Extent of asymmetry and unilaterality among juvenile onset primary open angle glaucoma patients

Background: Juvenile onset open angle glaucoma (JOAG) due to its rarity is not well characterized. We aimed to assess the extent of interocular asymmetry of baseline intraocular pressure (IOP), disc morphometry and visual field defects at presentation in patients with primary JOAG. Design: Retrospective, single‐centre, hospital‐based study. Participants: Fifty‐two consecutive JOAG patients who presented with glaucomatous optic neuropathy in at least one eye, without any secondary causes of glaucoma. Methods: Participants were evaluated for baseline clinical features. The optic disc parameters were measured using scanning laser ophthalmoscopy (Heidelberg Retina Tomograph). Reliable and reproducible visual field tests using standard 30‐2 Humphrey automated perimetry were analysed. Main Outcome Measures: Interocular asymmetry of baseline IOP, vertical cup:disc ratio and mean deviation. Results: Fourteen patients (27%) had glaucomatous optic neuropathy in only one eye at initial presentation; the fellow eyes of which had IOP <21 mmHg in eight whereas six had IOP >21 mmHg. In 20 out of 52 patients (39%) one eye remained perimetrically unaffected. Patients presenting with bilateral optic neuropathy were found to be significantly younger (24.4 ± 10.6 years) in age compared to those with unilateral optic neuropathy (32 ± 8.2 years) (P = 0.02). Conclusions: One‐fourth of primary JOAG patients present as a unilateral optic neuropathy with 60% of these having normal IOP in the fellow eyes. Primary JOAG may present with considerable asymmetry with a small proportion presenting as a unilateral disease.     

Genetic ground of primary open angle glaucoma

Among basic risk factors for primary open-angle glaucoma (POAG), the leading place takes positive family history. It is generally accepted that this type of glaucoma presents multifactored determination, however pedigrees that follow autosomal dominant way of inheritance are also described. Genetic studies made by linkage analysis enabled to map six loci, linked to development of primary open-angle glaucoma: GLC1A - in 1q21-q31 region, GLC1B - in 2cen-q13 region, GLC1C- in 3q14-q24 region, GLC1D - in 8q23 region, GLC1E- in 10p15-p14 region and GLC1F - in 7q35-q36 region. During last years, in GLC1A locus the TIGR gene that codes for myocilin was cloned and in GLC1E locus the OPTN gene that codes for optineurin was cloned. It was also proved that their mutations are responsible for development of several forms of POAG. Simultaneously it was shown that there are some additional modifier genes, such as CYP1B1 gene, mapped in 2p22-p21 region and coding one of the cytochrome P450 polypeptide, what indicates a possibility of digenic inheritance of POAG.     

Genetic studies on primary open angle glaucoma

Case work presents the newest studies on molecular genetics in primary open angle glaucoma. The molecular genetics in all types of glaucoma have been a subject of investigations for the last few years. As a result, two loci (GLC3A and GLC3B) have been identified for primary congenital glaucoma, one locus (GLC1A) for juvenile primary open angle glaucoma and further two loci (GLC1B and GLC1C) for adult-onset primary open angle glaucoma. The gene TIGR (trabecular meshwork inducible glucocorticoid response protein) localised in GLC1A was described last year for the first time, thereafter there were trials on mutations within this gene conducted successfully. In this review there are studies presenting the mapping of the first five GLC loci and identification of mutations.     

A recurrent G367R mutation in MYOC associated with juvenile open angle glaucoma in a large Chinese family

AIM: To identify the mutations of MYOC, OPTN, CYP1B1 and WDR36 in a large Chinese family affected by juvenile open angle glaucoma (JOAG). METHODS: Of 114 members of one family were recruited in this study. Blood samples from twelve members of this pedigree were collected for further research. As a control, 100 unrelated subjects were recruited from the same hospital. The exon and flanking intron sequences of candidate genes were amplified using the polymerase chain reaction and direct DNA sequencing. RESULTS: The proband (III:10) was a seventy-three years old woman with binocular JOAG at the age of 31. A recurrent heterozygous mutation (c.1099G>A) of MYOC was identified in the three JOAG patients and another suspect. This transition was located in the first base pair of codon 367 (GGA>AGA) in exon 3 of MYOC and was predicted to be a missense substitution of glycine to arginine (p.G367R) in myocilin. Mutations in OPTN, CYP1B1 or WDR36 were not detected in this study. The G367R mutation was not present in unaffected family members or in 100 ethnically matched controls. Other variants of the coding regions of candidate genes were not detected in all participants. To date, this family was the largest to have been identified as carrying a certain MYOC mutation in China, further evidence of a founder effect for the G367R MYOC mutant was provided by our data. CONCLUSION: A MYOC c.1099G>A mutation in an autosomal dominant JOAG family is identified and the characteristic phenotypes among the patients are summarized. Genetic testing could be utilized in high-risk populations and be helpful not only for genetic counseling, but also for early diagnosis and treatment of affected patients or carriers of inherited JOAG.     

一个中国原发性开角型青光眼家系致病基因研究

目的:鉴定一个江苏省南通市原发性开角型青光眼(POAG)家系的青光眼致病基因,分析该基因的临床表型和致病机制。方法:于2020-01/12回顾并招募了一个POAG家系,该家系跨越5代共33名,有13名家庭成员参与了研究,其中4名诊断为POAG,1名诊断为高眼压症,剩余8名未受影响。详细询问病史并进行全面的眼科检查,采用高通量测序筛选可能的致病基因,Sanger测序验证候选致病基因。结果:该家系患者均在青年时期发现眼压升高并诊断为青光眼,需手术治疗控制眼压,先证者最高眼压(IOP)达55mmHg。全外显子测序在先证者LTBP2基因上发现了一个杂合突变(c.1197C>A, p.Phe399Leu),Sanger测序验证该突变位点与家系疾病并不分离。结论:LTBP2 (c.1197C>A)突变不是该家系POAG的致病基因。但是LTBP2突变在POAG病例中的致病作用值得研究。     

Clinical and genetic characterization of a large primary open angle glaucoma pedigree

Purpose: To both characterize the clinical features of large primary open angle glaucoma (POAG) pedigree from a village in southern India and to investigate the genetic basis of their disease.

Materials and methods: Eighty-four members of a large pedigree received complete eye examinations including slit lamp examination, tonometry, gonioscopy, and ophthalmoscopy. Some were further studied with perimetry. Those diagnosed with POAG were tested for disease-causing mutations in the myocilin and optineurin genes with Sanger sequencing.

Results: Fourteen of 84 family members were diagnosed with POAG, while eight were clinically judged to be POAG-suspects. The family structure and the pattern of glaucoma in the pedigree are complex. Features of glaucoma in this pedigree include relatively early age at diagnosis (mean 50 ± 14 years) and maximum intraocular pressures ranging from 14 to 36 mm Hg with a mean of 23 mm Hg ± 6.5 mm Hg. Patients had an average central corneal thickness (mean 529 ± 37.8 microns) and moderate cup-to-disc ratios (0.74 ± 0.14). No mutations were detected in myocilin, optineurin, or TANK binding kinase 1 (TBK1).

Conclusions: We report a five-generation pedigree with a complex pattern of POAG inheritance that includes 22 POAG patients and glaucoma suspects. Although the familial clustering of POAG in this pedigree is consistent with dominant inheritance of a glaucoma-causing gene, mutations were not detected in genes previously associated with autosomal dominant glaucoma, suggesting the involvement of a novel disease-causing gene in this pedigree.     

基于眼底照相的原发性开角型青光眼人群筛查成本-效果分析

目的 基于“北京眼病研究”与“邯郸眼病研究”获得的基础数据,对采用眼底照相在人群开展原发性开角型青光眼（POAG）筛查的成本-效果进行评价,为POAG人群筛查策略的制定提供数据支持。设计 成本-效果分析。研究对象 “北京眼病研究”及“邯郸眼病研究”中关于POAG流行病学调查结果。方法 采用R软件计算40岁以上POAG在人群筛查和医院机会就诊两种诊疗模式下的伤残调整生命年,并基于2014年的成本,计算两种诊疗模式的直接成本费用（筛查成本、诊断成本、干预成本）,然后比较两种模式的成本-效果。主要指标 成本费用,伤残调整生命年。结果 以1万例40岁以上社区人口为拟合基数,分析结果提示：如果每5年筛查一次,可及早发现POAG患者并及时药物控制,其视功能损害率为30%左右;而医院就诊方式,其视功能损害率均在50%以上;采用眼底照相完成POAG的筛查、确诊及治疗所需直接医疗成本为175万;通过医院机会就诊模式,需直接成本为406万,但开展社区筛查发生的疾病负担,即伤残调整生命年（1.33）却低于医院机会就诊模式（2.76）。结论 POAG的社区筛查可降低由于其导致的伤残调整生命年,对患者视功能的维持及改善生命质量具有重要意义,且可降低直接医疗成本。     

Outcomes of trabeculectomy in juvenile open angle glaucoma

Purpose:

This study was aimed at reporting the outcomes of trabeculectomy in primary juvenile open angle glaucoma (JOAG).

Design:

This study was a retrospective noncomparative case series.

Materials and Methods:

We included 60 eyes of 41 JOAG patients who underwent primary trabeculectomy without mitomycin-C (MMC) between 1995 and 2007. The primary outcome was success, defined as complete, if intraocular pressure (IOP) was >5 and ≤21 mmHg without medications or qualified if IOP was >5 and ≤21 mmHg with or without antiglaucoma medications. Secondary outcome measures were mean and percentage IOP reduction, complications, and risk factors for the failure of trabeculectomy.

Results:

The mean (±standard deviation) age at presentation was 24.1 ± 6.8 years (range, 12–35). Mean follow-up was 67 ± 41 months (range, 12–156). At 1 year, the probability of complete success was 92% (n = 56, 95% CI: 81–96%), at 3 years it was 89% (n = 47, 95% CI: 78–95%), and at the end of 5 years, it was 80% (n = 34, 95% CI: 65–89%). The probability of qualified success was 100% (n = 60) at 1 year, 98% (n = 51, 95% CI: 87–100%) at 3 years, and 96% (n = 36, 95% CI: 84–99%) at the end of 5 years. The mean IOP reduced from 35 ± 10 to 13 ± 2.5 mmHg (P < 0.001) after trabeculectomy. There was no serious postoperative complication. Young age was the only significant risk factor associated with the failure (odds ratio = 0.89, P = 0.03).

Conclusion:

Primary trabeculectomy without MMC has good success rates in JOAG.     

OPTN基因突变与一原发性开角型青光眼家系的关系研究

目的　探讨视神经病变诱导基因OPTN与一原发性开角型青光眼 (POAG)家系的关系。方法　通过遗传学调查并对该家系中 11例POAG患者和 9例一级亲属的OPTN基因进行荧光标记自动测序 ,寻找OPTN基因 4～ 16外显子的单核苷酸多态性 (SNP) ,用限制性内切酶分析技术检测 3 2例对照组人群相应的SNP。结果　OPTN基因 4～ 16外显子共检测出 5种SNP :412G >A、60 3T >A、12 67 12 68insC并 12 71 12 72insC、15 3 7 15 3 8insC和 1878 1879insA。其中除412G >A外 ,其他突变均将改变氨基酸的编码 ,和对照人群分布有显著性差异。结论　OPTN基因突变可能是本家系POAG发病的原因之一     

Detection of a new TIGR gene mutation in a Japanese family with primary open angle glaucoma.

PURPOSE: To describe a new mutation of the trabecular meshwork-inducible glucocorticoid response protein (TIGR) gene in a Japanese patient with familial primary open angle glaucoma (POAG). METHODS: Standard ocular examinations were performed on the 44-year-old patient, his sister, and mother. DNA sequencing was used to identify the mutation. We also developed a DNA diagnostic method for detecting this missense mutation by polymerase chain reaction-induced mutation restriction analysis (PCR-IMRA). RESULTS: The patient, father, and sister had been diagnosed as having POAG. The patient and his sister had a Thr448Pro mutation (C-->A transition at the nucleotide number 1419) in exon 3. This mutation has not been reported before. CONCLUSIONS: Gene analysis is promising for an early diagnosis among the family members of familial POAG patients and will contribute to early therapy before an occurrence of irreversible visual impairment.     

Physical activity of patients with a primary open angle glaucoma

AIM: To assess physical activity (PA) including its intensity in primary open angle glaucoma (POAG). METHODS: PA was characterized by the use of questionnaires: Seven-Day Physical Activity Recall and Historical Leisure Activity Questionnaire. A questionnaire of 36 questions, developed by the authors, was used to assess the level of knowledge about glaucoma RESULTS: The study was conducted among 625 adults. The study group comprised 312 POAG patients aged over 40y, including 238 women (76%) and 74 men (24%). The control group consisted of 313 adults (>40 years old), including 202 (65%) women and 111 men (35%). The duration of current PA with an intensity of 4 metabolic equivalents (METs) was significantly shorter among people with POAG. PA in the past was significantly lower among people from the study group, regardless of gender. The level of glaucoma knowledge in patients with POAG was poor and significantly lower in men. CONCLUSION: Regular PA is an important and underestimated factor predisposing to the progression of POAG. There is a necessity to undertake educational and preventive actions with a view to modify the health behavior of glaucoma patients.     

Targeting relatives of patients with primary open angle glaucoma: the help the family glaucoma project

PURPOSE: To assess the knowledge of patients with open angle glaucoma (OAG) and their family members about OAG risk factors and to study the referral of family members for eye examinations. DESIGN: Cross-sectional survey and prospective cohort study. METHODS: We interviewed OAG patients (probands) at the Wilmer Eye Institute and their biologically related parents, siblings, and children about their knowledge of OAG risk factors. Qualified family members were offered an eye examination through the EyeCare America program. Three months after initial contact, a follow-up telephone questionnaire determined the outcome of the referral. RESULTS: Among 102 probands and 100 (of 230 eligible) family members who were interviewed, there was high awareness that OAG is related to older age (85% both groups). More probands knew of the association with higher intraocular pressure (95%) compared with family (78%). Yet, 21% of both groups were not aware that OAG is hereditary, and only 53% of probands and 30% of family members knew that OAG is more common in certain ethnic groups. Only two-thirds of probands had suggested that family members have an eye examination. Eighty percent of family members had had an eye examination within the last year; of 21 with no recent examination, 66% (13/21) accepted referral. CONCLUSIONS: The Help the Family Glaucoma project developed a novel approach to identify those at high-risk for OAG. Screening of relatives of OAG patients deserves further study in a more representative selection of the general population.     

Genetics of primary open angle glaucoma

Glaucoma is a neurodegenerative disease and one of the leading causes of irreversible blindness, affecting over 60 million people worldwide. At the present time, glaucoma is clinically defined, but the exact etiology is unknown. Genetic studies are one approach to identify the molecules and pathways involved in disease pathogenesis. Familial aggregation of primary open-angle glaucoma (POAG) has long been recognized, and the analysis of POAG families with a Mendelian inheritance form of this disease has been employed to identify multiple loci linked to them. Some causative genes, such as myocilin, optineurin and WD repeat domain 36, have been identified. However, most cases of POAG are considered to be a prevalent, multifactorial disorder. Several association studies have been conducted for candidate genes, and genome-wide association studies recently identified new susceptibility loci for POAG, namely, S1 RNA binding domain 1 region on chromosome 2p21, the caveolin 1 and caveolin 2 regions on 7q31, transmembrane and coiled-coil domain 1 region on 1q24, cyclin-dependent kinase inhibitor 2B antisense RNA on 9p21, the SIX1 and SIX6 regions on 14q24 and, possibly, the regulatory region of 8q22. Further analysis of clinical manifestations caused by specific genes and functional analysis of these genes will contribute to the development of new strategies for the diagnosis and treatment of POAG.     

Surgery of primary open angle glaucoma

The selection of the surgical approach to glaucoma depends primarily on the type of glaucoma. Filtration surgery (trabeculectomy) is considered the gold standard for the most common form of glaucoma, primary open angle glaucoma. The technique of surgery has been continuously improved during the past years resulting in less immediate postoperative complications such as flat anterior chamber, choroidal detachment and hypotony. The major problem of glaucoma surgery nowadays is wound healing with scarring of the outflow area. By intensified postoperative care using antimetabolites at the time of surgery and during postoperative care, many problems of scar formation can be managed. The absolute success rate may be doubled by using intensified postoperative care. Non-penetrating surgery such as deep sclerectomy or trabeculotomy are effective; however, the amount of IOP lowering achieved is inferior to that of trabeculectomy. To select a special glaucoma surgical procedure, the individual target pressure for the respective patient has to be defined. Recent large randomised prospective studies have shown that a low target pressure is needed to preserve and stabilise the visual field in advanced cases. Glaucoma filtration surgery is an important mainstay of advanced glaucoma treatment.     

Cataract surgery in primary open angle glaucoma

Cataract surgery has a moderate lowering effect on the intraocular pressure. When glaucoma seems controlled by medication, phacoemulsification gives a chance of improving the situation. Those eyes are most likely to get an intraocular pressure rise by retention of visco-elastic substance.     

Postural stability in primary open angle glaucoma

BACKGROUND: This study evaluated the visual contribution to postural steadiness in primary open angle glaucoma (POAG), in correlation with the mean deviation (MD) measured through conventional perimetry, and with the Advanced Glaucoma Intervention Study (AGIS) score, which quantifies the extent of losses in the visual field. METHODS: In 35 POAG patients and 21 age-matched normal subjects, the sway of the centre of pressure of the feet, on a firm or foam support, was recorded. The subjects stood on a force-plate with eyes closed, or with one or two eyes open. RESULTS: For all subjects, the sway velocity was lower with vision than without vision, indicating the existence of a visual contribution to posture at all stages of glaucoma. This contribution was significantly lower for POAG patients than for normals in monocular and binocular vision, and decreased with the MD, or as the AGIS score increased. Among the maximum, minimum and average values of the two monocular MD, the MD of the worse eye presented the most significant negative correlation with the visual contribution to posture. The somatosensory contribution to postural steadiness was larger in POAG patients, as compared to normals, in monocular or binocular vision. CONCLUSION: Primary open angle glaucoma induces a deficit in the visual contribution to postural steadiness, which should be taken into account for the prevention of falls.