Purpose
Age‐related macular degeneration (AMD) is a degenerative disease of the macula, often leading to progressive vision loss. The rate of disease progression can vary among individuals and has ...been associated with multiple risk factors. In this review, we provide an overview of the current literature investigating phenotypic, demographic, environmental, genetic, and molecular risk factors, and propose the most consistently identified risk factors for disease progression in AMD based on these studies. Finally, we describe the potential use of these risk factors for personalised healthcare.
Recent findings
While phenotypic risk factors such as drusen and pigment abnormalities become more important to predict disease progression during the course of the disease, demographic, environmental, genetic and molecular risk factors are more valuable at earlier disease stages. Demographic and environmental risk factors such as age and smoking are consistently reported to be related to disease progression, while other factors such as sex, body mass index (BMI) and education are less often associated. Of all known AMD variants, variants that are most consistently reported with disease progression are rs10922109 and rs570618 in CFH, rs116503776 in C2/CFB/SKIV2L, rs3750846 in ARMS2/HTRA1 and rs2230199 in C3. However, it seems likely that other AMD variants also contribute to disease progression but to a lesser extent. Rare variants have probably a large effect on disease progression in highly affected families. Furthermore, current prediction models do not include molecular risk factors, while these factors can be measured accurately in the blood. Possible promising molecular risk factors are High‐Density Lipoprotein Cholesterol (HDL‐C), Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), zeaxanthin and lutein.
Summary
Phenotypic, demographic, environmental, genetic and molecular risk factors can be combined in prediction models to predict disease progression, but the selection of the proper risk factors for personalised risk prediction will differ among individuals and is dependent on their current disease stage. Future prediction models should include a wider set of genetic variants to determine the genetic risk more accurately, and rare variants should be taken into account in highly affected families. In addition, adding molecular factors in prediction models may lead to preventive strategies and personalised advice.
Nonsyndromic recessive retinal dystrophies cause severe visual impairment due to the death of photoreceptor and retinal pigment epithelium cells. These diseases until recently have been considered to ...be incurable. Molecular genetic studies in the last two decades have revealed the underlying molecular causes in approximately two-thirds of patients. The mammalian eye has been at the forefront of therapeutic trials based on gene augmentation in humans with an early-onset nonsyndromic recessive retinal dystrophy due to mutations in the retinal pigment epithelium-specific protein 65kDa (RPE65) gene. Tremendous challenges still lie ahead to extrapolate these studies to other retinal disease-causing genes, as human gene augmentation studies require testing in animal models for each individual gene and sufficiently large patient cohorts for clinical trials remain to be identified through cost-effective mutation screening protocols.
Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are ...major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD (P-value = 7.1 × 10
), whereas no difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch's membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 has the highest association with reduced FHR-4 levels (P-value = 2.2 × 10
), independently of the AMD-protective CFHR1-3 deletion, and even in those individuals that carry the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player contributing to complement dysregulation in AMD.
To describe the genotype and phenotype of patients with a late-onset Stargardt's disease (STGD1).
Retrospective case series.
Twenty-one unrelated STGD1 patients with an age at onset of ≥45 years and ...≥1 rare variant in the ABCA4 gene.
Ophthalmologic examination, including best-corrected visual acuity (VA), Amsler grid testing, fundus photography, fluorescein angiography (FA), spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, full-field electroretinography (ERG), multifocal ERG, and central visual field testing. Analysis of the ABCA4 gene was performed using microarray analysis, sequencing, and multiplex ligation-dependent probe amplification. In addition, the PRPH2 and CFH genes were sequenced.
Age at onset, VA, fundus appearance, FA, FAF, and OCT findings; ABCA4 mutations; and genotype-phenotype correlation.
The mean age at onset was 55 years (range, 45-72 years). Seven patients were diagnosed without visual symptoms (age range, 45-83 years). The VA was ≥20/40 in 24 eyes of 14 patients (59%) owing to foveal sparing. On ophthalmoscopy, late-onset STGD1 showed flavimaculatus flecks (15 patients), small flecks surrounding mottled foveal changes (3 patients), extensive chorioretinal atrophy (2 patients), or small yellowish spots in the macula (1 patient). The fundus flecks showed increased autofluorescence on FAF. The choroidal background fluorescence on FA was obscured in 16 patients (80%). We found a single heterozygous ABCA4 variant in 11 patients (52%), 2 compound heterozygous variants in 8 patients (38%), and a homozygous variant in 2 patients (10%). No PRPH2 or CFH mutations were detected.
Late-onset STGD1 is at the mild end of the spectrum of retinal dystrophies caused by ABCA4 mutations. The VA is frequently preserved in late-onset STGD1 patients owing to foveal sparing. This phenotype may be caused by 1 or 2 ABCA4 variants. The differential diagnosis between late-onset STGD1 and age-related macular degeneration may be challenging. A thorough clinical and genetic analysis makes a distinction possible, which is important for clinical and genetic counseling.
The authors have no proprietary or commercial interest in any of the materials discussed in this article.
Primary cilia are sensory organelles present on most mammalian cells. The assembly and maintenance of primary cilia are facilitated by intraflagellar transport (IFT), a bidirectional protein ...trafficking along the cilium. Mutations in genes coding for IFT components have been associated with a group of diseases called ciliopathies. These genetic disorders can affect a variety of organs including the retina. Using whole exome sequencing in three families, we identified mutations in Intraflagellar Transport 172 Homolog IFT172 (Chlamydomonas) that underlie an isolated retinal degeneration and Bardet-Biedl syndrome. Extensive functional analyses of the identified mutations in cell culture, rat retina and in zebrafish demonstrated their hypomorphic or null nature. It has recently been reported that mutations in IFT172 cause a severe ciliopathy syndrome involving skeletal, renal, hepatic and retinal abnormalities (Jeune and Mainzer-Saldino syndromes). Here, we report for the first time that mutations in this gene can also lead to an isolated form of retinal degeneration. The functional data for the mutations can partially explain milder phenotypes; however, the involvement of modifying alleles in the IFT172-associated phenotypes cannot be excluded. These findings expand the spectrum of disease associated with mutations in IFT172 and suggest that mutations in genes originally reported to be associated with syndromic ciliopathies should also be considered in subjects with non-syndromic retinal dystrophy.
Primary congenital glaucoma (PCG) is the most common form of glaucoma in children. PCG occurs due to the developmental defects in the trabecular meshwork and anterior chamber of the eye. The purpose ...of this study is to identify the causative genetic variants in three families with developmental and primary congenital glaucoma (PCG) with a recessive inheritance pattern.
DNA samples were obtained from consanguineous families of Pakistani ancestry. The CYP1B1 gene was sequenced in the affected probands by conventional Sanger DNA sequencing. Whole exome sequencing (WES) was performed in DNA samples of four individuals belonging to three different CYP1B1-negative families. Variants identified by WES were validated by Sanger sequencing.
WES identified potentially causative novel mutations in the latent transforming growth factor beta binding protein 2 (LTBP2) gene in two PCG families. In the first family a novel missense mutation (c.4934G>A; p.Arg1645Glu) co-segregates with the disease phenotype, and in the second family a novel frameshift mutation (c.4031_4032insA; p.Asp1345Glyfs*6) was identified. In a third family with developmental glaucoma a novel mutation (c.3496G>A; p.Gly1166Arg) was identified in the PXDN gene, which segregates with the disease.
We identified three novel mutations in glaucoma families using WES; two in the LTBP2 gene and one in the PXDN gene. The results will not only enhance our current understanding of the genetic basis of glaucoma, but may also contribute to a better understanding of the diverse phenotypic consequences caused by mutations in these genes.
•The complement system plays a central role in age-related macular degeneration (AMD).•Common and rare genetic variants in complement genes have been identified in AMD.•Several of the rare variants ...affect the functioning of the complement system.•However, a genetic association with AMD cannot always be proven.•Functional assays can help identify patients for complement inhibiting therapies.
Age-related macular degeneration (AMD) is a progressive retinal disease and the major cause of irreversible vision loss in the elderly. Numerous studies have found both common and rare genetic variants in the complement pathway to play a role in the pathogenesis of AMD. In this review we provide an overview of rare variants identified in AMD patients, and summarize the functional consequences of rare genetic variation in complement genes on the complement system. Finally, we discuss the relevance of this work in light of ongoing clinical trials that study the effectiveness of complement inhibitors against AMD.
Non-syndromic retinitis pigmentosa Verbakel, Sanne K.; van Huet, Ramon A.C.; Boon, Camiel J.F. ...
Progress in retinal and eye research,
September 2018, 2018-09-00, 20180901, Letnik:
66
Journal Article
Recenzirano
Odprti dostop
Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, ...with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20–30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options.
Age-related macular degeneration (AMD) is the main cause of vision loss among the elderly in the Western world. While AMD is a multifactorial disease, the complement system was identified as one of ...the main pathways contributing to disease risk. The strong link between the complement system and AMD was demonstrated by genetic associations, and by elevated complement activation in local eye tissue and in the systemic circulation of AMD patients. Several complement inhibitors have been and are being explored in clinical trials, but thus far with limited success, leaving the majority of AMD patients without treatment options to date. This indicates that there is still a gap of knowledge regarding the functional implications of the complement system in AMD pathogenesis and how to bring these towards clinical translation. Many different experimental set-ups and disease models have been used to study complement activation in vivo and in vitro, and recently emerging patient-derived induced pluripotent stem cells and genome-editing techniques open new opportunities to study AMD disease mechanisms and test new therapeutic strategies in the future. In this review we provide an extensive overview of methods employed to understand the molecular processes of complement activation in AMD pathogenesis. We discuss the findings, advantages and challenges of each approach and conclude with an outlook on how recent, exciting developments can fill in current knowledge gaps and can aid in the development of effective complement-targeting therapeutic strategies in AMD.
Age-related macular degeneration (AMD) is a disease that affects the macula – the central part of the retina. It is a leading cause of irreversible vision loss in the elderly. AMD onset is marked by ...the presence of lipid- and protein-rich extracellular deposits beneath the retinal pigment epithelium (RPE), a monolayer of polarized, pigmented epithelial cells located between the photoreceptors and the choroidal blood supply. Progression of AMD to the late nonexudative “dry” stage of AMD, also called geographic atrophy, is linked to progressive loss of areas of the RPE, photoreceptors, and underlying choriocapillaris leading to a severe decline in patients’ vision. Differential susceptibility of macular RPE in AMD and the lack of an anatomical macula in most lab animal models has promoted the use of in vitro models of the RPE. In addition, the need for high throughput platforms to test potential therapies has driven the creation and characterization of in vitro model systems that recapitulate morphologic and functional abnormalities associated with human AMD. These models range from spontaneously formed cell line ARPE19, immortalized cell lines such as hTERT-RPE1, RPE-J, and D407, to primary human (fetal or adult) or animal (mouse and pig) RPE cells, and embryonic and induced pluripotent stem cell (iPSC) derived RPE. Hallmark RPE phenotypes, such as cobblestone morphology, pigmentation, and polarization, vary significantly betweendifferent models and culture conditions used in different labs, which would directly impact their usability for investigating different aspects of AMD biology. Here the AMD Disease Models task group of the Ryan Initiative for Macular Research (RIMR) provides a summary of several currently used in vitro RPE models, historical aspects of their development, RPE phenotypes that are attainable in these models, their ability to model different aspects of AMD pathophysiology, and pros/cons for their use in the RPE and AMD fields. In addition, due to the burgeoning use of iPSC derived RPE cells, the critical need for developing standards for differentiating and rigorously characterizing RPE cell appearance, morphology, and function are discussed.
•In vitro models of the RPE provide a powerful tool to study RPE biology and AMD pathogenesis.•Key hallmarks of AMD pathophysiology have been replicated in several in vitro models.•Primary RPE and RPE cell lines are easily accessible and useful in biochemical and cell biology studies.•iPSC-derived RPE have been validated to present native-RPE like features and can provide patient-specific models.•Organ-on-chips and 3D organoids provide physiologically relevant models combining RPE with other ocular cell types.
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