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The methionine – homocysteine cycle contains re-methylation and transsulfuration components. The enzyme S-adenosyl homocysteine hydrolase (SAH) contributes to methylation of DNA and RNA. Other abbreviations: CBS = cystathionine–b–synthase; MTR = 5-methylterathydrofolate-homocyteine methyltransferase; MTHFR = methyltetrahydrofolate reductase; THF-tetrahydrofolate; MTHF = methyltetrathydrofolate.

The methionine – homocysteine cycle contains re-methylation and transsulfuration components. The enzyme S-adenosyl homocysteine hydrolase (SAH) contributes to methylation of DNA and RNA. Other abbreviations: CBS = cystathionine–b–synthase; MTR = 5-methylterathydrofolate-homocyteine methyltransferase; MTHFR = methyltetrahydrofolate reductase; THF-tetrahydrofolate; MTHF = methyltetrathydrofolate.

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Purpose: To summarize various topics and the cutting edge approaches to refine XFS pathogenesis that were discussed at the 21st annual Glaucoma Foundation Think Tank meeting in New York City, Sept. 19-20, 2014. Methods: The highlights of three categories of talks on cutting edge research in the field were summarized. Results: Exfoliation syndr...

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... Mendelian mutations in MTHFR and cystathionine b-synthase (CBS) can produce plasma Hcy levels >300 lM (Kim et al. 1997) because these patients are unable to remove Hcy from the methionine -Hcy cycle (Fig. 1). These patients have pheno- typic features (severe myopia, ectopia lentis, long limbs, arachnodactyly, hyperlaxity thromboembolism, devel- opmental delay and intellectual disabil- ity) that share similarity with Marfan syndrome but bear little resemblance to XFS. Homocystinuria or CBS defi- ciency is a rare autosomal recessive disorder ...
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... unrelated to local Hcy levels and may result from abnormal lysosomal enzyme activity (SchlotzerSchrehardt & Naumann 1994). If Hcy is not a causative marker in XFS then exactly what is its role in disease pathogenesis? Vitamin B 6 , vita- min B 12 and folic acid are important co- substrates for proper functioning of the methionine-Hcy cycle (Fig. 1). A syn- thesis of the literature suggests that serum folate levels are reduced in XFS patients while vitamin B 6 and vitamin B 12 are not ( Xu et al. 2012). Further- more, a large prospective dietary study in the U.S. indicated that health profes- sionals were consuming more than ade- quate amounts of B 6 and B 12 but 50% were ...
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... reduced dietary folate intake (but not dietary B 6 and B 12 ) in association with XFG ( Kang et al. 2014a). Thus, a chronically unbalanced methionine -Hcy cycle due to low dietary folate intake could be important in XFS. Chronic folate deficiency may prevent Hcy from cycling back to methionine, resulting in hypomethyla- tion of key DNA loci (Fig. 1). The consequence is that local epigenetic mechanisms could cause altered LOXL1 expression and protein function, which could result in abnormal cross-linking of key macromolecules in XFM. Immunohistochemistry has shown LOXL1 as a component of XFM in early disease stages ( Zenkel et al. 2011;Zenkel & Schlotzer-Schrehardt 2014). Another ...

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... Exfoliation glaucoma (XFG) develops in patients with exfoliation syndrome (XFS), which is characterized by abnormal production and accumulation of fibrillary materials in various ocular tissues 8,9 . Besides the characteristic exfoliation materials observed at the pupil margin and lens capsules, the ONH in eyes with XFG is known to have different connective tissue and ECM properties of the LC 10 , which may determine the features of NRR thinning and LC deformation. ...
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The lamina cribrosa (LC) becomes shallower as intraocular pressure (IOP) decreases after trabeculectomy. The LC in eyes with exfoliation syndrome has distinctive properties in the connective tissue and extracellular matrix, but how these affect the changes in LC depth in response to IOP reduction after trabeculectomy is unknown. We analyzed pre- and postoperative spectral-domain optical coherence tomography of exfoliation glaucoma (XFG) and primary open-angle glaucoma (POAG) patients who underwent trabeculectomy and investigated whether LC depth differed between XFG and POAG eyes after trabeculectomy. In total, 30 XFG eyes and 30 visual field mean deviation-matched POAG eyes were included. LC depth was determined at an average of 3.9 months after trabeculectomy. Postoperatively, the LC depth became shallower and the BMO-MRW became thicker in both XFG and POAG eyes. XFG eyes showed lesser amount of LC depth shallowing than POAG eyes. Greater preoperative LC depth, lower postoperative IOP, and absence of XFG were all associated with a greater degree of postoperative LC depth shallowing. These findings suggest that the LC of XFG eyes may inherently possess the distinctive properties of the connective tissue and extracellular matrix contained within it, which could affect the LC response to the reduction in IOP after trabeculectomy.
... Some studies, [37][38][39] although not all, 37,40 have observed that low cortisone or cortisol may indicate greater UV exposure, a strong XFS and XFG risk factor. 41 Indeed, inverse cortisone associations were stronger in the subgroup residing in 41°N latitude or lower, where cortisone levels may be stronger markers of UV exposure. Finally, cortisone/cortisol are glucocorticoids, and higher levels in controls versus cases may indicate that controls may have had more frequent hyperglycemia. ...
Article
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Purpose: The etiology of exfoliation glaucoma (XFG) is poorly understood. We aimed to identify a prediagnostic plasma metabolomic signature associated with XFG. Methods: We conducted a 1:1 matched case-control study nested within the Nurses' Health Study and Health Professionals Follow-up Study. We collected blood samples in 1989-1990 (Nurses' Health Study) and 1993-1995 (Health Professionals Follow-up Study). We identified 205 incident XFG cases through 2016 (average time to diagnosis from blood draw = 11.8 years) who self-reported glaucoma and were confirmed as XFG cases with medical records. We profiled plasma metabolites using liquid chromatography-mass spectrometry. We evaluated 379 known metabolites (transformed for normality using probit scores) using multiple conditional logistic models. Metabolite set enrichment analysis was used to identify metabolite classes associated with XFG. To adjust for multiple comparisons, we used number of effective tests (NEF) and the false discovery rate (FDR). Results: Mean age of cases (n = 205) at diagnosis was 71 years; 85% were women and more than 99% were Caucasian; controls (n = 205) reported eye examinations as of the matched cases' index date. Thirty-three metabolites were nominally significantly associated with XFG (P < 0.05), and 4 metabolite classes were FDR-significantly associated. We observed positive associations for lysophosphatidylcholines (FDR = 0.02) and phosphatidylethanolamine plasmalogens (FDR = 0.004) and inverse associations for triacylglycerols (FDR < 0.0001) and steroids (FDR = 0.03). In particular, the multivariable-adjusted odds ratio with each 1 standard deviation higher plasma cortisone levels was 0.49 (95% confidence interval, 0.32-0.74; NEF = 0.05). Conclusions: In plasma from a decade before diagnosis, lysophosphatidylcholines and phosphatidylethanolamine plasmalogens were positively associated and triacylglycerols and steroids (e.g., cortisone) were inversely associated with XFG risk.
... In the pathogenesis of XFG, IOP elevation is thought to occur due to exfoliation material and pigment accumulation within the outflow system. 20 Cumulative evidence implies that this disorder is associated with low-grade chronic inflammation as well as cellular stress conditions such as oxidative stress and ischemia/hypoxia that play a role in the cascade from XFS to XFG. 21,22 Nevertheless, our results show that serum SIRT1 levels, known to have neuroprotective and anti-inflammatory effects, are not significantly different between XFG and control patients. Future studies are needed with larger populations further to clarify the role of serum SIRT1 in XFG. ...
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Purpose To compare plasma levels of sirtuin 1 (SIRT1) and adiponectin (APN) in patients with primary open-angle glaucoma (POAG), exfoliative glaucoma (XFG), and healthy control subjects. Methods This prospective case-control study collected plasma samples from 118 participants. All subjects underwent a comprehensive ophthalmologic examination before the acquisition of a plasma sample. Plasma samples were obtained from 40 POAG, 38 XFG, and 40 healthy control subjects without any evidence of systemic or ocular disease. Serum SIRT1 and APN levels were estimated by an enzyme-linked immunosorbent assay, ELISA (Elabscience, Houston, USA) method. Statistical analysis of results relied on Kolmogorov-Smirnov, Kruskal-Wallis, Chi-square, analysis of variance (ANOVA) tests, and linear regression analysis, where appropriate. Results A significant decrease in SIRT1 levels was observed in POAG patients compared to healthy controls (p = 0.004, Dunn's test). In contrast, no difference was detected between XFG and POAG patients or healthy controls (p = 0.32 and p = 0.34, respectively, Dunn's test). There was no significant difference in plasma APN levels between the three groups under investigation (p = 0.59, ANOVA). Conclusion Alterations in serum level of SIRT1 may suggest a possible role in POAG via potential effects in neuroprotection and oxidative stress.
... We believe that the difference in prevalence is related to climate conditions or dietary habits, with less folate intake in Upper Egypt [15]. Lower risk of XFS is associated with higher total folate intake, supporting a possible causal effect secondary to increased plasma homocysteine levels [16] which is a wellstudied potential biomarker for XFS [17]. We compared our XFS prevalence to those of neighboring countries sharing similar geographical features, ethnic backgrounds, climatic conditions, diet, and lifestyle, namely the Mediterranean and Middle Eastern countries. ...
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IntroductionExfoliation syndrome is an age-related disease leading to ocular and systemic complications. We aimed to evaluate the prevalence of exfoliation syndrome (XFS) in Egypt and its association with cataract as one of its comorbidities.Methods In a retrospective, hospital-based study, 155,032 Egyptians aged over 40 years from all 27 Egyptian governorates were evaluated for the prevalence of XFS and cataract in the period between January 2015 and June 2020.ResultsA total of 2448 (1.6%) of the studied subjects had XFS. Their mean age was 71.2 ± 9.62 years which was significantly higher than those of subjects with no XFS. Men comprised 1348 (55.1%) of those diagnosed with XFS and this association was statistically significant (OR 1.57, 95% CI 1.45–1.70). Considering the ratio between subjects in our cohort from each region and its real population, the overall corrected prevalence in Egypt was 4.49% (Territorial regions 6.89%, Upper Egypt 5.51%, Lower Egypt 4.38%, and Greater Cairo 3.29%). Among all subjects with XFS, cataract was found in 2150 subjects (87.8%) and XFS represented 6.4% of all subjects diagnosed with cataract in our cohort (n = 33,610). Among subjects with no cataract (n = 121,422), 298 subjects had XFS (OR 0.04, 95% CI 0.03–0.04).Conclusion Egypt has a moderate XFS prevalence compared to other countries. There is a strong association between XFS and cataract, and XFS was more common in elderly males. The results can be explained by differences in diet, ethnicity, climate, and maybe other factors.
... In the eye, the pupillary margin, the anterior part of the iris, the trabecular meshwork, and the anterior capsule of the lens are the most common sites where exfoliation material is displayed. Exfoliations at the trabecular meshwork may occlude the pores diminishing the outflow of aqueous humor, thus increasing the IOP [4][5][6][7]. Exfoliation material can be found in many different organs. Systemic associations include ischemic attacks, hypertension, angina, myocardial infarction, cerebrovascular and cardiovascular disease, aortic aneurysm, Alzheimer's disease, and hearing loss [6]. ...
Article
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Introduction: Glaucoma is an optic neuropathy that leads to visual field defects. Genetic mechanisms seem to be involved in glaucoma development. Lysyl Oxidase Like 1 (LOXL1) has been described in previous studies as a predictor factor for exfoliation glaucoma. The present article studied the association between three single nucleotide polymorphisms (SNPs) in the LOXL1 gene and the presence of exfoliation glaucoma in Southwestern Sweden. Methods: Case-control study for genetic association. In total, 136 patients and 1011 controls were included in the study. Patients with exfoliation glaucoma were recruited at the Eye Department of Sahlgrenska University Hospital and Skaraborgs Hospital, Sweden. Controls were recruited from the Gothenburg H70 Birth Cohort Study. Three different SNPs were genotyped: LOXL1_rs3825942, LOXL1_rs2165241 and LOXL1_rs1048661. Results: The distribution of allele frequencies was significantly different between controls and glaucoma patients; for rs3825942 (p = 2 × 10-12), for rs2165241 (p = 3 × 10-16) and for rs1048661 (p = 2 × 10-6). Logistic regression analyses using an additive genetic model, adjusted for sex and age, also showed associations between the studied SNPs and glaucoma (p = 9 × 10-6; p = 2 × 10-14; p = 1 × 10-4). Conclusion: A strong association was found between allele frequencies of three different SNPs (LOXL1_rs3825942, LOXL1_rs2165241, and LOXL1_rs1048661) and the presence of exfoliation glaucoma in a Southwestern Swedish population.
... The link between adrenal insufficiency and XFG is unclear; however, some speculative reasons for why cortisone may be inversely associated is that some studies [31][32][33] though not all, 31,34 have observed that low cortisone/cortisol may be a marker of greater UV exposure, which has been strongly implicated in the pathogenesis of XFS/XFG. 35 Indeed, inverse associations with cortisone appeared to be stronger in the subgroup residing in ≤41° N latitude, where cortisone levels may be a stronger marker of greater UV exposure. Finally, cortisone/cortisol are glucocorticoids, and higher levels in controls versus cases may indicate that controls may have had more frequent hyperglycemia, and several studies [36][37][38][39][40][41][42][43] have reported inverse associations between diabetes and XFG. ...
Preprint
Objective: To identify pre-diagnostic plasma metabolomic biomarkers associated with risk of exfoliation glaucoma (XFG). Methods: We conducted a metabolomic study using a 1:1 matched nested case-control study design within the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Participants provided blood samples in 1989-'90 (NHS) and 1993-'95 (HPFS); we identified 205 participants who newly developed XFG during follow-up to 2018 (average time to diagnosis from blood draw=11.8 years); XFG was confirmed with medical record review. We profiled plasma metabolites using liquid chromatography-mass spectrometry and identified 379 known metabolites that passed quality control checks. Metabolites were transformed using probit scores for normality. We used multivariable-adjusted logistic regression adjusting for matching factors (such as age, residential latitude, season and time of blood draw), glaucoma family history and other covariates. Metabolite Set Enrichment Analysis was used to identify metabolite classes associated with risk of XFG. Number of effective tests (NEF) and False Discovery Rate (FDR) were used to adjust for multiple comparisons. Results: Mean age of cases (n=205) at diagnosis was 71 years; 84% were women and >99% were Caucasian; matched controls (n=205) all reported eye exams as of the matched cases' index date. A total of 33 metabolites were nominally significantly associated with XFG risk (p<0.05) and 4 metabolite classes were significantly associated (FDR<0.05). Overall, adverse associations were observed for the classes of lysophosphatidylcholines (FDR=0.02) and phosphatidylethanolamine plasmalogens (FDR=0.004). Inverse associations were observed for triglycerides (FDR<0.001) and steroid and steroid derivatives (FDR=0.03); in particular, the multivariable-adjusted odds ratio for XFG risk associated with each 1 standard deviation increase in plasma cortisone levels was 0.49 (95% CI=0.32-0.74; NEF=0.05). Results did not differ materially by time between blood draw and diagnosis, latitude of residence (< or ≥41°N latitude), age (< or ≥60 years), sex or glaucoma family history. Conclusions: Four broad classes of metabolites (including steroids such as cortisone and 3 lipid classes) in pre-diagnostic plasma collected almost a decade before diagnosis were associated with XFG risk; these results should be confirmed in future studies.
... This reaction requires vitamin B12 as an enzymatic cofactor and folate derivate (5-methyl tetrahydrofolate) as a methyl donor. Also, Hcy can be converted to cysteine in a pathway that requires vitamin B6 involvement as an enzymatic cofactor (124). Consequently, homocysteine is considered a sensitive marker of folate and vitamin B12 deficiency since deficiencies in those vitamins lead to an unfavoured increase in Hcy levels (123). ...
Article
Despite the well-established roles of B-vitamins and their deficiencies in health and disease, there is growing evidence indicating a key role of those nutrients in functions of the central nervous system and in psychopathology. Clinical data indicate the substantial role of B-vitamins in various psychiatric disorders, including major depression, bipolar disorder, schizophrenia, autism, and dementia, including Alzheimer’s and Parkinson’s diseases. As enzymatic cofactors, B-vitamins are involved in many physiological processes such as the metabolism of glucose, fatty acids and amino acids, metabolism of tryptophan in the kynurenine pathway, homocysteine metabolism, synthesis and metabolism of various neurotransmitters and neurohormones including serotonin, dopamine, adrenaline, acetylcholine, GABA, glutamate, D-serine, glycine, histamine and melatonin. Those vitamins are highly involved in brain energetic metabolism and respiration at the cellular level. They have a broad range of anti-inflammatory, immunomodulatory, antioxidant and neuroprotective properties. Furthermore, some of those vitamins are involved in the regulation of permeability of the intestinal and blood-brain barriers. Despite the fact that a substantial amount of the above vitamins is acquired from various dietary sources, deficiencies are not uncommon, and it is estimated that micronutrient deficiencies affect about two billion people worldwide. The majority of gut-resident microbes and the broad range of bacteria available in fermented food, express genetic machinery enabling the synthesis and metabolism of B-vitamins and, consequently, intestinal microbiota and fermented food rich in probiotic bacteria are essential sources of B-vitamins for humans. All in all, there is growing evidence that intestinal bacteria-derived vitamins play a significant role in physiology and that dysregulation of the "microbiota-vitamins frontier" is related to various disorders. In this review, we will discuss the role of vitamins in mental health and explore the perspectives and potential of how gut microbiota-derived vitamins could contribute to mental health and psychiatric treatment.
... Exfoliation material has been isolated in different parts of the eye. The pupil, the anterior part of the iris, trabecular meshwork, anterior capsule of the lens, and even in other ocular and extraocular tissues [9][10][11][12] showed the presence of exfoliation material. The deposits at the trabecular meshwork occlude the pores at the trabecular meshwork diminishing the outflow, thus increasing the IOP. ...
Article
Full-text available
Background: The present study aimed to compare visual field progression in new-diagnosed exfoliation versus open-angle glaucoma patients. Methods: Retrospective study. The study included patients with new-diagnosed primary open-angle and exfoliation glaucoma. All patients were followed for 3 years with reliable visual fields. At least five reliable fields were needed for inclusion. Exfoliation and open-angle glaucoma were defined based on the European Glaucoma Society guidelines. Visual field evaluation was performed using the software threshold 24-2 of the Humphrey Field Analysis. Outcomes: Visual field progression. For visual field progression, three different strategies were used: mean deviation (MD), visual field index (VFI), and the guided progression analysis (GPA). Results: The study included 128 subjects, of the 54 in the open-angle and 74 in the exfoliation glaucoma group. The MD difference values were higher in the exfoliation (- 3.17 dB) than in the primary open-angle (- 1.25 dB) glaucoma group in the three-year follow-up period. The difference between groups was significant (t-test, p = < 0.001). The difference in VFI was calculated for the 3 years follow-up period. The difference was higher in the exfoliation (- 7.65%) than in the primary open (- 1.90%) glaucoma group (t-test, p = < 0.001). The GPA showed progression in 58% of cases in exfoliation, and 13% in primary open glaucoma group (Chi-square, p = < 0.001). Conclusion: The present study found a more frequent and faster visual field progression in exfoliation than in primary open-angle glaucoma patients. New-diagnosed exfoliation glaucoma patients must be controlled and treated more strictly than primary open-angle glaucoma patients to avoid visual field deterioration.
... Exfoliation material has been isolated in different parts of the eye. The pupil, the anterior part of the iris, trabecular meshwork, anterior capsule of the lens, and even in other ocular and extraocular tissues (9)(10)(11)(12) showed the presence of exfoliation material. The deposits at the trabecular meshwork occlude the pores at the trabecular meshwork diminishing the out ow, thus increasing the IOP. ...
Preprint
Full-text available
Background The present study aimed to compare visual field progression in new-diagnosed exfoliation versus open-angle glaucoma patients. Methods Retrospective study. The study included patients with new-diagnosed primary open-angle and exfoliation glaucoma. All patients were followed for three years with reliable visual fields. At least five reliable fields were needed for inclusion. Exfoliation and open-angle glaucoma were defined based on the European Glaucoma Society guidelines. Visual field evaluation was performed using the software threshold 24 − 2 of the Humphrey Field Analysis. Outcomes: Visual field progression. For visual field progression, three different strategies were used: mean deviation (MD), visual field index (VFI), and the guided progression analysis (GPA). Results The study included 128 subjects, of the 54 in the open-angle and 74 in the exfoliation glaucoma group. The MD difference values were higher in the exfoliation (-3.17 dB) than in the primary open-angle (-1.25 dB) glaucoma group in the three-year follow-up period. The difference between groups was significant (t-test, p = < 0.001). The difference in VFI was calculated for the three years follow-up period. The difference was higher in the exfoliation (-7.65%) than in the primary open (-1.90%) glaucoma group (t-test, p = < 0.001). The GPA showed progression in 58% of cases in exfoliation, and 13% in primary open glaucoma group (Chi-square, p = < 0.001). Conclusion The present study found a more frequent and faster visual field progression in exfoliation than in primary open-angle glaucoma patients. New-diagnosed exfoliation glaucoma patients must be controlled and treated more strictly than primary open-angle glaucoma patients to avoid visual field deterioration.
... Exfoliation material has been isolated in different parts of the eye. The pupil, the anterior part of the iris, trabecular meshwork, anterior capsule of the lens, and even in other ocular and extraocular tissues (9)(10)(11)(12) showed the presence of exfoliation material. The deposits at the trabecular meshwork occlude the pores at the trabecular meshwork diminishing the out ow, thus increasing the IOP. ...
Preprint
Full-text available
Background: The present study aimed to compare visual field progression in new-diagnosed exfoliation versus open-angle glaucoma patients. Methods: Retrospective study. The study included patients with new-diagnosed primary open-angle and exfoliation glaucoma. All patients were followed for three years with reliable visual fields. At least five reliable fields were needed for inclusion. Exfoliation and open-angle glaucoma were defined based on the European Glaucoma Society guidelines. Visual field evaluation was performed using the software threshold 24-2 of the Humphrey Field Analysis. Outcomes: Visual field progression. For visual field progression, three different strategies were used: mean deviation (MD), visual field index (VFI), and the guided progression analysis (GPA). Results: The study included 128 subjects, of the 54 in the open-angle and 74 in the exfoliation glaucoma group. The MD difference values were higher in the exfoliation (-3.17 dB) than in the primary open-angle (-1.25 dB) glaucoma group in the three-year follow-up period. The difference between groups was significant (t-test, p=<0.001). The difference in VFI was calculated for the three years follow-up period. The difference was higher in the exfoliation (-7.65%) than in the primary open (-1.90%) glaucoma group (t-test, p=<0.001). The GPA showed progression in 58% of cases in exfoliation, and 13% in primary open glaucoma group (Chi-square, p=<0.001). Conclusion: The present study found a more frequent and faster visual field progression in exfoliation than in primary open-angle glaucoma patients. New-diagnosed exfoliation glaucoma patients must be controlled and treated more strictly than primary open-angle glaucoma patients to avoid visual field deterioration.