Juvenile-onset Primary Open-angle Glaucoma Research Articles

Machine learning-assisted prediction of trabeculectomy outcomes among patients of juvenile glaucoma by using 5-year follow-up data.

To develop machine learning (ML) models, using pre and intraoperative surgical parameters, for predicting trabeculectomy outcomes in the eyes of patients with juvenile-onset primary open-angle glaucoma (JOAG) undergoing primary surgery. The study included 207 JOAG patients from a single center who met the following criteria: diagnosed between 10 and 40 years of age, with an IOP of >22 mmHg in the eyes on two or more occasions, open angle on gonioscopy in both eyes, with glaucomatous optic neuropathy, and requiring a trabeculectomy for IOP control. Only the patients with a minimum 5-year follow-up after surgery were included in the study. A successful surgical outcome was defined as IOP ≤18 mmHg (criterion A) or 50% reduction in IOP from baseline (criterion B) 5 years after trabeculectomy. Feature selection techniques were used to select the most important contributory parameters, and tenfold cross-validation was used to evaluate model performance. The ML models were evaluated, compared, and prioritized based on their accuracy, sensitivity, specificity, Matthew correlation coefficient (MCC) index, and mean area under the receiver operating characteristic curve (AUROC). The prioritized models were further optimized by tuning the hyperparameters, and feature contributions were evaluated. In addition, an unbiased relationship analysis among the parameters was performed for clinical utility. Age at diagnosis, preoperative baseline IOP, duration of preoperative medical treatment, Tenon's thickness, scleral fistulation technique, and intraoperative mitomycin C (MMC) use, were identified as the main contributing parameters for developing efficient models. The three models developed for a consensus-based outcome to predict trabeculectomy success showed an accuracy of >86%, sensitivity of >90%, and specificity of >74%, using tenfold cross-validation. The use of intraoperative MMC and a punch for scleral fistulation compared to the traditional excision with scissors were significantly associated with long-term success of trabeculectomy. Optimizing surgical parameters by using these ML models might reduce surgical failures associated with trabeculectomy and provide more realistic expectations regarding surgical outcomes in young patients.

Study of myocillin gene variants alleles in primary open angle glaucoma patients and their first degree relatives in North West Rajasthan, India

Glaucoma is defined as progressive optic neuropathy leading to irreversible blindness if not treated on time. Primary open angle glaucoma (POAG) is most common form of glaucoma. Mutations in myocilin gene (MYOC) account for 2–4% of POAG cases. To identify and evaluate MYOC variants alleles among patients with POAG and their healthy first degree relatives. 66 POAG patients and 26 healthy first degree relatives recruited for study. All patients underwent complete ophthalmic examination followed by genomic DNA (deoxyribonucleic acid) isolation from peripheral blood and quantification of DNA on spectrophotometer. All samples were amplified with each primer by PCR (Polymerase Chain Reaction) technique and amplified DNA and primer sequence checked again by electrophoresis for confirmation of specified MYOC gene mutation. We identified a known MYOC missense mutation, Pro370leu in 16 POAG cases and found consistent genotypic but not phenotypic correlation in 4 of their first degree relatives. Out of 16 cases, pathogenic MYOC gene variant was found in 12 adult onset POAG, 3 juvenile onset POAG, and 1 case of OHT. This study is first of its kind in North India. Our study showed frequency of MYOC gene mutation in POAG cases was 24.24% which is much higher than found elsewhere in India and other countries (2-5%). Frequency of transmission of pathogenic MYOC gene variant in first degree relatives was 25%. The future outcome of our study is promising since early diagnosis and management of high risk family members is possible.

Exome sequencing identifies procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 mutations in primary congenital and juvenile glaucoma.

Purpose:To report the association of procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2) mutations with bilateral primary congenital glaucoma (PCG) in monozygotic twins and with nondominant juvenile-onset primary open-angle glaucoma (JOAG).Methods:We utilized family-based whole-exome sequencing to detect disease-causing mutations in a pair of monozygotic twins with de-novo PCG and compared its existence in 50 nonfamilial cases of JOAG and 30 healthy controls. To validate the identified mutations, direct Sanger sequencing was performed. For further evaluation of gene expression in the ocular tissues, we performed whole-mount in situ hybridization in zebrafish embryos.Results:We identified a novel missense mutation (c.1925A>G, p.Tyr642Cys) in the PLOD2 gene in the monozygotic twin pair with PCG and another missense mutation (c.1880G>A, p.Arg627Gln) in one JOAG patient. Both mutations identified were heterozygous. Neither the parents of the twins nor the parents of the JOAG patient harbored the mutation and it was probably a de-novo change. The zebrafish in situ hybridization revealed expression of the PLOD2 gene during embryogenesis of the eye.Conclusion:We observed an association of PLOD2 mutations with PCG and with nonfamilial JOAG. This new gene needs to be further investigated for its role in pathways associated with glaucoma pathogenesis.

Outcomes of gonioscopy-assisted transluminal trabeculotomy in juvenile-onset primary open-angle glaucoma.

To report the outcomes of gonioscopy-assisted transluminal trabeculotomy (GATT) for juvenile-onset primary open-angle glaucoma (JOAG). A consecutive case series of JOAG patients who underwent GATT was reviewed with follow-up period of up to 18 months. Intraocular pressure (IOP), number of glaucoma medications and success rate were compared between eyes with and without prior glaucoma surgery, and between mild-to-moderate and severe cases defined based on Humphrey Visual Field mean deviation. In total, 59 eyes of 48 patients were included. Overall, IOP was reduced from 26.5 ± 9.0 mmHg on 3.7 ± 0.9 medications preoperatively to 14.7 ± 3.0 mmHg on 0.7 ± 1.2 medications at 12 months and to 14.1 ± 2.3 mmHg on 0.4 ± 0.8 medications at 18 months postoperatively (P < 0.001). The complete and qualified success rates were 70.8% and 81.2% at 12 months, and 58.6% and 81.2% at 18 months, respectively. Eyes with and without prior glaucoma surgery did not differ significantly in terms of postoperative IOP, glaucoma medication and success rate. In addition, GATT was effective for both mild-to-moderate and severe cases; the latter achieved a surgical success of 79.1%. GATT is effective for JOAG. In particular, this case series suggests that GATT is promising in treating severe JOAG and those with prior glaucoma surgery.

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.

Classifying juvenile onset primary open angle glaucoma using cluster analysis

AimTo classify unrelated patients with juvenile onset primary open angle glaucoma (JOAG) into clinically useful phenotypes using cluster analysis.MethodsOut of the 527 unrelated patients with JOAG, the study included 414...

Visual Disability Among Juvenile Open-angle Glaucoma Patients.

Juvenile onset primary open-angle glaucoma (JOAG) unlike adult onset primary open-angle glaucoma presents with high intraocular pressure and diffuse visual field loss, which if left untreated leads to severe visual disability. The study aimed to evaluate the extent of visual disability among JOAG patients presenting to a tertiary eye care facility. Visual acuity and perimetry records of unrelated JOAG patients presenting to our Glaucoma facility were analyzed. Low vision and blindness was categorized by the WHO criteria and percentage impairment was calculated as per the guidelines provided by the American Medical Association (AMA). Fifty-two (15%) of the 348 JOAG patients were bilaterally blind at presentation and 32 (9%) had low vision according to WHO criteria. Ninety JOAG patients (26%) had a visual impairment of 75% or more. Visual disability at presentation among JOAG patients is high. This entails a huge economic burden, given their young age and associated social responsibilities.

Selective laser trabeculoplasty for primary open-angle glaucoma patients younger than 40 years

ObjectiveTo evaluate the efficacy of selective laser trabeculoplasty (SLT) among patients with juvenile-onset primary open-angle glaucoma (JOAG). MethodsPatients diagnosed with JOAG who were not controlled on medical therapy were offered a trial of SLT. The patients were followed up prospectively for 1, 3, 6, and 12 months postlaser to evaluate the efficacy of SLT as second-line therapy. Success was defined as an intraocular pressure (IOP) reduction of ≥20% at 12 months without the need for further medication, laser, or surgery. Factors associated with success/failure, prelaser IOP, age, and angle dysgenesis on gonioscopy were analysed. ResultsThe average prelaser IOP in these JOAG eyes (n = 30) was 25.3 ± 6.5 mm Hg, which reduced to 17.3 ± 5.8 mm Hg at 12 months (p = 0.01). All patients were of Indian ethnicity. Out of 30 eyes, at 12 months post-SLT, 13 (43%) eyes had at least a 20% reduction in IOP. In the eyes that achieved success, the average reduction of IOP was 37.6%. There was no difference in the prelaser IOP between those with success (25.5 ± 5.6 mm Hg) and those that failed (25.1 ± 8 mm Hg; p = 0.8), nor was there a difference in the mean age between successful cases (34.4 ± 9.4 years) and failures (31.6 ± 8.9 years; p = 0.4). However, those without angle dysgenesis were 4 times (CI 1.1–15.2) more likely to succeed with SLT than those with angle dysgenesis (p = 0.03). ConclusionsA significant proportion of patients with JOAG can benefit from an IOP reduction after SLT. Those with gonioscopically normal-appearing angles are more likely to respond to SLT.

Glaucoma in iran and contributions of studies in iran to the understanding of the etiology of glaucoma.

Epidemiologic and genetic/molecular research on glaucoma in Iran started within the past decade. A population-based study on the epidemiology of glaucoma in Yazd, a city in central Iran, revealed that 4.4% of studied individuals were affected with glaucoma: 1.6% with high tension primary open angle glaucoma (POAG), 1.6% with normal tension POAG, and 0.4% each with primary angle closure glaucoma (PACG) and pseudoexfoliation glaucoma (PEXG), and other types of secondary glaucoma. Two notable observations were the relatively high frequency of normal tension glaucoma cases (1.6%) and the large fraction of glaucoma affected individuals (nearly 90%) who were unaware of their condition. The first and most subsequent genetic studies on glaucoma in Iran were focused on primary congenital glaucoma (PCG) showing that cytochrome P450 1B1 (CYP1B1) is the cause of PCG in the majority of Iranian patients, many different CYP1B1 mutations are present among Iranian patients but only four mutations constitute the vast majority, and the origins of most mutations in the Iranians are identical by descent (IBD) with the same mutations in other populations. Furthermore, most of the PCG patients are from the northern and northwestern provinces of Iran. A statistically significant male predominance of PCG was observed only among patients without CYP1B1 mutations. Clinical investigations on family members of PCG patients revealed that CYP1B1 mutations exhibit variable expressivity, but almost complete penetrance. A great number of individuals harboring CYP1B1 mutations become affected with juvenile onset POAG. Screening of JOAG patients showed that an approximately equal fraction of the patients harbor CYP1B1 and (myocilin) MYOC mutations; MYOC is a well-known adult onset glaucoma causing gene. Presence of CYP1B1 mutations in JOAG patients suggests that in some cases, the two conditions may share a common etiology. Further genetic analysis of Iranian PCG patients led to identification of Latent-transforming growth factor beta-binding protein 2 (LTBP2) as a causative gene for both PCG and several diseases which are often accompanied by glaucomatous presentations, such as Weill-Marchesani syndrome 3 (WMS3). The findings on LTBP2 have contributed to recognize the importance of the extracellular matrix in pathways leading to glaucoma.

Single nucleotide polymorphism of MYOC affected the severity of primary open angle glaucoma.

To detect the mutations in two candidate genes, myocilin (MYOC) and cytochrome P450 1B1 (CYP1B1), in a Chinese family with primary open angle glaucoma (POAG). The family was composed of three members, the parents and a daughter. All members of the family underwent complete ophthalmologic examinations. Exons of MYOC and CYP1B1 genes were screened for sequence alterations by polymerase chain reaction (PCR) and direct DNA sequencing. The mother was the proband, she was diagnosed as POAG in both eyes. Her daughter was diagnosed as juvenile-onset POAG. The father was asymptomatic. One MYOC heterozygous mutation c.1150 G>A (D384N) in exon 3 was identified in the mother, another MYOC heterozygous variation c.1058 C>T (T353I) in exon 3 was identified in the father, and the daughter inherited both of the variations. Meanwhile, three single nucleotide polymorphisms (SNPs) in CYP1B1 gene were found in the family. The D384N mutation of MYOC has been reported as one of disease-causing mutations in POAG, whereas T353I variation of MYOC was thought as a high risk factor for POAG. The two variations of MYOC were first reported in one juvenile-onset POAG patient who presented with more severe clinical manifestations, suggesting that T353I polymorphism of MYOC may be associated with the severity of POAG.

Clinical correlates to the goniodysgensis among juvenile-onset primary open-angle glaucoma patients

To evaluate gonioscopic features and relate them to clinical characteristics in eyes with juvenile-onset primary open-angle glaucoma (JOAG). Goniophotographs of unrelated JOAG patients, presenting between 10-40 years of age, were evaluated and compared with 60 healthy subjects in the same age group. Age of onset, family history of glaucoma, highest untreated IOP and visual field defect (mean deviation) were analyzed and correlated with the gonioscopic features among JOAG patients. Of 126 patients included in the study, 44 (34 %) had a normal open angle (group 1), while 82 (66 %) had developmental anomalies (group 2). Developmental anomalies of the angle were classified as: high iris insertion with or without prominent iris processes (n=42), a featureless angle (n=30), and those with prominent iris processes alone (n=10). There was no difference in age of onset (group 1, 30.5 ± 7 years and group 2, 26.3 ± 9.6 years) (p=0.07) or the untreated IOP at presentation (group 1; 36 ± 12.5 mmHg and group 2, 38.8 ± 12.3 mmHg; p=0.37) between the groups. However, those with angle anomalies presented with a greater visual field defect (MD -23.5 ± 10.5 vs -14.8 ± 13 dB; p=0.02) compared to those with normal appearing angle. While two thirds of JOAG patients present with developmental anomalies of the angle, one third have normal appearing angles. High insertion of the iris is the most common form of gonio dysgenesis observed. Those with angle dysgenesis are more likely to present with severe disease.

Non-Native Structural Properties of the Glaucoma-Associated Olfactomedin Domain of Myocilin Lead to Amyloid Fibrils

Approximately 4% of adult-onset and 10-33% of juvenile-onset primary open angle glaucoma cases are caused by mutations in the gene encoding for myocilin. The vast majority of mutations are within the 30 kDa C-terminal olfactomedin (OLF) domain. Disease-causing myocilin variants aggregate within human trabecular meshwork (HTM) cells instead of secretion to the extracellular matrix. This accumulation taxes the cells and leads to HTM cell death, resulting in increased intraocular pressure, and a hastening of glaucoma-associated vision loss. In spite of reports on the intracellular accumulation of myocilin in HTM cells and model organisms, these aggregates have not been structurally characterized. Our lab recently provided biophysical evidence for the hallmarks of amyloid fibrils in aggregated forms of WT and mutant myocilin localized to the C-terminal OLF domain (myoc-OLF). Under mildly destabilizing conditions, WT myoc-OLF has a distinct non-native structure capable of forming amyloid fibrils. In the case of disease-causing myocilin variants, this non-native structure is accessible under physiological conditions, leading to accelerated fibril growth. Building on the hypothesis that partial unfolding of myoc-OLF is necessary for fibril growth, this study also investigates the structural and biophysical effects of adding stabilizing agents, such as osmolytes and Ca2+, to the myoc-OLF domain as a strategy to prevent myoc-OLF amyloid aggregation. The results of this study suggest a novel protein-based hypothesis for glaucoma pathogenesis and the need for further testing in a clinical setting.

Association analysis of cigarette smoking with onset of primary open-angle glaucoma and glaucoma-related biometric parameters

BackgroundTo date, studies on the role played by cigarette smoking in primary open-angle glaucoma (POAG) remains controversial. The current study evaluated cigarette smoking as a risk factor of POAG and its relationships with vertical cup-to-disc ratio (VCDR), central corneal thickness (CCT) and intraocular pressure (IOP) in a Chinese cohort.MethodsIn a total of 248 unrelated individuals including 30 juvenile-onset POAG (JOAG), 92 adult-onset POAG (AOAG) and 126 sex-matched senile cataract controls, underwent comprehensive ophthalmic examination. Their smoking was obtained and documented by questionnaire. Association of cigarette smoking with POAG was performed using logistic regression controlled for age and sex. Effects of cigarette smoking on VCDR, IOP and CCT were analyzed with multiple linear regression.ResultsIn either JOAG or AOAG, no association of cigarette smoking was found with disease onset (P = 0.692 and 0.925 respectively). In controls and JOAG, no significant effects of smoking were found on VCDR, IOP or CCT (all P > 0.05). Smoking was found to be correlated with decreased CCT in AOAG and combined POAG (JOAG + AOAG) (P = 0.009 and 0.003), but no association with VCDR or IOP was observed (P > 0.05).ConclusionsAlthough cigarette smoking was not found to be risk factor for onset of POAG, it was correlated with CCT in AOAG, and thus might still play a role in the disease course, especially for AOAG.

Severe Loss and Recovery of Vision After Glaucoma Filtration Surgery

To report a case of sudden, severe, unexplained, bilateral loss of vision after glaucoma filtration surgery in both eyes; the vision returned 2 months later. The clinical records of the patient were reviewed retrospectively. Observations were made and collated as the case progressed. A 25-year-old man previously diagnosed with poorly controlled, far-advanced, juvenile-onset primary open-angle glaucoma underwent bilateral guarded filtration procedures. Preoperative visual acuity was 20/40 in the right eye and 20/100 in the left eye. After the procedure visual acuity was severely diminished to no light perception in the right eye and light perception in the left eye. There was no apparent cause for the visual reduction other than the decrease in intraocular pressure caused by the surgery. Two months postoperatively, the patient had visual acuity of 20/80 in the right eye and 20/200 in the left eye. Ten months postoperatively, visual acuity was 20/70 in the right eye and 20/200 in the left eye. Twenty-three months postoperatively, visual acuity was 20/100 in the right eye and 20/200 in the left eye. This case provides evidence for the potential reversibility of severe visual loss after glaucoma filtration surgery.

Long-Term Structural and Functional Outcomes of Therapy in Juvenile-Onset Primary Open-Angle Glaucoma : A Five-Year Follow-Up

Objective: To evaluate long-term structural and functional changes of the optic nerve head in medically and surgically treated juvenile-onset primary open-angle glaucoma (JOAG). Methods: Forty-two eyes of 42 consecutive primary JOAG patients presenting between January 2000 and January 2003. Results were analysed for long-term intra-ocular pressure (IOP) control, IOP fluctuation, disc characteristics on a Heidelberg Retinal Tomograph II and for visual field changes over a 5-year period. The parameters were compared between medically and surgically treated eyes. Results: The average age of the patients was 26.8 ± 6.1 years. The average baseline IOP was 35.3 ± 14.9 mm Hg. An IOP control <18 mm Hg was achieved in 84% of eyes that underwent filtering surgery (n = 17), compared to 63% on medical therapy alone (n = 25) at the end of 5 years; log rank test p = 0.38. Over 5 years, 4 eyes showed progression (9.5%) of which 3 had been medically treated and 1 had failed surgery (p = 0.45). Conclusion: A tenth of JOAG eyes showed progression over 5 years, and this was more common in those treated medically. Aggressive IOP lowering may thus be needed in eyes with JOAG.

Effect of Glaucoma on the Quality of Life of Young Patients

To evaluate the quality of life (QOL) of juvenile-onset primary open-angle glaucoma (JOAG) patients by using a utility-based assessment. QOL using time-tradeoff utility values was analyzed in 70 JOAG patients and compared with 108 adult-onset POAG patients. The relationships of utility values to parameters like age at diagnosis, visual acuity, mean deviation, number of medications and surgery, duration of the disease, level of education, and socioeconomic status were assessed. The mean age at diagnosis of JOAG patients was 26 ± 9.8 years, whereas that of the adult onset POAG patients was 62 ± 11.2 years. Overall, there was a decrease in utility values with increasing age (r = -0.3; P < 0.001). The mean utility score among JOAG patients was (0.80 ± 0.18) significantly greater than among adult POAG patients (0.64 ± 0.28; P < 0.001). The differences in utility scores between JOAG and adult POAG patients were significant when adjusted for differences in better eye visual acuity, mean deviation, and the presence of systemic comorbidity among adults (P = 0.02). Among JOAG patients, those needing topical antiglaucoma medications and those with visual acuity worse than 6/12 in the better eye had lower utility values (P = 0.008 and P = 0.002, respectively). Utility values among glaucoma patients in the juvenile age group are better than those of adult POAG patients. Decreasing vision in the better eye and having to use medication decrease the utility scores among young patients with glaucoma.

Dorzolamide, in combination with timolol, improves retinal blood flow in patients with juvenile-onset primary open-angle glaucoma,

Dorzolamide, in combination with timolol, improves retinal blood flow in patients with juvenile-onset primary open-angle glaucoma,

A Genome-wide Scan Maps a Novel Juvenile-Onset Primary Open-Angle Glaucoma Locus to 15q

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

Correlation between genotype and phenotype in primary open angle glaucoma of Brazilian families with mutations in exon 3 of the TIGR/MYOC gene

To investigate the phenotype of primary open-angle glaucoma (POAG) in Brazilian families with mutation in exon 3 of TIGR/MYOC. Seventy-eight POAG patients with a positive family history and eighteen unrelated patients with POAG were screened by automated DNA sequencing for mutations in exon 3 of the TIGR/MYOC gene. The pedigrees of POAG patients with mutations that lead to amino acid change were built. All available relatives of the index cases were also examined and genotyped by sequencing. Four sequence variants were identified in exon 3 of the TIGR/MYOC gene (Tyr347Tyr, Pro370Pro, Lys398Arg and Cys433Arg) from the 96 initially screened patients. The Lys398Arg mutation was previously described as a polymorphism and in our study did not segregate with POAG. The most prevalent mutation was Cys433Arg, affecting 3 index cases (3.1% or 3/96). In two different families, 8/56 subjects presented Cys433Arg mutation and had POAG, 5/56 had ocular hypertension and 8/56 had no disease manifestation. POAG patients had a median age at diagnosis of 43.25 yr (17-58 yr) and intraocular pressure (IOP) with a mean of 36.3 +/- 3.8mmHg for the right eye and 37.6 +/- 9.75 mmHg for the left eye. The group of patients with Cys433Arg mutation had significantly higher IOP (p<0.0007) and vertical cup/disc ratio when compared to the patients without mutation (p<0.023). Cys433Arg mutation in exon 3 of the TIGR/MYOC gene is related to juvenile-onset POAG (J-POAG) in Brazilian families and autosomal dominant inheritance. The phenotype of this mutation is characterized by varied ages at diagnosis, causing J-POAG and late-onset POAG, associated with high IOP.

Distribution ofWDR36DNA Sequence Variants in Patients with Primary Open-Angle Glaucoma

To determine the distribution of WDR36 sequence variants in a cohort of patients with primary open-angle glaucoma (POAG) in the United States. All of the 23 coding exons and flanking introns of the WDR36 gene were sequenced in 118 probands from families with at least two members affected by POAG, 6 probands from juvenile-onset POAG families, and 108 control individuals. Thirty-two WDR36 sequence variants were found in this population of patients with POAG. Nonsynonymous single-nucleotide polymorphisms (SNPs), including those previously described as "disease-causing" and "disease susceptibility," were found in 17% of POAG patients and 4% of control subjects. Although the distribution of WDR36 variants in the pedigrees did not show consistent segregation with the disease, the WDR36 sequence variants were found more frequently in patients with more severe disease. The results of this study suggest that abnormalities in WDR36 alone are not sufficient to cause POAG. The association of WDR36 sequence variants with more severe disease in affected individuals suggests that defects in the WDR36 gene can contribute to POAG and that WDR36 may be a glaucoma modifier gene.