Homozygous females for a X-linked RPGR-ORF15 mutation in an Iranian family with retinitis pigmentosa.

Mutations in Retinitis pigmentosa GTPase regulator gene (RPGR) are the most common cause of X-linked retinitis pigmentosa (RP). Almost 60% of disease-causing RPGR mutations are located in ORF-15 region which cannot be detected by Next Generation Sequencing (NGS) due to the existence of highly repetitive regions. An Iranian family with a priori diagnosis of autosomal dominant RP was studied by Sanger sequencing of ORF15 of RPGR gene after an inconclusive NGS result. A frameshift two-base-pair deletion (c.2323_2324del, p.Arg775Glufs*59) in this region was segregating in both affected hemizygous males and affected homozygous females. To our knowledge, this is the first example of homozygous females for RPGR-ORF15 mutations.

Autosomal Recessive Bestrophinopathy: Clinical and Genetic Characteristics of Twenty-Four Cases.

BACKGROUND: To describe ocular manifestations, imaging characteristics, and genetic test results of autosomal recessive bestrophinopathy (ARB). The study design is an observational case series. METHODS: Forty-eight eyes of 24 patients diagnosed with ARB underwent complete ophthalmic examinations including refraction, anterior and posterior segment examination, enhanced depth imaging optical coherence tomography (EDI-OCT), fluorescein angiography (FA), electroretinography (ERG), and electrooculography (EOG). Optical coherence tomography angiography (OCTA) and BEST1 gene sequencing were performed in selected patients. RESULTS: The age at onset was 4-35 years (mean: 18.6 years). The male-to-female ratio was 0.45. All patients were hyperopic, except one with less than one diopter myopia. EOG was abnormal in 18 cases with near-normal ERGs. Six patients did not undergo EOG due to their young age. Eighteen patients (75%) had a thick choroid on EDI-OCT, of which three had advanced angle-closure glaucoma, 15 patients were hyperopic, and eight of them had more than four diopters hyperopia in both eyes. Macular retinoschisis was observed in 46 eyes of 23 patients (95%) with cysts mostly located in the inner nuclear layer (INL) to the outer nuclear layer (ONL). Of the 18 patients who underwent FA, mild peripheral leakage was seen in eight eyes of four patients (22%). Subfoveal choroidal neovascularization (CNV) was seen in three eyes of two patients (6%) that responded well to intravitreal bevacizumab (IVB). Seven mutations of the bestrophin-1 (BEST1) gene were found in this study; however, only two of them (p.Gly34 = and p.Leu319Pro) had been previously reported as the cause of ARB based on ClinVar and other literature studies. CONCLUSIONS: ARB can be presented with a wide spectrum of ocular abnormalities that may not be easily diagnosed. Pachychoroid can occur alongside retinal schisis and may be the underlying cause of angle-closure glaucoma in ARB. Our study also expands the pathogenic mutation spectrum of the BEST1 gene associated with ARB.

Apparent but unconfirmed digenism in an Iranian consanguineous family with syndromic Retinal Disease.

BACKGROUND: Bardet-Biedl syndrome is an autosomal recessive disease characterized by rod-cone dystrophy, postaxial polydactyly, kidney defects, obesity, mental retardation and hypogonadism. Here, we report different genotypes in two Bardet-Biedl syndrome affected sisters with a different clinical phenotype regarding severity. MATERIALS AND METHODS: The proband of the family was examined by Next Generation Sequencing (NGS) using clinical exome and filtering by syndromic and non-syndromic genes associated with retinal dystrophies. RESULTS: Targeted NGS revealed two novel variants in the MKKS and CEP290 genes in homozygosis state in the proband. Segregation analysis revealed the presence of the same MKKS homozygous variant in her younger affected sister but not the CEP290 variant. Both sisters presented different clinical manifestation, at different ages, with a more severe renal and retinal defect in the case of the sister carrying mutations in both genes. Another unaffected sister showed only homozygosity for the CEP290 variant, thus supporting the non-pathogenic role of this mutation in BBS phenotype. CONCLUSIONS: In this study, NGS proved to be a powerful and efficient sequencing method to identify causal variants in different genes. However, it remarks the importance of the segregation analysis and clinical information to establish the pathogenicity of new variants. The two affected sisters present different genotypes and clinical manifestation, suggesting that the novel CEP290 variant could be acting as a modifier, making the phenotype more severe in the sister homozygote for MKKS and CEP290 genes. On the other hand, the difference in the age of both sisters highlight the important role of monitoring disease progression also to confirm the modifier role of genetic variants.

SLC30A8, CDKAL1, TCF7L2, KCNQ1 and IGF2BP2 are Associated with Type 2 Diabetes Mellitus in Iranian Patients.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a serious public health issue with significantly increasing rates across the world. The genome-wide association studies (GWAS) have previously manifested involved genes that remarkably enhance the risk of T2DM. In this study, the association of common variants with T2DM risk has been identified among Iranian population from Tehran province of Iran. METHODS: Here, the association of refSNPs with T2DM risk was examined on peripheral blood samples of 268 individuals including control group and patients with T2DM using the tetra amplification refractory mutation system (ARMS) methods and direct genomic DNA sequencing. RESULTS: Our study demonstrated that SLC30A8 rs13266634 (T/C), CDKAL1 rs10946398 (A/C), TCF7L2 rs7903146 (C/T), KCNQ1 rs2237892 (T/C), and IGF2BP2 rs1470579 (A/C) polymorphisms are significantly associated with type 2 diabetes, but no significant association was identified for FTO rs8050136 and MTNR1B rs10830963 polymorphisms. CONCLUSION: The prediction of refSNPs is remarkably needed for pharmacogenetics and pharmacogenomic approaches, in which the information would be useful for clinicians to optimize therapeutic strategies and adverse drug reactions in patients with T2DM.

Is there a relationship between body mass index and diabetic retinopathy in type II diabetic patients? A cross sectional study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is one of the most important leading causes of disability, premature mortality and Diabetic Retinopathy (DR) that is one of the diabetes-related complications in diabetic patients and the most common cause of vision loss in diabetic patients. The aim of the study was to evaluate the association between DR and body mass index (BMI) in those patients with T2DM. METHODS: This was a central-based, cross-sectional study on 518 diabetic patients. Their medical history and the laboratory data were collected. All the patients received examination of diabetic retinopathy by professional ophthalmologist. Based on their optic fundi findings, they were classified into five groups: No retinopathy, Mild Non-proliferative Diabetic Retinopathy (NPDR), Moderate NPDR, Severe NPDR, Proliferative diabetic retinopathy (PDR). To analysis data SPSS v18 software used. Frequency, percent, mean and standard deviation were used for population description. t test, spearman correlation, partial correlation, analysis of variance (ANOVA) and Chi-square test (χ2) were used for analytic analysis. Multivariate logistic regression was used to estimate the odds ratio. RESULTS: 518 patients with T2DM 198 male (38%), 320 female (62%) included in this study. The mean age of patients was 61.02 ± 10.18 years. The mean age at onset was 49.06 + 10.52 years and the mean duration of diabetes was 12.09 ± 7.81 years. There was a strong relationship between duration of diabetes and DR (P = 0.001). There were strong significant association between the development of DR and Insulin therapy (OR = 5.975). Correlation analysis between Retinopathy and BMI showed that BMI had inverse relationship with DR when BMI considered as a continuous variable (p-value = 0.009 and correlation coefficient = -0.467). CONCLUSION: BMI in diabetic patient is one of the most important clinical parameter for their health and disease progression. We conclude that BMI had inverse relationship with DR when BMI considered as a continuous variable.

Intravitreal Injection of Anti-vascular Endothelial Growth Factor Agents for Ocular Vascular Diseases: Clinical Practice Guideline.

PURPOSE: To provide the clinical recommendations for the administration of intravitreal anti-vascular endothelial growth factor (VEGF) drugs especially bavacizumab for ocular vascular diseases including diabetic macular edema, neovascular age-related macular degeneration, myopic choroidal neovascularization, retinal vein occlusion and central serous chorioretinopathy. METHODS: Twenty clinical questions were developed by the guideline technical committee. Relevant websites and databases were searched to find out the pertinent clinical practice guidelines to answer the questions. The technical committee provided possible answers (scenarios) according to the available evidences for each question. All scenarios along with their levels of evidence and the supported articles were sent to the experts for external review. If the experts did not agree on any of the scenarios for one particular clinical question, the technical committee reviewed all scenarios and their pertinent evidences and made the necessary decision. After that, the experts were asked to score them again. All confirmed scenarios were gathered as the final recommendations. RESULTS: All the experts agreed on at least one of the scenarios. The technical committee extracted the agreed scenario for each clinical question as the final recommendation. Finally, 56 recommendations were developed for the procedure of intravitreal anti-VEGF injection and their applications in the management of ocular vascular diseases. CONCLUSION: The implementation of this guideline can standardize the management of the common ocular vascular diseases by intravitreal injection of anti-VEGF agents. It can lead to better policy-making and evidence-based clinical decision by ophthalmologists and optimal evidence based eye care for patients.

Diabetic Retinopathy Clinical Practice Guidelines: Customized for Iranian Population.

PURPOSE: To customize clinical practice guidelines (CPGs) for management of diabetic retinopathy (DR) in the Iranian population. METHODS: Three DR CPGs (The Royal College of Ophthalmologists 2013, American Academy of Ophthalmology [Preferred Practice Pattern 2012], and Australian Diabetes Society 2008) were selected from the literature using the AGREE tool. Clinical questions were designed and summarized into four tables by the customization team. The components of the clinical questions along with pertinent recommendations extracted from the above-mentioned CPGs; details of the supporting articles and their levels of evidence; clinical recommendations considering clinical benefits, cost and side effects; and revised recommendations based on customization capability (applicability, acceptability, external validity) were recorded in 4 tables, respectively. Customized recommendations were sent to the faculty members of all universities across the country to score the recommendations from 1 to 9. RESULTS: Agreed recommendations were accepted as the final recommendations while the non-agreed ones were approved after revision. Eventually, 29 customized recommendations under three major categories consisting of screening, diagnosis and treatment of DR were developed along with their sources and levels of evidence. CONCLUSION: This customized CPGs for management of DR can be used to standardize the referral pathway, diagnosis and treatment of patients with diabetic retinopathy.

The rs3917779 polymorphism of P-selectin's significant association with proliferative diabetic retinopathy in Yazd, Iran.

PURPOSE: This study aims at investigating possible associations of P-selectin polymorphisms with proliferative diabetic retinopathy (PDR) in Yazd, Iran. METHODS: The subjects of the study included of 55 PDR and 55 diabetic no retinopathy (DNR) cases attending Yazd Diabetes Research Center (YDRC). P-selectin genotyping was done by an ARMS-PCR method. RESULTS: The P-selectin variants rs6128, rs6133, and rs3917779 were not in Hardy-Weinberg equilibrium. The frequency of the rs3917779 C allele (P < 0.0001), but not the rs6133 G allele (P = 0.19) or rs6128 allele (P = 0.20), was higher in PDR cases than in control DNR cases. Significant differences in the distribution of rs3917779 (P < 0.001), but not rs6128 (P = 0.52) or rs6133 (P = 0.18), genotypes were observed between cases and controls, and only rs3917779 showed a significant association with PDR, with increments of 49.2 (14.72-125.07) in disease risk seen for CC genotypes. Among the eight three-locus P-selectin haplotypes constructed (rs6128 / rs6133 / rs3917779), there was no significant difference between frequencies of haplotypes in the DNR and PDR groups. CONCLUSIONS: P-selectin gene polymorphisms and haplotypes can contribute to PDR development.

Single cotton wool spot as a late manifestation of head trauma.

PURPOSE: To report a patient with a single cotton wool spot (CWS) following head trauma. CASE REPORT: A 37-year-old male electrician presented with painless paracentral blurred vision in his left eye of one month duration together with three transient episodes of obscuration of vision in the same eye lasting for 10 minutes. He reported blunt head trauma due to a fall 40 days before referral. Fundus examination at presentation was normal but after 4 months, revealed the appearance of a white spot along the superotemporal arcade in the absence of other fundus lesions. A comprehensive systemic workup was performed revealing no specific findings. Ophthalmoscopic examination after 6 weeks disclosed resolution of the CWS with no intervention. The patient's complaint of paracentral visual field defect improved and subsequent optical coherence tomography showed retinal thinning in that area. CONCLUSION: Herein, we report a patient with a single CWS near the optic disc four months after head trauma along with normal systemic and paraclinical evaluations. Head trauma may thus be considered as a cause of CWS.

Effect of pan retinal photocoagulation on the serum levels of vascular endothelial growth factor in diabetic patients.

This study tests the hypothesis that subjects with proliferative diabetic retinopathy (PDR) have a detectable rise in levels of serum vascular endothelial growth factor (VEGF), which is an important regulator of angiogenesis. Our investigation aims to evaluate plasma VEGF changes after pan-retinal photocoagulation (PRP) in diabetic patients. Twenty-nine type two diabetic patients (17 male, 12 female: mean age 53.13±12.22 years) with PDR secondary to diabetes were studied. Blood samples were obtained before and at 2 months after the last PRP session. Serum VEGF levels were measured by ELISA. After PRP, the mean serum VEGF decreased, but this reduction was not remarkable (88.68±71.09 vs. 77.01±60.33 ng/ml) (P=0.18). There was a statistically significant difference in serum VEGF changes between patients who had regressed PDR with patients who had progressed PDR (-25.98±47.37 vs. 56.44±31.7 ng/ml) (P=0.003). Our results showed a significant reduction in levels of serum VEGF in the patients who had successful laser treatment. Our findings suggest that serum VEGF levels could be used for monitoring diabetic retinopathy outcome.

Subconjunctival bevacizumab injection in treatment of pterygium.

This study determined the clinical effect of subconjunctival administration of bevacizumab in patients with primary and recurrent pterygium. The study was an off-label, single-dosing, interventional case series involving 22 patients with primary and recurrent pterygium. They received subconjunctival bevacizumab (0.2 cc). Pterygium vascularity and thickness was graded. The size of the pterygium (measured by surface area in cm2) was recorded from baseline to 12 weeks, after injection. Treatment-related complications and adverse events were reported. The main outcome of measurements was the change in size, vascularity, thickness, color intensity. There were 15 males (68.2%) and 7 females (31.8%) of 22 patients with a mean age of 45.5 years (SD 11.68 years). One cases didn't cooperate, and excluded. There was a significant difference in the mean surface area of pterygium at different intervals (P < 0.05) and the size of pterygium was reduced. On comparison of the mean pterygium size, there was no significant difference between men and women (P >0.05). There was a significant reduction in the mean pterygium size of patients younger than 45 years in comparison to those older than 45 years after three month (P =0.037), but after 6 months, this difference was not significant (P = 0.338). Average changes in pterygium size for both eyes were not different. The reduction of color intensity in both eyes was significant (P =0.031). Subconjuctival bevacizumab injection is useful in management of patients with primary and recurrent pterygium without significant local or systemic adverse effects.

Corneal topographic changes in healthy siblings of patients with keratoconus.

AIM: To describe the involvement in relatives of keratoconus (KCN) patients with corneal topography map. METHODS: A total of 150 siblings of 300 eyes of 75 KCN patients referred to corneal clinic were studied and experienced complete slit-lamp, refraction examinations and topographic cornea maps provided by videophotoker-atography. ANOVA, Fisher exact and Chi-square tests performed to compare of results. RESULTS: Of 150 siblings, 56% were female and 44% were male with average age of 21 (range 15-39) years. KCN and suspect KCN diagnosed in 12.3% and 6.6% respectively. The central keratometry (CK) was 46.5±4.51 dioptr (D) in KCN and 45.66±1.52D in suspect KCN. Inferior-superior value (I-S) was 3.51±2.5D in KCN and 1.56±1.22D in suspect KCN. In KCN condition the oval pattern was 67.6% (n=25) and Round pattern detected 32.4% (n=12). In suspect KCN these patterns detected 90% and 10% respectively. Refractive errors in KCN were -7.5 to +1.25 dioptr (-1.25±1.83), in suspect KCN 0.45 to -4.2 dioptr (-0.68±0.76) and in healthy group 2.75 to -7.5 dioptr (-0.6±1.12). Astigmatism was mild in 22.7%, moderate and sever astigmatism in 18.3% in KCN and suspect KCN CONCLUSION: Increasing KCN condition in healthy siblings of KCN patients shows require to screening plan to early diagnose and cautionly treatment of contact lens in these individuals.

Wolfram Syndrome presenting with optic atrophy and diabetes mellitus: two case reports.

Wolfram syndrome is the constellation of juvenile onset diabetes mellitus and optic atrophy, known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness).Patients demonstrate diabetes mellitus followed by optic atrophy in the first decade, diabetes insipidus and sensorineural deafness in the second decade, dilated renal outflow tracts early in the third decade, and multiple neurological abnormalities early in the fourth decade.This study reports two siblings with late diagnosed wolfram syndrome with diabetes insipidus, diabetes mellitus, optic atrophy, deafness and severe urological abnormalities.In conclusion, cases having early onset insulin-dependent diabetes mellitus and optic atrophy together need to be evaluated with respect to Wolfram.

Prevalence of dry eye syndrome and diabetic retinopathy in type 2 diabetic patients.

BACKGROUND: This study was performed to assess the prevalence of dry eye syndrome and diabetic retinopathy (DR) in type 2 diabetic patients and their contributing factors. METHODS: 199 type 2 diabetic patients referred to Yazd Diabetes Research Center were consecutively selected. All Subjects were assessed by questionnaire about other diseases and drugs. Dry eye syndrome was assessed with Tear break up time tests and Schirmer. All the subjects underwent indirect ophthalmoscopy and retinal color photography. DR was graded according to early Treatment Diabetic Retinopathy (ETDRS) criteria. RESULTS: Of 199 subjects, 108 patients (54.3%) suffer from dry eye syndrome. Although dry eye syndrome was more common in older and female patients, this association was not significant. But there was significantly association between dry eye syndrome and duration of diabetes (P = 0.01). Dry eye syndrome was more frequent in diabetic patients with DR (P = 0.02). DR was found in 140 patients (70.35%), which included 34 patients (17.1%) with mild non proliferative DR (NPDR), 34 patients (17.1%) with moderate NPDR, 22 patients (11.1%) with severe NPDR and 25 patients (25.1%) with proliferative DR (PDR). There were significant relation between age, sex and duration of diabetes and DR. CONCLUSION: In this study the prevalence of dry eye syndrome was 54.3%. Diabetes and dry eyes appear to have a common association. Further studies need to be undertaken to establish an etiologic relationship. However, examination for dry eye should be an integral part of the assessment of diabetic eye disease.