Prevalence of FOXC1 Variants in Individuals With a Suspected Diagnosis of Primary Congenital Glaucoma.

Importance: Both primary and secondary forms of childhood glaucoma have many distinct causative mechanisms, and in many cases a cause is not immediately clear. The broad phenotypic spectrum of secondary glaucoma, particularly in individuals with variants in FOXC1 or PITX2 genes associated with Axenfeld-Rieger syndrome, makes it more difficult to diagnose patients with milder phenotypes. These cases are occasionally classified and managed as primary congenital glaucoma. Objective: To investigate the prevalence of FOXC1 variants in participants with a suspected diagnosis of primary congenital glaucoma. Design, Setting, and Participants: Australian and Italian cohorts were recruited from January 1, 2007, through March 1, 2016. Australian individuals were recruited through the Australian and New Zealand Registry of Advanced Glaucoma and Italian individuals through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Milan, Italy. We performed exome sequencing, in combination with Sanger sequencing and multiplex ligation-dependent probe amplification, to detect variants of FOXC1 in individuals with a suspected diagnosis of primary congenital glaucoma established by their treating specialist. Data analysis was completed from June 2015 to November 2017. Main Outcome and Measures: Identification of single-nucleotide and copy number variants in FOXC1, along with phenotypic characterization of the individuals who carried them. Results: A total of 131 individuals with a suspected diagnosis of primary congenital glaucoma were included. The mean (SD) age at recruitment in the Australian cohort was 24.3 (18.1) years; 37 of 84 Australian participants (44.0%) were female, and 71 of 84 (84.5%) were of European ancestry. The mean (SD) age at recruitment was 22.5 (18.4) years in the Italian cohort; 21 of 47 Italian participants (44.7%) were female, and 45 of 47 (95.7%) were of European ancestry. We observed rare, predicted deleterious FOXC1 variants in 8 of 131 participants (6.1%), or 8 of 166 participants (4.8%) when including those explained by variants in CYP1B1. On reexamination or reinvestigation, all of these individuals had at least 1 detectable ocular and/or systemic feature associated with Axenfeld-Rieger syndrome. Conclusions and Relevance: These data highlight the genetic and phenotypic heterogeneity of childhood glaucoma and support the use of gene panels incorporating FOXC1 as a diagnostic aid, especially because clinical features of Axenfeld-Rieger syndrome can be subtle. Further replication of these results will be needed to support the future use of such panels.

Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants.

This corrects the article DOI: 10.1038/ejhg.2017.59.

Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants.

Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry. All coding exons of FOXC1 and PITX2 were directly sequenced and multiplex ligation-dependent probe amplification was performed to detect copy number variation. The cohort included 53 individuals from 24 families with disease-associated FOXC1 or PITX2 variants, including one individual diagnosed with primary congenital glaucoma and five with primary open-angle glaucoma. The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P=0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0±13.0 years) compared with PITX2 carriers (18.0±10.6 years, P=0.04). The penetrance at 10 years old was significantly lower in PITX2 than FOXC1 carriers (13.0% vs 42.9%, P=0.03) but became comparable at 25 years old (71.4% vs 57.7%, P=0.38). These findings have important implications for the genetic counselling of families affected by Axenfeld-Rieger syndrome, and also suggest that FOXC1 and PITX2 contribute to the genetic architecture of primary glaucoma subtypes.

Persistency rates for prostaglandin and other hypotensive eyedrops: population-based study using pharmacy claims data.

BACKGROUND: Effective management of ocular hypertension requires patients to be persistent with their treatment regimen. We evaluated patients' persistency with hypotensive eyedrops commonly used to treat glaucoma and ocular hypertension. METHODS: This large, population-based, retrospective, cohort study used pharmacy claims data for concessional patients from the Australian Pharmaceutical Benefits Scheme (July 1999-June 2005). Resupply rates for prostaglandins, beta-blockers, alpha-agonists and carbonic anhydrase inhibitors were analysed using life tables and Cox regression. Two populations, based on patients' supply histories, were examined: (i) 'new to this eyedrop'- patients who had used other hypotensive eyedrops before (presumably, previously diagnosed with glaucoma or ocular hypertension); and (ii) 'new to any eyedrop'- patients who were using their first hypotensive eyedrop (presumably, newly diagnosed with glaucoma or ocular hypertension). RESULTS: Data were obtained for 14,359,618 supplies of commonly used hypotensive eyedrops to 357,099 concessional patients. For both populations, resupply rates were highest for prostaglandins or the dorzolamide-timolol combination eyedrops, compared with beta-blockers, alpha-agonists or carbonic anhydrase inhibitors. Among the prostaglandins, there was no significant difference in the risk of ceasing supply between latanoprost and bimatoprost, but the risk was significantly higher for travoprost. CONCLUSIONS: Based on resupply rates from a national pharmacy claims database, patients supplied with ocular hypotensive eyedrops were most persistent with prostaglandin (bimatoprost, latanoprost and travoprost) and dorzolamide-timolol combination eyedrops. Among the prostaglandins, persistency was highest with, and similar between, bimatoprost and latanoprost. Persistency should be taken into account when selecting the most appropriate eyedrop to treat glaucoma and ocular hypertension.

Progression of visual field loss in open angle glaucoma in the Melbourne Visual Impairment Project.

PURPOSE: To quantify the progression of visual field loss in participants with open angle glaucoma. METHODS: Cluster random samples of 3271 participants participated in this study. Each participant underwent a standardized ophthalmic examination, which included intraocular pressure measurement, Humphrey 24-2 Fastpac visual field testing and stereophotography of the optic disc. At baseline 118 participants were identified as possible, probable or definite open angle glaucoma and 74 (62.7%) of these were seen again at the follow-up examination. Progression of visual field loss was defined using three methods: the Advanced Glaucoma Intervention Study criteria, the modified Anderson criteria and the Blumenthal method. RESULTS: In total, 49% of subjects showed progressive visual field loss with at least one method. The Blumenthal criteria yielded the highest rate of progression (37%), followed by the modified Anderson method (33%) and the Advanced Glaucoma Intervention Study method (16%). The progressive visual field loss was associated with baseline glaucoma status (P = 0.02); 65% of the definite glaucoma progressed, compared with 57% of the probable glaucoma and 25% of the possible glaucoma. Participants who had been previously diagnosed with glaucoma had a higher rate of progression (54%) when compared with those who had not been diagnosed previously (47%). In total, 50% (four of eight) of those receiving glaucoma medication at baseline had progressive visual field loss; all were in the definite glaucoma category. CONCLUSION: Despite use of glaucoma medications the majority of glaucoma patients managed by their regular ophthalmologist experienced progressive visual field loss over a 5-year period.

Detection of undiagnosed glaucoma by eye health professionals.

PURPOSE: To examine the clinical features of undiagnosed open-angle glaucoma (OAG) in people who have attended an eye care provider within the previous 12 months and to suggest strategies to assist in the early detection of glaucoma. DESIGN: Population based cross-sectional study. PARTICIPANTS: Permanent residents aged 40 years and older at recruitment during 1992 through 1996. METHODS: A cluster-stratified random sample of 4744 participants from the urban and rural cohorts was studied. Structured standardized interviews and dilated ocular examinations were conducted in all eligible participants. Data on demographic characteristics, prior knowledge of eye disease, use of eye care services, intraocular pressures, cup-to-disc ratios, visual fields, and photography of optic discs were obtained. All suspected glaucoma cases were submitted to a panel of 6 ophthalmologists to determine glaucoma diagnosis. MAIN OUTCOME MEASURES: Clinical features of participants seen by eye health professionals within the previous 12 months who have previously undiagnosed OAG, previously diagnosed OAG, and no glaucoma. RESULTS: Thirty-five previously undiagnosed and 43 previously diagnosed participants had visited an optometrist or ophthalmologist or both in the previous 12 months. Age and gender were not significantly different between the undiagnosed and diagnosed glaucoma cases. After logistic regression, the type of eye professional seen (odds ratio [OR], 45.17; 95% confidence interval [95% CI], 5.89-346.17; P = 0.0002) and the presence of visual field defects (OR, 0.06; 95% CI, 0.01-0.69, P = 0.020) were the only statistically significant variables between the diagnosed and undiagnosed glaucoma groups. CONCLUSIONS: Raised intraocular pressure should not be relied on as the only triggering factor in glaucoma investigations.

Inner retinal neurons display differential responses to N-methyl-D-aspartate receptor activation.

The N-methyl-D-aspartate (NMDA) responses of neurons from within the inner rabbit retina were mapped using a channel permeable cation, 1-amino-4-guanidobutane (agmatine, AGB). Serial sections were subsequently probed with immunoglobulins targeting AGB, glutamate, gamma-aminobutyric acid (GABA), and glycine to visualize the NMDA responses of neurochemical subpopulations of neurons. Most inner retinal subpopulations of neurons demonstrated an NMDA concentration-dependent increase in activation. This NMDA-induced activation displayed a distinct pattern, with the most sensitive class to least sensitive class ranking being GC > GABA cAC > GABA/Gly cAC > Gly cAC > GABA dAC (GC, ganglion cells; AC, amacrine cells; c, conventional; d, displaced; Gly, glycine). The variable NMDA response may reflect differences in NMDA receptor subunit disposition or differences in receptor density. In addition to the variable NMDA activation pattern, we found that virtually all ganglion cells (87%) showed NMDA-gated AGB entry, compared with only 58% of amacrine cells. We conclude that a large cohort of amacrine cells do not possess functional NMDA receptors. In addition to most ganglion cells being activated by NMDA, a large subpopulation displayed the highest sensitivity to NMDA application. The functional significance of this finding is that the ganglion cell population will be the first neuronal class to be susceptible to glutamate-induced neurotoxicity mediated through the NMDA receptor. The addition of betaxolol significantly reduced NMDA-mediated AGB entry into most neuronal groups (ganglion cells, GABA, and glycine amacrine cells), with the greatest effect being on ganglion cells. Betaxolol had no significant effect on NMDA-gated entry of AGB on the GABA/Gly amacrine cell population.

Glaucoma phenotype in pedigrees with the myocilin Thr377Met mutation.

OBJECTIVE: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the myocilin mutation Thr377Met. METHOD AND DESIGN: Cross-sectional genetic study. Four unrelated pedigrees carrying the Thr377Met mutation were ascertained from more than 2000 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania and from families with glaucoma referred to the study from throughout Australia. Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Thr377Met mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. RESULTS: From the 4 pedigrees carrying the Thr377Met mutation, 23 individuals with either ocular hypertension (OHT) or POAG were found, with a mean +/- SD age at diagnosis of 41.2 +/- 11.5 years, and a mean peak intraocular pressure of 31.7 +/- 9.9 mm Hg. A further 9 mutation carriers older than 18 years were studied who as yet showed no signs of OHT or POAG (6 of these 9 were younger than 30 years). A single individual with POAG was identified who did not carry the Thr377Met mutation. For Thr377Met carriers, age-related penetrance for OHT or POAG was 88% at age 30 years. A positive family history of POAG was present for 3 of the 4 index cases. Thirteen (57%) of the 23 Thr377Met carriers with OHT or POAG had undergone glaucoma drainage surgery. Although the glaucoma in these families appears to be pressure dependent, 2 individuals showed optic disc cupping before detected elevation in intraocular pressure. One family was of British origin, with a different background haplotype from the other 3 families from Greece or Macedonia, who shared a common haplotype. CONCLUSIONS: The GLC1A Thr377Met mutation is associated with POAG that, in the pedigrees studied, had a younger age at onset and higher peak intraocular pressure than in pedigrees with the more common Gln368STOP mutation. In addition, patients with glaucoma with the Thr377Met mutation were more likely to have undergone glaucoma drainage surgery.

Five-year incidence of open-angle glaucoma: the visual impairment project.

PURPOSE: To determine the incidence of open-angle glaucoma (OAG) in Melbourne, Victoria, Australia. DESIGN: Population-based cohort study. PARTICIPANTS: Total of 3271 participants aged 40 years and older from Melbourne, Victoria, Australia. MAIN OUTCOME MEASURES: Five-year incidence of OAG. METHODS: Participants were recruited through a cluster random sampling from nine urban clusters. Baseline examination was conducted from 1992 through 1994, and the follow-up data were collected from 1997 through 1999. Each participant both at baseline and follow-up underwent a standardized ophthalmic examination including intraocular pressure measurement, visual field assessment, cup-to-disc ratio measurement, and paired stereo photographs of the optic disc. Glaucoma was assessed by a consensus group of six ophthalmologists that included two glaucoma specialists. Glaucoma was diagnosed as possible, probable, or definite. RESULTS: The overall incidence of definite OAG was 0.5% (95% confidence limits [CL], 0.3, 0.7); probable and definite incidence of OAG was 1.1% (95% CL, 0.8,1.4); and possible, probable, and definite OAG incidence was 2.7% (95% CL, 1.8, 3.7). The incidence of possible, probable, and definite OAG increases significantly as age increases (P < 0.001). The incidence of definite OAG increases from 0% of participants aged 40 to 49 years to 4.1% of participants aged 80 years and older. The incidence of probable and definite OAG increases from 0.2% of participants aged 40 to 49 years to 5.4% of participants aged 80 years and older. The incidence of possible, probable, and definite OAG increases from 0.5% of participants aged 40 to 49 years to 11% of participants aged 80 years and older. A nonsignificant but higher incidence of definite OAG among men was observed in this study when compared with women (odds ratio, 2.2; 95% CL, 0.9, 5.9). Fifty percent of the definite OAG participants were undiagnosed. CONCLUSIONS: The incidence of OAG increases significantly with age. The undiagnosed cases suggest the need to develop novel community screening strategies for glaucoma.

Management of ocular hypertension and primary open angle glaucoma.

BACKGROUND: Glaucoma and ocular hypertension are among the most common pathologies encountered in clinical practice. Within the next 20 years, patients with these two problems will increase threefold as the population ages. The growing burden of glaucoma worldwide will also become a significant public health problem. The effective management of glaucoma will require the introduction of new screening strategies and better therapeutic approaches to these disorders. METHODS: Our current understanding of the epidemiology of primary open angle glaucoma and ocular hypertension is reviewed. Diagnosis and treatment strategies are discussed in the context of the current best available clinical trial and laboratory data. RESULTS: While few patients with ocular hypertension will require therapy, it is the conventional practice to lower the intraocular pressure by at least one-third once glaucomatous optic neuropathy is detected. Topical beta-adrenergic antagonists have been the preferred first-line therapy for primary open angle glaucoma for the past 20 years, but with the advent of topical prostaglandin analogues and alpha-2 agonists, the effectiveness of medical therapy has improved significantly. The decision to perform glaucoma filtering surgery or laser trabeculoplasty must be carefully considered and based on the past response to medication, the extent and rate of progression of any visual field loss, and on the life expectancy and wishes of the patient. CONCLUSION: The treatment of chronic glaucoma is directed at preserving vision and interfering with the quality of life of the patient as little as possible. Many older patients who develop primary open angle glaucoma may have a limited life expectancy and do not require aggressive medical therapy or surgery. Many new medications have become available that permit less frequent dosing with fewer local and systemic side-effects. In the near future, therapies that address the underlying molecular basis of glaucomatous optic neuropathy might become available and further reduce the risk of glaucoma blindness.