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Introduction: Adult-onset foveomacular vitelliform dystrophy is a prevalent form of macular degeneration and typically occurs between the fourth and sixth decades of life. Areas covered: A pubmed and medline search was performed using the relevant key words. Several variants of the term ‘adult-onset vitelliform macular dystrophy’ were searched in relation to different terms: ‘diagnosis’, ‘managment’ and ‘treatment’. Expert commentary: Multimodal diagnostic imaging methods such as autofluorescence, fluorescein angiography, indocyanine green angiography, structural spectral domain optical coherence tomography, and optical coherence tomography angiography have led to a better understanding of the pathophysiological features of macular diseases. Gene therapy is a promising future option for treating monogenic forms of adult-onset foveomacular vitelliform dystrophy. [ABSTRACT FROM AUTHOR]

Purpose:To evaluate the possible synergistic effect of at risk genotypes ofARMS2/LOC387715(A69S), DNA repairSMUG1rs3087404,CCL2–2518,C3(R102G),CFH Y402H, complement factor B(L9H), andcomplement factor I(CFI) (G119R) in advanced age-related macular degeneration compared to those of healthy controls. Elucidation of synergistic effects between different genetic loci may clarify their pathogenetic pathways. Methods:We calculated relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S) to estimate the additive or supra-additive effects of the mentioned genotypes. Results:ARMS2-CFH [RERI = 4.78 (95% CI 2.17–10.61), AP = 0.65 (95% CI 0.33–0.83), S = 4.11 (95% CI 1.40–12.06)], and CFH-C3 combinations [RERI = 2.71 (95% CI 0.04–7.01) AP = 0.47 (95% CI −0.03–0.7) S = 2.30 (95%CI 0.97–5.45)] have the most significant levels of synergism and C3-CFI combination [RERI = −1.65 (95%CI −4.34–0.06), AP = −0.92(95%CI −3.09 – −0.09), S = 0.32 (95%CI 0.09 = 1.20)] has the most significant level of antagonism. Conclusion:Among different genotype combinations ARMS2-CFH and CFH-C3 combinations have the most significant levels of synergism and C3-CFI combination has the most significant level of antagonism in AMD patients. [ABSTRACT FROM PUBLISHER]

Background:The clinical phenotype of patients presenting with autosomal recessiveCDHR1-related retinopathy has not been well described. Materials and Methods:This is a retrospective case series of patients presenting to a single institution. Clinical data, including age, visual acuity, dilated fundus exam, fundus photos, fundus autofluorescence (FAF), optical coherence tomography, full-field electroretinograms (ERGs), and results of genetic testing, were collected. Results:Four patients were identified to have biallelic mutations in theCDHR1gene. All four patients were found to have at least one c.783G>A (p.Pro261 = ) mutation. A novel splice site mutation, c.152-2A>G, was identified in two patients. Patients became symptomatic between the fourth and sixth decades of life. Three patients presented initially with nyctalopia and peripheral visual field constriction, and one patient presented with simultaneous onset of photophobia and nyctalopia. The fundus appearance was characterized by macular atrophy with or without peripheral retinal pigment epithelium changes and arteriolar attenuation. FAF showed a hyperautofluorescent ring surrounding a central area of speckled hypoautofluorescence. Full-field electroretinography was available on three patients and showed decreased cone-and-rod responses. Conclusions:CDHR1-related retinal dystrophy should be considered in adult patients with a retinal dystrophy who present with symptoms of cone-and-rod dysfunction and macular atrophy on ophthalmoscopic examination. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the clinical characteristics and genetic basis of inherited retinal degeneration (IRD) in six unrelated pedigrees from Mexico. Methods: A complete ophthalmic evaluation including measurement of visual acuities, Goldman kinetic or Humphrey dynamic perimetry, Amsler test, fundus photography, and color vision testing was performed. Family history and blood samples were collected from available family members. DNA from members of two pedigrees was examined for known mutations using the APEX ARRP genotyping microarray and one pedigree using the APEX LCA genotyping microarray. The remaining three pedigrees were analyzed using a custom-designed targeted capture array covering the exons of 233 known retinal degeneration genes. Sequencing was performed on Illumina HiSeq. Reads were mapped against hg19, and variants were annotated using GATK and filtered by exomeSuite. Segregation and ethnicity-matched control sample analyses were performed by dideoxy sequencing. Results: Six pedigrees with IRD were analyzed. Nine rare or novel, potentially pathogenic variants segregating with the phenotype were detected inIMPDH1, USH2A, RPE65, ABCA4, andFAM161Agenes. Among these, six were known mutations while the remaining three changes inUSH2A, RPE65, andFAM161Agenes have not been previously reported to be associated with IRD. Analysis of 100 ethnicity-matched controls did not detect the presence of these three novel variants indicating, these are rare variants in the Mexican population. Conclusions: Screening patients diagnosed with IRD from Mexico identified six known mutations and three rare or novel potentially damaging variants inIMPDH1, USH2A, RPE65, ABCA4, andFAM161Agenes that segregated with disease. [ABSTRACT FROM PUBLISHER]

Background: In this study, we present a juvenile retinoschisis patient with developmental delay, sensorineural hearing loss, and reduced axial tone. X-linked juvenile retinoschisis (XLRS) is a retinal dystrophy, most often not associated with systemic anomalies and also not showing any locus heterogeneity. Therefore it was of interest to understand the genetic basis of the condition in this patient. Materials and methods: RS1 gene screening for XLRS was performed by Sanger sequencing. Whole genome SNP 6.0 array analysis was carried out to investigate gross chromosomal aberrations that could result in systemic phenotype. In addition, targeted next generation sequencing (NGS) was employed to determine any possible involvement of X-linked syndromic and non-syndromic mental retardation genes. This NGS panel consisted of 550 genes implicated in several other rare inherited diseases. Results: RS1 gene screening revealed a pathogenic hemizygous splice site mutation (c.78+1G>T), inherited from the mother. SNP 6.0 array analysis did not indicate any significant chromosomal aberrations that could be disease-associated. Targeted resequencing did not identify any mutations in the X-linked mental retardation genes. However, variations in three other genes (NSD1, LARGE, and POLG) were detected, which were all inherited from the patient's unaffected father. Conclusions: Taken together, RS1 mutation was found to segregate with retinoschisis phenotype while none of the other identified variations were co-segregating with the systemic defects. Hereby, we infer that the multisystemic defects harbored by the patient are a rare coexistence of XLRS, developmental delay, sensorineural hearing loss, and reduced axial tone reported for the first time in the literature. [ABSTRACT FROM AUTHOR]

Background: Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration and can occur in non-syndromic and syndromic forms. Syndromic RP is accompanied by other symptoms such as intellectual disability, hearing loss, or congenital abnormalities. Both forms are known to exhibit complex genetic interactions that can modulate the penetrance and expressivity of the phenotype. Materials and methods: In an individual with atypical RP, hearing loss, ataxia and cerebellar atrophy, whole exome sequencing was performed. The candidate pathogenic variants were tested by developing anin vivozebrafish model and assaying for retinal and cerebellar integrity. Results: Exome sequencing revealed a complex heterozygous protein-truncating mutation inRP1L1, p.[(Lys111Glnfs 27; Gln2373 )], and a heterozygous nonsense mutation inC2orf71, p.(Ser512 ). Mutations in both genes have previously been implicated in autosomal recessive non-syndromic RP, raising the possibility of a digenic model in this family. Functional testing in a zebrafish model for two key phenotypes of the affected person showed that the combinatorial suppression ofrp1l1andc2orf71linduced discrete pathology in terms of reduction of eye size with concomitant loss of rhodopsin in the photoreceptors, and disorganization of the cerebellum. Conclusions: We propose that the combination of heterozygous loss-of-function mutations in these genes drives syndromic retinal dystrophy, likely through the genetic interaction of at least two loci. Haploinsufficiency at each of these loci is insufficient to induce overt pathology. [ABSTRACT FROM AUTHOR]

Purpose: Recessive mutations in CDH3 cause "hypotrichosis with juvenile macular dystrophy," typically recognized by the presence of prominent dermatological features. We report novel phenotypic observations and associated mutations in four patients from three families, including one who did not have frank hypotrichosis. Methods: Retrospective case series (2010-2014). Results: Four affected individuals from three consanguineous Arabian families were identified. All four subjects (two sisters and two unrelated males; 5, 13, 17, and 26 years old) had homozygous recessive CDH3 mutations not previously associated with the condition (c.307C>T; p.R103 in two sisters, c.1859_1862delCTCT in both unrelated males). Symptomatic visual loss was since birth or early childhood. One male subject did not have frank hypotrichosis, but review of symptoms revealed relatively slow hair growth and an inability to conceive children. None had dental or digital findings, although one female noted slow nail growth. All had a circumscribed central maculopathy with borders that did not respect posterior pole horizontal arterioles (typically extending beyond the major arcades) and associated with polygonal pigment clumping. Recognition of this pattern led us to suspect the diagnosis in the male without frank hypotrichosis. Retinal dysfunction was cone-rod (rather than macular only) by ERG in one patient, who developed severe central macular atrophy and a macular hole. Conclusions: Ophthalmologists should consider the diagnosis of CDH3-related retinopathy in individuals with such clinical features whether or not there is frank hypotrichosis. [ABSTRACT FROM AUTHOR]

Objective: A minority of patients with adult-onset foveomacular vitelliform dystrophy (AFVD) carry mutations in the PRPH2 gene. This gene is highly polymorphic and it was suggested that single-nucleotide polymorphisms (SNPs) in PRPH2 may also be associated with AFVD. We aimed to evaluate for such an association. Methods: A single center cohort from a tertiary referral center including 52 consecutive patients with a clinical diagnosis of AFVD and 91 unaffected individuals was assessed. Sanger sequencing was performed for the PRPH2, BEST1, and IMPG1/2 genes. Investigation as to the frequency of minor alleles for SNPs in PRPH2 was performed and compared to HapMap and Exome Variant Server (EVS) data. Results: None of the patients carry a mutation in PRPH2, BEST7, or IMPG1/2. Five of 14 known SNPs (rs835, rs361524, rs434102, rs425876, rs390659) in exon 3 of PRPH2 were identified in AFVD patients. A high frequency and percentage of minor alleles of these five SNPs was found in the Israeli AFVD patients and controls compared with European, Chinese, Japanese and African populations identified via HapMap and EVS (p < 0.05). Power calculation suggested that the sample size was sufficient (80%) to rule out an association with an odds ratio above 2.5. Conclusions: These results suggest that genetic variants in PRPH2 do not compose a major genetic risk factor for AFVD. The Israeli population shows a higher percentage of minor allele frequencies in SNPs in the PRPH2 gene, as compared with other populations. This emphasizes the need for appropriate genetic background when performing SNP association testing. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to investigate whether variations inLIPC, CETP, ABCA1andLPL, which are involved in high-density lipoprotein (HDL) metabolism, are associated with advanced age-related macular degeneration (AMD) in the Chinese population. Design and Methods: A total of 119 Chinese patients with advanced AMD and 99 control individuals were recruited. Genomic DNA was extracted from peripheral blood leukocytes. Genotypes of seven single nucleotide polymorphisms (SNPs) including rs1061170 and rs1410996 inCFH, rs10490924 inHTRA1, rs10468017 inLIPC, rs3764261 inCETP, rs1883025 inABCA1and rs12678919 nearLPLwere determined by polymerase chain reaction (PCR) followed by allele-specific restriction enzyme digestion or SNaPshot. Unconditional logistic regression analyses were performed to generate a risk predictive model. Results: We observed the frequency of allele A of rs3764261 inCETPto be significantly lower in advanced AMD after Bonferroni correction (15.5% in patients with AMD and 20.7% in controls; OR = 0.49, 95% CI: 0.29–0.85;p = 0.011). Furthermore, we found that it was also associated with reduced risk of both unilateral AMD (OR = 0.52, 95% CI: 0.28–0.98;p = 0.043) and bilateral AMD (OR = 0.45, 95% CI: 0.22–0.91;p = 0.026). Rs10468017 inLIPC, rs12678919 nearLPLand rs1883025 inABCA1were not found to be associated with advanced AMD (allp > 0.05). Conclusion: Our data suggested that the allele A in rs3764261 inCETPgene may be associated with a decreased risk of advanced AMD in Chinese population. [ABSTRACT FROM AUTHOR]

Purpose: Oxidative stress is considered a major factor in the deterioration of retinal pigment epithelium (RPE) cells in dry age-related macular degeneration (AMD). The MAPK ERK1/2 can be activated by oxidative stress, may exert both pro- and anti-apoptotic functions, and has recently been proposed as a major factor in RPE degeneration in atrophic changes. Nrf2 is a master regulator of oxidative stress defense and ERK1/2 is an upstream activator of Nrf2. In this study, we investigate the participation of ERK1/2 in oxidative stress pathways in connection with Nrf2. Methods: Nrf2 knock-out and wild-type primary RPE cells were prepared from mouse eyes. Oxidative stress was induced by different concentrations of t-butylhydroperoxide. Mitogen-activated protein kinases (MAPKs) were blocked by commercially available inhibitors (SB203580, U0126, SP600125). Cell viability was determined by MTT assay. ERK1/2 expression and activation were assessed by Western blotting. Results: Oxidative stress induced concentration dependent cell death, which occurred at lower concentrations in Nrf2 knock-out RPE. Western blot analysis displayed a biphasic activation of ERK1/2 in murine wild-type RPE and the inhibition of late, but not early activation of ERK1/2 exerted protection in wild-type murine RPE cells. The biphasic activation of ERK1/2 is lost in Nrf2 knock-out mice, and inhibition of ERK1/2 was generally protective. The inhibition of MAPK JNK or p38 exerted no protection, irrespective of Nrf2. Conclusion: RPE cells display a biphasic activation of ERK1/2 after oxidative insult, of which the late activation is pro-apoptotic. The biphasic activation is lost in Nrf2 knock-outs, suggesting that early ERK1/2 activation may be connected to Nrf2 signaling. In addition, ERK1/2 activation in Nrf2 knock-outs mediates oxidative stress-induced cell death. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate the association between complement factor H Y402H polymorphism and age-related macular degeneration (AMD) development in a cohort of Turkish patients. Methods: A total of 182 individuals, including 95 individuals with unrelated late age-related macular degeneration and 87 age-matched healthy individuals as a control group were genotyped with polymerase chain reaction followed by restriction enzyme digestion and direct sequence analysis. The statistical analysis was performed with statistical software R 2.9.2 and epicalc package. Results: The Y402H variant in the CFH gene was found to be associated with late AMD in our study population. Genotypic frequencies were highly different between all patients and control individuals compared for the heterozygotes carrying the risk allele C (AMD patients (CT) 70.5%, control individuals (CT) 54.02%; χ2= 5.285, d.f. = 1, p = 0.02). When all AMD patients were compared with the healthy control group, TC heterozygotes showed a significantly increased risk of AMD (O.R = 2.32, CI% 1.23-4.35). Conclusıon: This study suggests that the CFH Y402H polymorphism is associated with increased risk for both types of end-stage AMD in Turkish patients. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the feasibility of introducing brain-derived neurotrophic factor (BDNF) gene into retinal pigment epithelial cells in vivo by electroporation and whether this method can rescue photoreceptors of retinitis pigmentosa in Royal College Surgeons (RCS) rats. Methods: The BDNF-GFP fusion eukaryotic-expressing plasmid was constructed and subretinally or intravitreously injected into the eyes of RCS rats followed by in vivo electroporation. The expression of BDNF mRNA and protein was detected by RT-PCR and Western immunoblot analysis. The number of surviving photoreceptors was counted, and the TdT-dUTP terminal nick-end labeling (TUNEL) method was used to detect the apoptotic retinal cells at different timepoints after introduction of BDNF plasmid. Results: Treated eyes showed a significantly higher rescue ratio and a lower number of TUNEL-positive photoreceptors than did the control eyes at various timepoints. Conclusion: These findings provide evidence that electroporation is an effective method for gene transfer into retinal pigment epithelial cells, and the rescue of photoreceptors can be achieved by BDNF gene transfection with electroporation. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a multifactoral disorder occurring in individuals with the genetic predisposition. This article summarizes the AMD-susceptibility single nucleotide polymorphisms (SNPs) in different ethnicities, and the effect of SNPs on the efficiency of AMD therapies. The data show that the genes conferring risk to AMD in Caucasian population are often associated with AMD in other ethnicity groups. However, the strength of the association or particular SNPs within the gene may differ. The most global AMD alleles across ethnic groups are SNPs at the complement factor H and PLEKHA1/LOC387715/HtrA1. Individuals carrying AMD allele(s) might have an altered response to current available therapies. Alleles that alter the AMD therapy effects are not necessarily AMD-susceptibility SNPs. [ABSTRACT FROM AUTHOR]