Juvenile-onset Open-angle Glaucoma Research Articles

Genetic Insights and Epidemiological Models in Understanding Primary Open Angle Glaucoma

Primary open-angle glaucoma (POAG) is a multifactorial chronic optic neuropathy with significant genetic heterogeneity. The pathogenesis of POAG involves an imbalance between the production and drainage of aqueous humor (AH). Genetic theories suggest that transgenic mice demonstrating the GLU50LYS mutation in optineurin (OPTN) experience retinal ganglion cell apoptosis, while mutant myocilin (MYOC) proteins induce endoplasmic reticulum (ER) stress, leading to an unfolded protein response (UPR) and subsequent apoptosis of trabecular meshwork cells (TMC). Furthermore, the interaction between MYOC and mitochondria in the trabecular meshwork (TM) and astrocytes may lead to mitochondrial membrane depolarization and calcium channel dysregulation, contributing to POAG. Overexpression of MYOC variants (P370L, Q368X) is also implicated, as are epigenetic modifications and signaling pathways such as histone and DNA modification. POAG has been associated with autosomal dominant inheritance, with mutations in MYOC and OPTN being prominent causative factors, although many cases involve multiple genetic loci. Currently, over 20 genetic loci have been linked to POAG, with 14 chromosomal loci (GLC1A to GLC1N) identified, 5 of which contribute to juvenile-onset open-angle glaucoma (JOAG). Of these loci, MYOC, OPTN, WD repeat domain 36 (WDR36), and neurotrophin-4 (NTF4) are the most studied causative genes. The ongoing study of molecular genetics offers potential pathways for future therapeutic advances in the treatment of POAG.

Intraocular Pressure Response to Perceived Stress in Juvenile-Onset Open Angle Glaucoma.

High perceived stress from academic pressure is associated with intraocular pressure (IOP) elevation and reduced fluctuation in juvenile-onset open angle glaucoma patients. Personalized stress assessment and relief strategies may serve as an adjunct therapy in glaucoma. To evaluate the effect of higher perceived stress, resulting from academic pressure, on IOP in juvenile-onset open angle glaucoma (JOAG) patients compared with healthy individuals. The study included 48 university students aged 18-27 years, comprising 24 JOAG patients on antiglaucoma eyedrops and 24 healthy controls. In an examiner-blind pretest-posttest design, participants' IOP was measured weekly using Goldmann tonometry during three follow-up visits at the beginning and end of the academic semester. Perceived Stress Scale (PSS) scores were also evaluated at these 2-time points to capture the contrast in perceived stress between periods of low and high academic pressure. The baseline PSS score at the semester's start was lower in both groups (14.1±1.9 in glaucoma vs. 13.5±2.4 in control) and significantly increased by the end of the semester (29.2±2.1 vs. 28.5±1.3; P <0.001), indicating increased perceived stress. Concurrently, IOP rose from 22.01±5.87 to 25.08±5.84mmHg in the glaucoma group and from 11.36±2.03 to 13.65±2.11mmHg in the control group. Factorial analysis revealed a significant interaction between stress and JOAG ( F(1,94) =15.94, P =0.001), partial η 2 =0.08, with stress having a greater increase on IOP in the glaucoma group (+3.10mmHg) compared with the control group (+2.23mmHg) ( t(94) =4.457, P <0.001). Higher perceived stress significantly increases IOP, especially in JOAG patients, suggesting personalized stress management as a potential adjunct therapy for patients.

Gonioscopy-assisted transluminal trabeculotomy for open-angle glaucoma with failed incisional glaucoma surgery: two-year results

BackgroundTo evaluate the safety and efficacy of gonioscopy-assisted transluminal trabeculotomy (GATT) in treating patients with open-angle glaucoma (OAG) who had failed prior incisional glaucoma surgery.MethodsA consecutive case series of OAG patients aged ≥ 18 who underwent GATT with previous failed glaucoma incision surgery was retrospectively analyzed. Main outcome measures included intraocular pressure (IOP), the number of glaucoma medications, surgical success rate, and occurrence of complications. Success was defined as an IOP of ≤ 21 mmHg and a reduction of IOP by 20% or more from baseline with (qualified success) or without (complete success) glaucoma medications. For eyes with preoperative IOP of < 21 mmHg on 3 or 4 glaucoma medications, postoperative IOP of ≤ 18 mmHg without any glaucoma medications was also defined as complete success.ResultsForty-four eyes of 35 patients (21 with juvenile-onset open-angle glaucoma and 14 with adult-onset primary open-angle glaucoma) with a median age of 38 years were included in this study. The proportion of eyes with 1 prior incisional glaucoma surgery was 79.5%, and the others had 2 prior surgeries. IOP decreased from 27.4 ± 8.8 mm Hg on 3.6 ± 0.7 medications preoperatively to 15.3 ± 2.7 mm Hg on 0.5 ± 0.9 medications at the 24-month visit (P < 0.001). The mean IOP and the number of glaucoma medications at each follow-up visit were lower than the baseline (all P < 0.001). At 24 months postoperatively, 82.1% of the eyes had IOP ≤ 18 mmHg (versus 15.9% preoperatively, P < 0.001), 56.4% reached IOP ≤ 15 mmHg (versus 4.6% preoperatively, P < 0.001), and 15.4% achieved IOP ≤ 12 mmHg (compared to none preoperatively, P = 0.009). While 95.5% of eyes took 3 or more medications preoperatively, 66.7% did not take glaucoma medication 24 months after GATT. Thirty-four (77.3%) eyes achieved IOP reduction greater than 20% on fewer medications. The complete and qualified success rates were 60.9% and 84.1%, respectively. No vision-threatening complications occurred.ConclusionsGATT was safe and effective in treating refractory OAG patients who failed prior incisional glaucoma surgery.

A new association of PAX6 variation with Juvenile onset open angle glaucoma.

Mutations in the PAX6 gene are generally associated with aniridia. We describe a family with Juvenile onset open angle glaucoma (JOAG), where one of the two children had JOAG and the other Juvenile ocular hypertension. Whole exome sequencing was performed for the parents and their two affected children where the proband and her sibling were detected to have a de novo PAX6 gene variant in the absence of aniridia. All previously described gene mutations for glaucoma were looked for in the family. The potential pathogenicity of the identified variants was assessed by determining their frequency in large public exome databases; as well as using the current ACMG guidelines. The same heterozygous variant at NM_000280.6:c.1124 C > A; p. Pro375Gln in the PAX6 gene was detected in the proband and her affected brother. The variant has been described in aniridia patients before and has been shown to cause a weaker DNA binding using functional studies. This report expands the phenotypic spectrum of the PAX6 gene to include Juvenile onset open angle glaucoma.

TUBE VERSUS TRABECULECTOMY IN JUVENILE-ONSET OPEN ANGLE GLAUCOMA - TREATMENT OUTCOMES IN TERTIARY HOSPITALS IN MALAYSIA.

To compare the intraocular pressure (IOP) lowering effect and postoperative complications between primary augmented trabeculectomy and glaucoma drainage device (GDD) implantation as primary surgical intervention in patients with juvenile-onset open angle glaucoma (JOAG). A retrospective review study involving 20 eyes that underwent primary augmented trabeculectomy with mitomycin (MMC) and 10 eyes GDD implantation in 3 tertiary centres in Malaysia between 1 January 2013 and 31 December 2019. They were followed up for at least 12 months postsurgical intervention. Intraocular pressure (IOP), number of topical IOP lowering medication and complications were evaluated at 1, 3, 6 and 12 months post-intervention. Based on the IOP, the success was divided into complete and partial success, and failure. IOP and postsurgical complications were compared using the Repetitive Measure Analysis of Variance (RM ANOVA) and the Pearson chi-square test. Both methods were effective in lowering the IOP. Eyes with primary augmented trabeculectomy have significant lower IOP compared to GDD implantation (p = 0.037). There was a higher incidence of postoperative hypotony (30%) in the trabeculectomy group. There was also a significant reduction of mean number of topical pressure-lowering drugs required postoperatively (p = 0.015). Complete success was achieved in 100% of eyes with trabeculectomy and 67% in GDD implantation (p = 0.047). Primary augmented trabeculectomy and GDD implantation are good surgical options for the treatment of JOAG. Both methods provide IOP lowering at 1 year. However, trabeculectomy provides better pressure lowering, compared to GDD implantation in patients with JOAG.

Association of transforming growth factor beta induced mutations with congenital and juvenile onset open angle glaucoma

AbstractPurpose: To investigate the molecular basis of congenital glaucoma in a family with GAPO (growth retardation, alopecia, pseudoanodontia, and progressive optic atrophy) syndrome.Methods: We report ocular features of three girls with GAPO syndrome born of consanguineous marriage in a multi‐ generation consanguineous family. The proband (4 year old girl) and her younger sibling (1 year old girl) were operated for bilateral congenital glaucoma in both eyes. The elder sibling (10 year old female) had features of GAPO syndrome but did not manifest features of glaucoma.Results: A genetic evaluation using whole exome sequencing revealed a homozygous ANTXR1 mutation in all 3 affected siblings with GAPO. No other mutations were detected in the genes associated with glaucoma. A rare missense mutation in Transforming Growth Factor Beta Induced (TGFBI) gene was shared in the two siblings with congenital glaucoma and GAPO syndrome. We then looked for the presence of TGFBI gene mutations in another cohort of 54 unrelated patients with early onset glaucoma (before 25 years of age) in whom Whole exome sequencing was previously done and no known glaucoma mutations were detected. We found three TGFBI mutations present in three unrelated juvenile onset open angle glaucoma (JOAG) patients, one of whom also had an associated corneal granular dystrophy. None of these patients had any other mutations associated with known genes for glaucoma.Conclusions: Mutations in TGFBI gene could have a role in the pathogenesis of congenital and juvenile onset open angle glaucoma.

Juvenile glaucomas and multi locus disease causing genomic variations

AbstractPurpose: Multilocus disease‐causing genomic variations (MGVs) and multiple genetic diagnoses (MGDs) are increasingly being recognized in individuals and families with Mendelian disorders. This can mainly be attributed to the widespread use of next generation sequencing (NGS) for the evaluation of these disorders. We conducted an NGS study of 40 juvenile onset open angle glaucoma (JOAG) families to evaluate the known and unknown gene mutations.Methods: Whole Exome sequencing was undertaken for 40 unrelated trios (proband and both parents) where the proband had JOAG. Out of these, eight were autosomal dominant, while rest were non familial.Results: Out of the 8 autosomal dominant JOAG families, MYOC mutations were detected in 3 (37.5%) and LTBP2 in 1 (12.5%). The family with LTBP2 mutation also had a MYOC mutation. One autosomal dominant family (12.5%) out of 8 had a rare EFEMP1 mutation in both affected father and daughter. The daughter also had Stickler syndrome (STL), that was later identified on observing a pathogenic COL11A1 mutation.Conclusions: These findings underline the importance of genetic evaluation in systematic phenotyping families with JOAG for MGVs and MGDs.

In vivo identification of angle dysgenesis

AbstractAnterior segment Spectral domain–optical coherence tomography (SD‐OCT) is being increasingly used in glaucoma patients, primarily to investigate the anterior chamber angle and visualize the trabecular meshwork (TM) and Schlemm's canal (SC) in vivo. With the advent of angle surgery for glaucoma much interest has been generated in the aqueous outflow pathways. Our studies have shown that in vivo imaging of anterior chamber angle with ASOCT can been used to detect gross features of angle dysgenesis in primary congenital glaucoma (PCG), juvenile onset open angle glaucoma (JOAG) and adult onset primary open angle glaucoma (POAG), which has been described either as an absence of SC and/or the presence of abnormal tissue or a hyper‐reflective membrane within angle recess. This membrane is similar to what Barkan had described in PCG and was later described to be an angle cicatrization that portends a poorer success with goniotomy. Absence of development of SC was also shown by Hollander et al to be associated with a severe form of goniodysgenesis while its presence was seen in less severe goniodysgenesis on histopathological studies involving PCG. In fact, angle dysgenesis on ASOCT (ADoA), can be observed even in eyes with gonioscopically normal appearing angles. It is known that gonioscopy provides only a superficial representation of the histopathological anomalies affecting the angle. The presence of a thick compact tissue in the TM samples of Juvenile glaucoma patients has been observed, irrespective of whether they had an apparent goniodysgenesis or not. Hence, what appears to be morphologically normal angle on gonioscopy may harbour dysgenesis of the TM or even the SC. Primary congenital glaucoma, JOAG and adult onset POAG form a spectrum in terms of severity of angle dysgenesis. While most of the PCG eyes have features of ADoA, the same are present in 40% of JOAG eyes and in up to 35% of adult onset POAG. The size of the SC has also shown to be decreased in patients with adult‐onset open angle glaucoma based on in vivo OCT studies. We also present interesting observations of angle dysgenesis in fellow eyes of children with unilateral PCG.

Glaucoma gene mutations and their association with angle dysgenesis

AbstractAngle dysgenesis is associated with developmental immaturity of the outflow pathways regulated by genes, which can only be ascertained with the help of histopathological studies. Mutations in some of the commonly associated genes with glaucoma, namely CYP1B1,FOXC1 PITX2, and TEK have been shown to be associated with developmental abnormalities in the outflow pathways in experimental studies. The severity of angle dysgenesis has been correlated on histopathology with certain CYP1B1 gene mutations in patients with Primary congenital glaucoma (PCG). Though MYOC mutations are known to be associated with Juvenile onset open angle glaucoma (JOAG) and even with PCG, no studies have shown the involvement of MYOC mutations in causing angle dysgenesis. There is only one histopathological report of a JOAG patient with MYOC Tyr453His mutation, where no apparent changes of the Trabecular meshwork(TM) or Sclemm's canal were noted though intense MYOC immune‐reactivity was observed at the TM. Histopathological studies for angle dysgenesis in human glaucomatous eyes are difficult to perform and are inherently associated with tissue handling artefacts. While grossly identifiable features of Ange dysgenesis on ASOCT (ADoA) have been described before, many subtle changes may also be present on ASOCT scans which are challenging to detect or precisely quantify by human observers.We studied the ASOCT scans of patients with open angle glaucoma diagnosed between 10 to 40 years of age, who had undergone Whole Exome Sequencing (WES) followed by a bioinformatics analysis and were found to harbour a mutation (that was pathogenic) in a known glaucoma gens. We used Deep learning (DL) models to detect ADoA.We detected MYOC mutations in 15 patients, 10 had CYP1B1, 2 had FOXC1 and 2 had LTBP2 mutation. Among these patients, angle dysgenesis on ASOCT was observed as predicted by the DL models, among all patients with known gene mutations. Overall, our DL Model was predictive of angle dysgenesis in 81% scans among MYOC positive patients, 89% CYP1B1 patients, 85% FOXC1 and 96% among those with LTBP2 mutation on an average.Our findings demonstrated that different gene mutations affect different parts of the proximal outflow pathways. While CYP1B1 and LTBP2 was found to affect primarily the SC morphology, the MYOC and FOXC1 were found to be associated with morphological variations in the TM, since the SC in the latter was normally developed.

Comparisons of Schlemm's canal and trabecular meshwork morphologies between juvenile and primary open angle glaucoma

The histologic differences in Schlemm's canal (SC) and trabecular meshwork (TM), obtained from the trabeculectomy specimens of different age-group glaucoma patients, were compared. This study involved 44 trabeculectomy specimens of 37 juvenile-onset open-angle glaucoma (JOAG) patients (Group A) and 24 trabeculectomy specimens of 24 elderly-onset primary OAG (POAG) patients (age range: 70–79 years, Group B) with no familial history of POAG. Clinical parameters of gender, maximum intraocular pressure (IOP), and the number of glaucoma medications used prior to trabeculectomy were investigated and compared between the two groups. From light microscopy photographs of hematoxylin-eosin, and immunohistochemical staining of markers for SC endothelium (SCE), the total SC length (TSC), comprised of the opened-SC length (OSC) and the closed-SC length (CSC), the percentage of CSC in TSC (%CSC), the percentage of positive SCE marker in CSC (%PinCSC), and the percentage of negative SCE marker in OSC (%NinOSC) were analyzed. Moreover, podoplanin staining patterns in the TM were investigated and compared between the two groups. Among the clinical parameters, the mean maximum IOP in Group A (33.41 ± 9.24 mmHg) was the only significant parameter when compared to that in Group B (22.96 ± 7.17 mmHg, P = 0.000003). TSC in Group A was significantly shorter than that in Group B (P = 0.00092), and %CSC (P = 0.00004) and %PinCSC (P = 0.00342) in Group B were significantly higher than those in Group A. No statistically significant difference in %NinOSC was found between Group A and Group B (P = 0.76060). Juxtacanalicular tissue (JCT) in Group A showed compact and weak staining with podoplanin, while the JCT and closed-SC area in Group B showed intense staining. In the Group A subjects, TSC (P = 0.04819) and OSC (P = 0.02867) were significantly shorter in the non-familial cases than in the familial cases. Platelet coagulations 10–37 μm in size at the defect of the SCE in the inner wall of the SC were observed in 8 eyes (18%) and 4 eyes (17%) in Group A and Group B, respectively. The platelets appeared to repair the SCE damage for maintaining the blood aqueous barrier in both groups of POAG eyes. Smaller SC diameters and accompanying TM abnormality were features observed in the young-onset JOAG patients, thus suggesting developmental abnormalities in the outflow routes. The collapse of SC lumen, presumably due to aging, was the feature observed in the elderly-onset POAG patients. In Group A, the significantly higher IOP, despite of no significant number of topical medications used prior to trabeculectomy, also suggested that JOAG eyes can be categorized as a distinct type of POAG from the eyes of elder-aged POAG patients. The SCE drop out observed in the glaucomatous eyes of the different age groups suggested that worsening of IOP control may possibly occur equally in both groups.

In Vivo Imaging of the Schlemm's Canal and the Response to Selective Laser Trabeculoplasty

To evaluate the presence of angle dysgenesis on ASOCT (anterior segment optical coherence tomography) (ADoA) as a predictive factor in determining outcomes of selective laser trabeculoplasty (SLT). A prospective clinical cohort study. Patients with juvenile-onset open-angle glaucoma (JOAG) without angle dysgenesis on gonioscopy. JOAG patients with uncontrolled intraocular pressure (IOP), who were to undergo SLT, were evaluated for the presence or absence of ADoA, which was defined as the absence of Schlemm's canal (SC) and/or presence of a hyperreflective membrane (HM) over the trabecular meshwork, as identified on ASOCT before the SLT procedure. Furthermore, the number of ASOCT B-scans in which SC was identified as present, were then quantified. Success of SLT was defined as a reduction of IOP by 20% or more from pre-laser value at 6-month follow-up without any further IOP-lowering medication or surgery. Only 1 repeat SLT was admissible for defining SLT success over the 6-month period. A successful reduction in IOP at 6-month follow-up was correlated with the extent of ADoA. In comparison to pre-SLT IOP, 57.1% eyes (20/35) showed more than 20% reduction in IOP at 6 months with a mean reduction of 7.6 ± 1.8 mm Hg (29.6%). When all 3 observers agreed, SC was identified in 90% eyes (18/20) with success vs 26.6% eyes (4/15) with failure (P < .001). All eyes (5/5) with presence of HM showed failure (P < .001). All eyes (19/19) in which SC was present in >50% ASOCT B scans (>25/50 scans/eye) showed success (P < .001). On a bias-reduced regression analysis, the identification of SC on any 2 consecutive scans increased the chances of success at 6 months by 8.3 times, whereas the identification of SC in >50% of ASOCT scans was associated with a 21.4 times greater chance of success. The presence of SC on ASOCT is a strong predictor for successful IOP reduction after SLT in JOAG eyes.

Myopia and glaucoma progression among patients with juvenile onset open angle glaucoma: A retrospective follow up study.

To identify the risk factors for glaucoma progression, especially the association with myopia, among treated juvenile open angle glaucoma (JOAG) patients. Glaucomatous progression was analysed in the eyes of JOAG patients with at least 5-years of follow up in this retrospective study. Baseline variables such as age, inheritance pattern, baseline intraocular pressure (IOP), baseline central corneal thickness, visual acuity, baseline refractive error, spherical equivalent (SE) and duration of follow-up were noted. Stereoparametric global trend analysis and Moorfields Regression Analysis on confocal scanning laser ophthalmoscopy were used to detect progression. Variables associated with glaucoma progression, with respect to progressors (PG) and non-progressors (NPG) were analysed. Since both eyes of a patient were taken for analysis, a generalised estimating equation method was used to correct the bias. Among 74 eyes (37 subjects), glaucoma progression was noted in 11 eyes (14.9%) of 8 patients, with a median time to progression of 7.4years (range 5-15.5years). For myopes (SE≤-1.00D), glaucoma progression was 18 times more likely than mild and no myopes (>-1DS) (p=0.03, 95% CI: 1.14, 217.44). The prevalence of myopia in the JOAG, PG and NPG cohorts was 70.3%, 87.5%, and 65.5%, respectively. Myopia progression was noted at follow up in 70% patients. One-unit increase in baseline vertical cup disc ratio, 1mmHg increase in IOP fluctuations and 1dB year-1 depression of visual field were associated with 0.44, 0.06 and 0.07D year-1 increases in the rate of myopia progression, respectively. JOAG progressors had a greater baseline myopic refraction and a faster myopia development over time. The development of myopia in JOAG eyes could be an indicator of glaucoma progression, and hence progressing myopic (≤-1D) JOAG patients should be followed up more rigorously.

Retrospective analysis of paediatric glaucoma at a tertiary referral centre in Hong Kong.

To evaluate the epidemiological features, clinical interventions, and outcomes of paediatric glaucoma in Hong Kong. Retrospective chart review. Clinical data from the medical records of all patients under 18years of age diagnosed with glaucoma from January 2008 to December 2017 at a university-affiliated, tertiary referral centre were collected. The patients' demographics, etiological distribution, clinical interventions, and outcomes were analysed. A total of 33 subjects (53 eyes) were identified, 30 (49 eyes) of whom were Chinese. Primary glaucoma accounted for 21.2% of subjects, while 78.8% were diagnosed with secondary glaucoma. The most common subtype was juvenile-onset open angle glaucoma, followed by Sturge-Weber Syndrome related glaucoma. The most commonly performed surgical interventions were tube-shunt surgery (Ahmed Glaucoma Valve) and transscleral cyclophotocoagulation. Most eyes had significant reduction in intraocular pressure after medical or surgical intervention, but deterioration of visual acuity remained common. Most cases of childhood glaucoma in Hong Kong are secondary rather than primary, similar to other regions with low incidence of parental consanguinity. The large proportion of secondary glaucoma which generally has poorer prognosis, is reflected by the frequency of multiple surgery, and a high incidence of visual deterioration despite significant intraocular pressure reduction in most eyes.

Juvenile-onset Open-Angle Glaucoma at the University Teaching Hospitals - Eye Hospital, Lusaka Zambia

Purpose: To demonstrate the socioeconomic, demographic and clinical characteristics associated with patients of juvenile-onset open- angle glaucoma (JOAG) at the University Teaching Hospitals Eye Hospital (UTHs - EH).Methods: This was a cross-sectional survey for Juvenile Open Angle Glaucoma (JOAG) conducted at the UTHs - EH in, Lusaka, Zambia from January to December 2013. All participants aged between 18 and 39 years had a full ocular examination after capturing demographic and socioeconomic information. The ocular examination included visual acuity, intraocular pressure (IOP) and cup disc ratio (CDR) and tests performed were central corneal thickness (CCT) and visual fields. Severity was graded based visual field (VF) in the worse eye using the advanced glaucoma intervention study score. Univariate and multivariate logistic regression, stratified by age group and gender, was used to determine the association between demographic factors and JOAG and between clinical factors and JOAG.Results: Of the 1625 patients recruited for the study, 309 were POAG patients. Of the 309 POAG patients, 140 aged 20 to 39 years old had bilateral JOAG. The distribution of the 140 participants was 98 (70.9%) females and 42 (29.4%) males. Thirteen (9.3 %) were aged 20 – 24 years, 29 (20.7%) 25 – 29 years, 44 (31.4%) 30 – 34 years, and 54 (38.6%) 35 – 39 years. The mean age of the patients was 25.1 ± SD 8.7 years. The prevalence of JOAG was 8.6%

Juvenile-onset Open-Angle Glaucoma at the University Teaching Hospitals - Eye Hospital, Lusaka Zambia

Purpose: To demonstrate the socioeconomic, demographic and clinical characteristics associated with patients of juvenile-onset open-angle glaucoma (JOAG) at the University Teaching Hospitals Eye Hospital (UTHs - EH).&#x0D; Methods: This was a cross-sectional survey for Juvenile Open Angle Glaucoma (JOAG) conducted at the UTHs - EH in, Lusaka, Zambia from January to December 2013. All participants aged between 18 and 39 years had a full ocular examination after capturing demographic and socioeconomic information. The ocular examination includedvisual acuity, intraocular pressure (IOP) and cup disc ratio (CDR) and tests performed were central corneal thickness (CCT) and visual fields. Severity was graded based visual field (VF) in the worse eye using the advanced glaucoma intervention study score. Univariate and multivariate logistic regression, stratified by age group and gender, wasused to determine the association between demographic factors and JOAG and between clinical factors and JOAG.Results: Of the 1625 patients recruited for the study, 309 were POAG patients. Of the 309 POAG patients, 140 aged 20 to 39 years old had bilateral JOAG. The distribution of the 140 participants was 98 (70.9%) females and 42 (29.4%) males. Thirteen (9.3 %) were aged 20 – 24 years, 29 (20.7%) 25 – 29 years, 44 (31.4%) 30 – 34 years, and 54 (38.6%) 35 –39 years. The mean age of the patients was 25.1 ± SD 8.7 years. The prevalence of JOAG was 8.6% (140/1625) distributed as 2.6% (95% CI 1.3, 3.9) males and 6.0% (95% CI 4.7, 9.2) females. There was a female preponderance of (71.2% vs. 28.8%; OR 2.98, 95% CI 2.3, 6.7, p=0.021). Eighty-five (60.7%) had complained of poor vision and 24 (17.1%) of eye pain. However, 24 (17.1%) presented with no definite symptoms. Patients with a positive family history presented 3.7 years earlier (P = 0.034, CI; 1.37-7.9) compared to those without a family history. Lower socioeconomic status (Odds ratio [OR] 3.5, P = 0.013, CI: 1.2-17.2), and higher IOP (OR 6.7, P = 0.002, CI: 2.6-21.8) were associated with severe glaucomatous visual field defects. High myopia (-6.47 ± 5.00 Diopters) was present in 70.9% of patients. The patients with myopia also had a severe elevation of IOP of (35.8 ±18.5 mmHg).&#x0D; Conclusions: The study found a high prevalence of JOAG at 8.6%. The patients with JOAG presented late with advanced disease and high IOP. Clinical, socioeconomic, and demographic factors are contributory to the severity of JOAG among JOAG patients.&#x0D; Recommendation: Early detection of cases during eye health care outreach programmes such as school and community screening of children and adults could be of great benefit in creating awareness, d ema n d , e a r l y d e t e c t i o n a n d p r omp t commencement of treatment. Glaucoma should no longer be considered a condition of the people aged 40 years and above.

The mutational spectrum of Myocilin gene among familial versus sporadic cases of Juvenile onset open angle glaucoma.

Juvenile onset primary open angle glaucoma (JOAG) is a rare disorder associated with high IOP and progressive optic neuropathy in patients diagnosed before the age of 40 years. While in some populations it has primarily an autosomal dominant pattern of inheritance, in others it occurs in a primarily sporadic form. The main aim of the study was to assess the relative prevalence of Myocilin (MYOC) mutations in familial versus sporadic cases of JOAG. We screened 92 unrelated (sporadic) JOAG patients, and 22 affected families (70 affected members and 36 unaffected) for variations in the MYOC gene. We also analyzed the clinical features associated with these variations. Three coding sequence variants were identified as mutations causing JOAG. Four families segregated distinct mutations at Gly367Arg, and two families at Gln337Arg, while only two sporadic JOAG cases harbored MYOC mutations (Gly367Arg and Gln48His). The frequency of MYOC mutations in familial cases (27%) was significantly higher than in sporadic JOAG cases (2%); p = 0.001. A 90% penetrance for the Gly367Arg variant was seen by the age of 40 years in our patients. Characteristic allele signatures, indicative of specific founder effects, were not observed for the Gly367Arg mutation that was looked for in 12 patients among 2 geographically close families, which harbored this mutation. Our data demonstrated that genetic screening for MYOC mutations should be focused toward cases with familial rather than sporadically occurring JOAG.

Exome Sequencing Reveals a Heterozygous OAS3 Mutation in a Chinese Family With Juvenile-Onset Open-Angle Glaucoma.

Juvenile-onset open-angle glaucoma (JOAG), if left untreated, will lead to severe visual disability. The purpose of this study was to identify the disease-causing mutations in a Chinese JOAG family. We recruited a Chinese JOAG family and unrelated primary open-angle glaucoma (POAG) patients (270, Chinese), and performed whole-exome sequencing (WES) to screen the sequence variations. Variants identified by WES were validated by Sanger sequencing. Subsequently, qPCR and Western blotting were used to determine the expression of wild-type (WT) and its mutated-type (MT) of 2'-5'-oligoadenylate synthetase 3 (OAS3) genes. Seventeen heterozygous candidate variants were revealed in the JOAG family based on the screening of WES data. Of those, the heterozygous variant exon11:c.2299C>T: p.Arg767Cys in OAS3, a gene used to synthesize 2'-5'-oligoadenylate (2-5A), co-segregates with the disease phenotype. One unrelated POAG patient also carried this variant, but this variant was absent in 200 nonglaucoma healthy controls. Analysis of the Arg767Cys mutation with PolyPhen2, CADD, and SIFT all suggest that it is pathogenic. This arginine residue is highly conserved in all selected OAS3 orthologs. On the other hand, in peripheral blood samples, the mRNA expression of OAS3 in patients significantly decreased compared with unaffected controls. Moreover, the expression level of recombinant OAS3 protein (mutated Arg767Cys) also observably reduced compared with level of WT protein in HEK293T cells. Our study revealed a heterozygous mutation in OAS3 from a Chinese JOAG family. And this mutation showed a deleterious effect to the expression of OAS3.

Physiological function of myocilin and its role in the pathogenesis of glaucoma in the trabecular meshwork (Review).

Myocilin is highly expressed in the trabecular meshwork (TM), which plays an important role in the regulation of intraocular pressure (IOP). Myocilin abnormalities may cause dysfunction of the TM, potentially leading to increased IOP. High IOP is a well-known primary risk factor for glaucoma. Myocilin mutations are common among glaucoma patients, and they are implicated in juvenile-onset open-angle glaucoma (JOAG) and adult-onset primary open-angle glaucoma (POAG). Aggregation of aberrant mutant myocilins is closely associated with glaucoma pathogenesis. The aim of the present review was to discuss the recent findings regarding the major physiological functions of myocilin, such as intra- and extracellular proteolytic processes. We also aimed to discuss the risk factors associated with myocilin and the development of glaucoma, such as misfolded/mutant myocilin, imbalance of myocilin and extracellular proteins, and instability of mutant myocilin associated with temperature. Finally, we further outlined certain issues that are yet to be resolved, which may represent the basis for future studies on the role of myocilin in glaucoma.

Detection of mutations in MYOC, OPTN, NTF4, WDR36 and CYP1B1 in Chinese juvenile onset open-angle glaucoma using exome sequencing

Juvenile onset open-angle glaucoma (JOAG) affects patients before 40 years of age, causing high intraocular pressure and severe optic nerve damage. To expand the mutation spectrum of the causative genes in JOAG, with a view to identify novel disease-causing mutations, we investigated MYOC, OPTN, NTF4, WDR36 and CYP1B1 in a cohort of 67 unrelated Chinese JOAG patients. Whole exome sequencing was used to identify possible pathogenic mutations, which were further excluded in normal controls. After sequencing and the use of a database pipeline, as well as predictive assessment filtering, we identified a total of six mutations in three genes, MYOC, OPTN and CYP1B1. Among them, 2 heterozygous mutations in MYOC (c. 1109C > T, p. (P370L); c. 1150G > C, p. (D384H)), 2 heterozygous mutations in OPTN (c. 985A > G, p.(R329G); c. 1481T > G, p. (L494W)) and 2 homozygous mutations in CYP1B1 (c. 1412T > G, p.(I471S); c. 1169G > A, p.(R390H)) were identified as potentially causative mutations. No mutation was detected in NTF4 or WDR36. Our results enrich the mutation spectra and frequencies of MYOC, OPTN and CYP1B1 in JOAG among the Chinese population. Further studies are needed to address the pathogenicity of each of the mutations detected in this study.

In Vivo Analysis of Angle Dysgenesis in Primary Congenital, Juvenile, and Adult-Onset Open Angle Glaucoma.

The purpose of this study was to comparatively evaluate angle dysgenesis in vivo, among congenital, juvenile, and adult-onset open angle glaucoma patients. A cross-sectional evaluation of 96 glaucoma patients, 22 children with primary congenital glaucoma (PCG) old enough to cooperate for optical coherence tomography (OCT), 34 juvenile-onset open angle glaucoma (JOAG) patients, 40 adult-onset primary open angle glaucoma (POAG), and 30 healthy subjects, was carried out using high-resolution anterior segment spectral domain (SD)-OCT. Subgroup analysis was done for presence/ absence of angle dysgenesis as defined by presence of abnormal tissue/hyperreflective membrane within angle recess and/or absence of Schlemm's canal (SC). Morphologic features suggestive of angle dysgenesis such as the presence of abnormal tissue at the angle and a hyperreflective membranous structure covering the meshwork were seen in all PCG eyes (100%), in 14 (40%) JOAG eyes, and none of the POAG eyes in comparison to healthy eyes (P = 0.01, P = 0.03, and P = 0.23 for PCG, JOAG, and POAG, respectively). SC could be seen in 27 (90%) healthy eyes compared with only 7 (30%) in PCG (P = 0.01) 20 (60%) JOAG eyes (P = 0.03), and 26 (65%) adult-onset POAG eyes (P = 0.23; χ2 test). Angle dysgenesis in the form of abnormal tissue at the angle/hyperreflective membrane and/or absence of SC could be identified on anterior segment SD-OCT, which can be used for in vivo evaluation of eyes with developmental glaucoma.