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.     

Clinical phenotype of a Japanese family with primary open-angle glaucoma caused by a Ala 363 Thr mutation in the MYOC gene

BACKGROUND: Myocilin is a gene that causes primary open-angle glaucoma (POAG). We report a family whose members had an Ala 363 Thr mutation in the myocilin gene. We present the clinical phenotype of this family. CASE: The proband was a 57-year-old man diagnosed with POAG. His younger sister (50 years old) was also diagnosed with POAG. Visual field impairment did not worsen and ocular pressure decreased with eyedrop treatment. Although two of their children in their 30s had ocular hypertension, they did not have any sign of glaucomatous optic neuropathy. Genetic analysis revealed that all four family members had an Ala 363 Thr mutation in myocilin gene. CONCLUSION: Ala 363 Thr mutation was considered to be the cause of open-angle glaucoma. In this family, age at onset was comparatively high The two patients in their 30s had high intraocular pressure but no loss in visual acuity. The family members who had POAG and those who did not have POAG were not different from each other in the results of standard ocular examinations, only in age. Patients with this mutation will develop high intraocular pressure after 30 years of age and glaucomatous neuropathy after 50 years of age. When this gene mutation is detected in juvenile patients, careful follow-up and early therapy are necessary.     

原发性开角型青光眼MYOC- TIGR基因突变研究

目的 筛选并研究原发性开角型青光眼(POAG)小梁网糖皮质激素诱导反应蛋白MYOC- TIGR基因突变情况。方法 病例对照研究。抽取2002年1至12月就诊并诊断为POAG患者118例和150例非POAG对照者的外周静脉血4～8ml,采用酚-氯仿抽提全基因组DNA,应用聚合酶链反应(PCR)技术扩增全基因组DNA,以单核苷酸构象多态性(SSCP)分析MYOC基因的3个外显子（7对引物）编码区域序列改变。对SSCP分析异常者,采用双向测序法进一步证实。应用Cfr13I、Hinfl及BsmA1等限制性内切酶检测对照者MYOC基因编码区序列改变。POAG与非POAG人群MYOC基因各位点突变率比较采用x2检验。结果 基因序列分析发现G12R、I288M及Y353I共3个基因序列改变。118例POAG患者中仅有5例(4.23％)发生G12R位点突变,150例对照者中未见G12R位点改变;两组G12R位点突变率比较差异有统计学意义(x2=4.37,P=0.037)。POAG组和对照组均有I288M和Y353I位点改变,但两组突变率比较差异无统计学意义(x2=0.07,P=0.791和x2=0.56,P=0.453)。POAG患者基因突变率4.23％。结论 MYOC基因突变可能与POAG发病有关,MYOC基因突变可能是POAG发病的分子机制之一。     

Clinical phenotype of a Japanese family with primary open angle glaucoma caused by a Pro370Leu mutation in the MYOC/TIGR gene.

PURPOSE: To present the phenotype of two patients with primary open angle glaucoma (POAG) caused by a mutation of the myocilin/trabecular meshwork-inducible glucocorticoid response (MYOC/TIGR) gene. METHODS: Complete ocular examinations were performed on the 13-year-old proband, her father, mother, and sister. DNA analysis was performed to detect the mutant gene. RESULTS: The proband and her father were found to have a mutation of the MYOC/TIGR gene. Both patients carried a heterozygous mutation in the 1,109th nucleotide, which corresponds to the 370th amino acid residue of the MYOC/TIGR gene. The clinical characteristics of both patients were: (1) development of POAG at an early age, (2) high peaks of intraocular pressure. and (3) poor response to medical treatment. CONCLUSIONS: The phenotype of these patients with a mutation of the MYOC/TIGR gene agreed with reports of other patients with mutations at other loci in this gene. The discovery of the MYOC/TIGR gene not only makes early detection of glaucoma possible, but also presents a new direction for investigating the pathogenesis of glaucoma.     

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.     

Allelic variants in the MYOC/TIGR gene in patients with primary open-angle,exfoliative glaucoma and unaffected controls

One of the leading causes of blindness in the world is glaucoma. The most common form is primary open-angle glaucoma (POAG). The only gene identified so far as being associated with POAG is the MYOC gene; 2–4% of the patients have been reported to carry mutations in this gene. Exfoliative glaucoma is a secondary glaucoma, in which one of the symptoms is exfoliations on the lens capsule and anterior segment of the eye. No gene has been identified as being associated with this variant.The aim of the present study was to analyze Swedish patient material for allelic variants and mutations in the coding region of the MYOC gene. Two hundred patients with POAG and 200 with exfoliative glaucoma were analyzed using enzymatic cleavage assay and denaturing high-performance liquid chromatography (dHPLC). An age-matched control group (n = 200), in whom glaucoma had been excluded, was also analyzed using dHPLC. Eight allele variants were identified, two of which were determined to be diseasecausing mutations. These two disease-causing mutations were only found in POAG patients, indicating a prevalence of 1% in this patient group. This frequency is lower than that reported in other studies of other populations. No disease-causing mutations were found in the exfoliative glaucoma patients, indicating a fundamentally different genetic basis for that glaucoma variant.     

Allelic variants in the MYOC/TIGR gene in patients with primary open-angle,exfoliative glaucoma and unaffected controls

One of the leading causes of blindness in the world is glaucoma. The most common form is primary open-angle glaucoma (POAG). The only gene identified so far as being associated with POAG is the MYOC gene; 2-4% of the patients have been reported to carry mutations in this gene. Exfoliative glaucoma is a secondary glaucoma, in which one of the symptoms is exfoliations on the lens capsule and anterior segment of the eye. No gene has been identified as being associated with this variant. The aim of the present study was to analyze Swedish patient material for allelic variants and mutations in the coding region of the MYOC gene. Two hundred patients with POAG and 200 with exfoliative glaucoma were analyzed using enzymatic cleavage assay and denaturing high-performance liquid chromatography (dHPLC). An age-matched control group (n = 200), in whom glaucoma had been excluded, was also analyzed using dHPLC. Eight allele variants were identified, two of which were determined to be disease-causing mutations. These two disease-causing mutations were only found in POAG patients, indicating a prevalence of 1% in this patient group. This frequency is lower than that reported in other studies of other populations. No disease-causing mutations were found in the exfoliative glaucoma patients, indicating a fundamentally different genetic basis for that glaucoma variant.     

Metabolic abnormalities in patients with primary open-angle glaucoma

PURPOSE: Although there are few data on the underlying mechanisms of primary open-angle glaucoma (POAG), it has been suggested that metabolic diseases may play a role in the evolution of the disease. We carried out the present study to investigate the involvement of metabolic disturbances in POAG pathogenesis. MATERIAL/METHODS: Serum metabolic parameters were evaluated in 49 POAG patients without a known history of diabetes mellitus and 72 age and sex matched individuals without glaucoma (control group). RESULTS: Among the metabolic parameters examined, only fasting serum glucose and uric acid levels were found significantly higher in patients with glaucoma compared to the control population (117+/-17 mg/dl vs 105+/-11 mg/dl, p=0.05 and 6.2+/-1.9 mg/dl vs 5+/-1.2 mg/dl, p=0.006, respectively). Additionally, a considerably greater proportion of patients had disturbances of the carbohydrate metabolism and hyperuricemia. CONCLUSION: We conclude that disturbances of carbohydrate and uric acid metabolism could play a role in glaucoma damage and pathogenesis.     

Mitochondrial abnormalities in patients with primary open-angle glaucoma

PURPOSE: Primary open-angle glaucoma (POAG) is the second most common cause of blindness. It has been linked to mutations in the myocilin (MYOC) and optineurin (OPTN) genes, although mutations have been found in <5% of patients. The pathologic mechanism(s) of POAG remain unknown but may include retinal ganglion cell apoptosis, which causes progressive damage to axons at the optic nerve head. METHODS: In 27 patients with definite POAG, the MYOC and OPTN genes were sequenced, the entire mitochondrial (mt)DNA coding region was sequenced, relative mtDNA content was investigated, and mitochondrial respiratory function was assessed. RESULTS: Only three benign polymorphisms were identified in MYOC and OPTN in patients with POAG and in control subjects. Conversely, 27 different novel nonsynonymous mtDNA changes were found, only in patients with POAG (not control subjects), 22 of which (found in 14 patients) were potentially pathogenic. Unlike Leber hereditary optic neuropathy, most mtDNA sequence alterations in patients with POAG were transversions-sequence changes that alter the purine/pyrimidine orientation and imply oxidative stress. mtDNA content was relatively increased in 17 patients with POAG compared with age-matched control subjects, also implying a possible response to oxidative stress. Mean mitochondrial respiratory activity was decreased by 21% in patients with glaucoma compared with control subjects (P<0.001). CONCLUSIONS: These results reveal a spectrum of mitochondrial abnormalities in patients with POAG, implicating oxidative stress and implying that mitochondria dysfunction may be a risk factor for POAG. This concept may open up new experimental and therapeutic opportunities.     

Short-term results of canaloplasty surgery for primary open-angle glaucoma in Japanese patients

Purpose

To report surgical results of canaloplasty surgery for primary open-angle glaucoma (POAG) in Japanese patients.

Methods

Eleven eyes of 9 POAG patients underwent canalopasty surgery at Toyama University Hospital. Three eyes of 3 patients underwent canaloplasty alone and 8 eyes of 6 patients underwent canaloplasty combined with cataract surgery. Canaloplasty was performed with a 10-0 polypropylene tensioning suture and an iTrack™ 250A microcatheter. All patients were followed up for 12 months. Changes in intraocular pressure (IOP) and postoperative complications were examined.

Results

Mean preoperative IOP was 23.4 ± 5.5 mm Hg. Mean number of antiglaucoma drops was 2.8 ± 0.6 before canaloplasty and decreased to 1.2 ± 0.8 at 12 months after canaloplasty (p < 0.01). Mean IOP decreased postoperatively, being 13.7 ± 2.8 mm Hg at 1 month, 12.8 ± 3.5 mm Hg at 3 months, 14.0 ± 4.4 mm Hg at 6 months, and 15.0 ± 4.1 mm Hg at 12 months. The most frequent postoperative complication was mild hyphema (45.5%), which disappeared within 14 days after surgery.

Conclusions

Canaloplasty may be an alternative surgery for POAG patients to reduce IOP to a value of approximately 15 mm Hg.Key Words: Canaloplasty, Primary open-angle glaucoma, Intraocular pressure, Complications     

原发性开角型青光眼的系统性危险因素

眼压异常升高是原发性开角型青光眼最主要的危险因素。临床目前一直沿用以眼压为靶点的青光眼诊疗模式。近年来发现,循环血流、体质指数、颅内压、营养代谢、中医偏颇体质类型、某些系统性疾病等多种系统性危险因素可能与青光眼发生、发展和转归相关。纠正系统性危险因素能否延缓青光眼进展被日益关注,成为潜在的青光眼辅助诊疗靶点。本文对各类青光眼系统性危险因素进行介绍,倡导重视系统性危险因素,提出以系统危险因素评估和个性化眼体同治相结合的青光眼诊疗体系。（眼科,2022,31:325-329）     

Apolipoprotein E polymorphisms in patients with primary open-angle glaucoma

PURPOSE: To investigate apolipoprotein E (APOE) polymorphisms, which are known to influence the risk of Alzheimer disease (AD), in patients with primary open-angle glaucoma (POAG). DESIGN: Retrospective case-control association study. METHODS: Patients with POAG (n = 242) and controls (n = 187) were analyzed for the APOE epsilon 2/epsilon 3/epsilon 4 polymorphisms using minisequencing technique. RESULTS: The Alzheimer-associated APOE epsilon 4 allele had similar frequencies in the POAG group and in the control group. There was no difference between cases and controls with regard to APOE genotypes. CONCLUSIONS: If a common pathogenic mechanism exists for the two age-related neurodegenerative diseases, POAG and AD, it does not involve APOE polymorphisms.     

Long-term follow-up of initial trabeculectomy with mitomycin C for primary open-angle glaucoma in Japanese patients

PURPOSE: To determine the long-term intraocular pressure (IOP) control and postoperative complications after initial trabeculectomy with use of mitomycin C (MMC) in patients with primary open-angle glaucoma (POAG). PATIENTS AND METHODS: A retrospective review was conducted of a consecutive series of 123 eyes (87 patients) with POAG who underwent initial trabeculectomy with MMC and had at least 4 years of follow-up. All patients underwent standard trabeculectomy with 0.04% MMC applied intraoperatively for 3 minutes. The long-term outcomes (IOP control and bleb leak, long-standing hypotony, bleb-related infections) were analyzed with the Kaplan-Meier life-table method on the basis of three definitions of successful IOP control (defined as IOP <18 mmHg (definition 1), IOP <16 mmHg (definition 2), and IOP decrease of by > or =30% and <21 mmHg (definition 3)). RESULTS: The mean follow-up time was 6.8+/-1.4 (mean+/-SD) years. The cumulative survival rates were 67.0+/-4.6%, 44.5+/-5.4%, and 74.1+/-4.2%, respectively, based on definitions 1, 2, and 3, 8 years postoperatively by life-table analysis. At 8 years, bleb leak occurred in 7.9+/-2.6% of eyes, long-standing hypotony in 8.3+/-2.5%, and bleb-related infections in 5.9+/-2.4%. CONCLUSION: Long-term outcome after initial trabeculectomy with MMC in Japanese POAG patients is comparable with that reported in other populations and with that after trabeculectomy with 5-fluorouracil.     

The Gly367Arg mutation in the myocilin gene causes adult-onset primary open-angle glaucoma

PURPOSE: To present the phenotype of a family whose members showed the Gly367Arg mutation in the myocilin gene and developed primary open-angle glaucoma (POAG). METHODS: The proband developed POAG when she was 45 years old. Examination of the myocilin gene revealed that the patient had a mutation causing amino-acid change (Gly367Arg) in the myocilin gene. The available family members were given clinical and genetic examinations. RESULTS: Eight members of this family carried the same mutation. The age of disease onset of POAG in these patients with the mutation averaged 36.7 years. Four young members with the mutation, with an average age of 20.8 years, had not yet developed POAG. CONCLUSION: The Gly367Arg mutation of the myocilin gene in the pedigree causes the development of POAG in adulthood.     

Mutations in the third exon of the MYOC gene in Spanish patients with primary open angle glaucoma

Primary open angle glaucoma (POAG) is the second most common cause of blindness in developed countries. It is an optic neuropathy in which a degeneration of the retinal ganglion cells causes a characteristic excavation in the optic disc. Several loci have been identified to be responsible for different types of glaucoma, including the MYOC gene located on chromosome 1. In this work, six mutations have been identified in the third exon of the MYOC gene in patients with POAG. We studied 79 Galician patients with chronic POAG glaucoma and 90 control individuals from the same general population. We identified six mutations, including three novel ones. Two of the six mutations were considered to be polymorphisms, while the other four met the criteria for pathogenicity in this disease as they altered the amino acid sequence and were found in one or more patients with glaucoma and in less of 1% of the control population. These mutations were detected in eight patients suffering from POAG (7.5%) and in two people from the control population (2.2%). POAG can be due to mutations in the myocilin gene (MYOC) on chromosome 1. The glaucoma phenotype associated with this gene may vary from a juvenile severe form to a late-onset chronic open angle glaucoma.