Normal Tension Glaucoma Cases Research Articles

METTL23 Variants and Patients With Normal-Tension Glaucoma

This research confirms and further establishes that pathogenic variants in a fourth gene, METTL23, are associated with autosomal dominant normal-tension glaucoma (NTG). To determine the frequency of glaucoma-causing pathogenic variants in the METTL23 gene in a cohort of patients with NTG from Iowa. This case-control study took place at a single tertiary care center in Iowa from January 1997 to January 2024, with analysis occurring between January 2023 and January 2024. Two groups of participants were enrolled from the University of Iowa clinics: 331 patients with NTG and 362 control individuals without glaucoma. Patients with a history of trauma; steroid use; stigmata of pigment dispersion syndrome; exfoliation syndrome; or pathogenic variants in MYOC, TBK1, or OPTN were also excluded. Detection of an enrichment of METTL23 pathogenic variants in individuals with NTG compared with control individuals without glaucoma. The study included 331 patients with NTG (mean [SD] age, 68.0 [11.7] years; 228 [68.9%] female and 103 [31.1%] male) and 362 control individuals without glaucoma (mean [SD] age, 64.5 [12.6] years; 207 [57.2%] female and 155 [42.8%] male). There were 5 detected instances of 4 unique METTL23 pathogenic variants in patients with NTG. Three METTL23 variants-p.Ala7Val, p.Pro22Arg, and p.Arg63Trp-were judged to be likely pathogenic and were detected in 3 patients (0.91%) with NTG. However, when all detected variants were evaluated with either mutation burden analysis or logistic regression, their frequency was not statistically higher in individuals with NTG than in control individuals without glaucoma (1.5% vs 2.5%; P = .27). This investigation provides evidence that pathogenic variants in METTL23 are associated with NTG. Within an NTG cohort at a tertiary care center, pathogenic variants were associated with approximately 1% of NTG cases, a frequency similar to that of other known normal-tension glaucoma genes, including optineurin (OPTN), TANK-binding kinase 1 (TBK1), and myocilin (MYOC). The findings suggest that METTL23 pathogenic variants are likely involved in a biologic pathway that is associated with glaucoma that occurs at lower intraocular pressures.

Managing Normal Tension Glaucoma with Dietary Folate

Normal-Tension Glaucoma (NTG) is the most prevalent form of glaucoma among individuals in Asian countries. While lowering intraocular pressure (IOP) remains the standard of care, this approach is insufficient for most NTG patients. Recent evidence documents the role of ischemia and oxidative stress as critical factors affecting the optic nerve in NTG. Consequently, addressing these factors has been recommended as a neuroprotective strategy. While conventional treatment strategies primarily target the reduction of IOP, this yields limited efficacy and eventual blindness in many NTG cases. Recent studies document another crucial parameter: Retinal Venous Pressure (RVP). Elevated RVP impedes retinal perfusion, resulting in oxidative stress and localized ischemia, and exacerbating optic nerve damage in NTG. Elevated RVP also appears to be a contributing factor in small vessel ischemia associated with diabetic retinopathy and macular degeneration. The underlying cause of elevated RVP is small vessel endotheliopathy, which may result from alterations in methylation and B-vitamin metabolism, leading to changed microcirculation. This metabolic disruption can arise from dietary inadequacies, malabsorption, or genetic polymorphisms affecting the methylation pathways. Restoring plasma levels of folate and B-12 can be achieved through supplementation with natural forms of these vitamins, specifically L-methylfolate, and methylcobalamin. Unlike oxidized folate (folic acid), which must be enzymatically converted to methylfolate to penetrate the blood-retinal barrier, L-methylfolate can be directly utilized. Excess unmetabolized folic acid can impede methyl folate absorption into the retina, underscoring the necessity of using methyl folate for effective supplementation. We propose integrating RVP screening into NTG risk assessments and consider a targeted vitamin supplement, such as Ocufolin®, as a viable adjunct approach to manage elevated RVP and potentially mitigate NTG progression.

Familial normal tension glaucoma genetics.

Glaucoma is defined by characteristic optic nerve damage and corresponding visual field defects and is the leading cause of irreversible blindness in the world. Elevated intraocular pressure (IOP) is a strong risk factor for developing glaucoma. However, glaucoma can occur at any IOP. Normal tension glaucoma (NTG) arises with IOPs that are within what has been defined as a normal range, i.e., 21mm Hg or less, which may present challenges in its diagnosis and management. Identifying inheritance patterns and genetic mutations in families with NTG has helped elucidate mechanisms of NTG, however the pathophysiology is complex and not fully understood. Approximately 2% of NTG cases are caused primarily by mutations in single genes, optineurin (OPTN), TANK binding kinase 1 (TKB1), or myocilin (MYOC). Herein, we review pedigree studies of NTG and autosomal dominant NTG caused by OPTN, TBK1, and MYOC mutations. We review identified mutations and resulting clinical features of OPTN-associated and TBK1-associated NTG, including long-term follow up of these patients with NTG. In addition, we report a new four-generation pedigree of NTG caused by a Glu50Lys OPTN mutation, including six family members with a mean follow up of 17 years. Common features of OPTN -associated NTG due to Glu50Lys mutation included early onset of disease with an IOP <21mm Hg, marked optic disc cupping, and progressive visual field loss which appeared to stabilize once an IOP of less than 10mm Hg was achieved. Lastly, we review risk factor genes which have been identified to contribute to the complex inheritance of NTG.

Retinal vessel architecture and geometry are not impaired in normal-tension glaucoma

To investigate the associations between retinal vessel parameters and normal-tension glaucoma (NTG). We conducted a case–control study with a prospective cohort, allowing to record 23 cases of NTG. We matched NTG patient with one primary open-angle glaucoma (POAG) and one control per case by age, systemic hypertension, diabetes, and refraction. Central retinal artery equivalent (CRAE), central retinal venule equivalent (CRVE), Arteriole-To-Venule ratio (AVR), Fractal Dimension and tortuosity of the vascular network were measured using VAMPIRE software. Our sample consisted of 23 NTG, 23 POAG, and 23 control individuals, with a median age of 65 years (25–75th percentile, 56–74). No significant differences were observed in median values for CRAE (130.6 µm (25–75th percentile, 122.8; 137.0) for NTG, 128.4 µm (124.0; 132.9) for POAG, and 135.3 µm (123.3; 144.8) for controls, P = .23), CRVE (172.1 µm (160.0; 188.3), 172.8 µm (163.3; 181.6), and 175.9 µm (167.6; 188.4), P = .43), AVR (0.76, 0.75, 0.74, P = .71), tortuosity and fractal parameters across study groups. Vascular morphological parameters were not significantly associated with retinal nerve fiber layer thickness or mean deviation for the NTG and POAG groups. Our results suggest that vascular dysregulation in NTG does not modify the architecture and geometry of the retinal vessel network.

Association of Polymorphisms at the SIX1/SIX6 Locus With Normal Tension Glaucoma in a Korean Population.

We demonstrated that SIX1/SIX6 locus polymorphism (rs10483727 and rs33912345) was significantly associated with a genetic susceptibility to NTG in a Korean population. More studies are needed to investigate whether the SIX1/SIX6 locus is associated with NTG among various ethnic populations. Several previous studies have reported that the relevance of the SIX1/SIX6 locus to open angle glaucoma (OAG) in various ethnic populations. However, definitions of OAG patients were different among those studies. The relevance of the SIX1/SIX6 locus to normal tension glaucoma (NTG) in a Korean population remains uncertain. Therefore, the purpose of this study was to investigate the relationship of the SIX1/SIX6 locus with NTG in a Korean cohort. Patients with NTG and ethnically matched healthy controls were recruited from eye clinics in Korea (210 cases and 117 controls). Four polymorphisms (rs33912345, rs12436579, rs2179970, and rs10483727) of the SIX1/SIX6 locus were genotyped for 327 subjects using a TaqMan single nucleotide polymorphism genotyping assay. The rs33912345 polymorphism was significantly correlated with NTG in the recessive model [odds ratio (OR): 0.265; 95% confidence interval (CI): 0.078-0.898, P =0.033], but not in the allelic and dominant models (both P >0.05). The SNP rs10483727 was significantly associated with NTG in the allelic model (OR: 0.674; 95% CI: 0.464-0.979, P =0.038) and the recessive model (OR: 0.187; 95% CI: 0.058-0.602, P =0.005). Genetic association analysis of SNP rs12436579 and rs2179970 revealed no significant difference in genotype distribution between NTG cases and controls in the allelic, dominant, or recessive models (all P >0.05). The current study found that SIX1-SIX6 locus rs10483727 and rs33912345 polymorphisms were significantly associated with NTG risk in the Korean population.

Association between HSPA5 Promoter Polymorphisms and a Reduced Risk of Normal Tension Glaucoma

Introduction: In normal tension glaucoma (NTG), factors other than elevated intraocular pressure (IOP) are likely to play a role in the pathogenesis of optic neuropathy. The potential similarities between Alzheimer’s disease (AD) and NTG in cellular apoptosis leading to neurodegeneration have been shown in recent studies. Heat Shock Protein family A member 5 (HSPA5) promoter polymorphisms have been reported to be associated with a risk of AD. The purpose of our study was to investigate the role of HSPA5 promoter polymorphisms in NTG patients. Methods: A total of 222 patients with NTG, along with 236 normal controls were enrolled in this study. Genomic DNA was amplified through a polymerase chain reaction (PCR) and identified for the polymorphic HSPA5 (−415 and −370) by Xmn1 and BstY1 restriction digestion, respectively. PCR fragments with potential polymorphic HSPA5 (−180) were subjected to sequence-analyses by a Hex-labeled primer. Genotypes for both NTG patients and control groups were compared for statistically significant differences. Results: Polymorphisms (−415) G/A and (−180) del/G were completely linked in our population. The genotype and allele frequency distribution at the −415 G/A and −180 del/G sites showed a significant difference between the NTG cases and controls. The genotype frequency of HSPA5 (−415) AA/(−180) GG and the allele frequency of HSPA5 (−415) A/(−180) G were significantly lower (p = 0.04 and p = 0.01, respectively) in the NTG patients when compared with those in the control group. There was no significant difference in genotype or allele frequency distribution of the HSPA5 (−370) C/T between the NTG and control groups. There was a reduced risk of NTG associated with the carriers for the HSPA5 (−415) A/(−180) G allele compared with that in the control population (p = 0.01). Conclusion: HSPA5 (−415) A and (−180) G allele polymorphisms may be protective factors in the development of NTG.

English

BACKGROUND Open angle glaucoma forms a major proportion of glaucomas which is a leading cause of irreversible blindness worldwide. Anatomical variations in ocular structures and consequent secondary open angle glaucoma occurs in significant number of patients afflicted with pseudoexfoliation syndrome. Hence, a detailed workup and identification of glaucoma and appropriate management is essential to prevent further visual loss. We wanted to evaluate the incidence of open angle glaucoma among patients having pseudo exfoliation syndrome at Regional Institute of Ophthalmology, Trivandrum, Kerala. METHODS A cross sectional study comprising 142 individuals with pseudo exfoliation syndrome was conducted in Regional Institute of Ophthalmology, Trivandrum, Kerala, over a period of one year. Sociodemographic variables were collected through structured interviewer administered questionnaire followed by detailed ocular work up and visual field analysis. Data was analysed using Statistical Package for Social Sciences, SPSS 16. RESULTS Among 142 subjects, 70.4 % were males and 29.6 % were females. The mean age of participants was 65 years. In studied population, 83.1 % represented rural population. Incidence of open angle glaucoma among studied population with pseudoexfoliation was 10.56 % (95 % confidence interval; 5.50 % - 15.61 %). No case of normal tension glaucoma was identified during the study period. 29.57 % of subjects showed bilateral pseudoexfoliation. But among patients with pseudoexfoliation (PEX) glaucoma, 78.9 % had bilateral disease. Mean intra ocular pressure in eyes with PEX glaucoma was 27.38 ± 5.75 mm Hg and in PEX eyes without glaucoma was 23.20 ± 1.6 mmHg. Pupillary dilatation was observed to be less than the normal eyes and was 5.62 mm. 4 % of eyes with PEX had some form of zonulopathy. CONCLUSIONS Hospital based incidence of open angle glaucoma among patients with pseudo exfoliation is 10.56 %. KEYWORDS Pseudoexfoliation, Open Angle Glaucoma, Incidence, Intraocular Pressure, Gonioscopy

Normal tension glaucoma: Prevalence, etiology and treatment

Normal tension glaucoma is the most common type of glaucoma among people of east Asian countries. While a significant minority of cases of normal tension glaucoma respond to drugs or surgical procedures that lower intra-ocular pressure, most cases continue to progress, resulting in a continuing loss of visual field and blindness. We here review the current state of knowledge of this debilitating disease, and evaluate a promising pilot study showing a potential route to evaluate normal tension glaucoma and to effectively treat it with a vitamin and mineral supplement.

Normal tension glaucoma: Prevalence, etiology and treatment

Normal tension glaucoma is the most common type of glaucoma among people of east Asian countries. While a significant minority of cases of normal tension glaucoma respond to drugs or surgical procedures that lower intra-ocular pressure, most cases continue to progress, resulting in a continuing loss of visual field and blindness. We here review the current state of knowledge of this debilitating disease, and evaluate a promising pilot study showing a potential route to evaluate normal tension glaucoma and to effectively treat it with a vitamin and mineral supplement.

Central visual field change after fornix-based trabeculectomy in Japanese normal-tension glaucoma patients managed under 15mmHg.

To investigate how the central visual field would be changed after fornix-based trabeculectomy with mitomycin C in Japanese normal-tension glaucoma (NTG) patients monitored for more than 10years including before surgery. This is a retrospective cohort study. We identified twenty-eight eyes of 28 NTG cases regularly monitored for more than 5years and examined static visual field (VF) tests for more than five times before and after fornix-based trabeculectomy (including combined surgery). Based on preoperative data for 6.3years, we evaluated postoperative changes for 6.0years in 10-2 VF and 30-2 VF. Six patients were male and 22 females, the mean age was 57.9years, and the mean deviation was - 13.7 decibels. After surgery, mean IOP decreased from 13.9 to 9.0mmHg (P ≤ 0.01), and medication score also did. The rate of 10-2 VF deterioration was significantly suppressed from - 1.0dB/year preoperatively to - 0.4dB/year postoperatively (P ≤ 0.01). And when 30-2 VF was divided into six relevant sectors, the rate of deterioration at cecocentral and arcuate areas of the superior hemifield was suppressed postoperatively (P ≤ 0.01 and P = 0.042, respectively). Based on long-term preoperative data, a significant positive change in 10-2 VF was observed after fornix-based trabeculectomy with mitomycin C in Japanese NTG patients with a mean IOP of 13.9mmHg. Central vision could be expected to be maintained for NTG patients even if its preoperative IOP is low after successful trabeculectomy.

Lack of correlation between S1 RNA binding domain 1 SNP rs3213787/rs11884064 and normal‐tension glaucoma in a population from the Republic of Korea

PurposePrevious studies have reported the association of the S1 RNA binding domain 1 (SRBD1) gene with open‐angle glaucoma in various ethnic populations. However, in those studies, the definition of the patients differed, as did the results. Therefore, the relevance of the SRBD1 gene to normal tension glaucoma (NTG) appears uncertain at present. Thus, we investigated the relationship between the SRBD1 gene and NTG in a Korean NTG cohort.MethodsIn total, 159 unrelated Korean patients with NTG and 103 Korean control subjects were recruited. Thus, a total of 262 participants were analyzed for SRBD1 (rs3213787 and rs11884064) gene polymorphisms.ResultsThe minor allele frequency (MAF) of rs3213787 was found to be 0.13 and 0.19 in NTG cases and controls, respectively. The genetic association analysis of SNP rs3213787 revealed no significant difference in genotype distribution between NTG cases and controls in allelic (odds ratio [OR] = 0.634, p = 0.063), dominant (OR = 0.589, p = 0.066) or recessive models (OR = 0.639, p = 0.7716). The MAF of rs11884064 was found to be 0.24 and 0.25 in NTG cases and controls, respectively. For rs11884064, no significant difference in genotype distribution was observed between NTG cases and controls in allelic (OR = 0.938, p = 0.755), dominant (OR = 0.927, p = 0.798) or recessive models (OR = 0.920, p = 1.000).ConclusionsThe current study suggested that SRBD1 gene polymorphisms (rs3213787 and rs11884064) may not be associated with genetic susceptibility to NTG in a Korean cohort.

Lack of correlation between S1 RNA binding domain 1 SNP rs3213787/rs11884064 and normal-tension glaucoma in a population from the Republic of Korea.

Previous studies have reported the association of the S1 RNA binding domain 1 (SRBD1) gene with open-angle glaucoma in various ethnic populations. However, in those studies, the definition of the patients differed, as did the results. Therefore, the relevance of the SRBD1 gene to normal tension glaucoma (NTG) appears uncertain at present. Thus, we investigated the relationship between the SRBD1 gene and NTG in a Korean NTG cohort.In total, 159 unrelated Korean patients with NTG and 103 Korean control subjects were recruited. Thus, a total of 262 participants were analyzed for SRBD1 (rs3213787 and rs11884064) gene polymorphisms.The minor allele frequency of rs3213787 was found to be 0.13 and 0.19 in NTG cases and controls, respectively. The genetic association analysis of SNP rs3213787 revealed no significant difference in genotype distribution between NTG cases and controls in allelic (odds ratio [OR] = 0.634, P = .063), dominant (OR = 0.589, P = .066) or recessive models (OR = 0.639, P = .7716). The minor allele frequency of rs11884064 was found to be 0.24 and 0.25 in NTG cases and controls, respectively. For rs11884064, no significant difference in genotype distribution was observed between NTG cases and controls in allelic (OR = 0.938, P = .755), dominant (OR = 0.927, P = .798) or recessive models (OR = 0.920, P = 1.000).The current study suggested that SRBD1 gene polymorphisms (rs3213787 and rs11884064) may not be associated with genetic susceptibility to NTG in a Korean cohort.

Whole exome sequencing implicates eye development, the unfolded protein response and plasma membrane homeostasis in primary open-angle glaucoma.

PurposeTo identify biological processes associated with POAG and its subtypes, high-tension (HTG) and normal-tension glaucoma (NTG), by analyzing rare potentially damaging genetic variants.MethodsA total of 122 and 65 unrelated HTG and NTG participants, respectively, with early onset advanced POAG, 103 non-glaucoma controls and 993 unscreened ethnicity-matched controls were included in this study. Study participants without myocilin disease-causing variants and non-glaucoma controls were subjected to whole exome sequencing on an Illumina HiSeq2000. Exomes of participants were sequenced on an Illumina HiSeq2000. Qualifying variants were rare in the general population (MAF < 0.001) and potentially functionally damaging (nonsense, frameshift, splice or predicted pathogenic using SIFT or Polyphen2 software). Genes showing enrichment of qualifying variants in cases were selected for pathway and network analysis using InnateDB.ResultsPOAG cases showed enrichment of rare variants in camera-type eye development genes (p = 1.40×10–7, corrected p = 3.28×10–4). Implicated eye development genes were related to neuronal or retinal development. HTG cases were significantly enriched for key regulators in the unfolded protein response (UPR) (p = 7.72×10–5, corrected p = 0.013). The UPR is known to be involved in myocilin-related glaucoma; our results suggest the UPR has a role in non-myocilin causes of HTG. NTG cases showed enrichment in ion channel transport processes (p = 1.05×10–4, corrected p = 0.027) including calcium, chloride and phospholipid transporters involved in plasma membrane homeostasis. Network analysis also revealed enrichment of the MHC Class I antigen presentation pathway in HTG, and the EGFR1 and cell-cycle pathways in both HTG and NTG.ConclusionThis study suggests that mutations in eye development genes are enriched in POAG. HTG can result from aberrant responses to protein misfolding which may be amenable to molecular chaperone therapy. NTG is associated with impaired plasma membrane homeostasis increasing susceptibility to apoptosis.

Genetic Association at the 9p21 Glaucoma Locus Contributes to Sex Bias in Normal-Tension Glaucoma.

Many genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at the 9p21 glaucoma locus (CDKN2B/CDKN2B-AS1) to be significantly associated with primary open-angle glaucoma (POAG), with association being stronger in normal tension glaucoma (NTG) and advanced glaucoma. We aimed to determine whether any observed differences in genetic association at the 9p21 locus are influenced by sex. Sex was assessed as a risk factor for POAG for 2241 glaucoma participants from the Australian and New Zealand Registry of Advanced Glaucoma, the Glaucoma Inheritance Study in Tasmania, and the Flinders Medical Centre. A total of 3176 controls were drawn from the Blue Mountains Eye Study and South Australia: 1523 advanced POAG and 718 nonadvanced POAG cases were genotyped along with 3176 controls. We selected 13 SNPs at the 9p21 locus, and association results were subanalyszd by sex for high-tension glaucoma (HTG) and NTG. Odds ratios (ORs) between sexes were compared. A sex bias was present within advanced NTG cases (57.1% female versus 42.9% male, P = 0.0026). In all POAG cases, the strongest associated SNP at 9p21 was rs1063192 (OR, 1.43; P = 4 × 10-18). This association was stronger in females (OR, 1.5; P = 5 × 10-13) than in males (OR, 1.35; P = 7 × 10-7), with a statistically significant difference in female to male OR comparison (P = 1.0 × 10-2). An NTG to HTG subanalysis yielded statistically significant results only in females (OR, 1.63; P = 1.5 × 10-4) but not in males (OR, 1.15; P = 2.8 × 10-1), with a statistically significant difference in female to male OR comparison (P = 1.4 × 10-4). This study demonstrated that female sex is a risk factor for developing advanced NTG. The stronger genetic signals at the 9p21 locus among females may contribute at least in part to the observed sex bias for NTG.

No Evidence of Association of Heterozygous Galactosylceramidase Deletion With Normal-Tension Glaucoma in a Korean Population.

A significant association between primary open-angle glaucoma risk and copy-number variation in the galactosylceramidase (GALC) gene was reported recently. This study investigated whether a heterozygous deletion of the GALC gene plays a significant role in normal-tension glaucoma (NTG) in Koreans. A 3-primer polymerase chain reaction assay was used to examine the heterozygous deletion of GALC in all Korean NTG cases (n=276) and controls (n=135). We did not identify any deletion variant of GALC gene in the NTG patients. This is the first copy-number variation study of the GALC gene in the Korean population with NTG. We demonstrated that a heterozygous GALC deletion does not play a significant role in the pathogenesis of NTG in a representative clinic-based population of South Koreans, unlike whites.

Prospective study on the efficacy of treating normal tension glaucoma with a single session of selective laser trabeculoplasty.

The purpose of this study was to investigate the efficacy of selective laser trabeculoplasty (SLT) in the treatment of normal tension glaucoma (NTG). This prospective cohort study recruited consecutive cases of NTG on antiglaucoma medication. Cases were excluded for previous glaucoma surgery or laser. All patients underwent a 1-month washout of medication followed by a mean baseline intraocular pressure (IOP) measured at 9 AM, 1 PM, and 5 PM. A 30% reduction from baseline was set as the target IOP. A single session of SLT was performed to 360 degrees of the trabecular meshwork. IOP phasing was repeated at 1 month after SLT and medication was resumed to achieve the target IOP. Patients were followed up to 6 months after SLT. In 83 eyes of 46 subjects, the mean prestudy IOP was 14.2 ± 3.1 mm Hg when on 1.5 ± 0.9 antiglaucoma medication. The mean baseline IOP without medication was 16.1 ± 2.2 mm Hg. The mean SLT shots applied was 187.8 ± 27.5 using a mean energy of 1.0 ± 0.07 mJ. At 1-month post-SLT, the IOP was 12.7 ± 2.0 mm Hg (21.6% IOP reduction) from baseline without medication (P<0.05). The 6-month IOP was 11.4 ± 1.6 mm Hg when on 1.1± 1.0 medications, representing a 19.7% reduction from prestudy IOP, a 29.6% reduction from baseline IOP, and a 26.7% reduction in antiglaucoma medication (all P< 0.05). A higher baseline IOP was correlated with greater IOP reduction with SLT (r=0.3, P=0.009). A single session of SLT for NTG achieved an additional 20% reduction in IOP with 27% less medication at 6 months compared with prestudy levels while maintaining a 30% reduction from baseline IOP.

TBK1Gene Duplication and Normal-Tension Glaucoma

Normal-tension glaucoma (NTG) is a common cause of vision loss. To investigate the role of TANK binding kinase 1 (TBK1) gene duplications in NTG to gain insights into the causes of glaucoma that occurs at low intraocular pressure (IOP). In this multicenter case-control study, we investigated patients who met the criteria for NTG, including glaucomatous optic neuropathy, visual field defects, and maximum recorded untreated IOP of 21 mm Hg or less, and matched controls. Participants (N = 755) were recruited from Southampton, United Kingdom (180 patients and 178 controls), Rochester, Minnesota (65 patients and 12 controls), New York, New York (96 patients and 16 controls), and Iowa City, Iowa (208 controls). Detection of TBK1 gene duplications and comparison of the extent of the identified DNA that is duplicated with prior TBK1 copy number variations associated with NTG. A TBK1 gene duplication was detected in 1 of 96 patients (1.0%) from New York and none of the controls. Analysis of duplication borders with comparative genome hybridization demonstrated that this patient has a novel duplication that has not been previously reported. No gene duplications were detected in any of the other cohorts of patients or controls. Duplication of the TBK1 gene is a rare cause of NTG. The identification of another case of NTG attributed to TBK1 gene duplication strengthens the case that this mutation causes glaucoma.

Initial central scotomas vs peripheral scotomas in normal-tension glaucoma: clinical characteristics and progression rates

To investigate clinical characteristics and progression rates of the initial central scotomas (ICS) compared with the initial peripheral scotomas (IPS) in normal-tension glaucoma (NTG) patients. Among NTG patients showing a single hemifield defect and who performed more than five reliable standard visual field (VF) tests, medical records of ICS (involvement of ≥3 adjacent points with P<5% within the central 12° of fixation and one point with a P<0.01 within the central 6° of fixation) (n=32) or IPS (no VF abnormality within the central 6° of fixation) (n=34) were retrospectively analyzed. The changes of mean thresholds from 10 zones of the glaucoma hemifield test, central 6° and 12° zones, peripheral zones other than central 6° and 12°, and the entire hemifield were inspected. To calculate the progression rates, linear mixed-effect model was employed. There were no significant differences between the two groups in age, gender, ocular factors including baseline/mean treated intraocular pressure, and systemic factors including systolic or diastolic blood pressure/perfusion pressure, mean ocular perfusion pressure (all P>0.05). There were no significant differences in baseline mean deviation and pattern standard deviation (P>0.05) between the two groups, but VF index was significantly lower in ICS group than in IPS group (P=0.001). The progression rates between the two groups were not significantly different in all zones we investigated (all P>0.05). Newly diagnosed cases of NTG with ICS may not differ from those with IPS in clinical characteristics and progression rates under treatment.

Glaucoma in Atomic Bomb Survivors

Radiation has been associated with increases in noncancerous diseases. An effect of low-dose radiation on the prevalence of clinically detected glaucoma has not been previously reported. We therefore investigated the prevalence of glaucoma in A-bomb survivors and its possible association with radiation dose. A total of 1,589 people who participated in the clinical examination program for A-bomb survivors at the Radiation Effects Research Foundation (RERF) between October 2006 and September 2008 and who had reconstructed radiation doses, were recruited into this cross-sectional screening study. The prevalence of glaucoma and its dose-response relationship to A-bomb radiation were measured. Each subject underwent an initial screening consisting of an interview and ophthalmological examination. Questionable cases with any indication of ocular disease, including glaucoma, were referred to local hospitals for more comprehensive evaluation. A diagnosis of glaucoma was made based on specific optic disc appearance, perimetric results and other ocular findings. Of 1,589 eligible people, we detected 284 (17.9%) cases of glaucoma overall, including 36 (2.3%) cases of primary open-angle glaucoma with intraocular pressure levels greater than 21 mmHg, 226 (14.2%) cases of normal-tension glaucoma and 25 (1.6%) cases of primary angle-closure glaucoma. Seven glaucoma risk factors were examined as potential confounders but only two needed to be included in the final model. Binary regression using a generalized estimating equation method, with adjustment for gender, age, city, cataract surgery or diabetes mellitus, revealed an odds ratio at 1 Gy of 1.31 (95% confidence interval 1.11-1.53, P = 0.001) in the case of normal-tension glaucoma, but no association for other types of glaucoma. The prevalence of normal-tension glaucoma may increase with A-bomb radiation dose, but uncertainties associated with nonparticipation (59% participation) suggest caution in the interpretation of these results until they are confirmed by other studies.

Association study of genetic variants on chromosome 7q31 with susceptibility to normal tension glaucoma in a Japanese population

The caveolin 1 to caveolin 2 (CAV1-CAV2) gene region on chromosome 7q31 has been reported to be associated with susceptibility to primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) in previous studies. We investigated whether genetic variants in the CAV1-CAV2 region are associated with NTG in Japanese patients. Two hundred and ninety-two Japanese patients with NTG and 352 Japanese healthy controls were recruited. We genotyped three single-nucleotide polymorphisms; that is, rs1052990, rs4236601, and rs7795356, in the CAV1-CAV2 gene region and assessed the allelic diversity among cases and controls. The frequency of the minor allele (G) of rs1052990 was significantly decreased in NTG cases compared with controls (P=0.014, OR=0.71), whereas NTG or POAG cases had a significantly higher frequency of the allele than controls in previous studies. Conversely, rs7795356 did not show any significant association with NTG cases, and rs4236601 was monomorphic in the Japanese study population. Our findings did not correspond with previous positive results, suggesting that CAV1-CAV2 variants studied in the present study are not important risk factors for NTG susceptibility in all populations. Further studies are needed to elucidate the possible contribution of the CAV1-CAV2 region to the development of glaucoma.