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Purpose: To report the genotypes and clinical features of RHO-associated retinitis pigmentosa (RHO-RP) in the Kyushu region of Japan. Study Design: Retrospective, single-center study. Methods: Sixteen RP patients with pathogenic RHO variants seen at Kyushu University Hospital were investigated. Clinical data including age, best-corrected visual acuity (BCVA) in logarithm of the minimum angle of resolution (logMAR) units, visual field, fundus photography, and optical coherence tomography were retrospectively obtained. Visual outcomes were compared between classical and sector phenotypes and among genetic variants. Results: The mean age at the first visit was 54.0 ± 15.7 years, with a mean follow-up of 7.6 ± 4.0 years. Fourteen patients (87.5%) showed the classical RP phenotype, of whom four were associated with p.[Pro23Leu] and two had p.[Pro347Leu] variants. In addition, two patients with the sector phenotype harbored p.[Ala164Val] variants. Among the classical RHO-RP patients, the mean BCVA decreased from 0.60 to 1.08 logMAR over the follow-up period (7.4 ± 4.1 years) whereas BCVA was preserved at 0.04 logMAR in sector RHO-RP patients (9.0 ± 3.0 years). Genotype-to-phenotype analysis demonstrated that p.[Pro347Leu] was associated with severe vision loss at an earlier age. Macular complications such as epiretinal membrane and cystoid macular edema were observed in 5 classical RHO-RP patients. Conclusion: p.[Pro23Leu], but not p.[Pro23His], was a frequent variant causing RHO-RP in the Kyushu region of Japan. As reported in previous studies, patients with the p.[Pro347Leu] variant showed a more severe phenotype, and variants causing sector RHO-RP were associated with a good prognosis. [ABSTRACT FROM AUTHOR]

Bronchiectasis is a chronic respiratory condition characterized by irreversible bronchial dilation, often caused by infection or inflammation. It can be associated with primary ciliary dyskinesia (PCD), a hereditary disorder affecting cilia function in various organs and flagella. PCD's genetic heterogeneity leads to varying disease severity. PCD may be more prevalent in Asia, but its diagnosis is often delayed in Japan. This study reviewed a case of PCD and retinitis pigmentosa (RP) with the relevant literature. The patient had a persistent cough, sputum, and diffuse bronchiectasis. He was diagnosed with a combination of PCD and RP, with the presence of an X‐linked retinitis pigmentosa GTPase regulator (RPGR) variant confirmed through electron microscopy, retinal scan, and genetic testing. Although co‐occurrence of bronchiectasis and RP is rare, PCD should be considered in cases of persistent wet cough in childhood or unidentified bronchiectasis aetiology. Ophthalmologists should consider concomitant PCD in RP patients. [ABSTRACT FROM AUTHOR]

Purpose: To determine the status of visual impairment certification in Japan in the fiscal year 2019 and the impact of revising the criteria for visual impairment certification implemented in 2018. Study Design: Observational cross-sectional study. Methods: We requested welfare offices throughout Japan to submit data of age, sex, causative diseases, and visual impairment grades for newly certified visually impaired individuals aged ≥ 18 years during the fiscal year 2019. The certification was based on criteria of the Act on Welfare of Physically Disabled Persons. Results: Altogether, data were collected for 16,504 newly certified visually impaired individuals. The most common age group was 80–89 years (29.6%), followed by 70–79 (28.2%) and 60–69 (15.3%) years. The most common causative disease was glaucoma (40.7%), followed by retinitis pigmentosa (13.0%), diabetic retinopathy (10.2%), and macular degeneration (9.1%). The most common impairment grade was grade 2 (40.8%), followed by 5 (21.2%) and 1 (17.0%). Compared to the fiscal year 2015, there was a considerable increase in the number of individuals certified with glaucoma in the fiscal year 2019. Moreover, there was a significant increase in the number of individuals with certified grades 1 and 2 visual impairment, with a decrease in the number of individuals with certified grade 6 visual impairment. Conclusion: The changes revealed in this study were primarily due to the revised certification criteria implemented in July 2018, indicating that it is important to review the certification criteria and to repeat surveys similar to the present study. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) is the second leading cause of visual impairment in Japan and causes progressive vision loss in affected patients. Caregiving for patients with RP is associated with socioeconomic impacts; however, data on the magnitude and scope of these impacts are lacking. This cross-sectional study surveyed informal caregivers of patients with RP in Japan. The questionnaire assessed the socioeconomic status of participants; work impacts through the Work Productivity and Activity Impairment Questionnaire adapted for caregivers; and quality of life impacts through the Japanese version of the Caregiver Reaction Assessment (CRA) and the 5-level EQ-5D version (EQ-5D-5L). Of the 37 participating caregivers, 28 (75.7%) were employed. Among those, the average annual income was 2,722,080 yen (n = 20) and the mean loss of work productivity was 6.6%. The mean EQ-5D-5L index score was 0.882, and the mean CRA total score was 2.1. A mild to very severe impact on family life, leisure and hobbies, social life, and mental health was experienced by 83.8%, 78.4%, 75.7%, and 70.3%, respectively. These results suggest that caregivers of patients with RP may be disadvantaged in terms of employment and income and may experience wide-ranging impacts on their quality of daily life. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the relationships between macular complications and causative genes frequently found in Japanese patients with retinitis pigmentosa (RP)., Methods: In the retrospective and observational study, we analyzed the data of 75 patients with RP (EYS-RP: 42 patients; USH2A-RP: 19 patients; RHO-RP: 14 patients) who were followed-up at Kyushu University Hospital and whose causative genes had been identified. Macular complications including epiretinal membrane (ERM), macular edema (ME), and macular hole (MH) were evaluated using optical coherence tomography and fundus photography. Main outcome was the proportion of macular complications., Results: The proportion of ERM was 35.7% in the EYS group, 10.5% in the USH2A group and 14.3% in the RHO group. The proportion of ME was 7.1% in the EYS group, 5.3% in the USH2A group and 14.3% in the RHO group, and that of MH was 2.4% in the EYS group, 5.3% in the USH2A group and 0% in the RHO group. In the EYS group, the proportion of ERM was relatively higher (p = 0.06), and the presence of EYS was significantly associated with a higher age- and sex-adjusted OR for ERM (OR = 5.67, 95% CI = 1.59-25.20). There was no significant difference in the proportion of MH or ME among causative genes., Conclusions: EYS causative gene may be associated with higher rate of ERM complication in RP., Competing Interests: Declarations. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the Review Board of Kyushu University Hospital and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all subjects prior to participation in the study. The full name of the institution providing ethical approve was the Review Board of Kyushu University Hospital and the approval number was 536-08. Informed consent: Informed consent was obtained from all individual participants included in the study. Conflict of interest: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The phenotypes of RP1-related inherited retinal dystrophies (RP1-IRD), causing autosomal dominant (AD) and autosomal recessive (AR) diseases, vary depending on specific RP1 variants. A common nonsense mutation near the C-terminus, c.5797 C > T (p.Arg1933*), is associated with RP1-IRD, but the exact role of this mutation in genotype-phenotype correlation remains unclear. In this study, we retrospectively analyzed patients with RP1-IRD (N = 42) from a single center in Japan. AR RP1-IRD patients with the c.5797 C > T mutation (N = 14) mostly displayed macular dystrophy but rarely retinitis pigmentosa or cone-rod dystrophy. Conversely, AR RP1-IRD patients without the c.5797 C > T mutation, including those with other pathogenic RP1 variants, were mostly diagnosed with severe retinitis pigmentosa. Full-field electroretinograms were significantly better in patients homozygous or compound heterozygous for the c.5797 C > T mutation than in those without this mutation, corresponding to their milder phenotypes. Clinical tests also revealed a slower onset of age and a better mean deviation value with the static visual field in AR RP1-IRD patients with the c.5797 C > T mutation compared to those without. Therefore, the presence of c.5797 C > T may partly account for the phenotypic variety of RP1-IRD and may yield milder phenotypes. These findings may be useful for predicting the prognosis of RP1-IRD patients., (© 2024. The Author(s).)

In today's globalized society, ophthalmologists can examine people of different ethnicities regardless of where they live. The frequency of disease-causing genes varies according to a patient's ethnic background. We explain genetic findings for Japanese patients with inherited eye diseases. Ocular genetics has made great advances over the past 30 years. For example, detecting mutations at nucleotide position 11778 in mitochondrial DNA was useful in the genetic diagnosis of Leber's hereditary optic neuropathy (LHON). I evaluated the genotype-phenotype relationship in cases of corneal dystrophy and inherited retinal dystrophy (IRD). I identified the entire exon sequence of the eyes shut homolog (EYS) gene in patients with autosomal recessive retinitis pigmentosa (RP). EYS gene mutations are the most frequent cause of autosomal recessive RP. RPGRIP1 may be a common causative gene with early-onset severe retinal dystrophy, including Leber congenital amaurosis. However, some genes have complex structures that are difficult to analyze, including the OPN1LW/OPN1MW gene cluster in blue cone monochromacy and the IKBKG/NEMO genes in incontinentia pigmenti. This review will also present two cases with uniparental disomy, a case of IRD with double mutations, and a case with RP complicated with LHON-like neuropathy. Precise understanding of the effects of genetic variants may reveal differences in the clinical characteristics of patients with the same variant. When starting genome medicine, accurately diagnosing the patient, making accurate prediction, determining the genetic pattern, and providing genetic counseling are important. Above all, that both the doctors and patients understand genetic diseases correctly is important., (© 2024. The Author(s).)

Usher syndrome (USH) typically leads to deaf-blindness, requiring the provision of extensive education and rehabilitation services. Therefore, investigating the prevalence is crucial to requests for proper government support for USH patients. The aim was to perform a nationwide epidemiologic survey of USH in Japan to estimate the prevalence of USH and reveal the relative frequency and characteristics of the three USH subtypes. To estimate the number of USH patients visiting hospitals over a 1-year period, 1,628 hospitals were randomly selected from all Departments of Otorhinolaryngology and Ophthalmology in Japan. Subsequently, we collected data regarding the clinical characteristics of each patient treated and the results of genetic testing, if performed. We found that the prevalence of USH was at least 0.4 per 100,000 population. The frequency of clinical subtypes and causal genes for USH were consistent with previous reports. Also, we demonstrated the feasibility of genetic counseling for USH patients based on the results of genetic testing. USH is a rare disease, but requires social support due to the severity of symptoms. To minimize these issues, understanding the clinical characteristics and performing comprehensive genetic testing could allow early and accurate diagnosis as well as medical intervention. [ABSTRACT FROM AUTHOR]

Purpose: To describe relevant patient demographic characteristics and investigate the influence of known risk factors for late intraocular lens (IOL) dislocation. To explore the associations between these risk factors and the incidence of recurrent IOL dislocation.Study design: Retrospective cohort study.Methods: This study was performed using Nationwide Diagnostic Procedure Combination data in Japan from April 1, 2008 through July 31, 2016. Descriptive statistics for late and recurrent IOL dislocation, incidence rates, and risk factors for recurrent IOL dislocation were analyzed using a Cox proportional hazard model.Results: We identified 678 patients with late IOL dislocation. Most were men (72%, 488/678), and the men were younger than their women counterparts (mean age 65.2 years vs. 74.5 years). The incidence rate of recurrent IOL dislocation was 5.1 per 100 person-years. All 20 cases of recurrent IOL dislocation were observed within the year following surgery. There were no significant associations between potential risk factors and recurrent IOL dislocation (adjusted hazard ratio [HR] 1.53, 95% confidence interval [CI] 0.55-4.26 for diabetes mellitus; adjusted HR 0.77, 95%CI 0.09-6.40 for atopic dermatitis); no recurrences occurred in patients with pseudoexfoliation syndrome, retinitis pigmentosa, or connective tissue disease.Conclusions: Late IOL dislocation occurs more frequently in men. We found that recurrent IOL dislocation was rare during long-term follow-up and there were no significant associations between the potential risk factors and recurrent IOL dislocation. Further studies are needed to clarify the sex-related differences involved in IOL dislocation. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the visual impairment certification status in Japan.Study design: Observational cross-sectional study.Methods: We asked all welfare offices throughout Japan to submit data concerning age, sex, causative diseases, and visual impairment grades for newly certified visually impaired individuals aged ≥ 18 years in the fiscal year of 2015. The certification was based on criteria of the Act on Welfare of Physically Disabled Persons.Results: In total, data were collected for 12,505 newly certified visually impaired individuals. The most common age group for these individuals was 80-89 years (29.6%), followed by 70-79 (26.3%) and 60-69 (17.3%) years. The most common causative disease was glaucoma (28.6%), followed by retinitis pigmentosa (14.0%), diabetic retinopathy (12.8%), and macular degeneration (8.0%). Glaucoma was the most common causative disease in both sexes (30.2% in men and 27.0% in women). The most common impairment grade was grade 2 (31.8%), followed by grades 5 (24.3%) and grade 1 (16.1%). The number of visually impaired individuals with underlying glaucoma had increased in comparison with the number in the most recent surveys (from fiscal years 2007 to 2009), whereas the number of individuals with underlying diabetic retinopathy and macular degeneration had decreased.Conclusion: To our knowledge, this is the first nation-wide complete enumeration survey of newly certified visually impaired individuals in Japan. These findings may contribute to administrative activities concerning medical welfare as well as educational activities for preventing visual impairment. [ABSTRACT FROM AUTHOR]

Purpose. To investigate genetic and clinical features of patients with rhodopsin (RHO) mutations in two Japanese families with autosomal dominant retinitis pigmentosa (adRP). Methods. Whole-exome sequence analysis was performed in ten adRP families. Identified RHO mutations for the cosegregation analysis were confirmed by Sanger sequencing. Ophthalmic examinations were performed to evaluate the RP phenotypes. The impact of the RHO mutation on the rhodopsin conformation was examined by molecular modeling analysis. Results. In two adRP families, we identified two RHO mutations (c.377G>T (p.W126L) and c.1036G>C (p.A346P)), one of which was novel. Complete cosegregation was confirmed for each mutation exhibiting the RP phenotype in both families. Molecular modeling predicted that the novel mutation (p.W126L) might impair rhodopsin function by affecting its conformational transition in the light-adapted form. Clinical phenotypes showed that patients with p.W126L exhibited sector RP, whereas patients with p.A346P exhibited classic RP. Conclusions. Our findings demonstrated that the novel mutation (p.W126L) may be associated with the phenotype of sector RP. Identification of RHO mutations is a very useful tool for predicting disease severity and providing precise genetic counseling. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) is a highly heterogeneous genetic disease including autosomal recessive (ar), autosomal dominant (ad), and X-linked inheritance. Recently, arRP has been associated with mutations in EYS (Eyes shut homolog), which is a major causative gene for this disease. This study was conducted to determine the spectrum and frequency of EYS mutations in 100 Japanese arRP patients. To determine the prevalence of EYS mutations, all EYS exons were screened for mutations by polymerase chain reaction amplification, and sequence analysis was performed. We detected 67 sequence alterations in EYS, of which 21 were novel. Of these, 7 were very likely pathogenic mutations, 6 were possible pathogenic mutations, and 54 were predicted non-pathogenic sequence alterations. The minimum observed prevalence of distinct EYS mutations in our study was 18% (18/100, comprising 9 patients with 2 very likely pathogenic mutations and the remaining 9 with only one such mutation). Among these mutations, 2 novel truncating mutations, c.4957_4958insA (p.S1653KfsX2) and c.8868C>A (p.Y2956X), were identified in 16 patients and accounted for 57.1% (20/35 alleles) of the mutated alleles. Although these 2 truncating mutations were not detected in Japanese patients with adRP or Leber's congenital amaurosis, we detected them in Korean arRP patients. Similar to Japanese arRP results, the c.4957_4958insA mutation was more frequently detected than the c.8868C>A mutation. The 18% estimated prevalence of very likely pathogenic mutations in our study suggests a major involvement of EYS in the pathogenesis of arRP in the Japanese population. Mutation spectrum of EYS in 100 Japanese patients, including 13 distinct very likely and possible pathogenic mutations, was largely different from the previously reported spectrum in patients from non-Asian populations. Screening for c.4957_4958insA and c.8868C>A mutations in the EYS gene may therefore be very effective for the genetic testing and counseling of RP patients in Japan. [ABSTRACT FROM AUTHOR]

Usher syndrome (USH) is an autosomal recessive disorder characterized by retinitis pigmentosa and hearing loss. USH type 1 (USH1), the second common type of USH, is frequently caused by MYO7A and CDH23 mutations, accounting for 70-80% of the cases among various ethnicities, including Caucasians, Africans and Asians. However, there have been no reports of mutation analysis for any responsible genes for USH1 in Japanese patients. This study describes the first mutation analysis of MYO7A and CDH23 in Japanese USH1 patients. Five mutations (three in MYO7A and two in CDH23) were identified in four of five unrelated patients. Of these mutations, two were novel. One of them, p.Tyr1942SerfsX23 in CDH23, was a large deletion causing the loss of 3 exons. This is the first large deletion to be found in CDH23. The incidence of the MYO7A and CDH23 mutations in the study population was 80%, which is consistent with previous findings. Therefore, mutation screening for these genes is expected to be a highly sensitive method for diagnosing USH1 among the Japanese. [ABSTRACT FROM AUTHOR]

Usher syndrome (USH) is an autosomal recessive disorder characterized by retinitis pigmentosa and hearing loss. USH type 2 (USH2) is the most common type of USH and is frequently caused by mutations in USH2A, which accounts for 74–90% of USH2 cases. This is the first study reporting the results of scanning for USH2A mutations in Japanese patients with USH2. In 8 of 10 unrelated patients, we identified 14 different mutations. Of these mutations, 11 were novel. Although the mutation spectrum that we identified differed from that for Caucasians, the incidence of mutations in USH2A was 80% for all patients tested, which is consistent with previous findings. Further, c.8559-2A>G was identified in four patients and accounted for 26.7% of mutated alleles; it is thus a frequent mutation in Japanese patients. Hence, mutation screening for c.8559-2A>G in USH2A may prove very effective for the early diagnosis of USH2. [ABSTRACT FROM AUTHOR]

Abstract Purpose  To identify a mutation in the PRPF31 gene in a family (Family K) with autosomal dominant retinitis pigmentosa (adRP) linked to 19q13.4 (RP11) and to find the frequency of mutations in the PRPF31 gene among Japanese families with adRP. Methods  Genomic DNA specimens were prepared from five symptomatic and two asymptomatic members of Family K and an additional 39 patients of 39 unrelated families with adRP. Coding regions of the PRPF31 gene were amplified by polymerase chain reaction. The amplicons were analyzed by a direct sequencing method. Results  All seven family members had a heterozygous c.1142delG mutation in the PRPF31 gene, which was identical to the mutation previously reported in a different Japanese family. No other mutation was found in the PRPF31 gene among the 39 additional patients with adRP. Conclusion  Although the frequency of mutations in the PRPF31 gene is about 2.5% in Japanese families with adRP, it is possible that c.1142delG is a common mutation among Japanese patients with adRP associated with mutations in the PRPF31 gene. Jpn J Ophthalmol 2007;51:45–48 Japanese Ophthalmological Society 2007 [ABSTRACT FROM AUTHOR]

To clarify the prevalence and clinical profile of neuroretinitis associated with cat-scratch disease (CSD) in Japan. Japanese patients were searched using a computer web site, Japana Centra Revuo Medicina. Location of patients, medical history, systemic and intraocular findings, treatments and visual outcome were examined. We reviewed 15 eyes of 14 patients, including our own case. Incidences of the disease were more common in summer than in winter and presented in the warmer parts of Japan. All patients had been previously healthy and had been exposed to cats or flea bites. Of the 14 patients, 13 (93%) had febrile illness and seven of these (54%) had lymphadenopathy. Uveitis and macular stars were observed in 11 of 15 eyes (73%). Most patients were treated with antibiotics and systemic steroids and visual prognoses were good. The clinical features of CSD-associated neuroretinitis in Japan are similar to those in other countries. Its distribution may correlate with the prevalence of Bartonella henselae-seropositive cats in Japan. [ABSTRACT FROM AUTHOR]

We examined a Japanese family with X-linked retinitispigmentosa (RP) associated with a nonsense mutation, R120X, in the RP2 gene.The 26-year-old proband presented at the age of seven years with a two-yearhistory of night blindness. Visual disability worsened with increasing age.At age 24, visual acuity was 0.08 in both eyes. Testing for refractive errorindicated mild myopia. Visual fields showed bilateral-constriction to 10 degrees.He had central macular areolar sclerosis in both eyes. Two maternal uncleshad vision of light perception to hand movement in their early forties togetherwith dense bilateral cataracts. The ocular phenotype of this family with R120Xwas considered severe; reported phenotypes associated with this mutation havenot been uniform. [ABSTRACT FROM AUTHOR]

Inherited retinal disease (IRD) is clinically and genetically heterogeneous. Awareness of the importance of genetic testing for IRD in the clinical setting is increasing with the recent development of new therapeutic strategies, such as gene therapy. Here, the perception of genetic testing, including its benefits and potential challenges, among patients with IRD was investigated to establish strategies for IRD genetic testing and counseling practices that can meet the requirements of the patients in Japan. An anonymous self-administered questionnaire was distributed to 275 patients with IRD who underwent genetic testing after clinical consultation and genetic counseling to investigate the motivations for genetic testing, benefits, challenges, status of communication of results to family, and attitude to timing of genetic testing. In total, 228 (82.9%) responses were analyzed. Several major motivations for genetic testing were identified, including gaining information on future treatment options and clarification of the inheritance pattern, among others. No association was found between the sharing of results with family members and the results of genetic testing. Moreover, according to patients who received positive results, the benefits of genetic testing included information on the inheritance pattern, additional information on the diagnosis, and mental preparation for the future. Even patients who received negative or inconclusive (variant of uncertain significance) results reported certain informative and psychological benefits. Altogether, these findings suggest that provisions for genetic testing and genetic counseling are necessary within a certain period after clinical diagnosis and it is necessary to facilitate appropriate family communication about genetic testing results while paying attention to the background of family relationships. Moreover, the benefits of genetic testing can be influenced by the careful interpretation and information provided on the test results during genetic counseling and consultation., (© 2022 National Society of Genetic Counselors.)

Purpose: Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders. NRL-associated autosomal dominant (AD)-RP is a rare form of AD-RP in the Japanese population. This study aimed to report a clinical characterization of NRL-associated retinopathy in a three-generation Japanese family., Case Presentation: A total of 4 patients from a Japanese family were referred to The Jikei University School of Medicine for clinical and genetic examination. The patients included a male proband (41 years old), his daughters (5 and 6 years old), and his mother (71 years old); they underwent ophthalmic examinations, and genetic testing was performed using whole exome sequencing analysis, revealing a known variant [c.152C > T (p.Pro51Leu)] heterozygously in exon 2 of the NRL gene. Fundus photograph showed that retinal degeneration expanded to the macular and peripheral retina in an age-dependent manner. Fundus autofluorescence imaging showed hyper-autofluorescence (AF) within the macular with slightly hypo-AF in younger patients and obvious hypo-AF in older patients. Optical coherence tomography showed that the length of the ellipsoid zone tended to be longer in younger patients than in older patients. Goldmann perimetry showed an age-dependent decrease in the visual field. Furthermore, full-field electroretinographic findings revealed non-recordable rod and cone function in older patients and non-recordable rod function with preserved cone function in younger patients., Conclusions: Our results indicated that retinal construction and function were aggravated in an age-dependent manner, and retinal degeneration, especially in the macular region, revealed milder findings than in previous cases with NRL-associated AD-RP., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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. [ABSTRACT FROM AUTHOR]

Background: This study aimed to identify the features of ocular biometry in patients with EYS-related retinitis pigmentosa using IOLMaster 700., Methods: We retrospectively reviewed the medical records of patients with retinitis pigmentosa. Patients with records of the following were included: (1) ocular biometry measurements using the IOLMaster 700 and (2) genetic diagnostic tests. Axial length, keratometry, anterior chamber depth, aqueous depth, lens thickness, central corneal thickness (CCT), and corneal diameter (white to white) measurements were extracted. Based on keratometry measurements, (1) standard keratometric astigmatism, (2) posterior corneal astigmatism, and (3) total corneal astigmatism were obtained. Demographics and biometric parameters were compared between patients with EYS-related retinitis pigmentosa and other patients with retinitis pigmentosa., Results: A total of 86 eyes of 44 patients (23 females and 21 males; mean age: 47.7 years) with retinitis pigmentosa were included. Of these, 18 were identified as having EYS variants. CCT was significantly thinner (P < 0.001) and the posterior corneal curvature at the steepest meridian was significantly smaller (P = 0.024) in patients with EYS-related retinitis pigmentosa than in other patients with retinitis pigmentosa. The magnitudes of all corneal astigmatism measurements was higher in patients with EYS-related RP, although these differences were not statistically significant., Conclusion: Patients with EYS-related retinitis pigmentosa had unique features in ocular biometry, such as thinner central corneal thickness and smaller posterior corneal curvature radius at the steepest meridian compared with other patients with retinitis pigmentosa. The findings suggest that patients with retinitis pigmentosa have different ocular dimension features among the different causative genes., (© 2022. The Author(s).)

Background: Little is known about genotype–phenotype correlations of RP1-associated retinal dystrophies in the Japanese population. We aimed to investigate the genetic spectrum of RP1 variants and provide a detailed description of the clinical findings in Japanese patients. Methods: In total, 607 patients with inherited retinal diseases were examined using whole-exome/whole-genome sequencing (WES/WGS). PCR-based screening for an Alu element insertion (c.4052_4053ins328/p.Tyr1352AlafsTer9) was performed in 18 patients with autosomal-recessive (AR)-retinitis pigmentosa (RP) or AR-cone dystrophy (COD)/cone-rod dystrophy (CORD), including seven patients with heterozygous RP1 variants identified by WES/WGS analysis, and 11 early onset AR-RP patients, in whom no pathogenic variant was identified. We clinically examined 25 patients (23 families) with pathogenic RP1 variants, including five patients (five families) with autosomal-dominant (AD)-RP, 13 patients (11 families) with AR-RP, and seven patients (seven families) with AR-COD/CORD. Results: We identified 18 pathogenic RP1 variants, including seven novel variants. Interestingly, the Alu element insertion was the most frequent variant (32.0%, 16/50 alleles). The clinical findings revealed that the age at onset and disease progression occurred significantly earlier and faster in AR-RP patients compared to AD-RP or AR-COD/CORD patients. Conclusions: Our results suggest a genotype–phenotype correlation between variant types/locations and phenotypes (AD-RP, AR-RP, and AR-COD/CORD), and the Alu element insertion was the most major variant in Japanese patients with RP1-associated retinal dystrophies. [ABSTRACT FROM AUTHOR]

Researchers have been working towards the development of retinal prostheses, so called "bionic eyes" since the 1960s in an effort to restore functional vision to severely visually impaired patients. Groups from all around the world are involved in this research but in particular, groups from the United States, Germany, France, Japan and Australia have conducted clinical trials of these devices and three of these devices have achieved either FDA HDE (U.S. Food and Drug Administration Humanitarian Device Exception) or CE mark approval for commercial production. Despite this, all three of these devices are now not in commercial production. There are many challenges to overcome to develop devices suitable to implant in human patients and then reach commercial distribution. This is an exacting process and many hurdles need to be overcome to reach this point so that leaving the market after achieving this goal is a significant decision. Ongoing research is exploring the possibility of less complicated surgery with better visual processing algorithms to provide more useful visual information for our patients to provide a commercial alternative., (© 2021 Royal Australian and New Zealand College of Ophthalmologists.)

Purpose: To investigate the regional differences in the genes and variants causing retinitis pigmentosa (RP) in Japan STUDY DESIGN: Retrospective multicenter study METHODS: In total, 1204 probands of each pedigree clinically diagnosed with nonsyndromic RP were enrolled from 5 Japanese facilities. The regions were divided into the Tohoku region, the Kanto and Chubu regions, and the Kyushu region according to the location of the hospitals where the participants were enrolled. We compared the proportions of the causative genes and the distributions of the pathogenic variants among these 3 regions., Results: The proportions of genetically solved cases were 29.4% in the Tohoku region (n = 500), 29.6% in the Kanto and Chubu regions (n = 196), and 29.7% in the Kyushu region (n = 508), which did not differ statistically (P = .99). No significant regional differences in the proportions of each causative gene in genetically solved patients were observed after correction by multiple testing. Among the 29 pathogenic variants detected in all 3 regions, only p.(Pro347Leu) in RHO was an autosomal dominant variant; the remaining 28 variants were found in autosomal recessive genes. Conversely, 78.6% (275/350) of the pathogenic variants were detected only in a single region, and 6 pathogenic variants (p.[Asn3062fs] in EYS, p.[Ala315fs] in EYS, p.[Arg872fs] in RP1, p.[Ala126Val] in RDH12, p.[Arg41Trp] in CRX, and p.[Gly381fs] in PRPF31) were frequently found in ≥ 4 patients in the single region., Conclusion: We observed region-specific pathogenic variants in the Japanese population. Further investigations of causative genes in multiple regions in Japan will contribute to the expansion of the catalog of genetic variants causing RP.

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., (© 2020 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

X-linked retinitis pigmentosa (XLRP) is a type of severe retinal dystrophy, and female carriers of XLRP demonstrate markedly variable clinical severity. In this study, we aimed to elucidate the clinical findings of male patients with and female carriers of XLRP in a Japanese cohort and demonstrate the genetic contribution. Twelve unrelated families (13 male patients, 15 female carriers) harboring pathogenic mutations in RPGR or RP2 were included, and comprehensive ophthalmic examinations were performed. To identify potential pathogenic mutations, targeted next-generation sequencing was employed. Consequently, we identified 11 pathogenic mutations, of which five were novel. Six and five mutations were detected in RPGR and RP2, respectively. Only one mutation was detected in ORF15. Affected male patients with RP2 mutations tended to have lower visual function than those with RPGR mutations. Female carriers demonstrated varying visual acuities and visual fields. Among the female carriers, 92% had electroretinographical abnormalities and 63% had a radial autofluorescent pattern, and the carriers who had higher myopia showed worse visual acuity and more severe retinal degeneration. Our results expand the knowledge of the clinical phenotypes of male patients with and female carriers of XLRP and suggest the possibility that RP2 mutations are relatively highly prevalent in Japan. [ABSTRACT FROM AUTHOR]

Background: The genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population., Methods: A total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases., Results: We successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes ( EYS , USH2A , RP1L1 , RHO , RP1 and RPGR ) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in EYS [p.(Ser1653fs) and p.(Tyr2935*)] and four East Asian-specific variants [p.(Gly2752Arg) in USH2A , p.(Arg658*) in RP1L1 , p.(Gly2186Glu) in EYS and p.(Ile535Asn) in PDE6B ] and p.(Cys934Trp) in USH2A were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in RHO , p.(Arg872fs) in RP1 , p.(Arg41Trp) in CRX and p.(Gly381fs) in PRPF31 ] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases., Conclusions: East Asian-specific variants in causative genes were the major causes of RP in the Japanese population., Competing Interests: Competing interests: SU reports personal fees from Nidek, Chuo Sangio, Santen and Alcon outside the submitted work. AM reports grants from Pfizer Japan, Abbott Japan, Otsuka Pharmaceutical, Eisai, Alcon Japan, Novartis Pharma KK, SEED and Santen Pharmaceutical, and personal fees from Lion Japan outside the submitted work. In addition, AM has a patent hydrogel contact lens for gene treatment licensed. HT reports personal fees from Rohto Pharmaceutical, Takeda Pharmaceutical, Mitsubishi Tanabe, AbbVie, Daiichi Sankyo, Chuo Sangio, Sanofi, Nihon Tenganyaku, Alcon Pharma, Bayer and Graybug Vision, grants and personal fees from Nidek, Otsuka, Pfizer, Santen, Alcon, Novartis, Senju, Kowa and Wakamoto, grants from HOYA and Allergan Japan, and personal fees and non-financial support from Carl Zeiss Meditec outside the submitted work. In addition, HT has a patent pending with Nidek., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: This study reports the ophthalmic and genetic findings of a Japanese patient with autosomal recessive retinitis pigmentosa (arRP) caused by retinitis pigmentosa 1 (RP1) mutations., Patient and Methods: The 34-year-old female patient and her unaffected parents underwent comprehensive ophthalmic examinations, including visual acuity measurements, perimetry, electroretinography (ERG), and optical coherence tomography. Fundus autofluorescence was also evaluated in the patient. To identify potential pathogenic variants, 111 inherited eye disease genes were examined by targeted next-generation sequencing., Results: The patient had night blindness from the first decade of her life. Fundus examination revealed typical RP findings with additional macular degeneration. Her visual field and acuity were severely affected, and ERG scans showed undetectable responses. Bioinformatics analysis revealed two heterozygous potentially pathogenic variants in RP1 in the patient, one of which is novel. Co-segregation analysis in the unaffected parents confirmed that the two variants were in trans. The parents were both carriers of one RP1 variant but did not show any visual symptoms. Therefore, the identified compound heterozygous variants were proposed as the probable arRP-causing mutations in the family., Conclusion: This is the first description of a Japanese patient with arRP caused by RP1 mutations. Additional data are necessary to more accurately determine the clinical course and mutation spectrum in patients with RP1-related arRP.

Retinal degenerative diseases, such as glaucoma and retinitis pigmentosa (RP), are the leading causes of blindness in adults. In Japan, glaucoma is a leading cause, and RP is third major cause of acquired blindness. Specific types of neurons are injured in the patients of glaucoma and RP. Retinal ganglion cells (RGC) are specifically degenerated in glaucoma. Excitotoxicity caused by excess glutamate in the retinal extracellular space is thought to be one of the mechanisms of RGC death induced by glaucoma and retinal central artery occlusion. Retinal ischemia-reperfusion, intravitreal NMDA injection, intravitreal NO donor injection and knock out of glutamate aspartate transporter, which are used as the experimental models of glaucoma, are known to induce RGC death. RGCs are vulnerable for excess glutamate and oxidative stress related to NO, and this vulnerability may be involved in pathogenesis of glaucomatous optic neuropathy. RP, which is characterized by progressive photoreceptor-selective degeneration, is caused by mutation of the genes related to the function of photoreceptor and retinal pigment epithelium. It has not been thoroughly clarified how the mutations induce specific photoreceptor death. Tunicamycin is widely known to induce ER stress, and intravitreal tunicamycin cause photoreceptor-specific degeneration. Therefore, ER stress may cause photoreceptor-selective degeneration in RP.

Purpose: In this study, we aimed to detect mutations in the SLC7A14 cationic transporter gene, which has recently been reported as a causative gene for retinitis pigmentosa (RP), in Japanese patients with autosomal recessive (AR) or sporadic RP., Materials and Methods: We included 146 unrelated Japanese patients with AR or sporadic RP who lacked mutations in genes known to be associated with RP despite next-generation sequencing-based screening. We sequenced the seven SLC7A14 coding exons along with their flanking intronic DNA using the Sanger method. The detected polymorphisms were assessed for their pathogenicity with in silico prediction tools. For those who had heterozygous, nonsynonymous variants, we performed multiplex ligation-dependent probe amplification (MLPA) to search for additional deletion/duplication., Results: We detected four distinct SLC7A14 polymorphisms excluding synonymous polymorphisms. Two of these polymorphisms were assessed as detrimental by in silico prediction tools. However, all of the mutations were heterozygous. Neither homozygous polymorphisms nor compound heterozygous polymorphisms, which are considered detrimental variants, were detected. Neither deletion nor duplication was found with MLPA in patients with heterozygous variants., Conclusions: The four SLC7A14 mutations detected herein were unlikely to be pathogenic in this Japanese cohort. The frequency and pathogenicity of SLC7A14 mutations may vary depending on ethnicity, and these mutations may be rare in Japanese patients.

Purpose: Retinitis pigmentosa (RP), a major cause of blindness in developed countries, has multiple causative genes; its prevalence differs by ethnicity. Usher syndrome is the most common form of syndromic RP and is accompanied by hearing impairment. Although molecular diagnosis is challenging, recent technological advances such as targeted high-throughput resequencing are efficient screening tools., Methods: We performed comprehensive molecular testing in 329 Japanese RP and Usher syndrome patients by using a custom capture panel that covered the coding exons and exon/intron boundaries of all 193 known inherited eye disease genes combined with Illumina HiSequation 2500. Candidate variants were screened using systematic data analyses, and their potential pathogenicity was assessed according to the frequency of the variants in normal populations, in silico prediction tools, and compatibility with known phenotypes or inheritance patterns., Results: Molecular diagnoses were made in 115/317 RP patients (36.3%) and 6/12 Usher syndrome patients (50%). We identified 104 distinct mutations, including 66 novel mutations. EYS, USH2A, and RHO were common causative genes. In particular, mutations in EYS accounted for 15.0% of the autosomal recessive/simplex RP patients or 10.7% of the entire RP cohort. Among the 189 previously reported mutations detected in the current study, 55 (29.1%) were found commonly in Japanese or other public databases and were excluded from molecular diagnoses., Conclusions: By screening a large cohort of patients, this study catalogued the genetic variations involved in RP and Usher syndrome in a Japanese population and highlighted the different distribution of causative genes among populations., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)