Drug combination of topical ripasudil and brimonidine enhances neuroprotection in a mouse model of optic nerve injury.

PURPOSE: To determine whether combination of topical ripasudil and brimonidine has more effective neuroprotection on retinal ganglion cells (RGCs) following injury to axons composing the optic nerve. METHODS: Topical ripasudil, brimonidine, or mixture of both drugs were administered to adult mice after optic nerve injury (ONI). The influence of drug conditions on RGC health were evaluated by the quantifications of surviving RGCs, phosphorylated p38 mitogen-activated protein kinase (phospho-p38), and expressions of trophic factors and proinflammatory mediators in the retina. RESULTS: Topical ripasudil and brimonidine suppressed ONI-induced RGC death respectively, and mixture of both drugs further stimulated RGC survival. Topical ripasudil and brimonidine suppressed ONI-induced phospho-p38 in the whole retina. In addition, topical ripasudil suppressed expression levels of TNFα, IL-1ß and monocyte chemotactic protein-1 (MCP-1), whereas topical brimonidine increased the expression level of basic fibroblast growth factor (bFGF). CONCLUSIONS: Combination of topical ripasudil and brimonidine may enhance RGC protection by modulating multiple signaling pathways in the retina.

Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors.

Activation of neurotrophic factor signaling is a promising therapy for neurodegeneration. However, the transient nature of ligand-dependent activation limits its effectiveness. In this study, we solved this problem by inventing a system that forces membrane localization of the intracellular domain of tropomyosin receptor kinase B (iTrkB), which results in constitutive activation without ligands. Our system overcomes the small size limitation of the genome packaging in adeno-associated virus (AAV) and allows high expression of the transgene. Using AAV-mediated gene therapy in the eyes, we demonstrate that iTrkB expression enhances neuroprotection in mouse models of glaucoma and stimulates robust axon regeneration after optic nerve injury. In addition, iTrkB expression in the retina was also effective in an optic tract transection model, in which the injury site is near the superior colliculus. Regenerating axons successfully formed pathways to their brain targets, resulting in partial recovery of visual behavior. Our system may also be applicable to other trophic factor signaling pathways and lead to a significant advance in the field of gene therapy for neurotrauma and neurodegenerative disorders, including glaucoma.

Vogt-Koyanagi-Harada disease developed during chemotherapy for Hodgkin lymphoma: a case report.

BACKGROUND: Ocular manifestations are known for non-Hodgkin lymphoma, but are rare for Hodgkin lymphoma. We report a case of Vogt-Koyanagi-Harada (VKH) disease presenting as serous retinal detachment and uveitis in both eyes in a child undergoing chemotherapy for Hodgkin lymphoma. CASE PRESENTATION: The patient was a 7-year-old boy with stage IIB Hodgkin lymphoma (nodular lymphocyte predominant type) who was undergoing chemotherapy, including 2 cycles of the OEPA regimen and 1 cycle of the COPDAC regimen. Two days after the end of the COPDAC regimen, the patient complained of headache and of blurred and decreased vision in both eyes. On the basis of optic symptoms, such as uveitis and serous retinal detachment in both eyes, increased cell counts in cerebrospinal fluid, and positivity for human leukocyte antigen (HLA)-DR4 in peripheral blood cells, incomplete VKH disease was diagnosed. Intravenous treatment with high-dose prednisolone (60mg/m2/day) for 7 days improved both visual acuity and serous retinal detachment and enabled the remains of the COPDAC chemotherapy cycle to be administered. With prednisolone treatment, visual acuity improved from 20/500 to 20/20 in the right eye and from 20/63 to 20/25 in the left eye. Because multiple vitiligo lesions later appeared in the abdomen, complete VKH disease was finally diagnosed. CONCLUSION: The onset of VKH disease occurred during chemotherapy for Hodgkin lymphoma. The patient was HLA-DR4-positive and might have had a predisposition to develop autoimmune diseases, including VKH disease. However, the anticancer drugs administered to this patient have not been reported to cause uveitis. Whether Hodgkin lymphoma triggered the development of VKH remains unclear. Early diagnosis of VKH disease and prompt treatment with high-dose prednisone enabled the patient to maintain good visual function despite chemotherapy for Hodgkin lymphoma.

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.

RHOMBUS DEFORMATION OF RETINAL LATERAL DISPLACEMENT AFTER EPIRETINAL MEMBRANE REMOVAL REVEALED BY DIFFEOMORPHIC IMAGE REGISTRATION.

PURPOSE: To establish an analysis method using diffeomorphic image registration and evaluate microvascular displacement through epiretinal membrane (ERM) removal. METHODS: Medical records of eyes that underwent vitreous surgery for ERM were reviewed. Postoperative optical coherence tomography angiography (OCTA) images were converted to the corresponding preoperative images according to a configured algorithm using diffeomorphism. RESULTS: Thirty-seven eyes with ERM were examined. Measured changes in the foveal avascular zone (FAZ) area showed a significant negative correlation with central foveal thickness (CFT). The average amplitude of microvascular displacement calculated for each pixel was 69 ± 27 µ m in the nasal area, which was relatively smaller than that in other areas. The vector map, which included both the amplitude and the vector of microvasculature displacement, showed a unique vector flow pattern called the rhombus deformation sign in 17 eyes. Eyes with this deformation sign showed less surgery-induced changes in the FAZ area and CFT and a milder ERM stage than those without this sign. CONCLUSION: The authors calculated and visualized microvascular displacement using diffeomorphism. The authors found a unique pattern (rhombus deformation) of retinal lateral displacement through ERM removal, which was significantly associated with the severity of ERM.

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.

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.

Rotational stability and clinical outcomes of a new one piece toric intraocular lens with anchor-wing haptics.

BACKGROUND: To evaluate the safety and efficacy of a new toric intraocular lens (IOL) with anchor-wing haptics. METHODS: The new toric IOL with anchor-wing haptics (NS60YT, NIDEK Co., Ltd.) was implanted in eligible patients with age-related cataracts with preoperative corneal astigmatism of 1.0 D or greater at a university hospital and two private hospitals in Japan. The following IOL cylinder powers were evaluated: 1.50 D (NS60YT3), 2.25 D (NS60YT4), 3.00 D (NS60YT5) and 4.50 D (NS60YT7). All patients were assessed out to 12 months postoperatively. The primary endpoint was visual acuity (VA) with spherical addition at 6 months postoperatively, and the primary analysis calculated the proportion of eyes with VA with spherical addition of 0.1 logMAR or better. The magnitude of rotation was compared to the intended axis of IOL implantation at each postoperative examination. Adverse events were evaluated for the safety analysis. RESULTS: This study enrolled 64 eyes of 53 patients. At 6 months postoperatively, for all IOL powers, VA with spherical addition of 0.1 logMAR or better was achieved in 90% [95% confidence interval (CI): 80-96] of eyes. The mean IOL rotation was 5.3 ± 4.3° at 12 months postoperatively. The mean magnitude of rotation ranged from 1.9° to 2.5° between each postoperative examination from 1 day to 12 months. There were no vision-threatening intraoperative or postoperative complications for the duration of the study. CONCLUSIONS: The NS60YT IOL remained stable after implantation and was efficacious for treating 1.00 D or greater astigmatism in patients with senile cataracts. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov ( NCT03242486 ) on August 8, 2017 - Retrospectively registered.

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.

Refractive error induced by intraocular lens tilt after intrascleral intraocular lens fixation.

PURPOSE: To investigate the spherical shift of intraocular lens (IOL) tilt after intrascleral fixation. METHODS: We retrospectively reviewed the medical records of patients who underwent flanged intrascleral IOL fixation with transconjunctival 25- or 27-gauge pars plana vitrectomy at the Department of Ophthalmology of the Jikei University Hospital. The minimum follow-up duration was 3 months. Second-generation anterior segment optical coherence tomography (CASIA2; TOMEY) was used to obtain the values of tilt and decentration of the intrasclerally fixated IOL and postoperative anterior chamber depth. We investigated the relationship between refractive error and various parameters, such as IOL tilt and decentration, axial length, and keratometry. In addition to our clinical investigation, we conducted optical simulations using Zemax to evaluate the spherical shift of the IOL tilt by means of the through-focus response and change in spherical equivalent power. RESULTS: The study involved 72 eyes of 67 patients. The degree of IOL tilt was correlated with the amount of refractive error (Spearman's rank correlation coefficient [CC] = - 0.32; P = 0.006). In particular, a tilt angle greater than 10° strongly affected the refractive error. The postoperative anterior chamber depth also correlated with the refractive error (CC = 0.50; P < 0.001), as opposed to decentration (CC = - 0.17; P = 0.15), axial length (CC = - 0.08; P = 0.49), and keratometry (CC = - 0.06; P = 0.64). Optical simulations also revealed a myopic shift that exponentially increased as the tilt became greater. CONCLUSION: IOL tilts that are greater than 10° induce refractive error.

Intracellular ATP levels influence cell fates in Dictyostelium discoideum differentiation.

Multicellular organisms contain various differentiated cells. Fate determination of these cells remains a fundamental issue. The cellular slime mold Dictyostelium discoideum is a useful model organism for studying differentiation; it proliferates as single cells in nutrient-rich conditions, which aggregate into a multicellular body upon starvation, subsequently differentiating into stalk cells or spores. The fates of these cells can be predicted in the vegetative phase: Cells expressing higher and lower levels of omt12 differentiate into stalk cells and spores, respectively. However, omt12 is merely a marker gene and changes in its expression do not influence the cell fate, and determinant factors remain unknown. In this study, we analyzed cell fate determinants in the stalk-destined and spore-destined cells that were sorted based on omt12 expression. Luciferase assay demonstrated higher levels of intracellular ATP in the stalk-destined cells than in the spore-destined cells. Live-cell observation during development using ATP sensor probes revealed that cells with higher ATP levels differentiated into stalk cells. Furthermore, reducing the ATP level by treating with an inhibitor of ATP production changed the differentiation fates of the stalk-destined cells to spores. These results suggest that intracellular ATP levels influence cell fates in D. discoideum differentiation.

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.

Roles of Remote and Contact Forces in Epithelial Cell Structure Formation.

Cancer cells collectively form a large-scale structure for their growth. In this article, we report that HeLa cells, epithelial-like human cervical cancer cells, aggressively migrate on Matrigel and form a large-scale structure in a cell-density-dependent manner. To explain the experimental results, we develop a simple model in which cells interact and migrate using the two fundamentally different types of force, remote and contact forces, and show how cells form a large-scale structure. We demonstrate that the simple model reproduces experimental observations, suggesting that the remote and contact forces considered in this work play a major role in large-scale structure formation of HeLa cells. This article provides important evidence that cancer cells form a large-scale structure and develops an understanding into the poorly understood mechanisms of their structure formation.