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Homocysteine, an indicator of methylation pathway alternation in Down syndrome and its regulation by folic acid therapy  [cached]
Hala M El-Gendy,Hala M Mokhtar
Journal of Research in Medical Sciences , 2007,
Abstract: BACKGROUND: Down syndrome (DS) is a complex genetic disease. Some clinical features of patients with this syndrome could be related to functional folate deficiency. The purpose of this study was to evaluate the total homocysteine (T-Hcy) metabolism in DS children and to determine whether the supplementation with folic acid therapy would shift the genetically induced metabolic imbalance or not. METHODS: Thirty-five infants with DS, with the mean age of 17.66 ± 12.24 months were included in this study. They were selected from those attending the Genetic Outpatients Clinic in Children hospital. RESULTS: Our results revealed that Down syndrome children had a significant decrease in serum plasma T-Hcy level after the treatment with folic acid [11.79 ± 0.92 vs. 14.41 ± 4.93 μmol/L]. A significant negative correlation was found between T-Hcy and folic acid serum levels [r = -0.112; P<0.05].CONCLUSIONS: We concluded that the regulation of methylation pathways in Down syndrome patients becomes important in the light of possible normalization of the metabolic imbalance and the detection of increased sensitivity to therapeutic interventions. KEY WORDS: Down syndrome, hyperhomocysteine, folic acid, vitamin B-12.
Homocysteine: An Indicator of Methylation Pathway Alternation in Down Syndrome Children and its Regulation by Folic Acid Therapy  [PDF]
Hala D. El-Gindi,Hala M. Hussien
Journal of Medical Sciences , 2007,
Abstract: The purpose of this research was to evaluate the total homocysteine (t-Hcy) metabolism in Down Syndrome (DS) children and to determine whether the supplementation with folic acid therapy would shift the genetically induced metabolic imbalance. Thirty-five infants with DS (17 male and 18 females), their mean age 17.66"12.24 months were included in this study. They were selected among those attending the Genetic out Patients Clinic, Children Hospital. Present results revealed that Down syndrome=s children had a significant increase of serum folic acid after treatment with folic acid therapy (18.91±3.59 vs 11.95±1.55 ng mLG1), while no significant change in vitamin B12 (323.17±38.42 vs 358.36±57.43 pg mLG1). There was a significant decrease in plasma t-Hcy level after treatment with folic acid therapy (11.79±0.92 vs 14.41±4.93 μ mol LG1). A significant negative correlation was found between t-Hcy and folic acid serum levels (r = -0.112; p< 0.05). The present study concluded that, the regulation of methylation pathways in Down syndrome becomes important in light of possible normalization of the metabolic imbalance and the detection of increased sensitivity to therapeutic interventions.
Neural Tube Defects, Folic Acid and Methylation  [PDF]
Apolline Imbard,Jean-Fran?ois Benoist,Henk J. Blom
International Journal of Environmental Research and Public Health , 2013, DOI: 10.3390/ijerph10094352
Abstract: Neural tube defects (NTDs) are common complex congenital malformations resulting from failure of the neural tube closure during embryogenesis. It is established that folic acid supplementation decreases the prevalence of NTDs, which has led to national public health policies regarding folic acid. To date, animal studies have not provided sufficient information to establish the metabolic and/or genomic mechanism(s) underlying human folic acid responsiveness in NTDs. However, several lines of evidence suggest that not only folates but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs. This raises the question whether supplementation with B12 vitamin, betaine or other methylation donors in addition to folic acid periconceptional supplementation will further reduce NTD risk. The objective of this article is to review the role of methylation metabolism in the onset of neural tube defects.
Methoxistasis: Integrating the Roles of Homocysteine and Folic Acid in Cardiovascular Pathobiology  [PDF]
Jacob Joseph,Joseph Loscalzo
Nutrients , 2013, DOI: 10.3390/nu5083235
Abstract: Over the last four decades, abnormalities in the methionine-homocysteine cycle and associated folate metabolism have garnered great interest due to the reported link between hyperhomocysteinemia and human pathology, especially atherothrombotic cardiovascular disease. However, clinical trials of B-vitamin supplementation including high doses of folic acid have not demonstrated any benefit in preventing or treating cardiovascular disease. In addition to the fact that these clinical trials may have been shorter in duration than appropriate for modulating chronic disease states, it is likely that reduction of the blood homocysteine level may be an oversimplified approach to a complex biologic perturbation. The methionine-homocysteine cycle and folate metabolism regulate redox and methylation reactions and are, in turn, regulated by redox and methylation status. Under normal conditions, a normal redox-methylation balance, or “methoxistasis”, exists, coordinated by the methionine-homocysteine cycle. An abnormal homocysteine level seen in pathologic states may reflect a disturbance of methoxistasis. We propose that future research should be targeted at estimating the deviation from methoxistasis and how best to restore it. This approach could lead to significant advances in preventing and treating cardiovascular diseases, including heart failure.
Birth Outcomes of Newborns after Folic Acid Supplementation in Pregnant Women with Early and Late Pre-Eclampsia: A Population-Based Study  [PDF]
Ferenc Bánhidy,Abdallah Dakhlaoui,István Dudás,Andrew E. Czeizel
Advances in Preventive Medicine , 2011, DOI: 10.4061/2011/127369
Abstract: Objective. To evaluate the rate of preterm birth and low birth weight in the newborns of pregnant women with early and late onset pre-eclampsia according to folic acid supplementation. Study design. Birth outcomes of newborns were evaluated in 1,017 (2.7%) pregnant women with medically recorded pre-eclampsia and 37,134 pregnant women without pre-eclampsia as reference in the Hungarian Case-Control Surveillance System of Congenital Abnormalities, 1980–1996, in addition these study groups were differentiated according to the supplementation of high dose of folic acid alone from early pregnancy. Results. Pregnant women with pre-eclampsia associated with a higher rate of preterm birth (10.2% versus 9.1%) and low birthweight (7.9% versus 5.6%). There was a lower risk of preterm birth (6.8%) of newborn infants born to pregnant women with early onset pre-eclampsia after folic acid supplementation from early pregnancy though the rate of low birthweight was not reduced significantly. There was no significant reduction in the rate of preterm birth and low birthweight in pregnant women with late onset pre-eclampsia after folic acid supplementation. Conclusion. The rate of preterm birth in pregnant women with early onset pre-eclampsia was reduced moderately by high doses of folic acid supplementation from early pregnancy. 1. Introduction Pre-eclampsia (PE) is frequent (2–8%) and severe complications of pregnancy, and this multisystem disorder of pregnancy is characterized by pregnancy-induced hypertension and new-onset proteinuria during the second half of pregnancy [1–3]. PE is a major contributor to maternal mortality if associates with eclampsia and HELLP syndrome [4, 5]. Furthermore, since delivery is the only cure of PE, there is a higher risk of preterm birth up to 15% [6] and intrauterine growth retardation [7] with an increase in infant mortality and morbidity. Two important hypotheses have been generated for the pathogenesis of PE during the last decades. The first hypothesis was based on the differentiation of early and late onset PE [3] or on the two-stage model of PE [8]. The second hypothesis was based on PE associated with placental insufficiency due to hyperhomocysteinemia-related vasculopathy because 3.2–7.7-fold higher risk of PE was found in pregnant women with elevated homocysteine levels [9–16]. Folic acid supplementation lowers plasma homocysteine in general [17] and in patients with PE [18], thus folic acid containing multivitamins was tested in pregnant women with gestational hypertension [19] and in pregnant women with PE [20, 21] with
Elevated Serum Levels of Homocysteine as an Early Prognostic Factor of Psychiatric Disorders in Children and Adolescents  [PDF]
Laura Kevere,Santa Purvina,Daiga Bauze,Marcis Zeibarts,Raisa Andrezina,Arnis Rizevs,Sergejs Jelisejevs,Linda Piekuse,Madara Kreile,Indulis Purvins
Schizophrenia Research and Treatment , 2012, DOI: 10.1155/2012/373261
Abstract: Background and Goal. The aim was to examine the serum levels of homocysteine (Hcy) and their associations with the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism in patients with schizophrenia and mood disorders as well as controls. Materials and Methods. There were 198 patients: 82 with schizophrenia spectrum disorders, 22 with mood disorders, and 94 controls. The level of Hcy was determined by an isocratic high-performance liquid chromatography system. MTHFR C677T polymorphism was analysed using the restriction fragment length polymorphism-polymerase chain reaction method. Results. The average level of Hcy was μmol/L for patients with schizophrenia, μmol/L for patients with affective disorders, versus μmol/L in a control. The highest level of Hcy has been observed in patients with episodic-recurrent course of schizophrenia ( μmol/L), paranoid schizophrenia continuous ( μmol/L), and in patients with affective disorders ( μmol/L). An association between the MTHFR gene C677T polymorphism and Hcy level was found by linear regression analysis ( , ). Conclusions. The data indicate a link between Hcy levels and schizophrenia and mood disorders. No associations between the level of Hcy in patients with schizophrenia and mood disorders and the MTHFR C677T polymorphism were found. 1. Introduction Hcy was first described by Butz and du Vigneud in 1932 [1]. They obtained the product by treating methionine with a concentrated acid. Three enzymes are directly involved in the Hcy metabolism: methionine synthase (MS), betaine homocysteine methyltransferase, and cystathionine β-synthase. Several other enzymes are indirectly involved. Vitamins B6 and B12 are cofactors to these enzymes, and folate is a substrate in the MS-mediated reaction [2]. Deficiencies in vitamins B6, B12, and folate can lead to high Hcy levels. Supplementation with pyridoxine, folic acid, B12, or folic acid, respectively, reduces the concentration of Hcy in the bloodstream. Methionine is the immediate precursor of S-adenosylmethionine, the methyl donor of numerous methylation reactions in the brain, including many that are directly involved in the synthesis and metabolism of monoamines such as dopamine, norepinephrine, and serotonin [3]. This suggests that an association between elevated Hcy and schizophrenia is biologically plausible. Another way of investigating the association between Hcy and mental disorders is via the MTHFR gene. MTHFR converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is needed for the remethylation of Hcy to methionine [4]. MTHFR
The Metabolic Burden of Methyl Donor Deficiency with Focus on the Betaine Homocysteine Methyltransferase Pathway  [PDF]
Rima Obeid
Nutrients , 2013, DOI: 10.3390/nu5093481
Abstract: Methyl groups are important for numerous cellular functions such as DNA methylation, phosphatidylcholine synthesis, and protein synthesis. The methyl group can directly be delivered by dietary methyl donors, including methionine, folate, betaine, and choline. The liver and the muscles appear to be the major organs for methyl group metabolism. Choline can be synthesized from phosphatidylcholine via the cytidine-diphosphate (CDP) pathway. Low dietary choline loweres methionine formation and causes a marked increase in S-adenosylmethionine utilization in the liver. The link between choline, betaine, and energy metabolism in humans indicates novel functions for these nutrients. This function appears to goes beyond the role of the nutrients in gene methylation and epigenetic control. Studies that simulated methyl-deficient diets reported disturbances in energy metabolism and protein synthesis in the liver, fatty liver, or muscle disorders. Changes in plasma concentrations of total homocysteine (tHcy) reflect one aspect of the metabolic consequences of methyl group deficiency or nutrient supplementations. Folic acid supplementation spares betaine as a methyl donor. Betaine is a significant determinant of plasma tHcy, particularly in case of folate deficiency, methionine load, or alcohol consumption. Betaine supplementation has a lowering effect on post-methionine load tHcy. Hypomethylation and tHcy elevation can be attenuated when choline or betaine is available.
Homocysteine, Vitamin B12 and Folic Acid in Children with Acute Glomerulonephritis  [PDF]
Duangkamol Viroonudomphol, Saowanee Kanjanachumpol, Sarinya Sirisate
World Journal of Engineering and Technology (WJET) , 2018, DOI: 10.4236/wjet.2018.63042
Abstract: Homocysteine (Hcy) is an intermediate product of methionine formed by its demethylation. Hcy can be metabolized via remethylation to methionine or transsulfuration to cysteine which is dependent on several enzymes and cofactors. It is deleterious to blood vessel including glomeruli. Kidney is a major organ that metabolizes Hcy. More than 80% of patients with chronic renal disease develop hyperhomocysteinemia (hHcy). Accessible data of plasma Hcy in nephritic syndrome (NS) patients are controversial with increased, decreased and unchanged values reported. In renal patients, plasma Hcy concentration can be reduced by administration of folic acid. Absolute or relative deficiencies of folate, vitamin B6, or vitamin B12 may also play a role. Therefore, plasma Hcy, folic acid, vitamin B6, and vitamin B12 in children with acute glomerulonephritis (AGN) were accessed in this study. Hcy, folic acid vitamin B12, B6 and renal function such as blood urea nitrogen (BUN), creatinine (Cr) were analyzed 12 pediatric patients with AGN and 15 age and sex matched healthy children served as controls. The results revealed that a?significant increase in plasma Hcy in children with acute AGN when compared with controls. For simple regression analysis, Hcy was positively correlated with BUN, Cr, ferritin and uric acid but negatively correlated with serum glutathione. This research indicated hHcy suggests enhanced risks for inflammation and endothelial injury,?which lead to kidney disease. Folic acid has also been shown to improve endothelial function, suggesting an alternative explanation for the effect of folic acid on endothelial function. Careful considerations of not only dietary measures are necessary but also folate and vitamin B supplementation for reducing hHcy in AGN need to be investigated.
Genomic DNA Methylation Changes in Response to Folic Acid Supplementation in a Population-Based Intervention Study among Women of Reproductive Age  [PDF]
Krista S. Crider, Eoin P. Quinlivan, Robert J. Berry, Ling Hao, Zhu Li, David Maneval, Thomas P. Yang, Sonja A. Rasmussen, Quanhe Yang, Jiang-Hui Zhu, Dale J. Hu, Lynn B. Bailey
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028144
Abstract: Folate is a source of one-carbons necessary for DNA methylation, a critical epigenetic modification necessary for genomic structure and function. The use of supplemental folic acid is widespread however; the potential influence on DNA methylation is unclear. We measured global DNA methylation using DNA extracted from samples from a population-based, double-blind randomized trial of folic acid supplementation (100, 400, 4000 μg per day) taken for 6 months; including a 3 month post-supplementation sample. We observed no changes in global DNA methylation in response to up to 4,000 μg/day for 6 months supplementation in DNA extracted from uncoagulated blood (approximates circulating blood). However, when DNA methylation was determined in coagulated samples from the same individuals at the same time, significant time, dose, and MTHFR genotype-dependent changes were observed. The baseline level of DNA methylation was the same for uncoagulated and coagulated samples; marked differences between sample types were observed only after intervention. In DNA from coagulated blood, DNA methylation decreased (?14%; P<0.001) after 1 month of supplementation and 3 months after supplement withdrawal, methylation decreased an additional 23% (P<0.001) with significant variation among individuals (max+17%; min-94%). Decreases in methylation of ≥25% (vs. <25%) after discontinuation of supplementation were strongly associated with genotype: MTHFR CC vs. TT (adjusted odds ratio [aOR] 12.9, 95%CI 6.4, 26.0). The unexpected difference in DNA methylation between DNA extracted from coagulated and uncoagulated samples in response to folic acid supplementation is an important finding for evaluating use of folic acid and investigating the potential effects of folic acid supplementation on coagulation.
Effect of Folic Acid Supplementation on Cardiovascular Outcomes: A Systematic Review and Meta-Analysis  [PDF]
Yu-Hao Zhou,Jian-Yuan Tang,Mei-Jing Wu,Jian Lu,Xin Wei,Ying-Yi Qin,Chao Wang,Jin-Fang Xu,Jia He
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0025142
Abstract: Folic acid is widely used to lower homocysteine concentrations and prevent adverse cardiovascular outcomes. However, the effect of folic acid on cardiovascular events is not clear at the present time. We carried out a comprehensive systematic review and meta-analysis to assess the effects of folic acid supplementation on cardiovascular outcomes.
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