statistically significant association between phenotype severity and genotype severity was revealed. The clinical and genetic spectrum of RP2-RD was illustrated in the Japanese population, identifying the characteristic features of a severe form of RP with early macular involvement.

DOI： 10.1002/ajmg.c.31830

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Language：English   Publishing type：Research paper (scientific journal)  

Purpose: To investigate the longitudinal changes of the macular curvature in eyes with retinitis pigmentosa (RP) and to determine the factors associated with the changes. Methods: We reviewed the medical charts of 107 RP patients, for whom the axial length of their right eyes ranged from 21.5 to 26.0 mm and who had had been followed by spectral-domain optical coherence tomography (OCT). The OCT images at the initial and the most recent examinations were compared. The mean curvature of Bruch’s membrane within 6 mm of the central macula obtained from the OCT images was evalu-ated as the mean macular curvature index (MMCI). Changes in the MMCI and their relationships with other clinical factors, including the ellipsoid zone (EZ) width, were assessed. Results: The MMCI decreased significantly in the vertical OCT images, from –15.47 × 10−5 μm−1 to –16.36 × 10−5 μm−1 (P = 0.008) during the mean observation period of 3.4 ± 1.4 years (mean ± SD). This indicated that the macular shape became more concave. The change to a steeper shape was more prominent in eyes with less photoreceptor degeneration and for which the EZ width was preserved at >2000 μm. In three eyes, the MMCI increased markedly by >5 × 10−5 μm−1, and this was accompanied by absorption of the macular edema. Conclusions: The macular curvature in RP eyes becomes more concave in eyes with preserved EZ width. Translational Relevance: Longitudinal changes of the macular curvature in RP should be considered in future therapies, such as the implantation of the retinal prosthesis.

DOI： 10.1167/tvst.9.10.11

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Language：Japanese   Publishing type：Research paper (scientific journal)  

PURPOSE. To determine the relationship between the macular curvature and the causative genes of retinitis pigmentosa (RP). METHODS. We examined the medical records of the right eyes of 65 cases with RP (31 men and 34 women; average age, 47.6 years). There were 31 cases with the EYS variants, 11 cases with the USH2A variants, six cases with the RPGR variants, 13 cases with the RP1 variants, and four cases with the RP1L1 variants. The mean curvature of Bruch’s membrane was calculated within 6 mm of the fovea as the mean macular curvature index (MMCI, 1/μm). We used multiple linear regression analysis to determine the independence of the causative genes contributing to the MMCIs after adjustments for age, sex, axial length, and width of the ellipsoid zone. RESULTS. The median MMCI was -31.2 × 10-5/μm for the RPGR eyes, -16.5 × 10-5/μm for the RP1L1 eyes, -13.0 × 10-5/μm for the RP1 eyes, -9.8 × 10-5/μm for the EYS eyes, and -9.0 × 10-5/μm for the USH2A eyes. Compared with the EYS gene as the reference gene, the RPGR gene was significantly related to the MMCI values after adjusting for the other parameters (P = 5.30 × 10-6). In contrast, the effects of the other genes, USH2A, RP1, and RP1L1, were not significantly different from that of the EYS gene (P = 0.26, P = 0.49, and P = 0.92, respectively). CONCLUSIONS. The RPGR gene had a stronger effect on the steep macular curvature than the other ciliopathy-related genes.

DOI： 10.1167/iovs.61.10.6

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Purpose: To study the changes in intraocular pressure (IOP) and aqueous flare in eyes with multiple evanescent white dot syndrome (MEWDS) during the disease course. Study design: Retrospective observational study. Methods: Twenty-one patients with unilateral MEWDS were retrospectively evaluated. IOP values were compared between the affected and fellow eyes 2 weeks, 1 month, and 3 months following disease onset in 17 patients, and within 7 days from disease onset in 11 patients. Aqueous flare values measured using a laser flare-cell meter in ten eyes between 1 weeks and 1 month from disease onset were compared between the affected and fellow eyes. Results: IOP values were significantly lower in the affected eyes than in the fellow eyes at both 2 weeks (P=0.002) and 1 month from disease onset (P=0.02). However, IOP values of affected eyes did not show significant differences from the fellow eyes within 7 days ((P=0.11) and 3 months of onset (P=0.30). Aqueous flare values were significantly increased in the affected eyes compared to those in the fellow eyes (P=0.010) and significantly correlated with IOP values (r=−0.67, P=0.035). Conclusion: IOP values mildly decreased in association with aqueous flare values in the acute phase in eyes with MEWDS.

DOI： 10.1007/s10384-020-00738-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/s41598-020-65737-z

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Other Link： http://www.nature.com/articles/s41598-020-65737-z

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1167/tvst.9.6.2

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Language：English  

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.

DOI： 10.1038/s41598-020-62119-3

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To assess the morphological changes of cone photoreceptors in eyes with autosomal recessive bestrophinopathy. METHODS: Both eyes of five patients with autosomal recessive bestrophinopathyunderwent spectral domain optical coherence tomography and adaptive optics fundus imaging. The cone photoreceptor densities were measured at intervals of 100 μm between 500 μm nasal and temporal eccentricities from the foveal center. RESULTS: The median age of the patients was 30 years (range, 23-45 years), and the best-corrected visual acuity ranged from 20/20 to 20/80. Adaptive optics fundus images showed reduced cone photoreceptor densities corresponding to the damages of the photoreceptor layer in the spectral domain optical coherence tomography images in four patients with relatively good best-corrected visual acuity. The cone photoreceptor densities at the center of the fovea were less than one-third of the normal cone densities (range 11,600-30,400 cells/mm). Cone photoreceptor mosaics were visible over the lesions with serous retinal detachment and retinal edema, although they were partially hyporeflective. CONCLUSION: There is a significant cone photoreceptor loss in the macular region of patients with autosomal recessive bestrophinopathy, although they had relatively good visual acuity. Monitoring cone photoreceptors by adaptive optics fundus imaging should provide accurate assessments of the disease status and indications for future therapeutic interventions.

DOI： 10.1097/IAE.0000000000002363

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Language：Japanese  

DOI： 10.1007/s10384-019-00702-6

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To report the clinical course of eyes with paraneoplastic retinopathy caused by an autoantibody against transient receptor potential cation channel, subfamily M, member 1 (TRPM1). METHODS: Ten paraneoplastic retinopathy patients with retinal ON-bipolar cell dysfunction, including six melanoma-associated retinopathy, from eight institutions in Japan were evaluated for the presence of an anti-TRPM1 antibody. The results of ophthalmic examinations and the presence of anti-TRPM1 antibody were analyzed. RESULTS: Five patients were positive for the anti-TRPM1 antibody. These patients had similar clinical findings in both eyes at the time of diagnosis; relatively preserved best-corrected visual acuity, absence of fundus and optical coherence tomography abnormalities, and specific abnormalities of the electroretinography (ERG); and negative-type ERGs with bright stimulus flashes. One patient whose retinal ON-bipolar cells remained dysfunctional for the entire testing period, although the anti-TRPM1 antibody had disappeared. On the other hand, the ERGs recovered in 2 cases within 2 years after the onset. One case progressed to additional impairment of the photoreceptors with deterioration of ERGs. One case died and the clinical course was unavailable. CONCLUSION: Paraneoplastic retinopathy patients with retinal ON-bipolar cell dysfunction possess autoantibodies against TRPM1 at the onset of the disease process; however, the clinical course of these eyes can be different.

DOI： 10.1097/IAE.0000000000002329

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Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1167/iovs.19-26650

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Academic Press  

Long living animal models of retinitis pigmentosa (RP) can provide important information on the retinal changes that occur at the late stages of photoreceptor degeneration. The rhodopsin Pro347Leu transgenic rabbit (P347L Tg) is a model of RP, and it has been used to analyze the functional and morphological changes in the retina following the degeneration of the photoreceptors. They have also been used to test newly-developed therapies to treat eyes with photoreceptor degeneration. However, assessments of the retinal changes in P347L Tg rabbits older than 1-year have not been reported even though the data are important for research on developing new therapies to restore vision at the end stages of RP. The purpose of this study was to determine the time course of the loss of photoreceptor function and the changes in the morphology of the retina of P347L Tg rabbits. The experiments were performed on 26 older P347L Tg rabbits. The results showed that the amplitudes of the ERGs of the P347L Tg rabbits gradually decreased and reached &lt
10 μV between 30- and 54-months-of-age. Histological analysis at these later stages showed a loss of the photoreceptor layer, and OCT analysis showed absence of the layering of the retina. However, the thickness between the inner limiting membrane and the outer plexiform layer was about 1.7 times thicker than the corresponding thickness of WT rabbits in the OCT images. This thickening was caused by a marked gliosis of the entire retina which was confirmed by light and transmission electron microscopy. In addition, immunohistochemical analysis showed there was excessive staining of the glial fibrillary acid protein in the older P347L Tg rabbits although the rod ON bipolar cells and horizontal cells were still present in the inner nuclear layer. Our results indicate that the P347L Tg rabbit progressed to complete photoreceptor loss within 30- and 54-months-of-age and severe gliosis altered the morphology of the retina.

DOI： 10.1016/j.exer.2019.04.026

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Language：English   Publishing type：Research paper (scientific journal)  

Purpose: A posterior staphyloma has been reported to be present in some eyes with retinitis pigmentosa (RP), and the purpose of this study was to determine the macular curvature of non-highly myopic RP eyes. Methods: This was a retrospective, observational study. The medical charts of the right eyes of 143 patients with RP and 60 controls whose axial length ranged from 21.5 mm to 26.0 mm were reviewed. The mean curvature of Bruch's membrane within 6 mm of the central macula obtained from the horizontal optical coherence tomographic images were evaluated as the mean macular curvature index (MMCI). The relationships between the MMCI and other clinical factors were assessed. Results: The mean MMCI of RP patients (-13.73 ± 9.63 × 10-5 μm-1) was significantly lower than that of the controls (-6.63 ± 5.63 × 10-5 μm-1). This indicated a deeper concave shape of the macula in RP eyes (P < 0.001). The MMCI was significantly correlated with the age (r = 0.20; P = 0.016) and the axial length (r = -0.24; P = 0.004). Further analysis suggested a nonlinear effect of the ellipsoid zone width on the macular curvature in the RP eyes. Conclusions: There is a high incidence of steeper macular curvatures even in non-highly myopic RP eyes, and the steepness was also affected by the degree of photoreceptor degeneration.

DOI： 10.1167/iovs.19-27334

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Language：Japanese   Publisher：眼科臨床紀要会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Association for Research in Vision and Ophthalmology Inc.  

PURPOSE. To determine the relationship between the amplitudes of the electrically evoked potentials (EEPs) and the number of optic nerve axons at a late stage of retinal degeneration in rhodopsin P347L transgenic (Tg) rabbits, a model of retinitis pigmentosa. METHODS. Six eyes of six wild-type (WT) (43.8 ± 7.5 months of age) and six eyes of six Tg (40.3 ± 2.6 months of age) rabbits were studied. The EEPs were elicited by 1 to 5 mA of transcorneal electrical stimulation. The first positive wave, the P1 component, was analyzed. After euthanasia, the number of axons in the optic nerve was counted. RESULTS. The threshold current to elicit a P1 was significantly higher in Tg rabbits than WT rabbits. The amplitude of P1 elicited by 5 mA in Tg rabbits was about 24% of that in WT rabbits (P &lt
0.01). The number of axons in the optic nerve of Tg rabbits was reduced to about 59% of that of WT rabbits (P &lt
0.01). The correlation between the axon number and the amplitude of the P1 in Tg and WT rabbits was not significant. The mean ratio of the P1 amplitude/axon in Tg rabbits was decreased to 53% of that in WT rabbits (P &lt
0.05). CONCLUSIONS. The degree of reduction in the EEP in Tg rabbits is more severe than the reduction in the number of optic nerve axons. The use of transcorneal electrical stimulation to determine the suitable candidates for prosthesis at the end-stage of retinitis pigmentosa may underestimate the condition of the optic nerves.

DOI： 10.1167/iovs.19-26972

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DOI： 10.1167/iovs.18-24635

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DOI： 10.1167/iovs.17-23202

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taylor and Francis Ltd  

Background: Biallelic variants of POC1B were recently reported to cause autosomal recessive non-syndromic cone dystrophy. However, the number of studies supporting this is limited, and the clinical phenotypes of cone dystrophy have not been definitively determined. The purpose of this study was to report the phenotype of a case of POC1B-associated cone dystrophy. Materials and methods: The medical chart of one case diagnosed with cone dystrophy was reviewed. Results: The patient was a 20-year-old Japanese man whose chief complaint was a progressive decrease in his central vision. His decimal best-corrected visual acuity was 0.2 for the right and 0.3 for the left. Fundus examinations showed no abnormalities. The photopic electroretinograms were nonrecordable, but the scotopic electroretinograms were within normal limits. Optical coherence tomography detected a blurry line in the region of the external limiting membrane and ellipsoid zone. Adaptive optics images showed sparsely distributed cone cells around the fovea. The patient was initially diagnosed with incomplete achromatopsia. Whole-exome sequence with targeted analysis identified new compound heterozygous mutations of c.G1355A (p R452Q) and c.C987A (pY329X) in the POC1B gene. The patient was then diagnosed with cone dystrophy. Conclusions: The cone dystrophy associated with POC1B variants has features similar to achromatopsia, and genetic analyses is useful in discriminating these two diseases.

DOI： 10.1080/13816810.2017.1408846

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The aim of this study is to determine the progress of the visual field defects obtained by the Humphrey Field Analyzer 10-2 program (HFA 10-2) in patients with retinitis pigmentosa (RP). The medical records of 45 eyes of 45 RP patients who had at least 3 visual field tests were reviewed. Linear mixed models were used to follow the changes of the mean deviation and the average sensitivity of 4, 12, and 20 points in three concentric squares, designated as S4, S12, and S20. The median follow-up time was 3.86 years [range: 1.93 to 9.86, IQR (Interquartile range): 3.01 to 4.93]. The median number of the visual field tests was 3 (range: 3 to 15, IQR: 3 to 4). The mean change of the MD was -0.46 dB/year (-5.80%/year). When the patients were grouped by the average initial MD, the less advanced group had slower progressions than the more advanced group in S4, S12, and S20. These results should be useful in understanding the pathological changes of RP in the central visual field.

DOI： 10.1038/s41598-017-16640-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

PURPOSE. Our earlier study showed that the width of the intact ellipsoid zone (EZ) of the photoreceptors was significantly but weakly correlated with the amplitudes of the focal macular ERGs (FMERGs). The aim of this study was to determine a microstructure of the photoreceptors in the spectral-domain optical coherence tomographic (SD-OCT) images that was more strongly correlated with the FMERG parameters in eyes with retinitis pigmentosa (RP).
METHODS. This was a retrospective, observational study. The medical records of 65 patients with RP were reviewed. FMERGs were elicited by a 15-degree stimulus spot. The width of the EZ and the outer segment (OS) area surrounded by EZ and retinal pigment epithelium in the SD-OCT images within 15 degrees of the fovea were evaluated. Spearman correlation tests and multiple stepwise regression analyses were performed.
RESULTS. There was a strong correlation between the amplitudes of FMERGs and the EZ width (r = 0.68 for a-wave amplitude; r = 0.64 for b-wave amplitude), and also between the amplitudes of the FMERGs and the OS area (r = 0.69 for a-wave amplitude; r = 0.67 for b-wave amplitude). However, some patients had long EZ widths but had severely reduced FMERGs. Multiple stepwise regression analyses showed that the OS area was the only significant independent predictor of the amplitudes of FMERGs (P &lt; 0.001).
CONCLUSIONS. The OS area might be a better morphological structure to use to predict the physiological function of the macula.

DOI： 10.1167/iovs.17-22040

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DOI： 10.1167/iovs.17-22332

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Precise transcriptional regulation controlled by a transcription factor network is known to be crucial for establishing correct neuronal cell identities and functions in the CNS. In the retina, the expression of various cone and rod photoreceptor cell genes is regulated by multiple transcription factors; however, the role of epigenetic regulation in photoreceptor cell gene expression has been poorly understood. Here, we found that Samd7, a rod-enriched sterile alpha domain (SAM) domain protein, is essential for silencing nonrod gene expression through H3K27me3 regulation in rod photoreceptor cells. Samd7-null mutant mice showed ectopic expression of nonrod genes including S-opsin in rod photoreceptor cells and rod photoreceptor cell dysfunction. Samd7 physically interacts with Polyhomeotic homologs (Phc proteins), components of the Polycomb repressive complex 1 (PRC1), and colocalizes with Phc2 and Ring1B in Polycomb bodies. ChIP assays showed a significant decrease of H3K27me3 in the genes up-regulated in the Samd7-deficient retina, showing that Samd7 deficiency causes the derepression of nonrod gene expression in rod photoreceptor cells. The current study suggests that Samd7 is a cell type-specific PRC1 component epigenetically defining rod photoreceptor cell identity.

DOI： 10.1073/pnas.1707021114

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Language：Japanese   Publisher：眼科臨床紀要会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Patients with complete achromatopsia (ACHM) lack cone function, and patients with incomplete ACHM have relatively good visual acuity with residual color vision. The pathological mechanism(s) underlying incomplete ACHM has not been determined. The purpose of this study was to determine the pathophysiology of ACHM in two siblings: one with complete ACHM and the other with incomplete ACHM.
The medical charts of the two siblings were reviewed.
The sibling with incomplete ACHM had decimal visual acuities that ranged from 0.4 to 0.6 and had moderate color blindness in both eyes. Her younger brother was diagnosed with complete ACHM and was not able to hold fixation, had severe pendular nystagmus, visual acuity that ranged from 0.08 to 0.1, and severe color vision abnormalities in both eyes. Optical coherence tomography (OCT) showed that the ellipsoid zone (EZ) was disruptive in the macular region in both patients. However, careful examination of the OCT images in the incomplete ACHM patient showed a high-density EZ in the central fovea. Adaptive optics (AO) fundus imaging of the sibling with incomplete ACHM revealed sparse cone mosaics remaining within 1A degrees of the foveal center with no mosaics visible outside the central fovea. AO fundus imaging could not be performed in Case 2 because of the severe nystagmus.
Our results showed that cone mosaics were present in the central fovea in the sibling with incomplete ACHM patient. This may explain the better visual acuity and color vision in this sibling.

DOI： 10.1007/s10633-017-9577-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

PURPOSE. To determine the contribution of second-and third-order retinal neurons to the photopic electroretinograms (ERGs) after the degeneration of the rods in rhodopsin P347L transgenic rabbits (Tg).
METHODS. Four wild-type (WT) rabbits and four Tg rabbits were studied at 18 months of age. The photopic ERGs elicited at stimulus onset and offset were analyzed. To block different retinal pathways, 2-amino-4-phosphonobutyric acid (APB), 6-cyano-7-nitroquinoxaline-2, 3 (1H,4H)-dione (CNQX), tetrodotoxin (TTX), and N-methyl-DL-aspartic acid (NMDA) were injected intravitreally. Digital subtraction of the postdrug ERGs from the predrug ERGs was used to determine the contributions of the ON-components blocked by APB, the OFF-components blocked by CNQX, and the third-order neurons blocked by TTX+NMDA.
RESULTS. Contribution of the cone photoreceptors to the photopic ERGs in Tg rabbits was approximately 10% of that in WT rabbits. The amplitudes of the positive waves of the ON-components at stimulus onset in Tg rabbits were approximately one-half as large as those in WT. On the other hand, the amplitudes of the positive waves of the OFF-components at stimulus offset in Tg rabbits were approximately 1.4 to 2.3 times larger than those in WT. Transgenic rabbits had a positive wave at stimulus offset, which was reduced after the TTX+NMDA injection.
CONCLUSIONS. A reduced ON-component and an augmented OFF-component with abnormal responses of the third-order neurons contributed to the cone ERGs after the loss of rod function in Tg rabbits. Our results suggest a complex synaptic remodeling of the residual retinal cells in the advanced stage in Tg rabbits.

DOI： 10.1167/iovs.16-20344

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

The 2 most common causative genes for achromatopsia (ACHM) are CNGA3 and CNGB3; other genes including GNAT2 account for only a small portion of ACHM cases. The cone mosaics in eyes with CNGA3 and CNGB3 variants are severely disrupted; the cone mosaics in patients with GNAT2-associated ACHM; however, have been reported to show a contiguous pattern in adaptive optics (AO) retinal images. The purpose of this study was to analyze the cone mosaic of another case of GNAT2-associated ACHM.
The patient was a 17-year-old Japanese boy. Comprehensive ocular examinations including fundus photography, electroretinography (ERGs), optical coherence tomography (OCT), and whole-exome analysis were performed. The cone mosaic was recorded with a flood-illuminated AO fundus camera, and the cone density was compared with those of 10 normal control eyes.
The patient had the typical phenotype of ACHM, and a novel homozygous variant, c.730_743del, in GNAT2 was identified. The fundus did not show any specific abnormalities, and the OCT images showed the presence of the ellipsoid zone. The AO fundus image showed a clearly defined cone mosaic around the fovea. The cone density at 500 mu m from the fovea was reduced by 15-30 % as compared with those of the normal eyes.
This is the first description of a Japanese patient with ACHM with a novel GNAT2 variant. The eyes of this patient had a preserved cone structure with loss of function.

DOI： 10.1007/s10384-016-0484-7

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Event date： 2017.11

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