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.

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.

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.

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.

Homozygous single nucleotide duplication of SLC38A8 in autosomal recessive foveal hypoplasia: The first Japanese case report.

PURPOSE: To characterize the clinical and genetic features of a Japanese male patient with foveal hypoplasia caused by a homozygous single nucleotide duplication in the SLC38A8 gene. METHODS: We performed a comprehensive ophthalmic examination including full-field electroretinography (FF-ERG) and pattern-reversal visual evoked potentials (PR-VEPs). Whole-exome sequencing (WES) was performed to identify the disease-causing variant; Sanger sequencing was used for confirmation. RESULTS: In the WES analysis, a homozygous single nucleotide duplication (c.995dupG; p.Trp333MetfsTer35) was identified in SLC38A8 of the patient. His unaffected mother carried the variant heterozygously. The patient exhibited hyperopia, congenital nystagmus, low visual acuity, and grade 4 foveal hypoplasia. Slit-lamp examination revealed mild posterior embryotoxon and goniodysgenesis. Fundus examination revealed the absence of foveal hyperpigmentation and foveal avascularity, but there were no retinal degenerative lesions. In the FF-ERG, the amplitudes of rod ERG, standard-flash, and bright-flash ERG were within the normal range; cone-mediated responses also showed nearly normal amplitudes. The PR-VEP findings revealed delayed P100 latencies and decreased amplitudes of the P100 components, but no chiasmal misrouting. CONCLUSIONS: This report is the first report on the clinical and genetic characteristics of SLC38A8-associated foveal hypoplasia in the Japanese population. This is also the first report of normal rod- and cone-mediated responses in a patient with this disorder.

Clinical and genetic characteristics of 10 Japanese patients with PROM1-associated retinal disorder: A report of the phenotype spectrum and a literature review in the Japanese population.

Variants in the PROM1 gene are associated with cone (-rod) dystrophy, macular dystrophy, and other phenotypes. We describe the clinical and genetic characteristics of 10 patients from eight Japanese families with PROM1-associated retinal disorder (PROM1-RD) in a nationwide cohort. A literature review of PROM1-RD in the Japanese population was also performed. The median age at onset/examination of 10 patients was 31.0 (range, 10-45)/44.5 (22-73) years. All 10 patients showed atrophic macular changes. Seven patients (70.0%) had spared fovea to various degrees, approximately half of whom had maintained visual acuity. Generalized cone (-rod) dysfunction was demonstrated in all nine subjects with available electrophysiological data. Three PROM1 variants were identified in this study: one recurrent disease-causing variant (p.Arg373Cys), one novel putative disease-causing variant (p.Cys112Arg), and one novel variant of uncertain significance (VUS; p.Gly53Asp). Characteristic features of macular atrophy with generalized cone-dominated retinal dysfunction were shared among all 10 subjects with PROM1-RD, and the presence of foveal sparing was crucial in maintaining visual acuity. Together with the three previously reported variants [p.R373C, c.1551+1G>A (pathogenic), p.Asn580His (likely benign)] in the literature of Japanese patients, one prevalent missense variant (p.Arg373Cys, 6/9 families, 66.7%) detected in multiple studies was determined in the Japanese population, which was also frequently detected in the European population.

Long-term observation of a Japanese mucolipidosis IV patient with a novel homozygous p.F313del variant of MCOLN1.

Mucolipidosis type IV (MLIV) is an autosomal recessively inherited lysosomal storage disorder characterized by progressive psychomotor delay and retinal degeneration that is associated with biallelic variants in the MCOLN1 gene. The gene, which is expressed in late endosomes and lysosomes of various tissue cells, encodes the transient receptor potential channel mucolipin 1 consisting of six transmembrane domains. Here, we described 14-year follow-up observation of a 4-year-old Japanese male MLIV patient with a novel homozygous in-frame deletion variant p.(F313del), which was identified by whole-exome sequencing analysis. Neurological examination revealed progressive psychomotor delay, and atrophy of the corpus callosum and cerebellum was observed on brain magnetic resonance images. Ophthalmologically, corneal clouding has remained unchanged during the follow-up period, whereas optic nerve pallor and retinal degenerative changes exhibited progressive disease courses. Light-adapted electroretinography was non-recordable. Transmission electron microscopy of granulocytes revealed characteristic concentric multiple lamellar structures and an electron-dense inclusion in lysosomes. The in-frame deletion variant was located within the second transmembrane domain, which is of putative functional importance for channel properties.

Improvement of reduced electroretinographic responses in thymoma-associated retinopathy: a case report and literature review.

PURPOSE: To report a patient with thymoma-associated retinopathy presenting as having a good visual prognosis. METHODS: Case report and literature review. CASE REPORT: A 42-year-old female patient was referred to our hospital for complaints of sudden visual-field defects bilaterally. Decimal corrected visual acuity (VA) was 1.5 and 1.2 in the right (RE) and left eyes (LE), respectively. Fundus autofluorescence revealed hyper-autofluorescence from the posterior pole to mid-peripheral retina in both eyes. Full-field electroretinography (ERG) amplitudes were reduced to 20-50% and 30-50% of our controls for the scotopic and photopic conditions, respectively. A systemic examination revealed the presence of thymoma, and the patient underwent thymectomy and immunosuppression therapies. Immunohistochemical analysis using the patient's serum showed immunolabeling on the photoreceptor inner segment and outer plexiform layer in the monkey retina. Two years later, VA remained at 1.5 and 1.2 in RE and LE. ERG amplitudes improved to 30-60% of the controls for the scotopic conditions. However, photopic ERG showed no remarkable change. CONCLUSIONS: To our knowledge, improvement of reduced rod-mediated ERG responses has not been described in seven previously reported patients with thymoma-associated retinopathy. The good visual prognosis of our patient may be associated with well-timed intervention.

Electroretinographic abnormalities associated with pregabalin: a case report.

PURPOSE: Pregabalin binds to the α2-δ1/α2-δ2 subunits of the voltage-gated L-type calcium channel (LTCC), which is expressed in rod/cone photoreceptor terminals. The purpose of this report was to describe electroretinographic abnormalities associated with pregabalin treatment. CASE PRESENTATION: This is an observational case report. A 49-year-old female reported photophobia and night blindness in her left eye after 10 months of pregabalin administration. One month after the symptoms, ophthalmic examinations were performed, which revealed good visual acuity and no remarkable fundus findings. However, full-field electroretinography (ERG) of the left eye revealed a decreased b-wave in rod ERG, a slightly decreased a-wave and severely decreased b-wave (negative ERG) in bright flash ERG, decreased a- and b-waves in cone ERG, and decreased b-waves in 30-Hz flicker ERG. These findings are similar to those seen in incomplete congenital stationary night blindness, whereas the right eye ERG showed normal responses, except for a square a-wave in cone ERG. The ERG gradually improved from 1 to 12 months after discontinuing pregabalin. Finally, b-waves in bright flash ERG and cone ERG responses largely recovered, but b-waves in rod ERG and a-waves in bright flash ERG only partially recovered in the left eye. The square a-wave recovered to normal in the right eye. CONCLUSIONS: This is the first report to indicate that ERG abnormalities might be associated with pregabalin treatment. Our results suggest that pregabalin may affect LTCC function via the α2-δ1/α2-δ2 subunits, which leads to defective synaptic transmission from rod/cone photoreceptors to bipolar cells.