Asymmetric Inter-Eye Progression in Stargardt Disease

PURPOSE. Asymmetry in disease progression between left and right eyes can occur in Stargardt disease (STGD1), and this needs to be considered in novel therapeutic trials with a fellow-eye paired controlled design. This study investigated the inter-eye discordance of best-corrected visual acuity (BCVA) and progression of RPE atrophy in STGD1. METHODS. We performed a retrospective cohort study collecting 68 STGD1 patients (136 eyes) with ‡1 ABCA4 variants and ‡0.5-year follow-up on BCVA and fundus autofluorescence. We compared inter-eye correlations of RPE atrophy progression between early-onset ( 10 years), intermediate-onset , and late-onset ( ‡45) STGD1 and ABCA4 variant combinations by v 2 tests. We identified associations of discordant baseline BCVA and RPE atrophy with discordant RPE atrophy progression by odds ratios (OR). We defined discordance by differences >1.5 interquartile ranges 6 first/third interquartiles. RESULTS. Progression of RPE atrophy correlated moderately between eyes (q ¼ 0.766), which decreased with later onset (P ¼ 9.8 3 10 À7 ) and lower pathogenicity of ABCA4 combinations (P ¼ 0.007). Twelve patients (17.6%) had discordant inter-eye RPE atrophy progression, associated with baseline discordance of RPE atrophy (OR,.34]), but not BCVA (OR, ]). CONCLUSIONS. Lower inter-eye correlations are more likely found in late-onset STGD1 and patients carrying low pathogenic ABCA4 combinations. To achieve the highest power in a therapeutic trial, early-phase studies should minimize inter-eye discordance by selecting earlyonset STGD1 patients carrying severe ABCA4 variants without evidence of asymmetry at baseline

PLoS One

Age-related macular degeneration (AMD) is a common, progressive multifactorial vision-threatening disease and many genetic and environmental risk factors have been identified. The risk of AMD is influenced by lifestyle and diet, which may be reflected by an altered metabolic profile. Therefore, measurements of metabolites could identify biomarkers for AMD, and could aid in identifying high-risk individuals. Hypothesis-free technologies such as metabolomics have a great potential to uncover biomarkers or pathways that contribute to disease pathophysiology. To date, only a limited number of metabolomic studies have been performed in AMD. Here, we aim to contribute to the discovery of novel biomarkers and metabolic pathways for AMD using a targeted metabolomics approach of 188 metabolites. This study focuses on non-advanced AMD, since there is a need for biomarkers for the early stages of disease before severe visual loss has occurred. Targeted metabolomics was performed in 72 patients with early or intermediate AMD and 72 control individuals, and metabolites predictive for AMD were identified by a sparse partial least squares discriminant analysis. In our cohort, we identified four metabolite variables that were most predictive for early and intermediate stages of AMD. Increased glutamine and phosphatidylcholine diacyl C28:1 levels were detected in non-advanced AMD cases compared to controls, while the rate of glutaminolysis and the glutamine to glutamate ratio were reduced in non-advanced AMD. The association of glutamine with non-advanced AMD corroborates a recent report demonstrating an elevated glutamine level in early AMD using a different metabolomics technique. In conclusion, this study indicates that metabolomics is a suitable method for the discovery of biomarker candidates for AMD. In the future, larger metabolomics studies could add to the discovery of novel biomarkers in yet unknown AMD pathways and expand our insights in AMD pathophysiology

Geographic distribution of rare variants associated with age-related macular degeneration

PURPOSE: A recent genome-wide association study by the International Age-related Macular Degeneration Genomics Consortium (IAMDGC) identified seven rare variants that are individually associated with age-related macular degeneration (AMD), the most common cause of vision loss in the elderly. In literature, several of these rare variants have been reported with different frequencies and odds ratios across populations of Europe and North America. Here, we aim to describe the representation of these seven AMD-associated rare variants in different geographic regions based on 24 AMD studies. METHODS: We explored the occurrence of seven rare variants independently associated with AMD (CFH rs121913059 (p.Arg1210Cys), CFIrs141853578 (p.Gly119Arg), C3 rs147859257 (p.Lys155Gln), and C9 rs34882957 (p.Pro167Ser)) and three non-coding variants in or near the CFH gene (rs148553336, rs35292876, and rs191281603) in 24 AMD case-control studies. We studied the difference in distribution, interaction, and effect size for each of the rare variants based on the minor allele frequency within the different geographic regions. RESULTS: We demonstrate that two rare AMD-associated variants in the CFH gene (rs121913059 [p.Arg1210Cys] and rs35292876) deviate in frequency among different geographic regions (p=0.004 and p=0.001, respectively). The risk estimates of each of the seven rare variants were comparable across the geographic regions. CONCLUSIONS: The results emphasize the importance of identifying population-specific rare variants, for example, by performing sequencing studies in case-control studies of various populations, because their identification may have implications for diagnostic screening and personalized treatment

Hyperreflective foci on optical coherence tomography associate with treatment outcome for anti-VEGF in patients with diabetic macular edema.

PURPOSE:To investigate the relationship between baseline number of hyperreflective foci (HF) on spectral domain optical coherence tomography (SD-OCT) in patients with diabetic macular edema (DME), as well as the dynamics of HF during treatment with anti-vascular endothelial growth factor (VEGF), and treatment response. METHODS:We evaluated patients diagnosed with DME scheduled for treatment with intravitreal bevacizumab. Eyes were classified as adequate or insufficient treatment responders based on logMAR visual acuity improvement and central retinal thickness (CRT) decrease after three consecutive injections. Associations between number of HF at baseline and treatment response, the change in HF over the course of treatment, and the distribution of HF within the retinal layers were evaluated. RESULTS:In 54 eyes of 41 patients, mean number of HF and CRT decreased after intravitreal treatment with bevacizumab (p = 0.002 and p<0.001 respectively). Decrease in CRT after 3 months was independently associated with a higher number of HF at baseline (estimated effect -2.61, 95% CI [-4.42--0.31], p = 0.006). Eyes with adequate treatment response presented with more HF at baseline (OR 1.106, 95% CI [1.012-1.210], p = 0.030) than eyes with insufficient treatment response. Most HF were located within the inner retinal layers, and decrease of HF was mostly due to a decrease of inner retinal HF. CONCLUSIONS:In patients with DME treated with anti-VEGF, higher baseline numbers of HF have predictive value for treatment response in terms of visual acuity improvement and CRT decrease after 3 months. In addition, HF were responsive to anti-VEGF therapy

Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease.

BACKGROUND:Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options-including gene therapy-are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. METHODS AND FINDINGS:We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30-0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33-0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. CONCLUSIONS:These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders

Analysis of Risk Alleles and Complement Activation Levels in Familial and Non-Familial Age-Related Macular Degeneration.

AIMS:Age-related macular degeneration (AMD) is a multifactorial disease, in which complement-mediated inflammation plays a pivotal role. A positive family history is an important risk factor for developing AMD. Certain lifestyle factors are shown to be significantly associated with AMD in non-familial cases, but not in familial cases. This study aimed to investigate whether the contribution of common genetic variants and complement activation levels differs between familial and sporadic cases with AMD. METHODS AND RESULTS:1216 AMD patients (281 familial and 935 sporadic) and 1043 controls (143 unaffected members with a family history of AMD and 900 unrelated controls without a family history of AMD) were included in this study. Ophthalmic examinations were performed, and lifestyle and family history were documented with a questionnaire. Nine single nucleotide polymorphisms (SNPs) known to be associated with AMD were genotyped, and serum concentrations of complement components C3 and C3d were measured. Associations were assessed in familial and sporadic individuals. The association with risk alleles of the age-related maculopathy susceptibility 2 (ARMS2) gene was significantly stronger in sporadic AMD patients compared to familial cases (p = 0.017 for all AMD stages and p = 0.003 for advanced AMD, respectively). ARMS2 risk alleles had the largest effect in sporadic cases but were not significantly associated with AMD in densely affected families. The C3d/C3 ratio was a significant risk factor for AMD in sporadic cases and may also be associated with familial cases. In patients with a densely affected family this effect was particularly strong with ORs of 5.37 and 4.99 for all AMD and advanced AMD respectively. CONCLUSION:This study suggests that in familial AMD patients, the common genetic risk variant in ARMS2 is less important compared to sporadic AMD. In contrast, factors leading to increased complement activation appear to play a larger role in patients with a positive family history compared to sporadic patients. A better understanding of the different contributions of risk factors in familial compared to non-familial AMD will aid the development of reliable prediction models for AMD, and may provide individuals with more accurate information regarding their individual risk for AMD. This information is especially important for individuals who have a positive family history for AMD

Clinical Characteristics of Familial and Sporadic Age-Related Macular Degeneration: Differences and Similarities

PURPOSE. We describe the differences and similarities in clinical characteristics and phenotype of familial and sporadic patients with age-related macular degeneration (AMD). METHODS. We evaluated data of 1828 AMD patients and 1715 controls enrolled in the European Genetic Database. All subjects underwent ophthalmologic examination, including visual acuity testing and fundus photography. Images were graded and fundus photographs were used for automatic drusen quantification by a machine learning algorithm. Data on disease characteristics, family history, medical history, and lifestyle habits were obtained by a questionnaire. RESULTS. The age at first symptoms was significantly lower in AMD patients with a positive family history (68.5 years) than in those with no family history (71.6 years, P = 1.9 x 10(-5)). Risk factors identified in sporadic and familial subjects were increasing age (odds ratio [OR], 1.08 per year; P = 3.0 x 10(-51), and OR, 1.15; P = 5.3 x 10(-36), respectively) and smoking (OR, 1.01 per pack year; P = 1.1 x 10(-6) and OR, 1.02; P = 0.005). Physical activity and daily red meat consumption were significantly associated with AMD in sporadic subjects only (OR, 0.49; P = 3.7 x 10(-10) and OR, 1.81; P = 0.001). With regard to the phenotype, geographic atrophy and cuticular drusen were significantly more prevalent in familial AMD (17.5% and 21.7%, respectively) compared to sporadic AMD (9.8% and 12.1%). CONCLUSIONS. Familial AMD patients become symptomatic at a younger age. The higher prevalence of geographic atrophy and cuticular drusen in the familial AMD cases may be explained by the contribution of additional genetic factors segregating within families

Clinical Characteristics of Familial and Sporadic Age-Related Macular Degeneration: Differences and Similarities

PURPOSE. We describe the differences and similarities in clinical characteristics and phenotype of familial and sporadic patients with age-related macular degeneration (AMD). METHODS. We evaluated data of 1828 AMD patients and 1715 controls enrolled in the European Genetic Database. All subjects underwent ophthalmologic examination, including visual acuity testing and fundus photography. Images were graded and fundus photographs were used for automatic drusen quantification by a machine learning algorithm. Data on disease characteristics, family history, medical history, and lifestyle habits were obtained by a questionnaire. RESULTS. The age at first symptoms was significantly lower in AMD patients with a positive family history (68.5 years) than in those with no family history (71.6 years, P = 1.9 x 10(-5)). Risk factors identified in sporadic and familial subjects were increasing age (odds ratio [OR], 1.08 per year; P = 3.0 x 10(-51), and OR, 1.15; P = 5.3 x 10(-36), respectively) and smoking (OR, 1.01 per pack year; P = 1.1 x 10(-6) and OR, 1.02; P = 0.005). Physical activity and daily red meat consumption were significantly associated with AMD in sporadic subjects only (OR, 0.49; P = 3.7 x 10(-10) and OR, 1.81; P = 0.001). With regard to the phenotype, geographic atrophy and cuticular drusen were significantly more prevalent in familial AMD (17.5% and 21.7%, respectively) compared to sporadic AMD (9.8% and 12.1%). CONCLUSIONS. Familial AMD patients become symptomatic at a younger age. The higher prevalence of geographic atrophy and cuticular drusen in the familial AMD cases may be explained by the contribution of additional genetic factors segregating within families