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Next-generation sequencing (NGS) has greatly advanced the studies of causative genes and variants of inherited diseases. While it is sometimes challenging to determine the pathogenicity of identified variants in NGS, the American College of Medical Genetics and Genomics established the guidelines to help the interpretation. However, as to the genetic screenings for patients with retinitis pigmentosa (RP) in Japan, none of the previous studies utilized the guidelines. Considering that EYS is the major causative gene of RP in Japan, we conducted stepwise genetic screening of 220 Japanese patients with RP utilizing the guidelines. Step 1–4 comprised the following, in order: Sanger sequencing for two major EYS founder mutations; targeted sequencing of all coding regions of EYS; whole genome sequencing; Sanger sequencing for Alu element insertion in RP1 , a recently determined founder mutation for RP. Among the detected variants, 2, 19, 173, and 1 variant(s) were considered pathogenic and 8, 41, 44, and 5 patients were genetically solved in step 1, 2, 3, and 4, respectively. Totally, 44.5% (98/220) of the patients were genetically solved, and 50 (51.0%) were EYS -associated and 5 (5.1%) were Alu element-associated. Among the unsolved 122 patients, 22 had at least one possible pathogenic variant.

Inherited retinal dystrophy (IRD) patients often experience photophobia. However, its mechanism has not been elucidated. This study aimed to investigate the main wavelength of light causing photophobia in IRD and difference among patients with different phenotypes. Forty-seven retinitis pigmentosa (RP) and 22 cone-rod dystrophy (CRD) patients were prospectively recruited. We designed two tinted glasses: short wavelength filtering (SWF) glasses and middle wavelength filtering (MWF) glasses. We classified photophobia into three types: (A) white out, (B) bright glare, and (C) ocular pain. Patients were asked to assign scores between one (not at all) and five (totally applicable) for each symptom with and without glasses. In patients with RP, photophobia was better relieved with SWF glasses {“white out” (p < 0.01) and “ocular pain” (p = 0.013)}. In CRD patients, there was no significant difference in the improvement wearing two glasses (p = 0.247–1.0). All RP patients who preferred MWF glasses had Bull’s eye maculopathy. Meanwhile, only 15% of patients who preferred SWF glasses had the finding (p < 0.001). Photophobia is primarily caused by short wavelength light in many patients with IRD. However, the wavelength responsible for photophobia vary depending on the disease and probably vary according to the pathological condition.

ObjectivesWe investigated in vivo light-induced photoreceptor damage in retinitis pigmentosa (RP) using spectral-domain optical coherence tomography (SD-OCT) images.MethodsWe retrospectively reviewed patients with genetic diagnosis of EYS-associated RP. The outer nuclear layer (ONL) thickness under retinal vessels was measured on SD-OCT vertical scans. As a control, we measured adjacent ONL thickness 100 μm superior and inferior from the vessel. Same measurements were performed in healthy subjects. We calculated the ratio of ONL thickness under vessel divided by the average of adjacent ONL thickness and defined as ONL preservation ratio. In patients with RP, the length of ellipsoid zone (EZ) from the fovea was also measured with SD-OCT vertical scans.ResultsThirty EYS-associated RP patients and 25 healthy subjects were included. In both groups, ONL thickness overshadowed by retinal vessels was not significantly different from that of adjacent area. However, ONL preservation ratio of RP was larger than that of healthy control in both superior and inferior retina (1.03 vs 0.97; p < 0.01, 1.15 vs 0.95; p < 0.01, respectively). In RP, ONL preservation ratio was significantly larger in the inferior retina than superior retina (p < 0.01). Furthermore, in RP patients, the EZ length from the fovea was always shorter in the inferior than superior retina and there was a significant difference (p < 0.01).ConclusionsPatients with EYS-associated RP exhibited inferior-dominant photoreceptor death and the relative ONL preservation under retinal vessels. These results suggest that longitudinal environment light exposure may be correlated with the photoreceptor death.

Background/AimsThis study aimed to evaluate blood flow in the choriocapillaris in patients with Bietti crystalline dystrophy (BCD) with CYP4V2 mutations using optical coherence tomography angiography (OCTA), and to explore the parameters associated with visual function.MethodsThis prospective case-series study included 13 eyes of 13 consecutive patients with BCD with CYP4V2 mutations and 20 healthy eyes. Using OCTA, we obtained en face images of blood flow in the choriocapillaris. The residual choriocapillaris area on en face images in a 10°×10° macular cube was manually measured and graded according to whether the choriocapillaris remained at the subfovea. We also investigated factors associated with visual acuity (VA) and the mean deviation (MD) value using a Humphrey field analyser with a 10–2 Swedish Interactive Threshold Algorithm standard program among OCTA-derived parameters.ResultsChoriocapillaris blood flow deficit was observed in 12 eyes (92%), whereas this was observed in none of healthy eyes. The adjusted residual choriocapillaris area was 2.47±1.79 mm2. The presence of the choriocapillaris at the subfovea was significantly correlated with VA and the MD value (P=0.006, r=0.71; P=0.04, r=−0.59, respectively).ConclusionsUsing OCTA, choriocapillaris blood flow deficit could be observed in most patients with BCD with CYP4V2 mutations. The presence of the choriocapillaris at the subfovea was significantly correlated with visual function in these patients. Analysis of choriocapillaris blood flow using OCTA allows non-invasive assessment of the patient’s state.

Background Inherited retinal degeneration (IRD) refers to a heterogenous group of progressive diseases that cause death of photoreceptor cells and subsequent vision loss. These diseases often affect the peripheral retina, objective evaluation of which has been difficult until recently. Fundus autofluorescence (FAF) is a non-invasive retinal imaging technique that depicts the distribution of intrinsic fluorophores in the retina. The primary source of retinal autofluorescence is lipofuscin, which is contained in the retinal pigment epithelium (RPE). Excessive accumulation of lipofuscin and a window defect attributable to loss of photoreceptor pigment result in increased FAF whereas loss of the RPE results in decreased FAF. These changes can be seen during the course of IRD. Mainbody While conventional modalities are limited in their angle of view, recent technologic advances, known as wide-field and ultra-widefield FAF imaging, have enabled visualization of the far peripheral retina. Although clinical application of this technique in patients with IRD is still in its infancy, some studies have already indicated its usefulness. For example, an area with decreased FAF correlates well with a visual field defect in an eye with retinitis pigmentosa (RP) or cone-rod dystrophy. An abnormal FAF pattern may help in the diagnosis of IRD and associated diseases. In addition, female carriers of X-linked RP and female choroideremia show characteristic appearance. Conversely, absence of abnormal FAF despite severe retinal degeneration helps differentiation of cancer-associated retinopathy. Conclusion This paper reviews the principles of FAF, wide-field imaging, and findings in specific diseases. Wide-field imaging, particularly wide-field FAF, will provide further information for the characteristics, prognosis, and pathogenesis of IRD.

Background Retinitis pigmentosa (RP), a neurodegenerative disease, is occasionally accompanied by choroidal neovascularization (CNV) and cystoid macular oedema. It is presently treated with repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents. However, there are concerns regarding long-term inhibition of VEGF by the use of these agents, especially in cases involving neurodegenerative diseases, since VEGFs have a neuroprotective effect. Currently, there are no reports on the long-term safety of anti-VEGF therapy in patients with RP. Case presentation In this report, we describe the case of a 56-year-old female patient with CNV associated with RP who was treated with anti-VEGF therapy for 8 years. She had autosomal dominant RP with a heterozygous PRPH2 mutation (c.410G > A) and complained of metamorphopsia in her left eye. Examinations revealed CNV with serous retinal detachment. She was treated with as-needed injections for 2 years; however, she experienced a recurrence. Therefore, we switched to a bimonthly regimen that was continued for 6 years. In total, the patient received 34 injections of various types of anti-VEGFs over 8 years. No recurrences were noted during that time, and we have not detected any negative effects concerning the progression of visual field loss in comparison with the fellow eye. Conclusions No negative effects related to the progression of visual field loss were observed during continuous treatment with anti-VEGF agents for 8 years in our patient.

Concentric retinitis pigmentosa (RP), in which retinal degeneration is limited in the periphery, is rare and little information exists to date on the subject. Herein, we describe the clinical and genetic characteristics of this atypical form of RP. We retrospectively reviewed our database and identified 14 patients with concentric RP. Additionally, 14 patients with age-matched typical RP were also included. Patients with concentric RP had better visual acuity (logarithm of minimum angle of resolution −0.04 vs. 0.32, p = 0.047) and preserved ellipsoid zones (7630 µm vs. 2646 µm, p < 0.001) compared to typical RP. The electroretinogram showed subnormal but recordable responses in patients with concentric RP. Genetic testing was done in nine patients with concentric RP and revealed causative mutations in the EYS gene in one patient and the RP9 gene in one patient. Two patients had myotonic dystrophy and the diagnosis was revised as myotonic dystrophy-associated retinopathy. Concentric RP is a rare, atypical form of RP with better visual function. There is some overlap in the causative genes in concentric and typical RP. Myotonic dystrophy-associated retinopathy is an important differential diagnosis.

Bilateral neovascular age-related macular degeneration (AMD) causes much more handicaps for patients than unilateral neovascular AMD. Although several AMD-susceptibility genes have been evaluated for their associations to bilaterality, genome-wide association study (GWAS) on bilaterality has been rarely reported. In the present study, we performed GWAS using neovascular AMD cases in East Asian. The discovery stage compared 581,252 single nucleotide polymorphisms (SNPs) between 803 unilateral and 321 bilateral Japanese cases but no SNP showed genome-wide significance, while SNPs at six regions showed P -value < 1.0 × 10 −5 , STON1-GTF2A1L/LHCGR/FSHR, PLXNA1, CTNNA3 , ARMS2/HTRA1 , LHFP , and FLJ38725 . The first replication study for these six regions comparing 36 bilateral and 132 unilateral Japanese cases confirmed significant associations of rs4482537 ( STON1-GTF2A1L/LHCGR/FSHR ), rs2284665 ( ARMS2/HTRA1 ), and rs8002574 ( LHFP ) to bilaterality. In the second replication study comparing 24 bilateral and 78 unilateral cases from Singapore, rs4482537 ( STON1-GTF2A1L/LHCGR/FSHR ) only showed significant association. Meta-analysis of discovery and replication studies confirmed genome-wide level significant association ( P  = 2.61 × 10 −9 ) of rs4482537 ( STON1-GTF2A1L/LHCGR/FSHR ) and strong associations ( P  = 5.76 × 10 −7 and 9.73 × 10 −7 , respectively) of rs2284665 ( ARMS2/HTRA1 ) and rs8002574 ( LHFP ). Our GWAS for neovascular AMD bilaterality found new genetic loci STON1-GTF2A1L/LHCGR/FSHR and confirmed the previously reported association of ARMS2/HTRA1 .

To describe the peripheral autofluorescence images and clinical features of patients with retinal dystrophy who showed radial fundus autofluorescence (FAF) at the posterior pole. The authors retrospectively reviewed pooled wide-field FAF images of 711 patients with retinal dystrophy and 56 family members. Eleven eyes of seven women exhibited radial FAF at the posterior pole. Wide-field FAF showed extension of the radial pattern to the periphery in all eyes except one. One woman showed radial hyper-FAF only in the periphery, not at the posterior pole. These eight individuals were X-linked retinitis pigmentosa patients or carriers. The tapetal-like reflex was not observed in their color fundus photographs. The peripheral visual field showed wedge-shaped restriction in some individuals. Wide-field FAF imaging can depict radial FAF not only at the posterior pole but also in the periphery in X-linked retinitis pigmentosa carriers. The authors therefore agree with previous reports that radial FAF may be a hallmark of X-linked retinitis pigmentosa.

To assess contrast visual acuity (CVA) in patients with retinitis pigmentosa (RP) and compare the result with standard visual acuity (VA), retinal thickness, status of inner segment/outer segment junction, and central visual field. Thirty-nine eyes of 39 patients with RP and 39 eyes of 39 healthy individuals were studied. To see the difference in CVA between RP patients and normal controls, only subjects with standard VA of 1.0 (20/20) or better were included. This was a cross-sectional study. CVA in various light conditions was measured with CAT-2000 and was compared between patients and controls. CVA of patients was further analyzed for association with other parameters including foveal retinal thickness, outer nuclear layer thickness, the status of inner segment/outer segment junction measured with optical coherence tomography (OCT), and visual field mean deviation (MD) measured with Humphrey field analyzer 10-2 program. CVA impairment was evident in RP patients compared to controls (P < 0.01, in all measurement conditions). Multivariate analysis showed association of logarithm of the minimum angle of resolution (logMAR) with CVAs in several conditions. None of the OCT measurements was associated with CVA. When patients were divided into three groups based on MD, the most advanced group (MD worse than or equal to -20 dB) showed impairment of mesopic CVA (P < 0.05, under mesopic condition of 100% without glare, with glare, and 25% without glare). CVA impairment was confirmed in RP patients, especially in advanced cases. CVA measured with CAT-2000 may be a useful tool for assessing foveal function in RP patients.