Carbonic Anhydrase Inhibitors for the Treatment of Cystic Macular Lesions in Children With X-Linked Juvenile Retinoschisis.

PURPOSE: Little is known regarding the therapeutic effect of carbonic anhydrase inhibitors (CAIs) in the management of cystic macular lesions in children with X-linked juvenile retinoschisis (XLRS) despite the fact that this disease often manifests during childhood. Therefore, our goal was to determine the efficacy of CAIs in the treatment of cystic macular lesions in children with XLRS. METHODS: We used CAIs to treat cystic macular lesions in 18 eyes of nine children with XLRS. We evaluated the therapeutic effect of CAI treatment with the best-corrected visual acuity and foveal zone thickness (FZT) with spectral-domain optical coherence tomography. A reduction of at least 22.4% in FZT was defined as objective evidence of response. RESULTS: Five of nine (55.6%) XLRS patients showed a significant reduction of FZT in both eyes over a median treatment interval of 6.8 months (range, 1-23). In four of five (80.0%) patients, this reduction was already apparent after 1 month of treatment. An improvement of visual acuity was observed in five eyes (27.8%) of three patients (33.3%). Six patients (66.6%) reported minor side effects. CONCLUSIONS: Treatment with CAIs decreased FZT in more than half of the children with XLRS. This effect was observed within 1 month in the majority of patients. Carbonic anhydrase inhibitor treatment restores retinal anatomy and may contribute to creating optimal circumstances for gene therapy.

Analysis of rare variants in the CFH gene in patients with the cuticular drusen subtype of age-related macular degeneration.

PURPOSE: Age-related macular degeneration (AMD) and cuticular drusen (CD), a clinical subtype of AMD, have been linked to genetic variants in the complement factor H (CFH) gene. In this study, we aimed to investigate the frequency of rare variants in the CFH gene in 180 cases with CD. In addition, we aimed to determine the frequency of a previously reported rare, highly penetrant CFH variant (p.Arg1210Cys) in a Dutch-German non-CD-type AMD case-control cohort, and to describe the phenotype of patients carrying the p.Arg1210Cys variant. METHODS: Study subjects were selected from the European Genetic Database (EUGENDA), a joint AMD database of the Radboud University Medical Centre and the University Hospital of Cologne, and graded at the Cologne Image Reading Centre and Laboratory (CIRCL). Additionally, two CD cases were recruited from the VU Medical Centre in Amsterdam. The CFH gene was analyzed in 180 CD cases with Sanger sequencing. All identified variants were analyzed for potential damaging effects with prediction software tools Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping (PolyPhen). In addition, we genotyped the p.Arg1210Cys variant in 813 non-CD type AMD cases and 1175 controls. RESULTS: Sequencing identified 11 rare, heterozygous missense variants, one frameshift variant, and one splice acceptor site variant in 16 CD cases. The p.Arg1210Cys variant was identified in two CD cases but was not identified in our Dutch-German non-CD-type AMD case-control cohort. CONCLUSIONS: The present study identified the presence of rare variants in the CFH gene in 16 (8.8%) of 180 patients with the CD subtype of AMD. The carriers of rare CFH variants displayed a significantly earlier age at onset than non-carriers (p=0.016). The rare missense variant p.Arg1210Cys was identified in two CD cases, but was not detected in 813 non-CD type AMD cases or in the 1,175 controls of our Dutch-German cohort. The current study suggests that the p.Arg1210Cys variant may be restricted to a subset of patients with the CD subtype of AMD. Detailed clinical phenotyping, including fluorescein angiography, of patients with AMD carrying the p.Arg1210Cys variant in other cohorts is required to confirm this finding.

Association of Smoking and CFH and ARMS2 Risk Variants With Younger Age at Onset of Neovascular Age-Related Macular Degeneration.

IMPORTANCE: The age at which the first signs of age-related macular degeneration (AMD) manifest is variable. Better insight into factors that influence disease onset has direct implications for preventive measures and patient counseling. OBJECTIVE: To identify risk factors for an earlier age at onset of neovascular AMD. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study, including patient data from the European Genetic Database collected between April 2006 and July 2010. All patients had at least 1 documented visit to the outpatient AMD clinic of the Radboud University Medical Center, Nijmegen, the Netherlands, a tertiary referral center for retinal disorders. In total, 275 patients with a known age at onset of neovascular AMD and a genetic risk analysis were included. MAIN OUTCOMES AND MEASURES: Effects of several genetic, sociodemographic, behavioral, and ocular factors on the age at onset of neovascular AMD. The mean differences in the age at onset were determined using general linear models with the age at onset as the dependent variable. RESULTS: Past smokers and current smokers developed neovascular AMD on average 4.9 (95% CI, 3.0-6.8) and 7.7 (95% CI, 5.3-10.0) years earlier, respectively, than never smokers (P < .001 for both). Compared with the reference group, the age at onset was 5.2 (95% CI, 2.8-7.7) years earlier for homozygous carriers of the A69S risk allele in the age-related maculopathy susceptibility 2 (ARMS2) gene (P < .001). Homozygous carriers of the Y402H risk variant in the complement factor H (CFH) gene developed neovascular AMD 2.8 (95% CI, 0.5-5.0) years earlier (P = .02). Patients carrying 4 risk alleles in CFH and ARMS2 developed neovascular AMD 12.2 (95% CI, 6.2-18.3) years earlier than patients with zero risk alleles (P < .001). CONCLUSIONS AND RELEVANCE: Genetic and environmental risk factors influence the age at onset of neovascular AMD. Individuals at risk could be identified at an early age if and when preventive or therapeutic options become available. Insight into individual risk profiles might influence patients' consideration of interventions to increase their chance of avoiding vision loss from AMD.

Zinc supplementation inhibits complement activation in age-related macular degeneration.

UNLABELLED: Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. AMD is a multifactorial disorder but complement-mediated inflammation at the level of the retina plays a pivotal role. Oral zinc supplementation can reduce the progression of AMD but the precise mechanism of this protective effect is as yet unclear. We investigated whether zinc supplementation directly affects the degree of complement activation in AMD and whether there is a relation between serum complement catabolism during zinc administration and the complement factor H (CFH) gene or the Age-Related Maculopathy susceptibility 2 (ARMS2) genotype. In this open-label clinical study, 72 randomly selected AMD patients in various stages of AMD received a daily supplement of 50 mg zinc sulphate and 1 mg cupric sulphate for three months. Serum complement catabolism-defined as the C3d/C3 ratio-was measured at baseline, throughout the three months of supplementation and after discontinuation of zinc administration. Additionally, downstream inhibition of complement catabolism was evaluated by measurement of anaphylatoxin C5a. Furthermore, we investigated the effect of zinc on complement activation in vitro. AMD patients with high levels of complement catabolism at baseline exhibited a steeper decline in serum complement activation (p<0.001) during the three month zinc supplementation period compared to patients with low complement levels. There was no significant association of change in complement catabolism and CFH and ARMS2 genotype. In vitro zinc sulphate directly inhibits complement catabolism in hemolytic assays and membrane attack complex (MAC) deposition on RPE cells. This study provides evidence that daily administration of 50 mg zinc sulphate can inhibit complement catabolism in AMD patients with increased complement activation. This could explain part of the mechanism by which zinc slows AMD progression. TRIAL REGISTRATION: The Netherlands National Trial Register NTR2605.

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 × 10(-5)). Risk factors identified in sporadic and familial subjects were increasing age (odds ratio [OR], 1.08 per year; P = 3.0 × 10(-51), and OR, 1.15; P = 5.3 × 10(-36), respectively) and smoking (OR, 1.01 per pack year; P = 1.1 × 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 × 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.

Association analysis of genetic and environmental risk factors in the cuticular drusen subtype of age-related macular degeneration.

PURPOSE: To assess the association of gender, cigarette smoking, body-mass index, and nine genetic risk variants with cuticular drusen (CD), a well recognized subtype of age-related macular degeneration (AMD). METHODS: A total of 757 patients with AMD, including 217 patients with CD, and 553 control individuals were interviewed with a questionnaire and underwent an ophthalmic examination. Venous blood samples were obtained for genomic DNA extraction, and genotyping was performed of single nucleotide polymorphisms previously associated with AMD. Odds ratios were calculated for patients with CD, using unaffected control individuals as a reference. Furthermore, odds ratios in patients with CD were compared to those in patients with "non-CD" AMD. RESULTS: The CD subtype of AMD was significantly associated with current smoking as well as variants in the complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), complement factor B/complement component 2 (CFB/C2), complement component 3 (C3), and apolipoprotein E (APOE) genes. In patients with CD, the association with the CFH Y402H risk allele was significantly higher (p=0.022), whereas the association with current smoking was significantly lower (p<0.001) than in the heterogeneous group of patients with "non-CD" AMD. CONCLUSIONS: The AMD subtype of CD was associated with previously identified genetic AMD risk factors. However, the association with the CFH Y402H risk allele appeared to be stronger, whereas the association with smoking was less pronounced when compared to AMD as a whole. This study suggests a more important role for genetic factors than environmental factors in the development of this well defined subtype of AMD. These findings stress the importance of detailed phenotyping in AMD to identify homogeneous AMD subtypes, which may be associated with different risk factors and disease mechanisms. Such studies will improve the accuracy of predictive models and the effectiveness of preventive and therapeutic options in AMD.

Genetic, behavioral, and sociodemographic risk factors for second eye progression in age-related macular degeneration.

PURPOSE: This study was conducted to investigate the correlation of genetic, sociodemographic, and behavioral risk factors with second eye progression to end-stage AMD. METHODS: One hundred and eight patients with end-stage AMD in one or both eyes were included in a retrospective time-to-event analysis of the onset of end-stage AMD in the second eye. Multivariate Cox regression survival analysis was performed for sex, age, smoking, body mass index (BMI), education, and 16 single nucleotide polymorphisms (SNPs) associated with AMD. RESULTS: Except for education, all sociodemographic and behavioral risk factors analyzed were significantly associated with a more rapid progression toward second eye involvement. Hazard ratios (HRs) were 2.6 (95% confidence interval [CI], 1.4-5.0) for female sex; 5.0 (95% CI, 2.0-12.5) for age >80; 2.2 (95% CI, 1.1-4.1) for BMI >30; and 4.4 (95% CI, 1.4-14.3) for >40 pack years, compared with the referent groups. Carriers of the lipoprotein lipase (LPL; rs12678919) risk alleles were at risk for more rapid progression to end-stage AMD in the second eye compared with the referent wild-type genotype (HR 2.0; 95% CI, 1.0-3.6). For complement factor I (CFI; rs10033900), homozygous carriers of the risk allele progressed faster than wild-type individuals (HR 2.2; 95% CI, 1.1-4.3). CONCLUSIONS: Sociodemographic, behavioral, and genetic risk factors are associated with the rate of second eye progression toward end-stage AMD. The findings of this study underline the importance of lifestyle factors and the complement pathway in AMD progression and suggest a role of the high-density-lipoprotein metabolism in second eye progression.

Cumulative effect of risk alleles in CFH, ARMS2, and VEGFA on the response to ranibizumab treatment in age-related macular degeneration.

PURPOSE: Intravitreal ranibizumab injections currently are the standard treatment for neovascular age-related macular degeneration (AMD). However, a broad range of response rates have been observed, the reasons for which are poorly understood. This pharmacogenetic study evaluated the impact of high-risk alleles in CFH, ARMS2, VEGFA, vascular endothelial growth factor (VEGF) receptor KDR, and genes involved in angiogenesis (LRP5, FZD4) on the response to ranibizumab treatment and on the age of treatment onset. In contrast to previous studies, the data were stratified according to the number of high-risk alleles to enable the study of the combined effects of these genotypes on the treatment response. DESIGN: Case series study. PARTICIPANTS: A cohort of 420 eyes of 397 neovascular AMD patients. METHODS: The change in visual acuity (VA) between baseline and after 3 ranibizumab injections was calculated. Genotyping of single nucleotide polymorphisms in the CFH, ARMS2, VEGFA, KDR, LPR5, and FZD4 genes was performed. Associations were assessed using linear mixed models. MAIN OUTCOME MEASURES: The VA change after 3 ranibizumab injections and the age of neovascular disease onset. RESULTS: After ranibizumab treatment, AMD patients without risk alleles in the CFH and ARMS2 genes (4.8%) demonstrated a mean VA improvement of 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, whereas no VA improvement was observed in AMD patients with 4 CFH and ARMS2 risk alleles (6.9%; P = 0.014). Patients with 4 high-risk alleles in CFH and ARMS2 were 5.2 years younger than patients with 1 or 2 risk alleles, respectively (63.5%; P<0.0001). The mean age at which the first ranibizumab treatment was carried out among AMD patients with all 6 risk alleles in CFH, ARMS2, and VEGFA was 65.9 years (2%) versus 75.3 years in patients with 0 or 1 high-risk allele (8.8%; P = 0.001). After ranibizumab treatment, patients with 6 high-risk alleles demonstrated a mean VA loss of 10 ETDRS letters (P<0.0001). CONCLUSIONS: This study evaluated the largest pharmacogenetic AMD cohort reported to date. A cumulative effect of high-risk alleles in CFH, ARMS2, and VEGFA seems to be associated with a younger age of onset in combination with poor response rates to ranibizumab treatment.