A genome-wide scan maps a novel juvenile-onset primary open-angle glaucoma locus to 15q.

PURPOSE: To map the disease-associated locus of a family with autosomal dominant juvenile-onset primary open-angle glaucoma (JOAG). METHODS: A complete ophthalmic examination was conducted, and genomic DNA was obtained from 25 members of a Chinese family, of which eight were confirmed as having JOAG. Myocilin (MYOC), optineurin (OPTN), and WD repeat-domain 36 (WDR36) were screened for sequence alterations, by PCR and direct sequencing. Subsequently, a genome-wide scan was performed (Prism Linkage Mapping Set MD-10; Applied Biosystems, Inc., Foster City, CA). Two-point and multipoint linkage analyses were performed with the MLINK, ILINK, and LINKMAP programs. For fine mapping, additional markers flanking the most promising region on 15q were analyzed. The significance of the lod score was tested with simulation analyses by using FASTLINK. Haplotypes were constructed with Simwalk2. Three candidate genes, NR2E3, SMAD6, and CLN6, located within the critical region, were screened for mutations. RESULTS: MYOC, OPTN, and WDR36 mutations were excluded in all family members. A maximum two-point lod score of 3.31 at theta = 0.0 was obtained for the marker D15S125. Four adjacent markers, rs2030040, rs169169963, D15S153, and D15S131, gave two-point lod scores of 2.41, 2.90, 3.02, and 2.68, respectively, at theta = 0.0. Haplotype analysis and recombination mapping further confined this region to 15q22-q24 within a genetic distance of 16.6 Mb flanked by D15S1036 and rs922693. No mutations were found in the coding exons and splicing junctions of NR2E3, SMAD6, and CLN6. CONCLUSIONS: The results provide evidence for the mapping of a novel locus for JOAG at 15q22-q24. A further search for the disease-causing gene in this new JOAG locus is in progress.

Polymorphisms in the myocilin promoter unrelated to the risk and severity of primary open-angle glaucoma.

PURPOSE: To investigate the proximal 2.5 kb promoter in the myocilin (MYOC) gene for mutations in Chinese patients with primary open-angle glaucoma (POAG). PATIENTS AND METHODS: We screened for sequence alterations in the MYOC promoter in 88 unrelated Chinese patients with POAG and 94 unrelated individuals without glaucoma, aged 50 years or above, as control subjects. In addition, the specific MYOC.mt1 polymorphism was determined in a total of 212 POAG patients and 221 control subjects. The relationships between POAG phenotype and the identified polymorphisms were studied by univariate analysis, multivariable logistic regression analysis, and haplotype analysis. RESULTS: All polymorphisms identified in this study followed Hardy-Weinberg equilibrium (P > 0.12) both in POAG patients and controls. Both univariate and multivariable logistic regression analyses showed no polymorphism that was significantly associated with the risk of POAG, P > 0.08 and P > 0.044 respectively. Haplotype analysis further indicated no association of MYOC promoter polymorphisms with the susceptibility for POAG (P > 0.1). On the other hand, there was no difference of POAG phenotypes among different genotypes of MYOC.mt1 (P > 0.31). CONCLUSIONS: In this study on the Chinese population, polymorphisms in the MYOC promoter are not related to the risk of POAG. There is no association between the MYOC.mt1 promoter polymorphism with the severity of POAG.

Five-year follow up of selective laser trabeculoplasty in Chinese eyes.

PURPOSE: To study the effectiveness and safety of selective laser trabeculoplasty (SLT) on primary open-angle glaucoma and ocular hypertension in Chinese eyes. METHODS: This was a prospective randomized controlled clinical study in which 58 eyes of 29 patients with primary open-angle glaucoma or ocular hypertension were included. One eye of each patient was randomized to receive SLT (Group 1) and the fellow eyes received medical treatment (Group 2). Patients were evaluated after laser treatment at 2 h, 1 day, 1 week, 2 weeks, 1 month, 3 months, 6 months, and then yearly. RESULTS: All patients (13 male, 16 female) were Chinese. The mean age was 51.9 +/- 14.7 years. The mean baseline intraocular pressure was 26.8 +/- 5.6 mmHg in group 1 and 26.2 +/- 4.2 mmHg in group 2 (P = 0.62). The failure rate, defined as intraocular pressure >21 mmHg with maximal medications, was 17.2% in group 1 and 27.6% in group 2 at 5-year follow-up (P = 0.53). Eight eyes (27.6%) in group 1 required medications to control the intraocular pressure to below 21 mmHg. There was no statistically significant difference in the intraocular pressure reductions between the two groups at all time intervals (P > 0.05). The mean number of antiglaucoma medications was significantly lower in the SLT than the medical treatment group up to 5 years of follow up (P < 0.001). Transient post-SLT intraocular pressure spike >5 mmHg was observed in three eyes (10.3%). CONCLUSION: With fewer medications, SLT gives similar intraocular pressure reduction to medical therapy alone in Chinese patients with primary open-angle glaucoma or ocular hypertension.

Different optineurin mutation pattern in primary open-angle glaucoma.

PURPOSE: The optineurin gene (OPTN) is the second gene besides MYOC in which mutations have been identified to be associated with primary open-angle glaucoma (POAG). In this study, sequence alterations in the OPTN gene associated with POAG in Chinese subjects were investigated. METHODS: All the coding exons of OPTN were screened, including the intron-exon boundaries, for sequence alterations in a Chinese sample of 119 sporadic patients with POAG and 126 unrelated control subjects by polymerase chain reaction-conformation-sensitive gel electrophoresis and DNA sequencing. RESULTS: Sixteen sequence changes were identified: 3 had been reported (T34T, M98K, and R545Q) and 13 were novel (T49T, E103D, V148V, P199P, T202T, H486R, IVS6-5T-->C, IVS6-10G-->A, IVS7+24G-->A, IVS8+20G-->A, IVS13+21C-->G, IVS15+10G-->A, and IVS15-48C-->A). Among them, only E103D, H486R, V148V, and IVS13+21C-->G were found exclusively in patients with POAG, whereas P199P, T202T, and IVS8+20G-->A were present only in control subjects. The genotype of IVS7+24G-->A showed a significant association with POAG (P = 0.02, Fisher two-tailed exact test) and with and increased cup-to-disc ratio in these patients (P = 0.005, Mann-Whitney test). CONCLUSIONS: The findings in the current study enrich the evidence on the OPTN gene as a causative gene for POAG and suggest a different mutation pattern of OPTN in Chinese than in whites. The wide spectrum of putative mutations detected in this study suggests that both structural and functional disruptions in OPTN may contribute to the pathogenesis of glaucoma.

Laser peripheral iridoplasty as initial treatment of acute attack of primary angle-closure: a long-term follow-up study.

PURPOSE: To study the long-term clinical course and complications of patients with acute primary angle-closure treated with immediate laser peripheral iridoplasty followed by laser peripheral iridotomy. PATIENTS AND METHODS: Consecutive patients with acute primary angle closure treated with immediate laser peripheral iridoplasty, followed by laser peripheral iridotomy, at the Prince of Wales Hospital from July 1997 through January 2000 were followed up to document the clinical course of their disease and any complications from the laser treatment. Visual acuity, intraocular pressure, gonioscopic findings, corneal and lens clarity, iris appearance, pupillary reaction, and progression of glaucomatous optic neuropathy were evaluated. RESULTS: Thirty eyes of 29 Chinese patients with acute primary angle closure treated initially with either argon or diode laser peripheral iridoplasty were recruited. The mean follow-up period was 33.0 +/- 9.3 months. Twenty-one eyes (70%) had no further attack and maintained normal intraocular pressure without medications, and 9 eyes (30%) developed chronic angle-closure glaucoma with peripheral anterior synechiae. All eyes had pigmented laser marks on the peripheral iris, but none had peripheral corneal burn. CONCLUSIONS: Long-term follow-up data indicated that 30% of Chinese eyes with acute primary angle closure successfully treated with immediate laser peripheral iridoplasty followed by laser peripheral iridotomy developed peripheral anterior synechiae and an increase in intraocular pressure. There were minimal long-term complications on the cornea and the lens from the laser treatment.

TIGR/MYOC gene sequence alterations in individuals with and without primary open-angle glaucoma.

PURPOSE: To discover sequence alterations in the TIGR/MYOC gene associated with primary open-angle glaucoma (POAG) in Chinese subjects. METHODS: Two hundred one unrelated Chinese patients with POAG and 291 unrelated individuals without glaucoma, aged 50 years or more, were screened for sequence alterations in the TIGR/MYOC gene by polymerase chain reaction, conformation sensitive gel electrophoresis, and DNA sequencing. Up to 111 more control subjects were screened for some of the alterations. RESULTS: Fourteen sequence variants that lead to amino acid changes were identified. Seven were novel: Pro16Leu, Ala17Ser, Leu95Pro, Leu215Pro, Glu300Lys, Glu414Lys, and Tyr471Cys. Of these, Glu300Lys and Tyr471Cys were found only in POAG. Arg46Stop was found in 4 patients with POAG (2.0%) and 9 of 402 control subjects (2.2%); one control subject was homozygous. IOP showed a trend (P = 0.11) toward a decrease of 1.5 mm Hg among the control subjects, with Arg46Stop compared with matched control subjects without Arg46Stop. Gly12Arg occurred four times as frequently in control subjects as in patients, but the difference was not statistically significant. CONCLUSIONS: Gly12Arg might be negatively associated with POAG, suggesting a protective effect. Three patients with POAG had a sequence change not found in control subjects, for a frequency of possible disease-causing TIGR/MYOC mutations of 1.5% (95% confidence interval [CI] = 0.3%-4.3%). Arg46Stop occurred with similar frequency in patients with POAG and control subjects, suggesting that the reduced amount of TIGR/MYOC predicted to result from this truncation does not dramatically increase or decrease risk of glaucoma.

Argon laser peripheral iridoplasty versus conventional systemic medical therapy in treatment of acute primary angle-closure glaucoma : a prospective, randomized, controlled trial.

OBJECTIVE: To study whether argon laser peripheral iridoplasty (ALPI) is as effective and safe as conventional systemic medications in treatment of acute primary angle-closure glaucoma (PACG) when immediate laser peripheral iridotomy is neither possible nor safe. DESIGN: Prospective, randomized, controlled trial. PARTICIPANTS: Seventy-three eyes of 64 consecutive patients with their first presentation of acute PACG, with intraocular pressure (IOP) levels of 40 mmHg or more, were recruited into the study. INTERVENTION: The acute PACG eye of each consenting patient received topical pilocarpine (4%) and topical timolol (0.5%). The patients were then randomized into one of two treatment groups. The ALPI group received immediate ALPI under topical anesthesia. The medical treatment group was given 500 mg of intravenous acetazolamide, followed by oral acetazolamide 250 mg four times daily, and an oral potassium supplement until IOP levels normalized. Intravenous mannitol also was administered to the latter group if the presenting IOP was higher than 60 mmHg. The acute PACG eye of both groups continued to receive topical pilocarpine (1%) until peripheral iridotomy could be performed. MAIN OUTCOME MEASURES: Intraocular pressure profile, corneal clarity, symptoms, visual acuity, angle status by indentation gonioscopy, and complications of treatment. RESULTS: Thirty-three acute PACG eyes of 32 patients were randomized to receive immediate ALPI, whereas 40 acute PACG eyes of 32 patients had conventional systemic medical therapy. Both treatment groups were matched for age, duration of attack, and IOP at presentation. The ALPI-treated group had lower IOP levels than the medically treated group at 15 minutes, 30 minutes, and 1 hour after the start of treatment. The differences were statistically significant. The difference in IOP levels became statistically insignificant from 2 hours onward. The duration of attack did not affect the efficacy of ALPI in reducing IOP in acute PACG. No serious laser complications occurred, at least in the early postlaser period. CONCLUSIONS: Argon laser peripheral iridoplasty significantly is more effective than conventional systemic medications in reducing IOP levels in acute PACG in eyes not suitable for immediate laser peripheral iridotomy within the first 2 hours from the initiation of treatment. Argon laser peripheral iridoplasty is a safe and more effective alternative to conventional systemic medications in the management of acute PACG not amenable to immediate laser peripheral iridotomy.

Physical effects of reuse and repeated ethylene oxide sterilization on transscleral cyclophotocoagulation laser G-probes.

PURPOSE: The authors documented the physical effects of reuse and repeated ethylene oxide sterilization on transscleral cyclophotocoagulation laser G-probes. METHODS: Transscleral cyclophotocoagulation was performed using G-probes on fresh porcine eyes. Each of two G-probes was used for four transscleral cyclophotocoagulation procedures, with three cycles of ethylene oxide sterilization in between. The power output from the G-probes was measured by a laser output meter before and after each transscleral cyclophotocoagulation procedure. The G-probes were also examined under a slit lamp for signs of physical damage. RESULTS: Repeated use of the G-probe in transscleral cyclophotocoagulation, with ethylene oxide sterilization in between, resulted in an average decrease of 3% in laser energy delivered per repeated cycle of use up to the fourth cycle. No signs of physical damage were found. CONCLUSIONS: Laser G-probes remain functional after repeated use and ethylene oxide resterilization for up to four cycles. No visible physical damage to the probes was identified. It is safe and cost-effective to reuse G-probe for transscleral cyclophotocoagulation with ethylene oxide sterilization, provided the surgeon stays alert for signs of probe damage. This alertness should be retained regardless of whether new or old G-probes are used.

Efficacy and safety of immediate anterior chamber paracentesis in the treatment of acute primary angle-closure glaucoma: a pilot study.

OBJECTIVE: To study the safety and effectiveness of immediate anterior chamber paracentesis, combined with antiglaucomatous medications, in the intraocular pressure control and relief of symptoms of acute primary angle-closure glaucoma (PACG). DESIGN: Prospective noncomparative case series. PARTICIPANTS: Eight consecutive patients with their first attack of acute PACG, with intraocular pressure > or =50 mmHg, were recruited into the study. INTERVENTION: On presentation, each patient received topical pilocarpine (4%) and timolol (0.5%), immediate anterior chamber paracentesis, and systemic acetazolamide and mannitol as primary treatment. The intraocular pressures at 15 and 30 minutes, and then at 1, 2, 3, 12, and 24 hours, were documented by applanation tonometry. MAIN OUTCOME MEASURES: Symptoms, visual acuity, intraocular pressure, corneal edema, angle status on gonioscopy, pupillary size, and reaction. RESULTS: Ten eyes of eight patients seen with acute PACG were recruited. The mean intraocular pressure was reduced from 66.6 +/- 9.1 mmHg to 15.1 +/- 3.5 mmHg immediately after paracentesis, and then to 17.1 +/- 7.0 mmHg at 15 minutes, 21.7 +/- 10.2 mmHg at 30 minutes, 22.7 +/- 11.0 mmHg at 1 hour, and 20.1 +/- 14.6 mmHg at 2 hours after paracentesis. The mean intraocular pressure was less than 21 mmHg at 2 hours and beyond. There was instant symptomatic relief for all patients. No complications from the paracentesis were encountered. CONCLUSIONS: From this preliminary study, immediate paracentesis seems to be safe and effective in controlling the intraocular pressure and eliminating symptoms in acute PACG.