Lysyl oxidase-like 1 polymorphisms and exfoliation syndrome in the Japanese population

PURPOSE: To investigate the contribution of two single-nucleotide polymorphisms (SNPs) of the lysyl oxidase-like 1 (LOXL1) gene, recently shown to be associated with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) in the Nordic population, to the occurrence of XFS and XFG in the Japanese population. DESIGN: Case-control association study. METHODS: A total of 59 unrelated Japanese individuals with XFS, 27 XFG patients, and 190 population-based controls were recruited. The SNPs rs1048661 (R141L) and rs3825942 (G153D) in the LOXL1 gene were genotyped directly. Association tests were performed for the two SNPs and inferred haplotypes. RESULTS: The frequency of the G allele in rs1048661, reportedly a functional risk allele in White persons, existed in only 0.8% of Japanese XFS cases, but occurred with much higher frequency in controls (46.0%) and yielded a P value of 3.0x10(-19), and the odds ratio for the T allele in rs1048661 was 99.8 (95% confidence interval, 13.8 to 722). For rs3825942, the frequency of the G allele, which is another possible risk allele in White persons with XFS, was 1.000 vs 0.857 in the controls (P=1.4x10(-5)). The most frequent haplotype in Japanese XFS patients was haplotype (T,G) (99.2%). The (G,G) haplotype, which generates the highest risk in White persons, was present in only a small percentage of Japanese XFS cases (0.8%). CONCLUSIONS: The SNPs rs1048661 and rs3825942 of the LOXL1 gene seem to be highly associated with XFS in the Japanese population, but a different polymorphism of LOXL1 may cause the development of XFS in the Japanese population.     

Exfoliation syndrome

Exfoliation syndrome (XFS) is an age-related disease in which abnormal fibrillar extracellular material is produced and accumulates in many ocular tissues. Its ocular manifestations involve all of the structures of the anterior segment, as well as conjunctiva and orbital structures. Glaucoma occurs more commonly in eyes with XFS than in those without it; in fact, XFS has recently been recognized as the most common identifiable cause of glaucoma. Patients with XFS are also predisposed to develop angle-closure glaucoma, and glaucoma in XFS has a more serious clinical course and worse prognosis than primary open-angle glaucoma.There is increasing evidence for an etiological association of XFS with cataract formation, and possibly with retinal vein occlusion. XFS is now suspected to be a systemic disorder and has been associated preliminarily with transient ischemic attacks, stroke, systemic hypertension, and myocardial infarction. Further ramifications await discovery.Deposits of white material on the anterior lens surface are the most consistent and important diagnostic feature of XFS. The classic pattern consists of three distinct zones that become visible when the pupil is fully dilated. Whereas the classic picture of manifest XFS has been often described, the early stages of beginning exfoliation have not been well defined. Next to the lens, exfoliation material is most prominent at the pupillary border. Pigment loss from the iris sphincter region and its deposition on anterior chamber structures is a hallmark of XFS.Despite extensive research, the exact chemical composition of exfoliation material (XFM) remains unknown. An overproduction and abnormal metabolism of glycosaminoglycans have been suggested as one of the key changes in XFS. The protein components of XFM include both noncollagenous basement membrane components and epitopes of the elastic fiber system such as fibrillium. Regardless of etiology, typical exfoliation fibers have been demonstrated electron microscopically in close association with the pre-equatorial lens epithelium, the nonpigmented ciliary epithelium, the iris pigment epithelium, the corneal endothelium, the trabecular endothelium, and with almost all cell types of the iris stroma, such as fibrocytes, melanocytes, vascular endothelial cells, pericytes, and smooth muscle cells.The presence of XFS should alert the physician to the increased risks of intraocular surgery, most commonly zonular dehiscence, capsular rupture, and vitreous loss during cataract extraction. Heightened awareness of this condition and its associated clinical signs are important in the detection and management of glaucoma, and preoperative determination of those patients at increased risk for surgical complications.     

From epidemiology to lysyl oxidase like one (LOXL1) polymorphisms discovery: phenotyping and genotyping exfoliation syndrome and exfoliation glaucoma in Iceland

The first Icelandic articles on exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) appeared some 35 years ago in 1974. Articles since then have included epidemiology, pedigree‐based and twin‐studies as well as investigations into XFG response to medical therapy and XFS/XFG genetics. All studies found XFS/XFG to be common in Iceland and to be age‐related. The Reykjavik Eye Study (RES), a population‐based epidemiological study, was first conducted in 1996. The RES found that XFS and XFG prevalence in patients aged 50 years and older was 11% and that XFS/XFG was more common in women than in men. These results were confirmed in 5‐ and 12‐year incidence studies that also suggested that detailed characterization of the phenotype is important, including pupil dilation. In the RES, eyes with XFS were found to be clinically unilateral in about half of cases and to have higher mean intraocular pressure (IOP) than non‐XFS eyes. However, XFS was not found to be associated with central corneal thickness, corneal curvature, anterior chamber depth, lens thickness, lens opacification or optic disc morphology. About 15% of persons with XFS had XFG, and XFG eyes had higher risk of developing visual impairment and blindness than eyes with primary open‐angle glaucoma. The first genetic studies on Icelanders, conducted about 12 years ago, were linkage studies and were unsuccessful in discovering the genetics behind XFS/XFG. However, in 2007 a genome‐wide association study in Iceland using more than 300 000 markers [single nucleotide polymorphisms (SNPs)] on a relatively small number of patients did discover that lysyl oxidase like 1 (LOXL1) on chromosome 15q24 is a major gene for XFS/XFG. These results have now largely been replicated world‐wide.     

Effects of apolipoprotein E genotypes on the development of exfoliation syndrome

Apolipoprotein E (apo E) is directly involved in the amyloid deposition and fibril formation and is present in many cerebral and systemic amyloidoses immunologically. It is encoded by a polymorphic gene and it has three common alleles-epsilon2, epsilon3, and epsilon4. Exfoliation syndrome (XFS) is characterized by the deposition throughout the body of focal fibrillogranular aggregates in which there have been some reports of amyloid or amyloid-like features. We evaluated the possible association between apo E polymorphism and the occurrence of XFS. Using High Pure PCR Template Preparation Kits, genomic DNAs were extracted from whole blood and apo E polymorphisms were determined by using Lightcycler-Apo E Mutation Detection Kits in 76 patients with XFS and 74 controls. The E2/E2, E2/E3 and E2/E4 genotypes (OR 29.9, 95% CI 3.1-293.7; OR 56.1, 95% CI 12.5-252.7; OR 43.9, 95% CI 7.4-257.6, respectively) and the in2 allele are found to have an increased risk of developing XFS (p=0.0001); whereas the in3 allele was found to be protective (p=0.0001). Apo E polymorphism and the presence of in2 allele are seem to be significantly associated with the development of XFS.     

Combined exfoliation and pigment dispersion: paradigm of an overlap syndrome

OBJECTIVE: To describe a series of patients with combined pigment dispersion syndrome (PDS) and exfoliation syndrome (XFS) and to introduce a concept, the overlap syndrome, to aid in assessing multiple risk factors for glaucomatous damage. DESIGN: Clinic-based, cross-sectional study. SETTING: New York Eye and Ear Infirmary. PARTICIPANTS: Twenty-six patients identified from the glaucoma database as having combined pigment dispersion syndrome-glaucoma and exfoliation syndrome-glaucoma. MAIN OUTCOME MEASURES: Quantification of patients with both pigment dispersion syndrome-glaucoma (PDS/PG) and exfoliation syndrome-glaucoma (XFS/XFG) and its clinical implications. RESULTS: Among the 26 patients (all white) having both XFS/XFG and PDS/PG, the average age was 64.3 +/- 9.8 years and 19 of 26 were men. All patients had bilateral PDS/PG. Bilateral XFS/XFG was present in 9 of 26 patients and, of the 17 patients with unilateral involvement, the left eye was affected in 13. CONCLUSIONS: Both XFS and PDS are common. Middle-aged patients with known PDS/PG should be suspected of having the onset of XFS if one eye escapes intraocular pressure control. Patients with unilateral XFG at presentation may also have signs of PDS/PG, often remitted. We define the term overlap syndrome to describe the sequential appearance over time of two or more risk factors for glaucomatous damage. The appearance of a new risk factor in a patient whose condition has been stable can alter the course and prognosis of the disease. This concept should prove useful in dealing with secondary and normal-tension glaucomas.     

Systemic associations and prevalence of exfoliation syndrome in patients scheduled for cataract surgery

PURPOSE: To study the frequency of exfoliation syndrome (XFS) and its association with intraocular pressure (IOP) and systemic diseases in patients with age-related cataract scheduled for surgery. METHODS: All 1480 cataract patients had a comprehensive systemic and eye examination, including slit-lamp biomicroscopy before and after mydriasis, IOP measurement, gonioscopy, and fundus examination. RESULTS: The percentage of XFS among patients scheduled for cataract surgery was 16.4, with no gender difference (p=0.833). The mean age of XFS patients (74.3+/-7.0 years) was significantly higher when compared to the ones without XFS (66.5+/-10.9 years) (p<0.001). XFS was unilateral in 41.3% of the subjects and bilateral in 58.7%. The number of subjects with XFS increased significantly with aging (p<0.001) (OR=1.093, 95% CI=1.073-1.14) (p<0.001). The most common type of cataract was nuclear in the XFS group (33.5%) and 24.6% of patients with mature cataract had XFS. In the XFS group, 11.2% of the subjects had glaucoma, which was statistically higher than the non-XFS group (4.6%) (p<0.001) (OR=2.67, 95% CI=1.65-4.32). Eighty-four patients had glaucoma and 27 of them (32.1%) had exfoliative glaucoma. The only systemic disease that was found to be associated with XFS was coronary heart disease with an OR of 1.49 (95% CI=1.068-2.072) (p=0.019). CONCLUSIONS: XFS is a common problem in the aging cataract population of Turkey and increased IOP, glaucomatous optic neuropathy, and coronary heart disease occur more frequently in patients with XFS compared with subjects without XFS.     

Association of exfoliation syndrome and central retinal vein occlusion: an ultrastructural analysis

Purpose: To evaluate prospectively the frequency with which exfoliation syndrome (XFS) occurs in patients with central retinal vein occlusion (CRVO) by clinical examination and ultrastructural examination of conjunctival biopsy specimens. Methods: Prospective observational case series. Thirty‐six eyes of 36 consecutive patients with CRVO were investigated for XFS by slit‐lamp examination and conjunctival biopsy when XFS was not clinically visible on examination. Results: A clinical diagnosis of XFS or a positive biopsy result for exfoliation material (XFM) was present in 22 of the 36 patients (61%; 95% confidence interval 45–75%). Twelve of these 22 patients (54%) had a clinical diagnosis of XFS. Aggregates of XFM were identified ultrastructurally in the biopsy specimens in 10 of 24 patients with no clinical signs of XFS (42%). Patients with and without XFS had similar distribution of age, gender, race and prevalence of systemic disorders. Twelve of the 22 (54%) XFS patients had neither glaucoma nor ocular hypertension prior to the CRVO. Conclusion: In accordance with previous retrospective and histological studies, this prospective, in vivo study suggests that CRVO is commonly associated with XFS.     

The LOXL1 gene variations are not associated with primary open-angle and primary angle-closure glaucomas

PURPOSE: Glaucoma is a complex disease involving multiple genetic factors. Recently, single nucleotide polymorphisms (SNPs) in the LOXL1 gene have been implicated in exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) but not in the primary glaucomas. This study was conducted to determine the possible involvement of these SNPs in cases of primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). METHODS: The three associated SNPs of LOXL1 (rs1048661, rs3825942, and rs2165241) were screened in 208 unrelated and clinically well-characterized glaucoma cases comprising patients with POAG (n = 112) or PACG (n = 96) along with 105 ethnically matched normal control subjects from Indian populations. Subjects with exfoliative material on the lens and radial pigmentation in the periphery of the lens that could be earlier signs of XFS were excluded. These SNPs were screened by resequencing and further confirmed by PCR-based restriction digestions. Haplotypes were generated with the three SNPs in cases and control subjects, and linkage disequilibrium (LD) and haplotype analysis were performed with the Haploview software, which uses the EM (expectation-maximization) algorithm. RESULTS: The SNPs of LOXL1 did not exhibit any significant association with POAG or PACG, unlike previous studies from Icelandic, Swedish, U.S., and Australian populations with XFS/XFG. Haplotypes generated with these intragenic SNPs did not indicate any significant risk with POAG or PACG phenotypes. The risk haplotype G-G in XFS/XFG in other populations was present in 46% of the normal control subjects in the present cohort. CONCLUSIONS: The results from the present study do not indicate the involvement of the LOXL1 SNPs in POAG and PACG.     

Plasma and aqueous humour levels of homocysteine in exfoliation syndrome

Background Recent studies have suggested that the relationship between elevated plasma homocysteine (Hcy) and increased risk of vascular disease holds also for certain diseases of the eye with vascular aetiology. Elevated plasma Hcy levels have been noted among patients with exfoliation syndrome (XFS). The purpose of this study was to establish whether subjects with XFS have higher plasma and aqueous humour Hcy levels values than non-XFS subjects, particularly in relation to vitamin B status.Methods Using a cross-sectional study design, 36 subjects with XFS and 36 non-XFS subjects with intraocular pressure (IOP) lower than 23 mmHg, matched by age and gender, were first selected. The participant exclusion criteria included parameters known to alter Hcy metabolism. In the XFS group, 11 subjects had a concurrent diagnosis of exfoliative glaucoma (XFG). Fasting plasma and aqueous humour Hcy samples were collected, along with erythrocyte folate (E-Fol) and serum vitamin B6 and B12 samples. The Hcy samples were analysed using a fluorescence polarization immunoassay method.Results Plasma Hcy level was significantly higher (P=0.020, after Bonferroni correction for multiple testing) in the XFS group than in the controls. The Hcy concentrations in the aqueous humour did not differ statistically between the two groups. Plasma and aqueous humour Hcy concentrations were not statistically significantly correlated within the groups of exfoliation-positive and -negative subjects. E-Fol, and serum vitamin B6 and B12 levels did not differ statistically between the XFS group and the control group.Conclusions The finding that subjects with XFS are more prone to elevated plasma Hcy emphasizes exfoliation as a clinical sign and a marker of thromboembolic vasculopathies induced by hyperhomocysteinaemia.This work was not sponsored by any party or organization     

8-Isoprostaglandin F2a and ascorbic acid concentration in the aqueous humour of patients with exfoliation syndrome

BACKGROUND/AIMS: The authors investigated the concentrations of 8-isoprostaglandin F(2a), a marker of oxidative stress in vivo, and ascorbic acid, a protectant against oxidative damage, in the aqueous humour of patients with exfoliation syndrome (XFS) and cataract and compared the results with those in age matched patients with cataract, but without XFS, to determine whether XFS is associated with increased oxidative stress. METHODS: Aqueous humour was aspirated at the beginning of phacoemulsification cataract surgery from 27 eyes of 27 cataract patients with XFS and 27 eyes of 27 age matched cataract patients without XFS. 8-Isoprostaglandin F(2a)concentration in the aqueous was determined with a commercial immunoassay; ascorbic acid concentration was measured with a microplate assay method. RESULTS: The mean concentration of 8-isoprostaglandin F(2a)in the aqueous from patients with XFS (2429 (SD 2940) pg/ml; range 400-10500 pg/ml) was significantly higher than that measured in the aqueous of age matched control patients (529.1 (226.8) pg/ml; range 325-1000 pg/ml); (p = 0.0028). Furthermore, mean ascorbic acid concentration in XFS patients (0.75 (0.39) mM; range 0.28-1.70 mM) was significantly lower than that found in control patients (1.19 (0.47) mM; range 0.53-2.4 mM); (p = 0.0005). There was a reverse correlation between 8-isoprostaglandin F(2a)and ascorbic acid concentration. CONCLUSION: 8-Isoprostaglandin F(2a)was significantly increased in the aqueous of patients with XFS, and ascorbic acid was decreased, providing evidence of a role for free radical induced oxidative damage in the pathobiology of XFS.     

Association of Lysyl Oxidase-Like 1 Gene Polymorphisms in Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma in a Spanish Population

Purpose: To evaluate the association of the lysyl oxidase-like 1 (LOXL1) single nucleotide polymorphisms (SNPs) in a Spanish population with pseudoexfoliation syndrome (XFS) and pseudoexfoliation glaucoma (XFG).

Materials and methods: The present case-control study included 100 Spanish patients (60 patients with XFS and 40 patients with XFG) and 90 control subjects. Genotypes of the three single nucleotide polymorphisms of LOXL1 (rs1048661, rs3825942, and rs2165241) were analyzed with direct sequencing.

Results: The G allele and the GG genotype of SNP rs3825942 were detected at a statistically higher frequency in pseudoexfoliation patients than in control subjects (p?=?3.36?×?10^?5, OR?=?5.71, 95% CI: 2.30–14.18; p?=?3.38?×?10^?5, OR?=?6.91, 95% CI: 2.51–19.03 respectively). The T allele and the TT genotype of SNP rs2165241 presented at significantly higher frequencies in pseudoexfoliation patients than in controls (p?=?2.50?×?10^?4, OR?=?2.18, 95% CI: 1.43–3.33; p?=?1.21?×?10^?2, OR?=?2.13, 95% CI: 1.75–3.85 respectively). No significant association between XFS/XFG and the rs1048661 was observed. The GGT haplotype composed of all three risk alleles was determined to be significantly associated with pseudoexfoliation. The genotypic and allelic distributions of the three SNPs were similar between XFS and XFG.

Conclusions: This is the first study associating two SNPs of LOXL1 (rs3825942 and rs2165241) and XFS/XFG in a Spanish population, confirming findings in patients from Europe. However rs1048661 SNP did not show an association with XFS.     

Is GST gene polymorphism a risk factor in developing exfoliation syndrome?

PURPOSE: To evaluate the distribution of GSTM1, GSTP1, and GSTT1 gene polymorphisms in exfoliation syndrome (XFS) and the possible associations between the presence of exfoliation syndrome and glutathione S-transferase (GST) gene polymorphisms. METHODS: Using a real-time polymerase chain reaction, GSTM1, GSTP1, and GSTT1 gene polymorphisms were detected in 60 patients with exfoliation syndrome, among which 71.7% had exfoliative glaucoma (43 patients), 16.7% had XFS with elevated intraocular pressure (IOP) (10 patients), and 11.7% had XFS only (7 cases), and in 65 otherwise healthy control group of similar age. RESULTS: Although the exfoliation syndrome group presented a higher prevalence of the GSTM1 null and GSTP1 Ile/Val genotypes than the control group, this increase was not statistically significant. GSTT1 null and GSTP1 Val/Val polymorphisms were also not different among groups. The risk of exfoliation syndrome was not increased as the number of putative high-risk genotypes increase (p = 0.73). CONCLUSIONS: GSTM1, GSTP1, and GSTT1 gene polymorphisms were not different among exfoliation syndrome patients, with or without glaucoma, and the controls therefore GSTM1, GSTP1, and GSTT1 gene polymorphisms did not seem to be associated with the risk of development of exfoliation syndrome.     

Twelve‐year Incidence of Exfoliation Syndrome in the Reykjavik Eye Study

Purpose: To examine the 12‐year incidence of exfoliation syndrome (XFS) in persons aged 50–79 years at baseline and also to monitor changes in related ophthalmologic variables, to identify possible risk factors for incidence and to estimate the reliability of our diagnostic criteria. Methods: Baseline examination was performed in 1996 on a random sample of 1045 participants from the population of Reykjavik, 50 years and older. Five years later, in 2001, 88.2% of survivors returned for a follow‐up. In 2008, 12 years after the baseline examination, a total of 573 participants returned for the third examination (71.5% of survivors). On all three occasions, the participants underwent a thorough eye examination including slitlamp examination specifically looking for XFS and answered a comprehensive questionnaire. Results: A total of 8.0% of participants developed XFS during the follow‐up period in at least one eye, with women being more commonly affected than men, 9.2% versus 6.6%. The overall 12‐year incidence for either eye increased with increasing age, from 6.5% in those participants aged 50–59 years at baseline to 10.6% in those that were 70–79 years at baseline; 71% of clinically unilateral cases had converted to bilateral over 12 years. Conclusions: Twelve‐year incidence of XFS is higher in women than in men and higher in older age groups than in younger ones. Most persons deemed on the slitlamp to be unilaterally affected have converted to bilateral over 12 years. Eyes with XFS at baseline were 3–4 times more likely to have cataract surgery during the 12 years. Our definition of definite XFS generally holds, while our definition of probable XFS is of no prognostic value over 12 years.     

Intraocular pressure following phacoemulsification in patients with and without exfoliation syndrome: a 2 year prospective study

AIM: To determine the long term intraocular pressure (IOP) response to phacoemulsification in patients with and without exfoliation syndrome (XFS). METHODS: Prospective, multicentre, cohort study with the following inclusion criteria: age over 50 years, open iridocorneal angle, and cataract. Two groups were enrolled: those with XFS and those without. The main outcome was mean IOP reduction 2 years after phacoemulsification cataract extraction (PCE). Univariate and multivariate analyses were performed. RESULTS: 183 patients were enrolled, 71 with and 112 without XFS. There were 29 patients with glaucoma in both groups. Mean baseline IOP was higher in XFS compared to control eyes (17.60 (SD 3.23) mm Hg v 16.08 (3.18) mm Hg, p = 0.002). Overall IOP reduction was significantly greater in the XFS group at the 2 year time point (-1.85 mm Hg v -0.62 mm Hg in the controls (p = 0.0037)). Multivariate analysis demonstrated that the IOP lowering effect in the XFS group may be related to irrigation volume at the time of surgery. In the subgroup analyses IOP lowering was significantly greater in the XFS and XFG patients than in controls without glaucoma, and POAG controls, respectively. The percentage of patients with a postoperative IOP spike was similar and relatively high in both XFS and control groups (34% v 25%; p = 0.54). CONCLUSION: IOP decreases more in patients with XFS following PCE compared to control eyes without XFS. This effect is more pronounced in glaucoma patients and persists for at least 2 years.     

Prevalence of pseudoexfoliation syndrome in indigenous Australians within central Australia: The Central Australian Ocular Health Study

Background: Pseudoexfoliation syndrome (XFS) has been found to occur more commonly among indigenous Australians. This paper was designed to determine the prevalence of XFS within the indigenous Australian population living in central Australia. Design: Clinic‐based cross‐sectional study. Participants: One thousand eight hundred eighty‐four individuals living in one of 30 remote communities within the statistical local area of ‘Central Australia’ were recruited. This equated to 36% of those aged 20 years or older and 67% of those aged 40 years or older within this district. Methods: Participants aged 20 years or over were recruited as they presented to the eye clinic at each remote community. Slit‐lamp examination was performed, and the presence of XFS in each eye was recorded and presented. Main Outcome Measure: Prevalence and associations of XFS. Results: XFS was present in one or both eyes of 4.7% of the individuals recruited into the study. Prevalence increased with age (5.9% of those ≥40 years and 12.7% ≥ 60 years). There was a significant association between the presence of XFS and climatic keratopathy (χ² = 240.13; P < 0.00001). Notably, none of those with XFS had ocular hypertension or glaucoma. Conclusion: XFS was present in a significantly higher proportion of indigenous Australians compared with previously reported prevalence estimates among non‐indigenous Australians. The association found between XFS and climatic keratopathy may represent a common causal link between the two conditions. The lack of association of XFS with ocular hypertension and glaucoma appears to be a unique feature of the indigenous Australian population, and this merits further investigation.     

Evaluation of the acoustic function in pseudoexfoliation syndrome and exfoliation glaucoma: audiometric and tympanometric findings

PURPOSE: Previous studies have reported increased audiometric thresholds in patients with pseudoexfoliation syndrome (XFS), compared with normative data. This study examines mean audiometric thresholds and tympanometric peak values in patients with XFS and in a control group. METHODS: This is a prospective, nonrandomized control case study. Patients with XFS in one or both eyes constituted the study group (SG). Patients without XFS in either eye constituted the control group (CG). Patients with a history of conditions affecting hearing function were excluded. The SG and the CG included 54 and 48 patients, respectively. Pure tone hearing thresholds levels were measured at 0.25, 1, 2, 3, and 8 kHz. Tympanometric peak values were also recorded. Differences in audiometric mean threshold values and tympanometric peak values between SG and CG, as well as between glaucomatous and nonglaucomatous eyes, were examined. RESULTS: Bone and air audiometric thresholds were significantly increased in SG for 3 kHz and 8 kHz but not for 0.25 kHz, 1 kHz, and 2 kHz. Tympanometric peak values were significantly lower in SG compared with CG. In SG, glaucomatous patients had significantly higher air-conduction thresholds for 3 kHz and 8 kHz. Differences in bone and air audiometric findings as well as tympanometric findings between glaucomatous and nonglaucomatous patients were statistically not significant in CG. CONCLUSIONS: The results agree with previous reports on sensorineural hearing loss in XFS. The reduced tympanometric peak values in SG imply impairment in the elastic properties of the middle ear in XFS. The findings provide additional evidence for the systemic nature of XFS.     

Gillies lecture: dissecting glaucoma: understanding the molecular risk factors

WE Gillies was a major contributor to research in glaucoma, notably pseuodexfoliation (XFS), as well as strabismus, particularly in relation to axial length (AL). The latter work involved breaking down the geometry of the eye to its basic components and using the measured AL to tailor the amount of strabismus surgery required. Similarly, the search for glaucoma genes requires us to break down glaucoma into its component measures and associated risk factors. Over the last 14 years, our data from the Glaucoma Inheritance Study in Tasmania have shown the following: that a family history is present in 60% of glaucoma cases; that 27% of members of large glaucoma families were unaware of their family history of glaucoma; and that familial glaucoma is more severe than sporadic glaucoma. Myocilin mutations account for 3% of cases of primary open angle glaucoma. Some genotype–phenotype correlations have been identified. Notably, with respect to earlier age of onset, higher maximum recorded intraocular pressure and need for surgery, the Gln368Stop mutation confers mild risk, Thr377Met and Gly252Arg mutations intermediate risk, and the Pro370Leu mutation severe risk. To identify the other genes associated with glaucoma, we have examined normal twins in the Twins Eye Study to determine the heritability of parameters that are abnormal in glaucoma – intraocular pressure and cup-to-disc ratio and confounding factors for glaucoma such as central corneal thickness, disc area, refraction and AL. We have identified high heritabilities for all of these as well as a gene locus associated with AL on chromosome 5. Recently, the LOXL1 gene was associated with XFS. Identification of further genes will improve our understanding of glaucoma and allow cascade genetic screening.     

Investigation of Association between Autophagy-Related Gene Polymorphisms and Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma in a Spanish Population

Purpose: Cellular stress conditions are important mechanisms implicated in the pathogenesis of pseudoexfoliation syndrome. One of the potential cellular responses to these stress conditions is induction of autophagy. The purpose of this study was to evaluate whether genetic variants in three critical genes of autophagy (ATG16L, ATG2B, ATG5) may be involved in the development of pseudoexfoliation syndrome (XFS) and pseudoexfoliation glaucoma (XFG) in a Spanish population. Methods: 108 patients (64 XFS, 44XFG) and 118 healthy controls were evaluated. The analysis of genetic polymorphisms was performed by standard TaqMan allelic discrimination technique. Results: No significant differences in either genotype distributions or allelic frequencies of the tested polymorphisms were found between patients with XFS/XFG and control subjects. Conclusions: Our results suggest that these three genes that are critical components of the autophagy pathway (ATG16L, ATG2B, ATG5) are not significant risk factors among Spanish patients with either XFS or XFG.