Nationwide epidemiologic survey on incidence of macular dystrophy in Japan.

PURPOSE: The aim of this study was to estimate the number of patients in Japan who had visited an ophthalmologist for macular dystrophy of various types, including Best vitelliform macular dystrophy (BVMD), Stargardt disease, occult macular dystrophy (OMD), cone (-rod) dystrophy, X-linked retinoschisis (XLRS), and central areolar choroid dystrophy (CACD). STUDY DESIGN: Nationwide epidemiologic survey METHODS: Questionnaires were distributed to 965 major facilities, including all the university hospitals in Japan. The aim of the questionnaire was to determine the number of patients with each type of macular dystrophy who had visited an outpatient clinic during the past 5 years (January 2015 to December 2019). RESULTS: Over 70% of the patients were diagnosed and followed up at university hospitals. The estimated annual number of newly diagnosed cases was as follows: 55.3 for BVMD, 36.7 for Stargardt disease, 35.8 for OMD, 160.6 for cone (-rod) dystrophy, 31.0 for XLRS, 29.8 for CACD, and 174.1 for other types of macular dystrophy. The total number of patients with macular dystrophy diagnosed and followed at major institutions was estimated to be 6651. CONCLUSION: This was the first nationwide survey of macular dystrophy in Japan and provided an approximate number of affected patients. The diagnosis of macular dystrophy is primarily carried out at facilities with affiliated specialists, such as university hospitals. By examining the incidence of multiple diseases simultaneously, we were able to compare the incidence of each type of macular dystrophy.

Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases.

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.

Genetic and Clinical Features of ABCA4-Associated Retinopathy in a Japanese Nationwide Cohort.

PURPOSE: To clarify the genetic and clinical features of Japanese patients with ABCA4-associated retinopathy. DESIGN: Retrospective, multicenter cohort study. METHODS: Patients with retinal degeneration and biallelic ABCA4 variants were recruited from 13 different hospitals. Whole exome sequencing analysis was used for genetic testing. Comprehensive ophthalmic examinations were performed on matched patients. The primary outcome measure was identifying multimodal retinal imaging findings associated with disease progression. RESULTS: This study included 63 patients: 19 with missense/missense, 23 with missense/truncation, and 21 with truncation/truncation genotypes. In total, 62 variants were identified, including 29 novel variants. Six patients had a mild phenotype characterized by foveal-sparing or preserved foveal structure, including 4 with missense/missense and 2 with missense/truncation genotypes. The p.Arg212His variant was the most frequent in patients with mild phenotypes (4/12 alleles). Clinical findings showed a disease duration-dependent worsening of the phenotypic stage. Patients with the truncation/truncation genotype exhibited rapid retinal degeneration within a few years and definite fundus autofluorescence imaging patterns, including hyper autofluorescence at the macula and few or no flecks. CONCLUSIONS: Our results indicate that missense/missense or missense/truncation genotypes, including the p.Arg212His variant, are associated with a relatively mild phenotype. In contrast, the truncation/truncation genotype causes rapid and severe retinal degeneration in Japanese patients with ABCA4-associated retinopathy. These data are vital in predicting patient prognosis, guiding genetic counseling, and stratifying patients for future clinical trials.

A Phase 2 Study of Encorafenib in Combination with Binimetinib in Patients with Metastatic BRAF-Mutated Thyroid Cancer in Japan.

Background: Driver mutations at BRAF V600 are frequently identified in papillary thyroid cancer and anaplastic thyroid cancer (ATC), in which BRAF inhibitors have shown clinical effectiveness. This Japanese phase 2 study evaluated the efficacy and safety of a BRAF inhibitor, encorafenib, combined with an MEK inhibitor, binimetinib, in patients with BRAF V600-mutated thyroid cancer. Methods: This phase 2, open-label, uncontrolled study was conducted at 10 institutions targeted patients with BRAF V600-mutated locally advanced or distant metastatic thyroid cancer not amenable to curative treatment who became refractory/intolerant to ≥1 previous vascular endothelial growth factor receptor-targeted regimen(s) or were considered ineligible for those. The primary endpoint was centrally assessed objective response rate (ORR). The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: We enrolled 22 patients with BRAFV600E-mutated thyroid cancer: 17 had differentiated thyroid cancer (DTC), and 5 had ATC. At data cutoff (October 26, 2022), the median follow-up was 11.5 (range = 3.4-19.0) months. The primary endpoint of centrally assessed ORR was 54.5% (95% confidence interval [CI] 32.2-75.6; partial response in 12 patients and stable disease in 10). The ORRs in patients with DTC and ATC were 47.1% (8 of 17) and 80.0% (4 of 5), respectively. The medians for DOR and PFS by central assessment and for OS were not reached in the overall population, the DTC subgroup, or the ATC subgroup. At 12 months, the rate of ongoing response was 90.9%, and the PFS and OS rates were 78.8% and 81.8%, respectively. All patients developed ≥1 adverse events (AEs): grade 3 AEs in 6 patients (27.3%). No patients developed grade 4-5 AEs. The most common grade 3 AE was lipase increased (4 patients [18.2%]). Those toxicities were mostly manageable with appropriate monitoring and dose adjustment. Conclusions: Treatment with encorafenib plus binimetinib met the primary endpoint criteria and demonstrated clinical benefit in patients with BRAFV600E-mutated thyroid cancer regardless of its histological type, such as DTC or ATC, with no new safety concerns identified. Encorafenib plus binimetinib could thus be a new treatment option for BRAF V600-mutated thyroid cancer. Clinical Trial Registration number: Japan Registry of Clinical Trials: jRCT2011200018.

Silencing of ocular transthyretin, a gene responsible for hereditary transthyretin amyloidosis, by intravitreal injection of an siRNA conjugate into rabbit eyes.

The first small interfering RNA (siRNA) therapeutic received approval for hereditary transthyretin (ATTRv) amyloidosis, and the patients' lifespan extension by specific inhibition of hepatic synthesis of transthyretin (TTR) is expected. However, ocular amyloidosis in these patients has been a crucial issue. This study aims to evaluate the efficacy and safety of intravitreal TTR siRNA conjugate injection into rabbit eyes. Rabbit (r) TTR siRNA is a screened TTR siRNA conjugate from 53 candidates. The intraocular pressure (IOP) immediately after injection was high despite the 65.9 % decrease of aqueous humor TTR protein levels in the rTTR siRNA group compared with those in the Control siRNA group 2 weeks after the 50 µL siRNA injection. The IOP spike was milder after the 30 µL siRNA injection, and aqueous humor TTR levels decreased by ∼50 % in the rTTR siRNA group, which is consistent with the mRNA levels in the retina. The parameters of dark-adapted, light-adapted, and light-adapted 30 Hz electroretinogram and the thickness of each retinal layer in histological analysis demonstrated no significant differences between the groups. In conclusion, we developed TTR siRNA conjugates for rabbit eyes, and the results indicate that intravitreal TTR siRNA conjugate injection could be a therapeutic option for ocular amyloidosis caused by ATTRv amyloidosis.

Bilateral simultaneous endophthalmitis after immediately sequential bilateral cataract surgery.

Purpose: Immediately sequential bilateral cataract surgery (ISBCS) has recently been considered effective due to faster visual rehabilitation and further improvements in quality of life. We report on the treatment course of a case of early postoperative endophthalmitis in both eyes after ISBCS. Observations: The patient was a 75-year-old woman undergoing anticancer treatment for lung cancer, who had been receiving eye drops for bilateral uveitis and secondary glaucoma since 2019. She underwent ISBCS at another hospital in 2022. In that surgery, the same instruments were used for the surgery of both eyes, without resterilization between eyes. On the night of the following day, she became aware of vision loss in both eyes, and at the examination the next day, hypopyon and corneal edema were found and she was diagnosed with bilateral postoperative endophthalmitis, and referred to our hospital. On the same day, anterior chamber irrigation, posterior capsulotomy, and vitrectomy were performed on both eyes, and the intraocular lenses were preserved. There was no recurrence of postoperative inflammation, and visual acuity was 20/30 in both eyes 6 months after vitrectomy. Conclusion: ISBCS is recommended to be performed with complete aseptic separation of the patient's two procedures. This important rule was not followed in this case. ISBCS should be performed in accordance with accepted protocols, such as those of the International Society of Bilateral Cataract Surgeons, the Royal College of Ophthalmologists, and the Canadian Ophthalmological Society.

Functional Characteristics of Diverse PAX6 Mutations Associated with Isolated Foveal Hypoplasia.

The human fovea is a specialized pit structure in the central retina. Foveal hypoplasia is a condition where the foveal pit does not fully develop, and it is associated with poor vision. Autosomal dominant isolated foveal hypoplasia (FVH1) is a rare condition of foveal hypoplasia (FH) that lacks any other ocular manifestations. FVH1 is associated with hypomorphic mutations in the PAX6 gene that encodes a sequence-specific DNA-binding transcription factor for morphogenesis and evolution of the eye. We report our findings in 17 patients with PAX6 mutations associated with FVH1 or FH with aniridia and corneal opacities. Patients with three mutations, p.V78E, p.V83F and p.R128H, in the C-terminal subdomain of the paired domain (CTS) consistently have severe FH. Luciferase assays for a single reporter containing a representative PAX6 binding site indicated that the transcriptional activities of these mutations were significantly reduced, comparable to that of the truncation mutation of p.G65Rfs*5. Patients with p.P20S in the N-terminal subdomain of the paired domain, and a patient with p.N365K in the proline-serine-threonine-rich domain (PSTD) had mild FH. A patient with p.Q255L in the homeodomain had severe FH. The P20S and Q255L mutants did not affect the transcriptional activity. Mutant N365K has a retained DNA-binding activity but a reduced transcriptional activity, due to a low PSTD transactivation. These findings demonstrated that mutations associated with FVH1 underlie a functional divergence between DNA-binding ability and transcriptional activity. We conclude that a wide range of mutations in the PAX6 gene is not limited to the CST region and are responsible for FVH1.

Pathogenic variants of MFRP and PRSS56 genes are major causes of nanophthalmos in Japanese patients.

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.

Phase 1b study on the repurposing of meclizine hydrochloride for children with achondroplasia.

Achondroplasia (ACH) is a common skeletal dysplasia characterized by a disproportionately short stature. We found that meclizine, which is an over-the-counter drug for motion sickness, inhibited the fibroblast growth factor receptor 3 (FGFR3) gene using a drug repositioning strategy, and meclizine 1 and 2 mg/kg/day promoted bone growth in a mouse model of ACH. A previous phase 1a clinical trial for children with ACH demonstrated that a single dose of meclizine 25 and 50 mg was safe and that the simulated plasma concentration achieved steady state approximately 10 days after the first dose. The current study aimed to evaluate the safety and pharmacokinetics (PK) of meclizine in children with ACH after a 14-day-repeated dose of meclizine. Twelve patients with ACH aged 5-10 years were enrolled. Meclizine 12.5 (cohort 1) and 25 mg/day (cohort 2) were administered after meals for 14 days, and adverse events (AEs) and PK were evaluated. No patient experienced serious AEs in either group. The average (95% confidential interval [CI]) maximum drug concentration (Cmax), peak drug concentration (Tmax), area under the curve (AUC) from 0 to 24 h, and terminal elimination half-life (t1/2) after a 14-day-repeated administration of meclizine (12.5 mg) were 167 (83-250) ng/mL, 3.7 (3.1-4.2) h, 1170 (765-1570) ng·h/mL, and 7.4 (6.7-8.0) h, respectively. The AUC0-6h after the final administration was 1.5 times that after the initial dose. Cmax and AUC were higher in cohort 2 than in cohort 1 in a dose-dependent manner. Regarding the regimen of meclizine 12.5 and 25 mg in patients < 20 kg and ≥ 20 kg, respectively, the average (95% CI) AUC0-24h was 1270 (1100-1440) ng·h/mL. Compartment models demonstrated that the plasma concentration of meclizine achieved at a steady state after the 14th administration. Long-term administration of meclizine 12.5 or 25 mg/day is recommended for phase 2 clinical trials in children with ACH.

One-Year Outcomes of Oral Treatment With Alga Capsules Containing Low Levels of 9-cis-ß-Carotene in RDH5-Related Fundus Albipunctatus.

PURPOSE: This study aimed to clarify the effect of 1-year oral treatment with 9-cis-ß-carotene-rich alga Dunaliella bardawil (Dunaliella supplementation) using full-field electroretinography (ERG) in patients with RDH5-related fundus albipunctatus (FAP). DESIGN: Prospective, interventional case series. PARTICIPANTS: The study included 12 patients (23 eyes) with RDH5-related FAP. METHODS: Twelve patients (23 eyes) with RDH5-related FAP received Dunaliella supplementation (total daily dose of ß-carotene was 74.0 mg, comprising 28.4 mg 9-cis-ß-carotene and 45.6 mg all-trans-ß-carotene at a ratio of 1:1.6) for 1 year and underwent ophthalmic examinations, including full-field ERG at baseline, 3 months, and 1 year after the initial treatment. MAIN OUTCOME MEASURES: The main outcome was changes in the amplitudes of responses of full-field ERG before and after treatment. A linear mixed-effects model was used to evaluate the adjusted mean difference between the amplitude of each response pretreatment and posttreatment. RESULTS: Prolonged dark adaptation (DA) responses at 3 months revealed a significant impairment in the b-wave of DA 0.01 (adjusted mean difference, -34.7, 95% CI, -66.8 to -2.73, P = .041) and a-wave of DA 3.0 (-29.0, 95% CI, -50.6 to -7.41, P = .013) and DA 10.0 (-40.4, 95% CI, -67.8 to -13.0, P = .007), which were also observed at 1 year. Additionally, prolonged DA and light adaptation (LA) responses revealed statistically significant impairment at 1 year in the b-wave of DA 3.0 (-43.8, 95% CI, -82.9 to -4.78, P = .035), DA 10.0 (-59.7, 95% CI, -101.8 to -17.61, P = .009), LA 3.0 (-7.31, 95% CI, -13.6 to -1.04, P = .029), and LA 3.0 flicker (-7.53, 95% CI, -12.7 to -2.34, P = .007). CONCLUSIONS: Our study results suggest that Dunaliella supplementation comprising low levels of 9-cis-ß-carotene compared with those reported in a previous study (1:1 ratio) adversely affects ERG amplitudes in patients with RDH5-related FAP.

Blockade of glucagon increases muscle mass and alters fiber type composition in mice deficient in proglucagon-derived peptides.

AIMS/INTRODUCTION: Glucagon is secreted from pancreatic α-cells and plays an important role in amino acid metabolism in liver. Various animal models deficient in glucagon action show hyper-amino acidemia and α-cell hyperplasia, indicating that glucagon contributes to feedback regulation between the liver and the α-cells. In addition, both insulin and various amino acids, including branched-chain amino acids and alanine, participate in protein synthesis in skeletal muscle. However, the effect of hyperaminoacidemia on skeletal muscle has not been investigated. In the present study, we examined the effect of blockade of glucagon action on skeletal muscle using mice deficient in proglucagon-derived peptides (GCGKO mice). MATERIALS AND METHODS: Muscles isolated from GCGKO and control mice were analyzed for their morphology, gene expression and metabolites. RESULTS: GCGKO mice showed muscle fiber hypertrophy, and a decreased ratio of type IIA and an increased ratio of type IIB fibers in the tibialis anterior. The expression levels of myosin heavy chain (Myh) 7, 2, 1 and myoglobin messenger ribonucleic acid were significantly lower in GCGKO mice than those in control mice in the tibialis anterior. GCGKO mice showed a significantly higher concentration of arginine, asparagine, serine and threonine in the quadriceps femoris muscles, and also alanine, aspartic acid, cysteine, glutamine, glycine and lysine, as well as four amino acids in gastrocnemius muscles. CONCLUSIONS: These results show that hyperaminoacidemia induced by blockade of glucagon action in mice increases skeletal muscle weight and stimulates slow-to-fast transition in type II fibers of skeletal muscle, mimicking the phenotype of a high-protein diet.

NOTCH2NLC GGC repeat expansion causes retinal pathology with intranuclear inclusions throughout the retina and causes visual impairment.

The retinal pathology of genetically confirmed neuronal intranuclear inclusion disease (NIID) is yet unknown. We report the ocular findings in four NIID patients with NOTCH2NLC GGC repeat expansion to investigate the pathology of retinopathy. All four NIID patients were diagnosed by skin biopsy and NOTCH2NLC GGC repeat analysis. Ocular findings in patients with NIID were studied using fundus photographs, optical coherence tomographic images (OCT), and full-field electroretinograms (ERGs). The histopathology of the retina was studied on autopsy samples from two cases with immunohistochemistry. All patients had an expansion of the GGC repeat (87-134 repeats) in the NOTCH2NLC. Two patients were legally blind and had been diagnosed with retinitis pigmentosa prior to the diagnosis of NIID and assessed with whole exome sequencing to rule out comorbidity with other retinal diseases. Fundus photographs around the posterior pole showed chorioretinal atrophy in the peripapillary regions. OCT showed thinning of the retina. ERGs showed various abnormalities in cases. The histopathology of autopsy samples showed diffusely scattered intranuclear inclusions throughout the retina from the retinal pigment epithelium to the ganglion cell layer, and optic nerve glial cells. And severe gliosis was observed in retina and optic nerve. The NOTCH2NLC GGC repeat expansion causes numerous intranuclear inclusions in the retina and optic nerve cells and gliosis. Visual dysfunction could be the first sign of NIID. We should consider NIID as one of the causes of retinal dystrophy and investigate the GGC repeat expansion in NOTCH2NLC.

A mild form of POC1B-associated retinal dystrophy with relatively preserved cone system function.

PURPOSE: Biallelic variants in POC1B are rare causes of autosomal recessive cone dystrophy associated with generalized cone system dysfunction. In this report, we describe the clinical characteristics of a Japanese male patient with POC1B-associated retinopathy with relatively preserved cone system function. METHODS: We performed whole-exome sequencing (WES) to identify the disease-causing variants and a comprehensive ophthalmic examination, including full-field and multifocal electroretinography (ffERG and mfERG). RESULTS: Our WES analysis identified novel compound heterozygous POC1B variants (p.Arg106Gln and p.Arg452Ter) in the patient. His unaffected mother carried the p.Arg452Ter variant heterozygously. The patient experienced decreased visual acuity in his 50s. At the age of 63, his corrected visual acuity was 20/22 in the right and 20/20 in the left eye. Fundus and fundus autofluorescence images for each eye showed no remarkable finding, except for a subtle hyperautofluorescent spot in the fovea of the left eye. Cross-sectional optical coherence tomography demonstrated blurred but a relatively preserved ellipsoid zone. The ffERG showed that amplitudes of rod and standard-flash responses were within the reference range, whereas the cone and light-adapted 30-Hz flicker amplitudes were close to, or slightly below, the reference range. The mfERG revealed substantially reduced responses with relative preservation of central function. CONCLUSIONS: We reported the case of an older patient with POC1B-associated retinopathy, demonstrating late-onset visual decrease, good visual acuity, and relatively preserved cone system function. The disease condition was much milder than previously reported in patients with POC1B-associated retinopathy.

A light-gated cation channel with high reactivity to weak light.

The cryptophyte algae, Guillardia theta, possesses 46 genes that are homologous to microbial rhodopsins. Five of them are functionally light-gated cation channelrhodopsins (GtCCR1-5) that are phylogenetically distinct from chlorophyte channelrhodopsins (ChRs) such as ChR2 from Chlamydomonas reinhardtii. In this study, we report the ion channel properties of these five CCRs and compared them with ChR2 and other ChRs widely used in optogenetics. We revealed that light sensitivity varied among GtCCR1-5, in which GtCCR1-3 exhibited an apparent EC50 of 0.21-1.16 mW/mm2, similar to that of ChR2, whereas GtCCR4 and GtCCR5 possess two EC50s, one of which is significantly small (0.025 and 0.032 mW/mm2). GtCCR4 is able to trigger action potentials in high temporal resolution, similar to ChR2, but requires lower light power, when expressed in cortical neurons. Moreover, a high light-sensitive response was observed when GtCCR4 was introduced into blind retina ganglion cells of rd1, a mouse model of retinitis pigmentosa. Thus, GtCCR4 provides optogenetic neuronal activation with high light sensitivity and temporal precision.

Assessment of factors affecting flicker ERGs recorded with RETeval from data obtained from health checkup screening.

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 (ß = 0.28), the age (ß = 0.24), and the blood sugar level (ß = 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 (ß = -0.092), the platelet count (ß = 0.099), and the creatinine level (ß = -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.

A Japanese boy with Bardet-Biedl syndrome caused by a novel homozygous variant in the ARL6 gene who was initially diagnosed with retinitis punctata albescens: A case report.

PURPOSE: Bardet-Biedl Syndrome (BBS) is an autosomal recessive systemic disorder characterized by retinitis pigmentosa, polydactyly, obesity, intellectual disability, renal impairments, and hypogonadism. The purpose of this study was to determine the ocular characteristics of a boy with BBS caused by a novel homozygous variant in the ARL6 (alternative named BBS3) gene who had been originally diagnosed with retinitis punctata albescens. METHODS: This was an observational case study. The patient underwent ophthalmological examinations, electroretinography, and genetic analyses using whole-exome sequencing. RESULTS: A 7-year-old boy was examined in our hospital with complaints of a progressive reduction of his visual acuity and night blindness in both eyes. There was no family history of eye diseases and no consanguineous marriage. Fundus examinations showed numerous white spots in the deep retina and retinal pigment epithelium. Fundus autofluorescence showed hypofluorescence consistent with these spots. Both the scotopic and photopic components of the full-field electroretinographies were non-detectable. Based on these clinical findings, this boy was suspected to have retinitis punctata albescens. Subsequent genetic testing using whole-exome sequencing revealed a novel homozygous variants in the ARL6/BBS3 gene (NM_001278293.3:c.528G>A, (p.Trp176Ter)). A systemic examination by the pediatric department revealed that this boy had a history of a surgical excision of polydactyly on his left foot when he was born, and that he was mildly obese. There were no prominent intellectual or gonadal dysfunctions, no craniofacial or dental abnormalities, no congenital heart disease, and no hearing impairment. He was then clinically and genetically diagnosed with BBS. CONCLUSION AND IMPORTANCE: In children with night blindness and progressive visual dysfunction, it is important for ophthalmologists to consult clinical geneticists and pediatricians to rule out the possibility of systemic diseases such as BBS.

A case of herpes zoster ophthalmicus with optic neuritis of the total length of the optic nerve in the orbital space and ischemic optic neuropathy.

Purpose: We herein report a case of optic neuritis and ischemic optic neuropathy associated with herpes zoster ophthalmicus and decreased visual acuity. Observations: A 65-year-old man with no special medical history had a headache on the right side in December 2019, and a few days later, a facial rash appeared on the same side. A dermatologist diagnosed him with herpes zoster ophthalmicus and started antiviral drug therapy. On the same day, he was referred to a local ophthalmologist and was found to have inflammatory signs in his right cornea and conjunctiva. The next day, when he visited the ophthalmologist again, he had decreased visual acuity, optic disc swelling, and fundus hemorrhaging in his right eye, so he was referred to our department. At the first visit to our department, his best-corrected visual acuity was light sense OD, 1.0 OS. His right fundus showed optic disc swelling, spotted fundus hemorrhaging, and dilation/tortuosity of the retinal vein. Fluorescein angiography showed the near absence of optic disc filling as well as delayed retinal vein perfusion in his right eye, and magnetic resonance imaging confirmed high signals in the total length of the right optic nerve in the orbital space using the short inversion-time inversion recovery method. Based on these findings, we diagnosed him with optic neuritis and ischemic optic neuropathy associated with inflammation of the orbital part caused by herpes zoster ophthalmicus. We started systemic administration of antiviral drugs (acyclovir) and oral steroid. However, after treatment, his visual acuity improved only to hand motion OD, and the fundus appearance was ultimately optic atrophy OD. Conclusion and Importance: Various complications can occur with herpes zoster ophthalmicus, however, few reports have described cases of herpes zoster ophthalmicus associated with optic neuritis and ischemic optic neuropathy. Therefore, there is no consensus concerning the ideal treatment for these conditions. By referencing cases involving issues such as orbital apex syndrome and optic neuritis caused by herpes zoster ophthalmicus, antiviral drugs and oral steroids were administered, but the prognosis of the visual acuity was poor.

Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole-exome sequencing.

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.

ASSESSMENTS OF MACULAR FUNCTION BY FOCAL MACULAR ELECTRORETINOGRAPHY AND STATIC PERIMETRY IN EYES WITH RETINITIS PIGMENTOSA.

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 µ V) 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.

Likely pathogenic structural variants in genetically unsolved patients with retinitis pigmentosa revealed by long-read sequencing.

Despite the successful identification of causative genes and genetic variants of retinitis pigmentosa (RP), many patients have not been molecularly diagnosed. Our recent study using targeted short-read sequencing showed that the proportion of carriers of pathogenic variants in EYS, the cause of autosomal recessive RP, was unexpectedly high in Japanese patients with unsolved RP. This result suggested that causative genetic variants, which are difficult to detect by short-read sequencing, exist in such patients. Using long-read sequencing technology (Oxford Nanopore), we analysed the whole genomes of 15 patients with RP with one heterozygous pathogenic variant in EYS detected in our previous study along with structural variants (SVs) in EYS and another 88 RP-associated genes. Two large exon-overlapping deletions involving six exons were identified in EYS in two patients with unsolved RP. An analysis of an independent patient set (n=1189) suggested that these two deletions are not founder mutations. Our results suggest that searching for SVs by long-read sequencing in genetically unsolved cases benefits the molecular diagnosis of RP.