Priscila Hae Hyun Rim

Ophthalmic Aspects of GAPO Syndrome: Case Report and Review

This paper reports on a 36-year-old woman with GAPO syndrome, a rare autosomal recessive condition characterized by growth retardation (G), alopecia (A), pseudoanodontia (P), and optic atrophy (O). Her parents are consanguineous and one of her sisters is also affected. Since the first description by Anderson and Pindborg in 1947, 27 individuals have been reported with this diagnosis. They were from at least 19 different families (four of them from Brazil, including the present one), suggesting a founder effect. The phenotype of this condition, initially considered as the result of an ectodermal dysplasia, could be attributed to the accumulation of extracellular connective tissue matrix and its progressive character must be pointed out. The clinical findings, especially ophthalmological features that include bilateral glaucoma, are reviewed and discussed.

Genetics and prevention of blindness

PURPOSE To verify the perception of Brazilian ophthalmologists regarding the role played by Genetics in their routine medical activity and their conduct when dealing with patients, with hereditary diseases who need genetic counseling. METHODS A cross-sectional survey was conducted by means of invitations to participate in an interview on this subject. The questionnaires were sent to 200 ophthalmologists who work in the area of Campinas, SP, Brazil. RESULTS Among the 73 professionals who answered the questionnaire (36%), there was a high rate of positive answers (49-88%) concerning their knowledge of genetics and a low rate (10-33%) of use of this knowledge in their clinical practice. The frequency of genetic ophthalmopathies in clinical practice was relevant in the opinion of 68% of the interviewees; 92% indicated a relevant relationship between genetically determined ocular disorders and the prevention of blindness through detection, early treatment and genetic counseling. More extensive genetic knowledge was considered indispensable to 84% of the professionals, but 16% answered that it was irrelevant. CONCLUSIONS Although these ophthalmologists have basic notions of genetics (88,0%) and are aware of its importance in the prevention of blindness, a great majority of Brazilian ophthalmologists have not acquired adequate knowledge of genetics and, in practice, rarely use its therapeutic and preventive potential.

Association of LOC387715/ARMS2 (rs10490924) Gene Polymorphism with Age-related Macular Degeneration in the Brazilian Population

Abstract Background: An association between LOC387715/ARMS2 (rs10490924) gene polymorphism and AMD has been reported. The aim of this study was to evaluate whether this polymorphism is associated with AMD in a Brazilian cohort. Materials and Methods: In total, 126 unrelated AMD patients (mean age 74.17 ± 7.64) were compared with 86 healthy controls (mean age 71.82 ± 7.12). Study subjects were classified according to the International ARM Epidemiological Study Group definition for early and late-stage AMD. LOC387715/ARMS2 rs10490924 polymorphism was evaluated through polymerase chain reaction and direct sequencing. Results: The T allele frequency was significantly higher in AMD patients than in controls (39.6% compared to 20.3%). The odds ratio (OR) for AMD was 2.05 (95% CI 1.13–3.71) for heterozygotes (TG) and 8.32 (95% CI 2.30–45.99) for homozygotes (TT). Conclusions: These results suggest that there is a contribution of the rs10490924 SNP of the LOC387715/ARMS2 gene to AMD susceptibility in this sample of the Brazilian population.

Evaluation of CFH Y402H polymorphism and CFHR3/CFHR1 deletion in age-related macular degeneration patients from Brazil

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness worldwide. Considered a multifactorial disease, genetic and environmental factors corroborate for its development. Klein and colleagues mapped AMD to the 1q31 region in 1998 and variant Y420H (rs1061170) in the complement factor H (CFH) gene was the first variant related to AMD in this region. The substitution of tyrosine for histidine contributes to changes in how CFH interacts with heparin and C-reactive protein, affecting complement regulation mediated by the gene. Since its discovery this single nucleotide polymorphism (SNP) has been related to an increased risk for the disease in several populations from different ethnicities around the world. Furthermore, Spencer and co-workers suggested that the CFHR3/CFHR1 deletion leads to the loss of two complement regulators (CFHR1 and CFHR3), increasing regulation mediated by CFH, having a protective effect against AMD development. We aimed at evaluating the contribution of Y402H polymorphism in the CFH gene and CFHR3/CFHR1 deletion in the 1q32 region in relation to AMD’s etiology in a sample of the Brazilian population. A total of 175 subjects diagnosed with AMD (case group) and 165 without (control group) were analyzed. Both patients and control subjects were selected at the Clinical Hospital of the University of Campinas (UNICAMP), Campinas, São Paulo, located in the Southeast of Brazil. This study was approved by the Ethics Committee and all participants signed an informed consent. Details about ophthalmic examination, inclusion and exclusion criteria as well as classification were previously described. The Y402H variant was evaluated through PCR and enzymatic digestion, and the CFHR3/ CFHR1 deletion through PCR as published elsewhere. Statistical analysis was performed using SAS program (Statistical Analysis System, version 9.4, by SAS Institute Inc., 2002–2008, Cary, NC, USA). Chi-square and Fisher’s exact tests were used to compare categorical variables. Kruskal-Wallis and Mann-Whitney tests were used to compare quantitative variables. Univariate and multivariate logistic regression analysis were used to investigate risk factors for AMD. A p-value less than 0.05 was considered statistically significant. Hardy-Weinberg Equilibrium was employed to analyze genotype distribution in case and control groups. Overall, 340 individuals were involved in this study. Out of these, 130 patients (74.29%) had the advanced form of the disease (A) versus 45 patients (25.71%) with non-advanced AMD (NA). Sixty-six patients (37.71%) presented with the dry form and 109 (62.29%) with the wet form of AMD. Mean age was 74.44 ± 8.02 for cases and 71.36 ± 7.10 for controls. In the case group 42% were men against 47% in the control group and 45% were smokers in the case group against 25% in the control group.When the variables gender, smoking and genetic factors were evaluated in relation to the risk of developing AMD, no association was observed for gender and smoking. The C allele of the CFH Y402H SNP was more frequent in the case group than in the control group (47% compared to 31%) (p = .00002, chi-square test) and considered a risk factor for the disease. The genotype distribution was consistent with the Hardy-Weinberg Equilibrium (HWE) in both groups. The frequency of the CFHR3/CFHR1 deletion was higher in the control group (8.5%) than in the case group (1.7%) (p = .0097), suggesting a protective role against the disease. All possible combination of genotypes and respective odds ratios (OR) are depicted in Table 1. After stratifying AMD according to its subtypes, results were also significantly different between “wet vs. controls” (p = .0004) and “dry vs. controls” (p = .0004) for the CFH genotypes and allele frequency (p < .001). The highest OR was achieved for CC versus TT genotypes when comparing “wet versus controls.” Evaluating the role of the CFHR3/CFHR1 deletion in relation to AMD type, the risk for the absence of the deletion was higher in the wet type group compared to the control group (p = .0423). After the evaluation of theCFH genotypes in relation to the form of the disease results show that the CC genotype is significantly associated with both A and NA forms when compared to the control group, with the highest OR for the advanced form (p < .0001). Evaluating the role of the CFHR3/CFHR1 deletion in relation to AMD form, the presence of the deletion was not statistically different between groups. After the multivariate regression analysis only the CFH category CC/TC versus TT sustained the significance for all comparisons (Table 2).

Ocular findings in Brazilian identical twins with Cohen syndrome: case report

A case of identical male twins with Cohen syndrome who present multiple ophthalmic findings is reported. The patients were identical 16 year-old twin boys who showed down slanting eyelids, mild ptosis, high-grade myopia, small cortical lens opacities, posterior subcapsular cataracts, myotic and corectopic pupils with poor dilation due to focal iris atrophy and retinochoroidal dystrophy. Ophthalmologists must be aware of the ocular and systemic findings of Cohen syndrome in the evaluation of young patients with mental retardation and visual impairment.

Association of HTRA1 rs11200638 with age-related macular degeneration (AMD) in Brazilian patients

ABSTRACT Age-related macular degeneration is a multifactorial disease that can lead to vision impairment in older individuals. Although the etiology of age-related macular degeneration remains unknown, risk factors include age, ethnicity, smoking, hypertension, obesity, and genetic factors. Two main loci have been identified through genome-wide association studies, on chromosomes 1 and 10. Among the variants located at the 10q26 region, rs11200638, located at the HTRA1 gene promoter, has been associated with age-related macular degeneration in several populations and is considered the main polymorphism. We conducted a replication case–control study to analyze the frequency and participation of rs11200638 in the etiology of age-related macular degeneration in a sample of patients and controls from the State of São Paulo, Brazil, through polymerase chain reaction and enzymatic digestion. The frequency of the A allele was 57.60% in patients with age-related macular degeneration and 36.45% in controls (p value < 1e–07), representing a 2.369-fold higher risk factor for the disease. Both the AA and AG genotypes were observed more frequently in the age-related macular degeneration group compared to the control group (p = 1.21e–07 and 0.0357, respectively). No statistically significant results were observed after stratification in dry versus wet types or advanced versus non-advanced forms. To our knowledge, this is the first time the association between rs11200638 and overall age-related macular degeneration has been reported in South America.