A variant in OLFML3 is associated with pectinate ligament abnormality and primary closed‐angle glaucoma in Border Collies from the United Kingdom

PurposeTo study the factors affecting the corneal endothelium after selective laser trabeculoplasty (SLT) in primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG).MethodThis prospective interventional study included 56...

The aim of this study is to describe the ocular and demographic features of Caucasian patients newly presenting with primary angle closure glaucoma and the proportion of workload it represents at a tertiary university hospital glaucoma service. A retrospective case notes review was conducted for all Caucasian patients newly diagnosed with narrow angles, primary angle closure, acute primary angle closure and primary angle closure glaucoma that were seen over a period of 2 years. Demographic and ocular variables were compared and statistical analysis was carried out with the paired t-test and chi-squared test. Number of primary open angle closure glaucoma and acute angle closure cases were compared with total number of new referrals to the department, new patients diagnosed with glaucoma and population numbers for the North East of Scotland. One hundred and four patients were analysed. Twenty-four (23.1%) had narrow angles, 30 (28.8%) had primary angle closure and 50 (48.1%) had primary angle closure glaucoma. Twelve (11.5%) presented with acute primary angle closure. There was no significant difference for gender, age, hypermetropia or visual acuity between groups. Primary angle closure glaucoma constituted 22.9% (50/128) of newly diagnosed glaucoma cases. Based on the 2001 Scotland census, the crude annual incidence of newly diagnosed primary angle closure glaucoma was estimated at 14.8 per 100 000 and 3.6 per 100 000 for acute primary angle closure in the over-45-year-old population. Our study confirms that primary angle closure glaucoma is uncommon in Caucasians, but not as rare as originally perceived as it makes up a fair proportion (22.9%) of glaucoma workload.

Purpose:To quantitatively analyze central corneal thickness (CCT) in patients with primary angle closure glaucoma (PACG) and primary open-angle glaucoma (POAG), and to evaluate its correlation with severity of glaucoma.Methods:In this retrospective study, records of patients with previously diagnosed POAG or PACG at a tertiary glaucoma service were reviewed. CCT was measured by ultrasound pachymetry. Mean deviation (MD) on visual field (VF) testing was recorded for glaucoma severity determination. CCT and age- and sex-adjusted CCT were compared among the study groups using Student's t-test and analysis of covariance (ANCOVA), respectively. Univariate and multivariate regression models were used for correlation of age, MD and CCT.Results:A total of 115 patients with PACG, 215 with POAG, and 100 normal controls were included with mean age of 64.1 ± 10.4, 59.9 ± 10.5, and 62.04 ± 10.80 years, respectively. CCT was thicker in PACG eyes (545.5 ± 46.1 μm) as compared to POAG eyes (531.7 ± 37.3 μm) and controls (531.0 ± 38.3 μm) even after age and gender adjustment (ANCOVA, P = 0.05). CCT was found to decrease with increasing age only in the POAG group (β = -0.57, P = 0.01). Disease severity (MD of VF) was significantly and inversely correlated with CCT in both POAG and PACG eyes (β = 1.89, P = 0.02; and β = 1.38, P = 0.04, respectively) after age and sex correction.Conclusion:PACG eyes had thicker CCT as compared to POAG and normal healthy eyes in Iranian subjects. Severity of the disease was inversely correlated with CCT in eyes with both POAG and PACG.

Spectral-domain optical coherence tomography (SD-OCT) facilitates early glaucoma detection in the Chinese population in Taiwan. The best parameters for primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG), normal tension glaucoma (NTG), and suspected glaucoma (GS) detection are temporal inferior Bruch's membrane opening-minimum rim width (BMO-MRW), inner temporal macular ganglion cell layer (mGCL), temporal superior Circumpapillary retinal nerve fiber layer (cpRNFL), and mean global BMO-MRW, respectively. We investigated the diagnostic capability of SD-OCT for different types of early glaucoma among the Chinese population in Taiwan. One eye each was assessed from 113 individuals with healthy eyes, 125 individuals with suspected glaucoma (GS), and 156 patients with early glaucoma (POAG, 87; PACG, 50; and NTG, 19). Circumpapillary (cp) RNFL thickness (global and sectoral), BMO-MRW, and macular parameters, including the macular RNFL (mRNFL), mGCL, and macular inner plexiform layer (mIPL), were assessed using SD-OCT. The areas under receiver operator characteristic curves (AUCs) were calculated to evaluate the diagnostic capacity of the parameters to differentiate between healthy and early glaucomatous eyes. The parameters most suitable for detecting early POAG, PACG, NTG, and GS were temporal inferior BMO-MRW (AUC, 0.847), inner temporal mGCL (AUC, 0.770), temporal superior cpRNFL (AUC, 0.861), and mean global BMO-MRW (AUC, 0.768), respectively. Among the macular parameters, the mGCL exhibited the highest diagnostic capacity. The diagnostic capacity of the mGCL was lower than that of cpRNFL and BMO-MRW for POAG and NTG but not PACG. After adjusting for confounding variables in multivariable analysis, the AUC was determined to be 0.935 for POAG and 0.787 for GS. SD-OCT facilitates the detection of early POAG, PACG, and NTG. Using a combination of cpRNFL, BMO-MRW, and macular parameters may enhance their diagnostic capacities. Further studies are necessary to validate these findings.

Clear lens extraction in eyes with primary angle closure and primary angle-closure glaucoma

Association of body mass index and PXDNL gene variants with acute primary angle closure in southern Chinese population

Background Glaucoma is an optic neuropathy caused by structural damage of the optic nerve,and its early diagnosis is critical for arresting the irreversible damage of visual function. Optical coherence tomography (OCT) allows an early diagnosis of glaucoma by the measurements of the optic disc and retinal nerve fiber parameters. Objective This study was carried out to evaluate the effects of optic disc tomography and the measurement of the retinal nerve fiber layer (RNFL) thickness by spectral-domain OCT on the diagnosis of glaucomatous eye. Methods It was a noninterventional, cross-sectional study. The optic disc topographic parameters and total and regional RNFL thickness were measured by RTVue OCT in 62 normal eyes and 67 glaucomatous eyes. The area under the receiver operating characteristic curve( ROC ) was used to assess the ability to differentiate glaucoma eyes from normal eyes of each testing parameter. This trial complied with the Helsinki Declaration and was approved by the Clinical Trial Ethic Committee of Beijing Tongren Hospital. All of the participants signed the written informed consent before any medical examination. Results In the comparison of demography ,the ages of patients, the mean deficiency( MD ) and pattern standard difference( PSD ) of perimetry were obviously larger in the glaucoma group, primary open angle glaucoma ( POAG ) group and primary closure-angle glaucoma(PACG) group than those of normal controls( P＜0. 01 ). No significant differences were found in the disc area between a total glaucoma group, POAG group or PACG group and normal group ( P =0. 101,0. 741 and 0. 652, respectively) ;however, the average RNFL thickness between normal eyes and glaucomatous eyes were significantly different( 109. 758 μm versus 79. 539 μm, P＜0. 01 ). Among the eight regions around the optic disc, the thickest RNFL located at the inferotemporal( 150. 109 μm) and superotemporal( 146. 105 μm) regions in normal eyes,and at the superotemporal( 104. 354 μm) and inferotemporal( 102. 436 μm) regions in glaucomatous eyes. Both in normal and glaucomatous eyes,the thinnest RNFL located at the nasal(NU+NL) and temporal(TU + TL) regions. For optic disc topographic parameters,the highest ROC were observed in rim volume( ROC--0. 850,0. 841 and 0. 862 in total glaucoma,POAG and PACG, respectively) and vertical cup/disc ratio( ROC =0. 840,0. 849 and 0. 830 in total glaucoma,POAG and PACG,respectively), and the sensitivities for specificity cutoff set at 80％ were 73.1％ and 76. 1％ in total glaucoma,73.0％ and 81.1％ in POAG and 73.3％ and 70.0％ in PACG, respectively. For RNFL thickness ,the highest ROC was observed in average RNFL( ROC =0. 925,0. 910 and 0. 942 in total glaucoma, POAG and PACG,respectively) ,and the sensitivities for specificity cutoff set at 80％ were 89. 6％ ,89.2％ and 90. 0％ in total glaucoma,POAG and PACG, respectively. Among the eight regions around the optic disc, RNFL thickness of region IT achieved the highest ROC, RNFL thickness of region TU and TL had the lowest ROC. Conclusions RTVue OCT appears to be of fair discriminating ability in distinguishing normal from glaucomatous eyes. RTVue OCT shows promise for the diagnosis of glaucoma. Key words: Optical coherence tomography; Glaucoma; Optic disc; Retinal nerve fiber layer

Previous genome-wide studies have demonstrated significant pathogenic association between variants rs35934224 within TXNRD2 and rs6478746 near LMX1B in primary open-angle glaucoma. We investigated the association between these variants in primary angle-closure glaucoma (PACG) and pseudoexfoliation glaucoma (PXG) patients of Saudi origin. In a case-control study, DNA samples from 249 controls (135 men and 114 women), 100 PACG cases (44 men and 56 women), and 95 PXG cases (61 men and 34 women) were genotyped by TaqMan® based real-time PCR. Statistical tests were performed to evaluate genetic association with glaucoma types and related clinical indices. The allele frequencies of rs35934224 and rs6478746 did not show significant variation in PACG and PXG than controls, except that the rs35934224[T] allele was found to be significantly low among PXG women (0.10) as compared to controls (0.21) (odds ratio = 0.38, 95% confidence interval = 0.16-0.94, p = 0.024). Rs35934224 genotypes showed a nominal-to-borderline protective association with PACG and PXG among women in different genetic models. However, except for the over-dominant model in PACG (p = 0.0095), none of the effects survived Bonferroni's correction (p < 0.01). Rs6478746 showed no significant genotype or allelic association with PACG and PXG. Regression analysis showed no influence on disease outcome, and neither showed any correlation with intraocular pressure and cup/disk ratio in both PACG and PXG. Variants rs35934224 in TXNRD2 and rs6478746 near LMX1B are not associated with PACG and PXG in the Saudi cohort, but rs35934224 may confer modest protection among women. Further population-based studies are needed to validate these results.

Prevalence of Primary Angle Closure and Primary Angle-Closure Glaucoma in a Southwestern Rural Population of Japan: The Kumejima Study

BackgroundGlaucoma is a polygenic neurodegenerative disease and the second most common cause of blindness in Saudi Arabia. To test the hypothesis that genetic variants in the genes involved in the bone morphogenic protein (BMP) signaling pathway may be associated with glaucoma, we investigated the association between 3′ untranslated region variants, rs12997 in ACVR1 and rs1043784 in BMP6, and primary angle-closure glaucoma (PACG) and pseudoexfoliation glaucoma (PXG).MethodsIn a case-control study, TaqMan® real-time PCR-based genotyping was done in 444 subjects consisting of 250 controls, 101 PACG and 95 PXG cases, and tested for genetic association with glaucoma-types and other clinical phenotypes.ResultsRs12997[G] allele in ACVR1 exhibited significant 2-fold increased risk of PACG (p = 0.005) in women but not in men. Similarly, genotype analysis also showed that subjects carrying rs12997[G/G] genotype were at > 2-fold risk of PACG that remained significant after adjustment for age, sex, and Bonferroni correction in the recessive model. Furthermore, this effect was also significant in women only. In PXG, the rs12997[G/G] genotype showed a significant trend towards increased risk of the disease (OR = 2.04, 95% CI = 0.99–4.18, p = 0.049) but did not survive the Bonferroni correction. Regression analysis showed that rs12997[G/G] genotype was a significant predictor of PACG independent of age, sex, and rs1043784 genotypes. Likewise, age and rs12997[G/G] genotype showed significant effect on PXG outcome. The rs12997[A/G] genotype showed significant association with cup/disc ratio as compared to wild-type (p = 0.005) in PXG. Genotype and allele frequencies of rs1043784 in BMP6 did not show any significant association either with PACG or PXG.ConclusionsOur results suggest that the polymorphism rs12997 in the ACVR1 gene involved in the BMP signaling pathway is significantly associated with PACG and PXG in a Saudi cohort. This is the first study to associate this variant/gene with PACG and PXG. However, further studies would be needed to replicate these findings in a large population-based cohort.

To compare the patterns of retinal nerve fiber layer (RNFL) thickness loss in primary angle-closure glaucoma (PACG) and primary open-angle glaucoma (POAG) using optical coherence tomography (OCT). Forty-three participants with PACG and 60 with POAG underwent fast RNFL thickness measurement by OCT. Eyes were classified according to the visual field mean deviation (VF-MD) into mild (>-8 dB), moderate (-8 dB to >-16 dB), and advanced (≤ -16 dB) glaucoma subgroups. The raw RNFL thickness data were compared with data from the Thai normative database. Mean (SD) age was 67.0 (9.6) and 64.1 (11.6) years in the PACG and POAG groups, respectively (P = 0.19). In the mild subgroups, a focal RNFL thickness loss was found in the inferior area in the POAG group, but not in the PACG group. The RNFL defect involved sectors 1, 6, and 7 in the moderately advanced disease subgroups of both PACG and POAG and extended through almost all sectors in the advanced disease subgroups. The deepest RNFL defect, -17.25 μm, was found in sector 6 of the mild POAG subgroup, compared with -8.78 μm in the PACG group (P = 0.04). The number of affected points in each sector in the mild subgroups was greater in the POAG group than in the PACG group. Participants with mild POAG had deeper and more localized RNFL defects than did participants with PACG. The pattern was similar in participants with moderate or advanced disease.

Comparison of microvascular parameters and diagnostic ability of optical coherence tomography angiography between eyes with primary angle closure glaucoma and primary open angle glaucoma

&lt;p&gt;Primary angle closure glaucoma (PACG) is a chronic optic neuropathy that results in retinal ganglion cell (RGC) degeneration, cupping of the optic nerve head (ONH) and subsequent loss of vision. In humans, PACG occurs as a result of a plateau iris or more commonly, a pupillary block. Increased Intraocular pressure and reduced axial length are some of the predisposing factors to PACG. The condition occurs in several breeds of dogs and the prognosis for affected animals is typically poor. Unlike PACG in humans, the mechanism of PACG in canines involves the gradual collapse of the ciliary cleft with or without complete collapse of the irido-corneal angle. We have identified and examined several Basset Hound (BH) pedigrees with clinically confirmed PACG that segregates in an autosomal recessive manner. The goal of this proposal is to utilize the Basset Hound PACG model in order to characterize the genetics of PACG. In addition to investigating the underlying genetic mechanisms of PACG, a series of functional studies aimed at improving our understanding of the pathophysiology of PACG, were also performed to investigate the disease.&lt;/p&gt; &lt;p&gt;Extensive clinical phenotyping of all pedigree members was conducted by a veterinary ophthalmologist. We performed a genome-wide logistic regression test for association using 37 PACG cases and 41 unaffected controls. Population stratification and cryptic relatedness were assessed using a multidimensional scaling analysis. The expression of two candidate genes within the target tissues of the Basset Hound eye was assessed by immunohistochemistry. SNP-chip genotyping was additionally conducted in 9 affected and 15 unaffected pedigree members. Two-point and multipoint linkage analyses of genome-wide SNP data were performed using Superlink-Online SNP-1.1. Targeted exome capture was performed using the Agilent SureSelect exon kit.&lt;/p&gt; &lt;p&gt;A primary fibroblast cell culture was established from the sclera of three PACG, two wild type and two obligatory carrier Bassets. Total RNA extracted from fibroblast cells was assayed using the Affymetrix GeneChip Canine Genome 2.0 Array. The Robust Multichip Average expression summary method was used for background adjustment and normalization. A two class, unpaired, Wilcoxon statistical test was conducted to identify differentially expressed genes. qRT-PCR was performed to validate significantly expressed genes. Furthermore, a primary fibroblast cell culture was established from the skin of a PACG and an obligatory carrier BH. Microscope images and cell counts from all cell cultures were established at various time points.&lt;/p&gt; &lt;p&gt;Our findings reveal significant associations at two novel loci: BICF2P31912 in COL1A2 on chromosome 14 with a per-allele odds ratio OR(95% CI) 8.95(1.73-6.51); Pgenome = 3.6 x 10-4 and BICF2P893476 residing in proximity to RAB22A on chromosome 24 with a per-allele odds ratio OR(95% CI) = 12.03(1.78-8.66); Pgenome = 4.9 x 10-4. COL1A2 and RAB22A demonstrated wide-spread localization throughout the eye and were prominently noted in the ciliary body, trabecular meshwork and iris. A 1.82Mbp locus was additionally mapped to chromosome 19 with a maximum LOD score of 3.24. The locus contains 12 Ensemble predicted canine genes and shares synteny to a region on chromosome 2 in the human genome. Using exome-sequencing analysis, a possibly damaging, nonsynonymous variant was found to segregate with PACG in the gene Nebulin (NEB) (g.55885214 A-&gt;G, p.2051 K-&gt;R), which alters a conserved Lysine. Nebulin, a protein that promotes the contractile function of sarcomeres was found to be prominently expressed in the ciliary muscles of the anterior segment. Primary scleral fibroblast cells derived from PACG animals were found to exhibit severely reduced growth rates when compared to wild type derived cells. Genes with sharply reduced expression levels are of particular interest due to the possible involvement of a loss of- function mutation in PACG. More than 600 genes were found to be significantly under expressed in PACG derived cells. In contrast to unaffected-derived cell, PACG derived cells display significantly altered gene expression patterns for a number of possibly important candidate genes. Furthermore, PACG derived cells display aberrant and reduced motility in PACG versus wild type derived cell cultures.&lt;/p&gt; &lt;p&gt;The identification of two genetic associations supports the potential segregation of PACG risk-conferring variants in the Basset Hound. The genetic associations identified may contribute to mechanisms underlying the pathogenesis of PACG, which remain to be elucidated. Moreover, our studies provide the first evidence of a gene directly linked to PACG in the Basset Hound. Our findings may provide insight into the molecular mechanisms that underlie PACG. The phenotypic similarities of disease presentation in dogs and humans may enable the translation of findings made in this study to patients with PACG. The findings of our functional studies suggest that cellular dysfunction is an important aspect in the pathophysiology of PACG in the dog. The identification of genes with significantly altered expression levels may provide insight into the molecular pathways associated with the development of the disease and aid in the identification of the genetic defect underlying PACG.&lt;/p&gt;

Purpose The protein composition of aqueous humour (AH) has held significant relevance and remains to be the prime sample in the discovery of biomarkers in glaucoma. The purpose of this study is to analyze the AH protein concentrations in primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) and further examine the proteome changes compared to cataract control. Methods AH was collected from 90 POAG, 72 PACG, 78 cataracts (controls) in this study. The total protein was quantified using Bradford’s assay. Samples were subjected to trypsin digestion followed by liquid chromatography-mass spectrometry (LC-MS) for proteomic studies (n = 3 per group). The extracellular matrix has a major influence on the AH outflow, and the regulator proteins osteopontin (OPN), cathepsin D, and cystatin C detected by mass spectrometry are validated in AH samples by Western blot and turbidimetric immunoassay. Results We observed a significant increase in protein levels of POAG (p = .0009); interestingly, a similar increase in PACG compared to cataract (p < .0001) and POAG (p = .02). Proteomics analysis identified 184, 190, and 299 proteins in control, POAG and PACG. OPN was increased in POAG (p = .0319) and PACG (p = .0103) compared to control. The precursor form of cathepsin D was increased in POAG and decreased in PACG, though not significant compared to control. Cystatin C was also increased in both POAG (p = .0310) and PACG (p = .0125) compared to control. Conclusion In this study, we report for the first time that PACG cohort had higher total protein compared to controls. A qualitative comparison of proteomes revealed increased numbers of proteins identified in PACG. We assume that elevated levels of OPN and cystatin C in POAG and PACG along with altered cathepsin levels may contribute to ECM aberration in glaucoma.

Objective The onset of two eyes of primary angle-closure glaucoma often is not at the same time.Whether this difference is related with anterior chamber structure and axial length? The question had been discussed in this paper.Methods The anterior chamber depth,axial length,corneal thickness,corneal curvature of 82 patients with primary angle-closure glaucoma were observed with ultrasound biomicroscopy, I-OL-master,A-ultrasound and corneal topography.The result were compared between two eyes.Results The anterior chamber depth with UBM of primary acute angle-closure glaucoma had significant deviation between two eyes.The axial length,corneal thickness,corneal curvature had no deviation in APACG.The anterior cham-ber depth, axial length, corneal thickness, corneal curvature all had no deviation in chronic PACG.Conelusion The difference onset time of two eyes of primary acute angle-closure glaucoma is related to the deviation of an-terior chamber depth. Key words: Primary angle-closure glaucoma; Anterior chamber depth; Corneal thickness; Corneal curvature; The Axial length