Evaluation of outer nuclear layer overshadowed by retinal vessels in retinitis pigmentosa.

OBJECTIVES: We investigated in vivo light-induced photoreceptor damage in retinitis pigmentosa (RP) using spectral-domain optical coherence tomography (SD-OCT) images. METHODS: We 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. RESULTS: Thirty 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). CONCLUSIONS: Patients 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.

Detection Sensitivity of Retinitis Pigmentosa Progression Using Static Perimetry and Optical Coherence Tomography.

Purpose: To compare the detection sensitivities of the progression of retinitis pigmentosa (RP) by automated perimetry to obtain the mean deviation (MD) and total point score and by optical coherence tomography (OCT) to determine the residual ellipsoid zone (EZ) length and thickness of retinal layers. Methods: Twenty-two eyes of 22 patients with RP who underwent annual automated perimetry (Humphrey Field Analyzer 10-2) and OCT examinations during the same period more than four times were included. Disease progression was evaluated using linear regression analysis with the least-squares method. The disease progression speed and interinspection fluctuations for the different examinations were compared using standardized values. The progression detection ability factor, defined as the average of the least squares divided by the square of annual change, was used to compare the sensitivities of the examinations for detecting the progression of RP. Results: EZ length showed a high correlation with MD (R = 0.87; P = 1.12E-07) at baseline. Disease progression was detected more frequently using EZ length (12/22 eyes) than using MD (3/22 eyes; P = 0.004) or central retinal thickness (1/11 eyes; P = 0.012). Linear regression using standardized values showed that the EZ length had the fastest annual change, with the smallest least absolute values. EZ length was more sensitive for detecting RP progression than MD, total point score, visual acuity, or central retinal thickness. Conclusions: EZ measurement was sensitive for detecting RP progression, and the results of this study indicate that EZ length is appropriate for end points in clinical trials. Translational Relevance: The study provides a basis for conducting future clinical trials.

Clinical Characteristics, Differential Diagnosis and Genetic Analysis of Concentric Retinitis Pigmentosa.

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.

EYS is a major gene involved in retinitis pigmentosa in Japan: genetic landscapes revealed by stepwise genetic screening.

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.

Wavelength of light and photophobia in inherited retinal dystrophy.

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.

Concentric Choriocapillaris Flow Deficits in Retinitis Pigmentosa Detected Using Wide-Angle Swept-Source Optical Coherence Tomography Angiography.

Purpose: We investigate whether choriocapillaris deficits can be visualized in patients with retinitis pigmentosa (RP) using wide-angle swept-source optical coherence tomography angiography (OCTA), and whether angiography or structure en face images depict a wider area of residual choriocapillaris. Methods: This cross-sectional study included 43 eyes of 43 consecutive patients with RP with a visual acuity ≥0.1, and 12 healthy eyes of 12 volunteers. Using an OCTA device (PLEX Eite 9000), we obtained angiography and structure en face images in the choriocapillaris. The residual choriocapillaris area in a 12 × 12 mm macular cube was measured manually. Results: In patients with RP, the residual choriocapillaris area was 113.1 ± 41.9 and 64.0 ± 47.8 mm2 in angiography and structure images, respectively (P < 0.001). Concentric and vermicular choriocapillaris flow deficits were observed in 10 (23%) and 17 (40%) eyes of RP patients, respectively; no deficits were observed in 16 eyes (37%). Mean age was higher in eyes with concentric, vermicular, and nondeficit choriocapillaris. No healthy eye showed choriocapillaris deficits. Conclusions: Using wide-angle swept-source OCTA, concentric and vermicular choriocapillaris flow deficits were observed in the eyes of RP patients. A comparison of angiography and structure en face images of the choriocapillaris in RP cases suggests that angiography images can evaluate a wider area of the choriocapillaris than structure images.

Wide-field fundus autofluorescence imaging in patients with hereditary retinal degeneration: a literature review.

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.

Diabetic Nonperfused Areas in Macular and Extramacular Regions on Wide-Field Optical Coherence Tomography Angiography.

Purpose: To investigate the nonperfused areas (NPAs) in each subfield segmented by large arterioles on wide-field swept-source optical coherence tomography angiography (SS-OCTA) images in diabetic retinopathy. Methods: We retrospectively reviewed 101 consecutive eyes of 67 patients with severe nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR), for whom 12 × 12-mm SS-OCTA images centered on the optic disc were acquired. Both eyes were included in 34 patients. NPAs in the whole retinal layers were measured in each subfield segmented by large arterioles encompassing both the superficial and deep layers. We compared the percentage of NPAs between individual subfields, considering the overlapping of the feeding arterioles. Results: Extramacular areas had higher rates of NPAs than macular areas in the inner (0.75-3 mm) and outer (3-5.5 mm) rings (P < 0.001 in both comparisons). The arteriolar arcades contacting the NPAs on the extramacular side were significantly longer than those contacting the NPAs on the macular side (P < 0.001). In particular, the extramacular areas between two arteriolar branches had a higher percentage of NPAs than those between two arterioles. The macular NPAs were greater in eyes with PDR than in those with severe NPDR, whereas there were no differences in the NPAs in the outer ring of extramacular areas. Conclusions: Wide-field OCTA images delineated that large arterioles residing in both the superficial and deep layers appear to be the perfusion boundaries, and the overlapping perfusion mediated via collateral vessels may affect the likelihood of diabetic NPAs in each subfield.

Relationship between Ocular Deviation and Visual Function in Retinitis Pigmentosa.

In retinitis pigmentosa (RP), peripheral visual-field loss starts in early stages, whereas central vision loss occurs in advanced stages. Sensory strabismus gradually occurs in RP. We investigated the relationship between ocular deviation and visual function and explored for sensory strabismus risk factors in 119 consecutive patients with RP at various stages. We assessed ocular deviation at far and near distances, that is the central visual field, using the mean deviation (MD) value and visual acuity (VA), and the residual binocular field area, using Goldmann perimetry (GP), in 33 patients. The horizontal ocular deviation at near distance was >10° in 30% patients and correlated with residual visual function. Although there was no effective cut-off value for central visual function, a cut-off residual GP area of 40 cm2 distinguished patients with a larger from those with a smaller horizontal ocular deviation at far distance (P = 0.04). Our findings suggest that visual function is negatively associated with ocular deviation in patients with RP and that the sensory strabismus risk is relatively high for patients with a binocular visual field <40 cm2. Thus, screening for ocular alignment may be necessary for patients with RP-associated severe vision loss as part of their comprehensive care.

Long-term efficacy and safety of anti-VEGF therapy in retinitis pigmentosa: a case report.

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.

Decorrelation Signal of Diabetic Hyperreflective Foci on Optical Coherence Tomography Angiography.

Diabetic hyperreflective foci in the outer retinal layers are a clinically relevant finding on optical coherence tomography (OCT) images, although their characteristics remain to be elucidated. Here we investigated the decorrelation signal around hyperreflective foci on OCT angiography (OCTA) images in diabetic retinopathy (DR). We retrospectively reviewed sufficient quality OCTA images from 102 eyes of 66 patients that were obtained using split-spectrum amplitude-decorrelation angiography algorithm. Most confluent hyperreflective foci were randomly deposited or appeared in a radiating array on the en-face structural OCT images in the inner nuclear layer (INL) or Henle's fiber layer (HFL), respectively. Within the INL, hyperreflective foci were not accompanied by decorrelation signals and attached to capillaries on OCTA images. Decorrelation signals were sometimes delineated in hyperreflective foci in the HFL and other times appeared to be pseudopod-like or wrapping around hyperreflective foci, referred to as reflectance-decorrelated foci. The decorrelation signal intensity of hyperreflective foci in the HFL was associated with logMAR VA (R = 0.553, P < 0.001) and central subfield thickness (R = 0.408, P < 0.001) but not with DR severity. These data suggest that reflectance-decorrelated foci on OCTA images are clinically relevant as well as shed lights on the properties in diabetic hyperreflective foci.

Choriocapillaris flow deficit in Bietti crystalline dystrophy detected using optical coherence tomography angiography.

BACKGROUND/AIMS: This 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. METHODS: This 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. RESULTS: Choriocapillaris 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). CONCLUSIONS: Using 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.

Multimodal Imaging for Differential Diagnosis of Bietti Crystalline Dystrophy.

PURPOSE: To evaluate the diagnostic usefulness of multimodal imaging in patients with Bietti crystalline dystrophy (BCD). DESIGN: Retrospective cross-sectional study. PARTICIPANTS: Patients with chorioretinal dystrophy accompanied by crystalline-like deposits. The right eyes of the patients were analyzed. METHODS: Fundus photograph, near-infrared reflectance (NIR), fundus autofluorescence (FAF), and OCT images were evaluated. Presence of hyperreflectivity on NIR, well-demarcated areas of decreased FAF, hyperreflective material at or on the retinal pigment epithelium-Bruch's membrane complex, and outer retinal tubulation were graded for each patient. All exons and franking introns of CYP4V2 were screened using Sanger sequencing. MAIN OUTCOME MEASURES: Sensitivity and specificity of the findings to discriminate patients with and without CYP4V2 mutation. RESULTS: In total, 33 patients were included in the study. Sanger sequencing revealed homozygous or compound heterozygous CYP4V2 mutations in 20 patients and heterozygous mutations in 2 patients. Among the investigated factors, hyperreflective appearance on NIR imaging yielded 100% sensitivity and 100% specificity in this cohort. The presence of outer retinal tubulation also was sensitive (95%), but specificity was moderate (45%). The revised diagnoses of patients without CYP4V2 mutations included retinitis pigmentosa, late-onset macular dystrophy, and central areolar choroidal dystrophy. CONCLUSIONS: Multimodal imaging, especially NIR imaging, is useful to differentiate BCD patients with CYP4V2 mutations from patients with other chorioretinal dystrophies accompanied by crystalline-like retinal deposits.

A genome-wide association study identified a novel genetic loci STON1-GTF2A1L/LHCGR/FSHR for bilaterality of neovascular age-related macular degeneration.

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.

Structural Changes in Optical Coherence Tomography Underlying Spots of Increased Autofluorescence in the Perilesional Zone of Geographic Atrophy.

Purpose: To investigate structural correlates corresponding to the appearance of increased fundus autofluorescence (FAF) in the perilesional area of geographic atrophy (GA) secondary to age-related macular degeneration. Methods: Serial FAF images of 181 eyes with GA of 134 patients participating in the Directional Spread in Geographic Atrophy study (NCT02051998) were screened for increased FAF spots that had developed during the review period. Thickness and reflectivity of the retinal pigment epithelium (RPE)-basal lamina complex, as well as the integrity of the external limiting membrane (ELM) and the ellipsoid zone (EZ), respectively, in corresponding optical coherence tomography (OCT) scans were compared between the time points before and after the appearance of increased FAF. Adjacent areas without development of abnormal FAF were assessed as internal control. Results: A total of 36 areas (15 eyes) with de novo developed increased FAF spots and 54 control areas were included. Analysis of the corresponding OCT images revealed an increase in RPE-basal lamina complex thickness (31.8 ± 7.3 to 42.1 ± 11.9 µm [P < 0.001]) and reflectivity (reflectivity ratio: 1.42 ± 0.11 to 1.54 ± 0.27 [P = 0.009]) corresponding to an increased FAF signal while there was no significant change in control areas. Development of increased FAF spots was associated with disruption of the ELM and the EZ. Conclusions: Increase of RPE-basal lamina complex thickness and reflectivity was spatially and temporally associated with the development of increased FAF spots in eyes with GA. In addition, outer retinal disruption may contribute to the corresponding increased FAF signal.

Prevalence, Natural Course, and Prognostic Role of Refractile Drusen in Age-Related Macular Degeneration.

Purpose: To report prevalence, clinical characteristics, and prognostic significance of refractile drusen in eyes with intermediate age-related macular degeneration (AMD). Methods: Presence of refractile drusen by color fundus photography (CFP), corresponding findings by multimodal imaging, and longitudinal changes with annual examinations for up to 4 years were analyzed within a prospective natural history study of 98 eyes with non-late AMD of 98 patients (Age-Related Eye Disease Study [AREDS] stages 3 and 4). Results: A total of 115 refractile drusen were detected at baseline in 20 eyes (20.4%). Refractile drusen typically showed hyperreflectivity by infrared (80.9%) and blue (93.9%) reflectance imaging, appearing more distinct when compared to CFP. Laminar intense hyperreflectivity of Bruch's membrane was detected in 31 lesions by spectral-domain optical coherence tomography and was strongly related to atrophy development (23 out of 31 lesions). Presence of refractile drusen at baseline was overall associated with later development of geographic atrophy (GA) (9/20 eyes versus 6/78 eyes, P < 0.001). Spontaneous regression without evident atrophy occurred in seven lesions. Conclusions: Refractile drusen are a relative common phenotype in intermediate AMD and appear to confer risk for the development of late AMD. While not all lesions develop late AMD and regression may also occur, distinct subphenotypes as identified by multimodal imaging may not only be visible earlier but also be topographically associated with the risk for GA development. Recognizing the characteristic pattern on multimodal imaging would inform physicians for identification of the lesion and its clinical history.

Screening for SLC7A14 gene mutations in patients with autosomal recessive or sporadic retinitis pigmentosa.

PURPOSE: In this study, we aimed to detect mutations in the SLC7A14 cationic transporter gene, which has recently been reported as a causative gene for retinitis pigmentosa (RP), in Japanese patients with autosomal recessive (AR) or sporadic RP. MATERIALS AND METHODS: We included 146 unrelated Japanese patients with AR or sporadic RP who lacked mutations in genes known to be associated with RP despite next-generation sequencing-based screening. We sequenced the seven SLC7A14 coding exons along with their flanking intronic DNA using the Sanger method. The detected polymorphisms were assessed for their pathogenicity with in silico prediction tools. For those who had heterozygous, nonsynonymous variants, we performed multiplex ligation-dependent probe amplification (MLPA) to search for additional deletion/duplication. RESULTS: We detected four distinct SLC7A14 polymorphisms excluding synonymous polymorphisms. Two of these polymorphisms were assessed as detrimental by in silico prediction tools. However, all of the mutations were heterozygous. Neither homozygous polymorphisms nor compound heterozygous polymorphisms, which are considered detrimental variants, were detected. Neither deletion nor duplication was found with MLPA in patients with heterozygous variants. CONCLUSIONS: The four SLC7A14 mutations detected herein were unlikely to be pathogenic in this Japanese cohort. The frequency and pathogenicity of SLC7A14 mutations may vary depending on ethnicity, and these mutations may be rare in Japanese patients.

Next-generation sequencing-based comprehensive molecular analysis of 43 Japanese patients with cone and cone-rod dystrophies.

PURPOSE: To investigate the efficacy of targeted exome sequencing for mutational screening of Japanese patients with cone dystrophy (CD) or cone-rod dystrophy (CRD). METHODS: DNA samples from 43 Japanese patients with CD or CRD were sequenced using an exome-sequencing panel targeting all 193 known inherited eye disease genes and next-generation sequencing methodologies. Subsequently, candidate variants were screened using systematic data analyses, and their potential pathogenicity was assessed using distinct filtering approaches, which included the frequency of the variants in normal populations, in silico prediction tools, and cosegregation. RESULTS: Causative mutations were detected in 12 patients with CD or CRD (27.9%). In total, 14 distinct mutations were identified in the genes ABCA4, CDHR1, CRB1, CRX, GUCY2D, KCNV2, PROM1, PRPH2, and RDH5, including four novel mutations, c.3050+1G>A in ABCA4, c.386A>G in CDHR1, c.652+1_652+4del in CRB1, and c.454G>A in KCNV2. Moreover, a putative pathogenic mutation was identified in RGS9BP, a gene recognized as the source of bradyopsia. CONCLUSIONS: Targeted exome sequencing effectively identified causative mutations in Japanese patients with CD or CRD. The results confirmed the heterogeneity of the genes responsible for CD and CRD in Japanese populations, as well as the efficacy of targeted exome sequencing-based screening of patients with inherited retinal degeneration.

Efficacy of Column Scatter Plots for Presenting Retinitis Pigmentosa Phenotypes in a Japanese Cohort.

PURPOSE: We evaluated the efficacy of column scatter plots to describe genotype-phenotype correlations in a Japanese cohort with retinitis pigmentosa (RP). METHODS: Clinical records of 121 patients with RP with identified causative mutations were reviewed. Visual acuity, central and peripheral visual fields, electroretinography (ERG), lens status, and measurements of optical coherence tomography were evaluated according to causative genes using column scatter plots. Values for three common genes (EYS, USH2A, and RHO) were compared statistically. RESULTS: All patients with PDE6B, PRPH2, and RPGR mutations, those 55 years old or younger with RP1L1 and USH2A mutations, and those 45 years old or younger with EYS and RHO mutations retained visual acuity of at least 0.1. All patients with RPGR mutations showed at least -20 dB mean deviation. Goldmann perimeter measures of 4/6 patients with RHO mutations showed remaining peripheral visual fields. Dark-adapted 0.01 and 3.0 ERGs were extinguished for most genes. Half of the patients with RHO RP maintained cone responses in light-adapted 3.0 and 3.0 flicker ERG. All patients with PRPH2, those 55 years old or younger with USH2A and RP1L1, and those 45 years old or younger with PDE6B and EYS mutations maintained subfoveal ellipsoid zones. No differences were identified between EYS and USH2A or RHO and USH2A. CONCLUSIONS: Column scatter plots enabled comparisons of the associated severities and illustration of the ophthalmological measurements for every RP causative gene. TRANSLATIONAL RELEVANCE: Analysis of mutations in specific genes may be helpful for determining visual prognoses in the clinical setting.

Wide-Field Fundus Autofluorescence for Retinitis Pigmentosa and Cone/Cone-Rod Dystrophy.

Retinitis pigmentosa and cone/cone-rod dystrophy are inherited retinal diseases characterized by the progressive loss of rod and/or cone photoreceptors. To evaluate the status of rod/cone photoreceptors and visual function, visual acuity and visual field tests, electroretinogram, and optical coherence tomography are typically used. In addition to these examinations, fundus autofluorescence (FAF) has recently garnered attention. FAF visualizes the intrinsic fluorescent material in the retina, which is mainly lipofuscin contained within the retinal pigment epithelium. While conventional devices offer limited viewing angles in FAF, the recently developed Optos machine enables recording of wide-field FAF. With wide-field analysis, an association between abnormal FAF areas and visual function was demonstrated in retinitis pigmentosa and cone-rod dystrophy. In addition, the presence of "patchy" hypoautofluorescent areas was found to be correlated with symptom duration. Although physicians should be cautious when interpreting wide-field FAF results because the peripheral parts of the image are magnified significantly, this examination method provides previously unavailable information.