Shinji Ueno

Purpose: To evaluate the prevalence of achromatopsia (ACHM) associated with variants of RPGRIP1 , especially c.2710+374_2895+78del ( RPGRIP1 -ex18-DEL), and to confirm that these phenotypes were consistent with ACHM in Japanese patients. Methods: This retrospective observational study involved a review of medical records from 52 patients across 47 Japanese families; all clinically diagnosed with ACHM. Results: Causative variants for ACHM were identified in 39 families through whole-exome sequencing, whole-genome sequencing, or polymerase chain reaction: PDE6C (13 families), RPGRIP1 -ex18-DEL (11 families), CNGA3 (11 families), CNGB3 (2 families), and GNAT2 (2 families). Patients with ACHM associated with RPGRIP1 -ex18-DEL variants did not exhibit significant difference in phenotype, including spherical equivalent refractive error, best-corrected visual acuity (BCVA), fundus appearance, ellipsoid zone grading of optical coherence tomography, and fundus autofluorescence pattern, compared with those with variants in CNGA3 or PDE6C at baseline (all, P > 0.05). For five patients with ACHM with RPGRIP1 -ex18-DEL variants, no change in BCVA or ellipsoid zone grading was noted over a follow-up period of >10 years (all, P > 0.05). Conclusion: Variants in RPGRIP1 -ex18-DEL are unique hotspots with a high prevalence among Japanese patients with ACHM. Clinical findings in these patients are consistent with those in patients with ACHM from other causative genes.

Background Recording electroretinograms (ERGs) in eyes with intraocular gas tamponade is difficult, and the mechanism remains unclear. We evaluated the effect of intraocular gas on ERGs by comparing recordings at different body positions. Methods This study included 31 patients who underwent vitrectomy with sulfur hexafluoride (SF6) or air tamponade at Hirosaki University (between May 2023 and October 2024). The patients included those with retinal detachment (25 patients), macular holes (4 patients), and epiretinal membranes (2 patients). ERGs were recorded using skin electrodes when approximately 50% of the vitreous cavity was filled with the intraocular gas. ERGs were recorded in sitting, supine, and face-down positions. Amplitudes and latencies of the LA 3 b-wave and LA 30 Hz were compared using the Wilcoxon signed-rank and Friedman tests. Results In the gas-filled eyes, amplitudes in the face-down position were smaller, and latencies were longer than those in the other positions (p < 0.05). Median amplitudes in the gas-filled eyes in the sitting, supine, and face-down positions were 20.4, 19.5, and 10.1 µV for LA 3 and 14.4, 15.5, and 7.11 for LA 30 Hz, respectively; median latencies were 32.5, 33.0, and 34.3 ms for LA 3 and 30.8, 30.0, and 34.3 for LA 30 Hz, respectively. Conclusions ERG amplitudes were reduced and latencies were prolonged in the face-down position, which may be attributed to a larger retinal area being covered by intraocular gas. The gas acts as an insulator, and the gas-covered retina may not effectively generate or transmit electrical signals.

Purpose To characterize the clinical and genetic features of REEP6-associated retinopathy in 8 Japanese patients from 7 families Study design Retrospective, multicenter cohort study Methods Biallelic REEP6 variants were identified by use of whole-exome sequencing in patients with inherited retinal dystrophy (IRD). Comprehensive ophthalmic assessments were performed in all the patients. Results Among a nationwide cohort of 2011 patients with IRD, 8 patients from 7 families were found to carry biallelic REEP6 variants. Four distinct variants were identified: c.223G>A, p.Glu75Lys; c.268G>C, p.Val90Leu; c.280_281del, p.Leu94ValfsTer86 (novel frameshift), and c.598+1G>A. Five families (Families 1–5) carried the compound heterozygous p.Val90Leu and c.598+1G>A variants. The other two had either homozygous c.598+1G>A (Family 6) or compound heterozygous p.Glu75Lys/p.Leu94ValfsTer86 (Family 7). In Families 1–5, the patients exhibited relatively mild phenotypes with limited to peripheral retinal degeneration in the younger patients and gradual posterior pole involvement in the older patients. Optical coherence tomography revealed well-preserved outer retinal layers at the macula, and good visual acuity was maintained even in some of the older patients. In contrast, the 2 patients in Families 6 and 7 exhibited more severe phenotypes, including macular atrophy and visual acuity decline. Conclusions The combination of p.Val90Leu and c.598+1G>A variants was associated with a milder phenotype, supporting the hypothesis that p.Val90Leu is a hypomorphic variant. These findings expand the clinical and genetic spectra of REEP6-associated retinopathy, particularly among East Asian populations.

Purpose: Retinal arterioles are attenuated in eyes with retinitis pigmentosa, but dimensions such as lumen diameter and wall thickness have not been thoroughly investigated. The aim of the study was to determine the dimensions of reduced retinal arterioles in eyes with retinitis pigmentosa. Methods: The study included 66 patients with retinitis pigmentosa (66 eyes) and 36 control participants (36 eyes) for whom adaptive optics recordings of the retinal arteries were available. Lumen diameter and wall thickness were measured on the adaptive optics images. The correlations between arteriole dimensions and clinical parameters were determined. Results: The mean lumen diameter was significantly smaller in patients with retinitis pigmentosa than in controls, while the mean wall thickness did not differ significantly. Lumen diameter was significantly and positively correlated with the mean deviation of the Humphrey 10-2 field analyzer and ellipsoid zone width. The wall thickness and wall-to-lumen ratio were significantly and positively correlated with age and systolic blood pressure but not with mean deviation and ellipsoid zone width. Conclusion: Retinal arteriole dimensions were significantly correlated with retinal degeneration and systemic factors.

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

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.

Background: Nivolumab with modified FOLFIRINOX (mFOLFIRINOX) may have additive antitumour effects while minimising chemotherapy cytotoxicity. We assessed the efficacy and safety of nivolumab+mFOLFIRINOX in metastatic pancreatic cancer. Methods: Thirty-one treatment-naïve patients aged ≥20 years with metastatic unresectable/recurrent pancreatic cancer (≥1 measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1) and Eastern Cooperative Oncology Group 0/1 score and life expectancy ≥90 days received nivolumab (480 mg, every 4 weeks) plus mFOLFIRINOX. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS) and safety. Results: At the median follow-up of 13.4 months, the ORR was 32.3% (complete response 0%; partial response 32.3%) and the median duration of response was 7.4 (range: 3.5–21.9) months; the primary endpoint was not met. Median OS and PFS were 13.4 (95% confidence interval [CI]: 10.6–16.6) months and 7.4 (95% CI: 3.9–9.2) months, respectively. The 1-year survival rate was 54.8% (95% CI: 36.0%–70.3%). Drug-related serious adverse events were reported in 29.0% of the patients; 3.2% drug-related adverse events led to discontinuation, and none led to death within 30-day safety window. Conclusion: Nivolumab+mFOLFIRINOX was tolerable in patients with metastatic pancreatic cancer. ORR and survival were comparable to previously reported data. (JapicCTI-184230)

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 RP patients by applying the standardized variant interpretation guidelines for Japanese IRD patients (J-IRD-VI guidelines) built upon ACMG/AMP 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, all newly analyzed), 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 RP patients. This led to a genetic diagnostic rate in 38.6% of RP patients, 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 CRD patients 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 unique genetic findings for Japanese IRD patients; these findings serve as a foundation for the clinical application of gene-specific therapies.

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.