Stage of visual field loss and age at diagnosis in 1988 patients with different glaucomas: implications for glaucoma screening and driving ability.

PURPOSE: To compare stage of visual field loss (VFL) and age at diagnosis between patients with different types of glaucoma with regard to glaucoma screening and driving ability. METHODS: In a cross-sectional study of 1988 consecutive patients with different types of glaucoma VFL at diagnosis and age at diagnosis were assessed. Patients with binocular advanced or severe VFL were classified unable, patients with no VFL in one eye and VFL I-V (Aulhorn classification) in the other eye able, all other constellations questionably able to drive. RESULTS: There were significant differences in age at diagnosis between different glaucomas and between patients with different stages of VFL at diagnosis. Age-related assessment of VFL at diagnosis in normal tension glaucoma (NTG) compared to primary open-angle glaucoma (POAG) showed that NTG is not a disease of the elderly but a disease with late diagnosis at severe VFL. In POAG a solely age-related glaucoma screening, e.g. from the age of 50 years, does not sufficiently lead to diagnosis at an early stage of the disease. In POAG solely based on binocular VFL 11.5% of patients were judged unable, 29.2% questionably able to drive, in NTG 19.6%/43.1%, pigmentary glaucoma 16%/22%, pseudoexfoliation glaucoma 9.1%/16.7%, and in primary angle-closure glaucoma 14.6%/30%. CONCLUSIONS: Depending on type of glaucoma more than 50% of patients require counselling regarding safe driving as part of clinical care. A disease-specific, age-related perimetric examination considering additional risk factors like family history of glaucoma is essential for early detection of glaucoma and road safety.

Common genetic determinants of intraocular pressure and primary open-angle glaucoma.

Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p=1.4×10(-8)), and with rs7555523, located in TMCO1 at 1q24.1 (p=1.6×10(-8)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p=2.4×10(-2) for rs11656696 and p=9.1×10(-4) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.

Variants in ASB10 are associated with open-angle glaucoma.

The molecular events responsible for obstruction of aqueous humor outflow and the loss of retinal ganglion cells in glaucoma, one of the main causes of blindness worldwide, remain poorly understood. We identified a synonymous variant, c.765C>T (Thr255Thr), in ankyrin repeats and suppressor of cytokine signaling box-containing protein 10 (ASB10) in a large family with primary open angle glaucoma (POAG) mapping to the GLC1F locus. This variant affects an exon splice enhancer site and alters mRNA splicing in lymphoblasts of affected family members. Systematic sequence analysis in two POAG patient groups (195 US and 977 German) and their respective controls (85 and 376) lead to the identification of 26 amino acid changes in 70 patients (70 of 1172; 6.0%) compared with 9 in 13 controls (13 of 461; 2.8%; P = 0.008). Molecular modeling suggests that these missense variants change ASB10 net charge or destabilize ankyrin repeats. ASB10 mRNA and protein were found to be strongly expressed in trabecular meshwork, retinal ganglion cells and ciliary body. Silencing of ASB10 transcripts in perfused anterior segment organ culture reduced outflow facility by ∼50% compared with control-infected anterior segments (P = 0.02). In conclusion, genetic and molecular analyses provide evidence for ASB10 as a glaucoma-causing gene.

Common genetic variants associated with open-angle glaucoma.

Open-angle glaucoma (glaucoma) is a major eye disorder characterized by optic disc pathology. Recent genome-wide association studies identified new loci associated with clinically relevant optic disc parameters, such as the optic disc area and vertical cup-disc ratio (VCDR). We examined to what extent these loci are involved in glaucoma. The loci studied include ATOH7, CDC7/TGFBR3 and SALL1 for optic disc area, and CDKN2B, SIX1, SCYL1/LTBP3, CHEK2, ATOH7 and DCLK1 for VCDR. We performed a meta-analysis using data from six independent studies including: the Rotterdam Study (n= 5736), Genetic Research in Isolated Populations combined with Erasmus Rucphen Family study (n= 1750), Amsterdam Glaucoma Study (n= 296) and cohorts from Erlangen and Tübingen (n= 1363), Southampton (n= 702) and deCODE (n= 36 151) resulting in a total of 3161 glaucoma cases and 42 837 controls. Of the eight loci, we found significant evidence (P= 1.41 × 10(-8)) for the association of CDKN2B with glaucoma [odds ratio (OR) for those homozygous for the risk allele: 0.76; 95% confidence interval (CI): 0.70-0.84], for the role of ATOH7 (OR: 1.28; 95% CI: 1.12-1.47) and for SIX1 (OR: 1.20; 95% CI: 1.10-1.31) when adjusting for the number of tested loci. Furthermore, there was a borderline significant association of CDC7/TGFBR3 and SALL1 (both P= 0.04) with glaucoma. In conclusion, we found consistent evidence for three common variants (CDKN2B, ATOH7 and SIX1) significantly associated with glaucoma. These findings may shed new light on the pathophysiological protein pathways leading to glaucoma, and point to pathways involved in the growth and development of the optic nerve.

Heterozygous NTF4 mutations impairing neurotrophin-4 signaling in patients with primary open-angle glaucoma.

Glaucoma, a main cause of blindness in the developed world, is characterized by progressive degeneration of retinal ganglion cells (RGCs), resulting in irreversible loss of vision. Although members of the neurotrophin gene family in various species are known to support the survival of numerous neuronal populations, including RGCs, it is less clear whether they are also required for survival and maintenance of adult neurons in humans. Here, we report seven different heterozygous mutations in the Neurotrophin-4 (NTF4) gene accounting for about 1.7% of primary open-angle glaucoma patients of European origin. Molecular modeling predicted a decreased affinity of neurotrophin 4 protein (NT-4) mutants with its specific tyrosine kinase receptor B (TrkB). Expression of recombinant NT-4 carrying the most frequent mutation was demonstrated to lead to decreased activation of TrkB. These findings suggest a pathway in the pathophysiology of glaucoma through loss of neurotrophic function and may eventually open the possibility of using ligands activating TrkB to prevent the progression of the disease.

A splice site mutation in the PAX6 gene which induces exon skipping causes autosomal dominant inherited aniridia.

PURPOSE: To identify the underlying genetic cause in a two generation German family diagnosed with isolated aniridia. METHODS: All patients underwent full ophthalmic examination. Mutation screening of the paired box gene 6 (PAX6) was performed by bidirectional Sanger sequencing. A minigene assay was applied to analyze transcript processing of mutant and wildtype PAX6 variants in HEK293 cells. RESULTS: We identified a PAX6 sequence variant at the splice donor site (+5) of intron 12. This variant has been described before in another family with aniridia but has not been characterized at the transcript level. We could demonstrate that the mutant allele causes the skipping of exon 12 during transcript processing. The mutation is predicted to result in a 'run on' translation past the normal translational stop codon. CONCLUSIONS: A splice site mutation resulting in exon skipping was found in a family with autosomal dominant aniridia. The mutation is predicted to result in an enlarged protein with an extra COOH-terminal domain. This very likely affects the transactivation properties of the PAX6 protein.

Mitochondrial haplogroup U is associated with a reduced risk to develop exfoliation glaucoma in the German population.

BACKGROUND: Various lines of evidence demonstrate the involvement of mitochondrial dysfunction in the pathogenesis of glaucoma. Therefore, mitochondrial DNA is a promising candidate for genetic susceptibility studies on glaucoma. To test the hypothesis that mitochondrial haplogroups influence the risk to develop glaucoma, we genotyped 12 single-nucleotide polymorphisms that define the European mitochondrial DNA haplogroups in healthy controls and two German patient cohorts with either exfoliation glaucoma or the normal tension subgroup of primary open angle glaucoma. RESULTS: Mitochondrial haplogroup U was significantly under-represented in patients with exfoliation glaucoma (8.3% compared with 18.9% in controls; p = 0.004). CONCLUSIONS: People with haplogroup U have a lower risk to develop exfoliation glaucoma. Our results substantiate the suggestion that mitochondrial alterations have an impact on the etiology of glaucoma.

Open globe injuries induced by glass bottles containing carbonated drinks.

BACKGROUND: Reports on open globe injuries caused by exploding bottles containing carbonated drinks have already raised the demand to switch from multi-use glass bottles to plastic bottles. We retrospectively analyzed our files to find out whether this type of injury is limited to multi-use glass bottles, and to what extent carelessness contributed to the injury PATIENTS: Among 1,402 open globe injuries that were treated in the departments of ophthalmology at the universities of Freiburg and Würzburg between 1981 and 2004, we retrospectively identified 33 injuries caused by exploding bottles containing carbonated drinks. Patients were excluded from analysis when the destruction of the bottle was intended (destroyed with a hammer, or bottle used as a weapon). The circumstances of the injury, the treatment and the functional outcome was analyzed. RESULTS: 2.4% of all open globe injuries were related to exploding bottles, with a risk of one injury per 1 million inhabitants per year. Ten eyes suffered from a spontaneous explosion of the bottle when it was moved on a shelf or taken out of a box. Eighteen eyes received the injury after the bottle had fallen down and exploded (six of them in children 2 to 8 years). Five bottles exploded during opening of the bottle. In four cases, the bottle cap came off spontaneously and penetrated the eye. Eleven injuries (33%) occurred at work, five of them while moving the bottle and six during breaks at work. CONCLUSION: Spontaneous explosions in multi-use glass bottles could easily be avoided by changing to plastic bottles; however, exploding single-use glass bottles Containing sparkling wine also contributed to the injuries. In many cases, carelessness was involved. Glass bottles should be never exposed to heat or shaking, and children should never carry glass bottles containing carbonated drinks.

Evaluation of nine candidate genes in patients with normal tension glaucoma: a case control study.

BACKGROUND: Normal tension glaucoma is a major subtype of glaucoma, associated with intraocular pressures that are within the statistically normal range of the population. Monogenic forms following classical inheritance patterns are rare in this glaucoma subtype. Instead, multigenic inheritance is proposed for the majority of cases. The present study tested common sequence variants in candidate genes for association with normal tension glaucoma in the German population. METHODS: Ninety-eight SNPs were selected to tag the common genetic variation in nine genes, namely OPTN (optineurin), RDX (radixin), SNX16 (sorting nexin 16), OPA1 (optic atrophy 1), MFN1 (mitofusin 1), MFN2 (mitofusin 2), PARL (presenilin associated, rhomboid-like), SOD2 (superoxide dismutase 2, mitochondrial) and CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1). These SNPs were genotyped in 285 cases and 282 fully evaluated matched controls. Statistical analyses comprised single polymorphism association as well as haplogroup based association testing. RESULTS: Results suggested that genetic variation in five of the candidate genes (RDX, SNX16, OPA1, SOD2 and CYP1B1) is unlikely to confer major risk to develop normal tension glaucoma in the German population. In contrast, we observed a trend towards association of single SNPs in OPTN, MFN1, MFN2 and PARL. The SNPs of OPTN, MFN2 and PARL were further analysed by multimarker haplotype-based association testing. We identified a risk haplotype being more frequent in patients and a vice versa situation for the complementary protective haplotype in each of the three genes. CONCLUSION: Common variants of OPTN, PARL, MFN1 and MFN2 should be analysed in other cohorts to confirm their involvement in normal tension glaucoma.

Optic nerve head drusen and visual field loss in normotensive and hypertensive eyes.

OBJECTIVE: To compare visual field loss (VFL) in eyes with optic nerve head drusen (ONHD) with or without ocular hypertension (OHT). METHODS: The records of all patients aged 45 years or older with a diagnosis of ONHD at 2 centers were reviewed. OHT was defined as intraocular pressure >or=22 mm Hg. We categorized ONHD into 3 grades based on visibility on disc photographs. RESULTS: We identified 22 eyes (13 patients) with both ONHD and OHT and 81 normotensive eyes (47 patients) with ONHD. VFL was present in 20/22 (90.9%) of hypertensive eyes compared with 54/81 (66.7%) of normotensive eyes (P=0.03, Fisher exact test). Drusen grade III and OHT were both independently and significantly associated with greater incidence of VFL (logistic regression analysis). CONCLUSIONS: VFL occurs more frequently in eyes with ONHD that also have OHT. Eyes with grade III ONHD are at increased risk for VFL compared to eyes with grade I drusen with the same intraocular pressure status. Patients with OHT and ONHD should undergo close surveillance for disease progression and be treated appropriately to prevent additional VFL.