Defining the pathogenicity of optineurin in juvenile open-angle glaucoma

PURPOSE: Juvenile open-angle glaucoma (JOAG) differs from primary open-angle glaucoma in that it is usually a more severe phenotype and has an earlier age of onset. Optineurin was recently associated with a variant of POAG that is characterized by intraocular pressure within normal limits: normal-tension glaucoma. The present study tested whether OPTN sequence changes play a role in early-onset glaucoma characterized by elevated intraocular pressure. METHODS: Sixty-six patients with JOAG characterized by high intraocular pressure were screened for mutations. Mutational analysis was performed with a combination of restriction enzyme digestion, single-strand conformation polymorphism, and direct sequencing. The effects of select changes on exon splicing were assessed using bioinformatic modeling approaches and RT-PCR. RESULTS: Ten sequence changes were identified, of which H486R was strongly suggestive of pathogenicity. H486R represents the first reported OPTN mutation associated with JOAG. Also, L41L is proposed to confer an increased susceptibility to the development of JOAG. Most of the other sequence changes observed were not thought to be biologically significant. The frequency of the previously reported M98K allele was not increased in the JOAG population studied but showed the previously reported skewed distribution in the POAG study population. The changes identified were not shown to affect the splicing machinery. CONCLUSIONS: The results of this work support the hypothesis that mutations in OPTN are not specifically associated with low-pressure glaucoma, but can play a role in JOAG.     

Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma

PURPOSE: To investigate the association of sequence variations in the optineurin (OPTN) gene in patients with open-angle glaucoma. DESIGN: Prospective case control study. METHODS: The OPTN gene was screened for sequence variations using a combination of single-strand conformational polymorphism analysis and automated DNA sequencing. A total of 1,299 subjects (1048 glaucoma patients and 251 controls) were screened for variations in the four portions of the gene that had been previously associated with glaucoma. A subset of these subjects (376 patients and 176 controls) was screened for variations in the entire coding sequence. Twenty-four percent of the patients and 35% of the controls were Japanese, whereas the remainder were predominantly Caucasian. Allele frequencies were compared with the Fisher exact test. RESULTS: The OPTN sequence variations were not significantly associated with any form of high-tension open-angle glaucoma. One proband with familial normal-tension glaucoma was found to harbor the previously reported Glu50Lys variation. Another previously reported change, Met98Lys, was associated with normal-tension glaucoma in Japanese but not in Caucasian patients. CONCLUSIONS: This study provides some additional evidence for the association of the Glu50Lys OPTN sequence variation with familial normal tension glaucoma. However, because familial normal-tension glaucoma is so rare, this change seems to be responsible for less than 0.1% of all open-angle glaucoma. The Arg545Gln variation is likely to be a nondisease-causing polymorphism. The Met98Lys change may be associated with a fraction of normal-tension glaucoma in patients of Japanese ethnicity.     

MYOC mutation frequency in primary open-angle glaucoma patients from Western Switzerland

Purpose: To determine MYOC gene mutation frequency in patients with primary open-angle glaucoma (POAG) from Western Switzerland. Methods: A total of 117 unselected index patients with primary open-angle glaucoma were submitted to a full eye examination. DNA was extracted from blood and PCR amplicons of MYOC exon 3 were screened for mutations by single-strand conformation polymorphism (SSCP) analysis. Abnormal conformers were analyzed both by direct bidirectional sequencing and by enzymatic mutation detection (EMD) assay. Results: Ten occurrences of four different sequence changes were detected, including: 1) five times the same disease-causing mutation (Q368X) in five unrelated POAG patients and 2) three distinct polymorphisms in five patients. The patients carrying an MYOC mutant allele were characterized by a broad clinical variability in terms of age of onset (34–77 years) and highest intraocular pressure (IOP) values (23–47 mmHg). Conclusions: A pathogenic MYOC mutation (Q368X) was identified in 4.27% (5/117) of the studied population from Western Switzerland, which corresponds to the highest frequency yet reported for this mutation.     

Rate and pattern of visual field decline in primary open-angle glaucoma

PURPOSE: To study the rate and pattern of visual field decline in primary open-angle glaucoma. DESIGN: Retrospective observational case series. PARTICIPANTS: Forty eyes of 40 patients with primary open-angle glaucoma that were followed longitudinally with serial Goldmann visual fields for a minimum period of 8 years in an academic institution. Eyes with any other ocular disease except for mild cataract were excluded. METHODS: Visual fields obtained with worse than 20/50 Snellen visual acuity from cataract were excluded from analysis. In the remainder (671 Goldmann visual fields), the I4e isopter was quantified manually using a grid template previously described by Esterman. The visual field was divided into central and peripheral, superior and inferior, and nasal and temporal regions, all centered at the blind spot. The rate of visual field decline was estimated for each visual field region (including the four quadrants: superonasal [SN], superotemporal [ST], inferotemporal [IT], and inferonasal [IN]) using linear regression. Asymmetry of visual field progression was determined by comparing the rates of progression among the four quadrants. Pertinent clinical factors were evaluated for association with the asymmetry of visual field progression. MAIN OUTCOME MEASURES: Rates of visual field decline for the entire visual field and each region. Long-term clinical outcome measures, including visual acuity, cataract and cup-to-disc ratio progression, intraocular pressures, and medical and surgical interventions were also studied. RESULTS: The rate of visual field change was -1.3% per year for the entire visual field. The rates of visual field section change (in % per year) were -1.3 (central), -1.4 (peripheral), -1.5 (superior), -1.2 (inferior), -1.4 (nasal), -1.2 (temporal), -1.8 (SN), -1.3 (IT), -1.2 (IN), and -1.1 (ST). About half the patients showed symmetric visual field decline, whereas others showed a more asymmetric pattern. Asymmetric visual field progression was associated with the presence of disc hemorrhage, overall rate of visual field progression, and surgical intervention for glaucoma. CONCLUSIONS: In this group of selected patients with primary open-angle glaucoma with a long-term follow-up, all sections of the visual field declined over time. Disc hemorrhage was associated with more asymmetric visual field progression, implicating focal damage to the optic disc.     

Molecular genetic analysis of optineurin gene for primary open-angle and normal tension glaucoma in the Japanese population

PURPOSE: To determine whether mutations in the optineurin (OPTN) gene are associated with the incidence of primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG) in the Japanese. METHODS: Eighty-nine unrelated Japanese patients with POAG and 65 unrelated patients with NTG were studied. Genomic DNA was extracted from leukocytes of the peripheral blood, and thirteen exons of the OPTN gene were amplified by polymerase chain reaction (PCR) and directly sequenced. RESULTS: Sequence alterations in exons 4 (His26Asp), 5 (Met98Lys), and 16 (Arg545Gln) were found. The His26Asp and Arg545Gln mutations were not detected in 100 ethnically matched controls. The frequency of the missense Met98Lys variant was higher in the POAG and NTG groups than in the control group (16.9% versus 5%, 15.4% versus 5%; P = 0.009 and P = 0.029, and odds ratio 3.85 and 3.45, respectively, for the dominant effect of the OPTN A allele). Polymorphisms in exons 4 and 12, and in introns 6 and 7 were also detected. CONCLUSIONS: The association of the allelic variation (Met98Lys) in the OPTN gene and the prevalence of POAG and NTG in unrelated Japanese patients suggest that they are involved in the pathogenesis of POAG and NTG.     

Heredity in primary open-angle glaucoma

The past years have seen considerable progress in the characterization of hereditary factors in primary open-angle glaucoma. Epidemiologic studies strengthened our knowledge of the hereditary factors in this multifactorial disease. Several loci in the human genome have been described, which segregate with different glaucoma phenotypes. Mutations of the MYOC/TIGR (myocilin/trabecular meshwork inducible glucocorticoid response) gene on chromosome 1q account for most, but probably not all, cases of glaucoma linked to chromosome 1q, and other additional pathologic factors may be implicated. The properties of the normal myocilin protein point to a crucial role in the regulation of intraocular pressure. However, in spite of the knowledge obtained so far, routinely performed genetic screening of patients at risk for primary open-angle glaucoma is not yet clinically useful.     

Phacoviscocanalostomy in pseudoexfoliation glaucoma versus primary open-angle glaucoma

Objective: To compare the outcome of phacoviscocanalostomy in Pseudoexfoliation glaucoma (PEXG) versus that in primary open-angle glaucoma (POAG).Design: Prospective comparative study.Participants: Sixty eyes of 60 patients who underwent phacoviscocanalostomy for cataract and medically uncontrolled PEXG (30 eyes) or POAG (30 eyes).Methods: Success rate was based on intraocular pressure (IOP) reduction and need for antiglaucoma medication. Visual acuity (VA) and complication rates were secondary outcomes.Results: The mean follow-up was 19.7 months (range, 12–36 months). The mean IOP values in both groups were significantly less than the preoperative values at all postoperative intervals (p < 0.001). From 1 month onward, the decrease in IOP was more dramatic in PEXG eyes than in POAG eyes (p < 0.05). At last visit, the mean percentage of IOP reduction was 49.7% in the PEXG group and 30.9% in the POAG group. All study eyes required decreased antiglaucoma medications and showed improved VA postoperatively. Transient complications included Descemet's membrane microperforations, macroperforation, zonular dehiscence, and postoperative IOP spike. No eyes developed trabeculectomy-type bleb, hyphema, fibrin exudation, or bleb-related complications.Conclusions: Phacoviscocanalostomy achieved excellent IOP control and VA improvement in both PEXG and POAG groups. PEXG demonstrated greater IOP reduction and fewer postoperative medications than POAG. The complication rate was low and did not affect surgical outcome. Phacoviscocanalostomy can be an effective and safe surgical alternative to phacotrabeculectomy in both groups of patients.     

Genetic markers in primary open-angle glaucoma

Purpose: To investigate possible associations between genetic markers and Primary Open-Angle Glaucoma (POAG). Methods: A number of genetic markers were typed in 84 unrelated patients with POAG and compared with a random sample of healthy individuals. The markers were Transferrin, Group Specific Component, G1m (1), G1m (2) and G3m (5) Allotypes, Adenylate Kinase, Adenosin Deaminase, Glyoxalase I and Acid Phosphatase and PCR-based markers HLA-DQA1 and D1S80. Results: No significant differences were found except the strong association between the group of POAG patients and Acid Phosphatase ACP^*C allele (² = 32.86; p < 0.0001). Conclusions: Since Acid Phosphatase gene is localized to chromosome 2p23, this result could be a first comprehensive step in the localization of POAG genes.     

Race and primary open-angle glaucoma

A comparison of racial distributions for three groups of patients showed that 115 of 140 patients (81.6%) with open-angle glaucoma, 221 of 392 patients (56.4%) with ocular hypertension, and 1,028 of 2,109 patients (48.7%) in a random sample were black. Average age at diagnosis was significantly (P = .006) higher for whites than for blacks (69.1 years vs 63.7 years). Black patients with primary open-angle glaucoma had a significantly larger mean cup-disk ratio (P less than or equal to .002) and a higher but not significantly higher mean intraocular pressure at the time of diagnosis. Advanced glaucomatous visual field loss was more frequent at the time of diagnosis in blacks (43 of 129 patients or 33.3%) than in whites (five of 27 patients or 18.5%), but this difference was not significant.     

Oxidative stress in primary open-angle glaucoma

PURPOSE: To analyze oxidative stress in primary open-angle glaucoma (POAG). MATERIAL AND METHODS: A case-control study including 90 eyes of 90 patients who needed antiglaucomatous surgery in the course of POAG (glaucoma group, n=50) and from patients who were operated of nonpathologic cataracts (cataract group, n=40). Free radical formation via lipid peroxidation by malondialdehyde-thiobarbituric acid reactive substances (MDA-TBARS) test and total antioxidant status in the aqueous humor samples of both groups were determined. Statistical analyses were carried out in relation to MDA-TBARS and total antioxidant status and their correlations with glaucoma risk factors. RESULTS: Significantly higher MDA-TBARS were detected in the POAG with respect to the comparative group of cataract subjects (P<0.001). Antioxidant activity was significantly lower in the POAG than in the cataract group (P<0.001). CONCLUSIONS: Aqueous humor samples may be used for determining oxidative and antioxidant status in pathologic processes. Glaucomatous eyes had a significant increase in oxidative status and decreased antioxidant activity in the aqueous humor than the cataract eyes. Oxidative stress may play a pathogenical role in the POAG.     

Blood viscosity in primary open-angle glaucoma

To determine whether hemorrheologic factors play a part in optic nerve cupping and visual field loss in glaucoma, blood viscosity was measured at three shear rates in 27 patients with primary open-angle glaucoma and 18 healthy control subjects matched for sex, mean arterial blood pressure and smoking habits. The study was conducted between 1984 and 1986. The mean viscosity was significantly higher in the glaucoma group than in the control group at all three shear rates. The possible relevance of raised blood viscosity as a causal factor in optic nerve cupping in patients with glaucoma is discussed.     

Hypothyroidism and primary open-angle glaucoma

OBJECTIVE: To test if there is an association between hypothyroidism and primary open-angle glaucoma (POAG) and the utility of routine study of thyroid function in these patients. METHODS: The study was conducted in a case-control fashion. Seventy-five consecutive patients with a previous diagnosis of POAG and 75 control patients were prospectively evaluated for hypothyroidism. The levels of thyroid-stimulating hormone and free thyroxin were measured. RESULTS: Hypothyroidism was revealed in only 2 patients with previous diagnosis of POAG (2.67%) and 3 patients of the control group (4%). CONCLUSIONS: As we have not been able to demonstrate the previously reported relationship between hypothyroidism and POAG, we cannot recommend the systematic screening for hypothyroidism in patients with POAG.     

Immunopathogenesis of primary open-angle glaucoma

By means of direct immunofluorescence technique the trabecular meshwork of patients with primary open-angle glaucoma, obtained at the time of filtering surgery, and the trabecular meshwork of controls were investigated for the presence of immunoglobulins and the complement component C3. In neither group were such deposits found; this indicates a lack of immunogenic mechanisms in primary open-angle glaucoma.     

False-negative responses in primary open-angle glaucoma

To determine the false-negative response rate in patients with primary open-angle glaucoma (POAG) and its relationship with the mean deviation, we evaluated 286 visual fields of patients with POAG. A high false-negative response rate was found in glaucomatous patients compared with healthy controls. When the mean derivation was compared with the false-negative response rate, a logarithmic correlation was found with Pearson correlation analysis.     

Retinal oximetry in primary open-angle glaucoma

PURPOSE. To determine whether retinal vessel oxygen saturation is affected in primary open-angle glaucoma (POAG) patients. METHODS. Retinal oxygen saturation in patients with POAG was measured in retinal vessels with a spectrophotometric retinal oximeter in darkness, and visual fields were obtained. Oxygen tension (Po(2)) was calculated from oxygen saturation values. Statistical analysis was performed using Pearson's correlation and Student's t-test. RESULTS. Mean oxygen saturation in venules was higher in persons with poor visual fields (68% ± 4%, mean ± SD) than in those with good visual fields (62% ± 3%; P = 0.0018). The mean arteriovenous difference in oxygen saturation was lower in persons with poor visual fields (30% ± 4%, n = 9) than in those with good visual fields (37% ± 4%; P = 0.0003; n = 12). No correlation was found between saturation in retinal arterioles and visual field mean defect (n = 31; r = -0.16; P = 0.38). Oxygen saturation in retinal venules correlated positively with worsening visual field mean defect (r = 0.43; P = 0.015). Arteriovenous difference in oxygen saturation decreased significantly as the visual field mean defect worsened (r = -0.55; P = 0.0013). Mean Po(2) in venules was 38 ± 3 mm Hg. It was significantly higher in persons with poor visual field fields (40 ± 3 mm Hg) than in those with good visual fields (36 ± 2 mm Hg; P = 0.0016). CONCLUSIONS. Deeper glaucomatous visual field defects are associated with increased oxygen saturation in venules and decreased arteriovenous difference in retinal oxygen saturation. The data suggest that oxygen metabolism is affected in the glaucomatous retina, possibly related to tissue atrophy.     

正常眼压型青光眼与高眼压型原发性开角型青光眼是否为同一类型疾病

基于临床考虑,在《我国原发性青光眼诊断和治疗专家共识》中,将正常眼压型青光眼与高眼压型原发性开角型青光眼同归类为原发性开角型青光眼,归属于一类疾病的两个亚型,分界点在于眼压是在正常范围还是高于21 mm Hg(1 mm Hg=0.133 kPa)。但是正常眼压型青光眼与高眼压型原发性开角型青光眼是否应属同一类型疾病,眼...