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.

Clinical course of two siblings with potassium voltage-gated channel modifier subfamily V member 2 (KCNV2)-associated retinopathy.

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

Electroretinographic abnormalities in Alport syndrome with a novel COL4A5 truncated variant (p.Try20GlyfsTer19).

PURPOSE: Alport syndrome comprises a heterogeneous group of inherited kidney diseases that are associated with ocular complications. In this study, we aimed to detail the clinical characteristics of a patient with X-linked Alport syndrome. METHODS: We performed next-generation sequencing (NGS) with hybridization capture to identify the disease-causing variant of Alport syndrome and a comprehensive ophthalmic examination, including full-field electroretinography (FF-ERG). RESULTS: Genetic testing using NGS with hybridization capture revealed a novel hemizygous variant [c.51_52delGA (p.Trp20GlyfsTer19)] in exon 1 of COL4A5. The patient underwent cataract surgery in both eyes because of decreased visual acuity and photophobia. The best-corrected visual acuity improved from 0.9 and 0.7 in the right and left eyes, respectively, to 1.5 in both eyes. Anterior-segment optical coherence tomography (OCT) revealed anterior and posterior lenticonus. Fundus photographs showed central and peripheral fleck retinopathy. Wide-field fundus autofluorescence (AF) imaging showed mottled hyper- and hypo-AF in the peripheral retina, which was consistent with peripheral fleck retinopathy. Furthermore, OCT revealed thinning of the inner retinal layers, especially at the temporal macular, but the outer retinal layers were preserved. Ganglion cell analysis showed no progression for 5 years. FF-ERG was performed at 41 (phakia) and 46 (pseudophakia) years of age. The amplitudes of dark-adapted (DA) and light-adapted (LA) responses showed selective b-wave abnormalities. The b/a-wave ratios of DA 3.0 were 1.22 and 1.16 in the right and left eyes, respectively. The amplitudes of DA 3.0 oscillatory potentials (OP) were reduced. Five years later, the amplitudes of DA and LA responses revealed no remarkable changes, except for an OP wave of DA 3.0, which was substantially reduced. CONCLUSIONS: Our findings revealed electroretinographic abnormalities in a patient with Alport syndrome, which predominantly indicated impairment of the inner retina. Notably, little short-term progression was observed.

Bardet-Biedl syndrome associated with novel compound heterozygous variants in BBS12 gene.

BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by 6 primary features of rod-cone dystrophy, central obesity, polydactyly, cognitive impairment, hypogonadism and/or genitourinary malformations, and kidney abnormalities. At least 21 genes associated with BBS have been reported. To date, BBS associated with BBS12 variants has never been described in the Japanese population. We report a Japanese infant female with BBS with compound heterozygous BBS12 variants. METHODS: In addition to the pediatric examination, fundus photography, full-field electroretinogram(ffERG) and whole exome sequencing (WES) were underwent. RESULTS: The infant exhibited obesity, polydactyly, cognitive impairment, genitourinary malformations, and kidney dysfunction. At the age of 2 years, ffERG revealed severe reduction in both rod- and cone-mediated electroretinographic responses consistent with a severe form of rod-cone dystrophy, with minimal retinal abnormalities. WES revealed novel compound heterozygous BBS12 variants (c.591T > A, p.Tyr197* and c.1372dupA, p.Thr458Asnfs*5) in the infant. Her parents carried each of the variants, as confirmed by Sanger sequencing. CONCLUSIONS: The current observations will contribute to an expanded understanding of genotype-phenotype associations in BBS12-associated BBS.

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.

Elective neck dissection for T3-T4N0 laryngeal carcinoma: evidence from Japan's National Head and Neck Cancer Registry.

BACKGROUND: Although total laryngectomy is the standard treatment for advanced laryngeal cancer, the significance of elective neck dissection (END) for N0 laryngeal cancer remains unclear in Japan, which is an aging society. METHODS: We conducted a retrospective nationwide observational study on patients with T3-T4N0 laryngeal squamous cell carcinoma treated with curative total laryngectomy from 2011 to 2018 in Japan. RESULTS: A total of 1,218 patients were analyzed. The median patient age was 72 years, with 735 cases of T3N0 and 483 cases of T4N0. END was performed on the affected side in 850 patients (70%) and on the contralateral side in 502 patients (41.2%). END on the affected side was omitted in patients aged > 80 years (40.4%) and in patients with an advanced performance status. The occult lymph-node metastasis rate did not differ by age (18.8%-19.6%); it tended to increase chronologically from 2011 (11.1%) and was higher in cT4a (22.5%) and pT4a (24.3%) cases. In this study, coherent clinical information and follow-up data were available for 252 patients. Both univariate and multivariate analyses showed no significant prognostic factors for overall survival or recurrence-free survival for either affected or contralateral END. Older age and subglottic location were poor prognostic factors, but death due to factors other than laryngeal cancer could not be ignored in older patients. CONCLUSION: Omission of END during laryngectomy for T3-T4N0 laryngeal cancer is acceptable for older patients who want their operation to be completed in a short time.

The Structural Abnormalities Are Deeply Involved in the Cause of RPGRIP1-Related Retinal Dystrophy in Japanese Patients.

Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy. RPGRIP1-related LCA accounts for 5-6% of LCA. We performed whole-exome sequencing and whole-genome sequencing (WGS) on 29 patients with clinically suspected LCA and examined ophthalmic findings in patients with biallelic pathogenic variants of RPGRIP1. In addition to five previously reported cases, we identified five cases from four families with compound heterozygous RPGRIP1 variants using WGS. Five patients had null variants comprising frameshift variants, an Alu insertion, and microdeletions. A previously reported 1339 bp deletion involving exon 18 was found in four cases, and the deletion was relatively prevalent in the Japanese population (allele frequency: 0.002). Microdeletions involving exon 1 were detected in four cases. In patients with RPGRIP1 variants, visual acuity remained low, ranging from light perception to 0.2, and showed no correlation with age. In optical coherence tomography images, the ellipsoid zone (EZ) length decreased with age in all but one case of unimpaired EZ. The retinal structure was relatively preserved in all cases; however, there were cases with great differences in visual function compared to their siblings and a 56-year-old patient who still had a faint EZ line. Structural abnormalities may be important genetic causes of RPGRIP1-related retinal dystrophy in Japanese patients, and WGS was useful for detecting them.

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.

Clinical characterization of autosomal dominant retinitis pigmentosa with NRL mutation in a three-generation Japanese family.

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.

Polypoidal choroidal vasculopathy in a patient with DMPK-associated myotonic dystrophy.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disorder that affects multiple organs, including the muscle and eye, caused by a CTG triplet expansion of the 3' untranslated region (UTR) of the DMPK gene. Cataracts and retinal degeneration are major eye complications in patients with DM1. We reported the case of a Japanese patient with DM1 who exhibited submacular hemorrhage unilaterally, rarely complicating DM1. CASE REPORT: A 56-year-old woman presented with loss of visual acuity in the left eye (LE). The patient was diagnosed with DM1, who carried expanded CTG repeats (1100) of the 3' UTR of DMPK. Her corrected visual acuities were 20/100 and 20/2000 in the right eye (RE) and LE, respectively. Cataracts were observed in both eyes. Fundoscopy and angiography revealed submacular hemorrhage in the LE due to polypoidal choroidal vasculopathy (PCV, also known as aneurysmal type 1 neovascularization). The patient underwent intravitreal injections of an anti-vascular endothelial growth factor drug and sulfur hexafluoride gas in the LE. Full-field electroretinography was performed, showing that the rod and standard-flash responses were reduced to 50% and below 10% in the RE and LE, whereas the cone and 30-Hz flicker responses were reduced to 40-50% and 15-20% in the RE and LE, respectively, compared with the controls. Multifocal electroretinography revealed that the overall responses were extinguished in the LE and considerably attenuated in the RE. CONCLUSIONS: This is the first patient with DM1 complicated with PCV. Widespread retinal dysfunction may be associated with expanded CTG repeats, which is significantly longer than the mean repeat number of patients with DM1.

The second Japanese family with Malattia Leventinese/Doyne honeycomb retinal dystrophy.

PURPOSE: To describe the clinical and genetic findings of patients in the second Japanese family with Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD). METHODS: Two patients (a 41-year-old male proband and his third son) underwent comprehensive ophthalmic examinations, including full-field and multifocal electroretinography (ERG). Sanger sequencing was performed to detect an EFEMP1 gene variant (p.Arg345Trp), which was identified as the only causative pathogenic variant. RESULTS: Genetic analysis revealed that both patients carried the heterozygous variant, but the other unaffected family members did not. Although the proband exhibited innumerable radially distributed drusen in both the posterior poles and good visual acuity at initial presentation, bilateral choroidal neovascularization (CNV) developed during the 15-year follow-up. The proband received 15 intravitreal anti-vascular endothelial growth factor (VEGF) injections in the left eye (LE) and two injections in the right eye (RE). At 56 years of age, his decimal best-corrected visual acuity was 0.1 and 1.2 in the LE and RE, respectively. Full-field ERG showed that while the rod and combined responses were within normal amplitudes, the cone and 30-Hz flicker responses had slightly decreased amplitudes. Multifocal ERG revealed attenuated central responses in the LE and decreased temporal responses in the RE. In the 20-year-old son, multifocal ERG showed normal responses in both eyes. CONCLUSION: This is the first report of ML/DHRD in a patient who developed bilateral CNV and received anti-VEGF treatment in both eyes. Although multifocal ERG exhibited worsening of macular function, the generalized photoreceptor function was preserved until middle age.

Clinical findings in eyes with BEST1-related retinopathy complicated by choroidal neovascularization.

PURPOSE: To determine the characteristics of eyes diagnosed with Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB) complicated by choroidal neovascularization (CNV). METHODS: This was a retrospective, multicenter observational case series. Fourteen genetically confirmed BVMD patients and 9 ARB patients who had been examined in 2 ophthalmological institutions in Japan were studied. The findings in a series of ophthalmic examinations including B-scan optical coherence tomography (OCT) and OCT angiography (OCTA) were reviewed. RESULTS: CNV was identified in 5 eyes (17.9%) of BVMD patients and in 2 eyes (11.1%) of ARB patients. Three of 5 eyes with BVMD were classified as being at the vitelliruptive stage and 2 eyes at the atrophic stage. The CNV in 2 BVMD eyes were diagnosed as exudative because of acute visual acuity reduction, retinal hemorrhage, and intraretinal fluid, while the CNV in 3 BVMD eyes and 2 ARB eyes were diagnosed as non-exudative. The visual acuity of the two eyes with exudative CNV did not improve despite anti-VEGF treatments. None of the eyes with non-exudative CNV had a reduction of their visual acuity for at least 4 years. All of the CNV were located within hyperreflective materials which were detected in 16 eyes (57.1%) of the BVMD eyes and in 7 eyes (38.9%) of the ARB eyes. CONCLUSIONS: CNV is a relatively common complication in BEST1-related retinopathy in Asian population as well. The prognosis of eyes with exudative CNV is not always good, and OCTA can detect CNV in eyes possessing hyperreflective materials.

Case Report: Improved Choroidal Circulation in a Patient with Unilateral Acute Idiopathic Maculopathy.

SIGNIFICANCE: Unilateral acute idiopathic maculopathy is a rare retinochoroidal disorder, the cause of which is unknown. Multimodal retinal imaging obtained in this case suggests that the cause of unilateral acute idiopathic maculopathy is impaired choroidal circulation. PURPOSE: This study aimed to report a patient with unilateral acute idiopathic maculopathy who showed improvement of choroidal circulation over time in optical coherence tomography angiography images. CASE REPORT: A 33-year-old woman with a prodromal flu-like illness noticed a sudden central visual field abnormality in the right eye. Five days after the onset, best-corrected visual acuity was 0.15 in the right eye. Fundus photography showed a yellowish lesion at the macula in the right eye. Optical coherence tomography showed a blurred ellipsoid zone and a thickened retinal pigment epithelium at the fovea and a disrupted/blurred ellipsoid zone and retinal pigment epithelium at the parafovea. Optical coherence tomography angiography segmentation of the choriocapillaris revealed a hypointense region at the fovea with a hyperintense region surrounding it. One week after the onset, best-corrected visual acuity was improved from 0.15 to 2.0 in the right eye. Furthermore, the yellowish macula lesion shrank, and the outer retinal layers showed improvement in optical coherence tomography. Optical coherence tomography angiography showed reduction of the hypointense region and enlargement of the hyperintense region. Approximately 1 year after the onset, the yellowish lesion was faded. Optical coherence tomography revealed an almost normal ellipsoid zone but a thickened interdigitation zone. Optical coherence tomography angiography also revealed an apparent hyperintense instead of the hypointense region and increased choroidal blood flow. CONCLUSIONS: The current patient showed a gradual recovery of choroidal circulation and outer retinal layer morphology 1 year after the onset of unilateral acute idiopathic maculopathy. Optical coherence tomography angiography findings indicated that the primary cause of unilateral acute idiopathic maculopathy was impaired choroidal circulation, and choroidal vessels improved morphologically over the disease course.

New variants and in silico analyses in GRK1 associated Oguchi disease.

Biallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify disease causing GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients' genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function in-silico.

Broad locations of antigenic regions for anti-TRPM1 autoantibodies in paraneoplastic retinopathy with retinal ON bipolar cell dysfunction.

PURPOSE: Cancer-associated retinal ON bipolar cell dysfunction (CARBD), which includes melanoma-associated retinopathy (MAR), has been reported to be caused by autoantibodies against the molecules expressed in ON bipolar cells, including TRPM1. The purpose of this study was to determine the antigenic regions of the autoantibodies against TRPM1 in the sera of CARBD patients, in whom we previously detected anti-TRPM1 autoantibodies. METHODS: The antigenic regions against TRPM1 in the sera of eight CARBD patients were examined by Western blots using HEK293T cells transfected with the plasmids expressing FLAG-tagged TRPM1 fragments. The clinical course of these patients was also documented. RESULTS: The clinical course differed among the patients. The electroretinograms (ERGs) and symptoms were improved in three patients, deteriorated in one patient, remained unchanged for a long time in one patient, and were not followable in three patients. Seven of the eight sera possessed multiple antigenic regions: two sera contained at least four antigen recognition regions, and three sera had at least three regions. The antigen regions were spread over the entire TRPM1 protein: five sera in the N-terminal intracellular domain, six sera in the transmembrane-containing region, and six sera in the C-terminal intracellular domain. No significant relationship was observed between the location of the antigen epitope and the patients' clinical course. CONCLUSIONS: The antigenic regions of anti-TRPM1 autoantibodies in CARBD patients were present not only in the N-terminal intracellular domain, which was reported in an earlier report, but also in the transmembrane-containing region and in the C-terminal intracellular domain. In addition, the antigenic regions for TRPM1 were found to vary among the CARBD patients examined, and most of the sera had multiple antigenic regions.

Multifunctional Traceable Liposomes with Temperature-Triggered Drug Release and Neovasculature-Targeting Properties for Improved Cancer Chemotherapy.

Poor distribution of nanocarriers at the tumor site and insufficient drug penetration into the tissue are major challenges in the development of effective and safe cancer therapy. Here, we aim to enhance the therapeutic effect of liposomes by accumulating doxorubicin-loaded liposomes at high concentrations in and around the tumor, followed by heat-triggered drug release to facilitate low-molecular-weight drug penetration throughout the tumor. A cyclic RGD peptide (cRGD) was incorporated into liposomes decorated with a thermosensitive polymer that allowed precise tuning of drug release temperature (i.e., Polymer-lip) to develop a targeted thermosensitive liposome (cRGD-Polymer-lip). Compared with conventional thermosensitive liposomes, cRGD-Polymer-lip enhanced the binding of liposomes to endothelial cells, leading to their accumulation at the tumor site upon intravenous administration in tumor-bearing mice. Drug release triggered by local heating strongly inhibited tumor growth. Notably, tumor remission was achieved via multiple administrations of cRGD-Polymer-lip and heat treatments. Thus, combining the advantages of tumor neovascular targeting and heat-triggered drug release, these liposomes offer high potential for minimally invasive and effective cancer chemotherapy.

Novel biallelic TRPM1 variants in an elderly patient with complete congenital stationary night blindness.

BACKGROUND: Little is known about whether patients with complete congenital stationary night blindness (CSNB) maintain visual function throughout their lifetime. The purpose of this report was to describe clinical and genetic features of an elderly female patient with complete CSNB that we followed for 5 years. METHODS: Molecular genetic analysis using whole-exome sequencing (WES) was performed to detect disease-causing variants. We performed a comprehensive ophthalmic examination including full-field electroretinography (ERG). RESULTS: In the patient, WES identified two novel variants (c.1034delT; p.Phe345SerfsTer16 and c.1880T>A; p.Met627Lys) in the TRPM1 gene. Her unaffected daughter has one of the variants. The patient reported that her visual acuity has remained unchanged since elementary school. At the age of 68 years old, fundus and fundus autofluorescence imaging showed no remarkable findings except for mild myopic changes. Goldmann perimetry showed preserved visual fields with all V-4e, I-4e, I-3e and I-2e isopters. Optical coherence tomography demonstrated preserved retinal thickness and lamination. Rod ERG showed no response; bright-flash ERG showed an electronegative configuration with minimally reduced a-waves, and cone and 30-Hz flicker ERG showed minimally reduced responses. Overall, the ERG findings of ON bipolar pathway dysfunction were consistent with complete CSNB. CONCLUSIONS: This is the oldest reported patient with complete CSNB and biallelic TRPM1 variants. Our ophthalmic findings suggest that some patients with TRPM1-related CSNB may exhibit preserved retinal function later in life.

Vitamin A deficiency after prolonged intake of an unbalanced diet in a Japanese hemodialysis patient.

BACKGROUND: In industrialized countries, vitamin A deficiency (VAD) is extremely rare, except association with bariatric surgeries and hepatobiliary disorders. It is unusual that VAD develops during hemodialysis due to reduced glomerular filtration of vitamin A-binding protein. We reported the case of a 58-year-old Japanese male hemodialysis patient diagnosed with VAD. CASE PRESENTATION: The patient undergoing hemodialysis for more than 15 years presented with progressive photophobia and night blindness and was ophthalmologically examined. He denied a history of cancer or hepatobiliary disease and reported that he loved eating prepackaged noodle bowls and foods, with prolonged low intake of fruits/vegetables. He had good visual acuity. Fundus images showed numerous white dots in the midperipheral retinae, but no degenerative changes. In baseline full-field electroretinography (ERG), b-wave responses were extremely reduced in rod ERG, a-wave amplitudes in standard-flash/strong-flash ERG were reduced to 20-25% of our controls, a- and b-wave amplitudes in cone ERG were reduced to 40-50% of the controls. Whole-exome sequencing identified no pathogenic variant for any inherited retinal disorder. He was diagnosed with VAD because of reduced serum vitamin A levels and treated with retinol palmitate. Two months after treatment commencement, the serum vitamin A level was within the normal range. Full-field ERG showed that the scotopic ERG responses markedly improved compared with baseline. CONCLUSIONS: This is the first report of VAD associated with undernutrition in the Japanese hemodialysis population.

A new PDE6A missense variant p.Arg544Gln in rod-cone dystrophy.

PURPOSE: Thus far, only one Japanese patient with autosomal recessive rod-cone dystrophy (AR-RCD) associated with the phosphodiesterase 6A gene (PDE6A) has been reported. The purpose of this study was to analyze the clinical features of a Japanese female patient with AR-RCD with a novel missense variant in PDE6A. METHODS: We performed whole-exome sequencing (WES) to identify the disease-causing variant and a comprehensive ophthalmic examination including full-field electroretinography (ERG). RESULTS: WES analysis revealed that the patient carried a novel homozygous missense variant (c.1631G > A; p.Arg544Gln) in PDE6A. Her unaffected parents carried the heterozygous variant. The patient reported night blindness in her early 20 s. At the age of 25 years, she underwent a comprehensive ophthalmic examination. Her corrected visual acuity was 20/13 in the right and 20/10 in the left eyes. Fundus images showed degenerative changes with bone spicule pigmentation in the mid-peripheral retina, and peripheral retinal vessels were not attenuated. Ultra-wide-field fundus autofluorescence images demonstrated large hypoautofluorescent regions corresponding to the degenerative changes, surrounded by hyperautofluorescence. Cross-sectional optical coherence tomography demonstrated a preserved ellipsoid zone and retinal thickness in the center of the macula, with perifoveal atrophy. ERG responses were subnormal, revealing that rod-mediated responses were more affected than cone-mediated responses, consistent with findings observed in RCD. CONCLUSIONS: This is the second case of a patient with AR-RCD associated with PDE6A in the Japanese population. These findings will contribute to a better clinical understanding of PDE6A-associated RCD and valuable insights for gene therapy trials.

Transient electroretinographic abnormalities that mimic those of KCNV2 retinopathy: a case report.

PURPOSE: The purpose of this report was to describe the case of a 68-year-old male patient with stage IV colon cancer who exhibited electroretinographic abnormalities that are similar to those of KCNV2 retinopathy. METHODS: The patient presenting with photophobia, reduced visual acuity, and poor general conditions, the onset of which occurred ten days before presentation, was examined using fundoscopy, full-field electroretinography, blood tests, and abdominal computed tomography. RESULTS: The patient's decimal best-corrected visual acuity (BCVA) was 0.4 in each eye. Fundoscopy showed bull's eye-like maculopathy in both eyes. Electroretinographic findings were similar to the characteristic findings of KCNV2 retinopathy: Rod electroretinogram showed delayed and preserved b-wave amplitudes; bright-flash electroretinogram showed double troughs of a-waves; b/a ratios shown by bright-flash electroretinogram were higher than those shown by standard-flash electroretinogram; and both cone and 30-Hz flicker electroretinograms showed extinguished responses. His serum potassium level increased to 6.2 mmol/L (normal range 3.6-4.8 mmol/L) owing to hydronephrosis resulting from disseminated carcinoma. After performing an emergency surgery to treat this condition, the serum potassium level immediately decreased to a normal range. Eleven days after presentation, rod and standard/bright-flash electroretinography showed improvement in the implicit time of the rod b-waves and the a-waves. Unexpectedly, the responses recorded by cone and 30-Hz flicker electroretinography became normal. The symptoms and maculopathy disappeared, and his BCVA improved to 1.2. CONCLUSIONS: The abnormal electroretinographic findings might be associated with the transient increase in serum potassium level.