Remethylation Of Homocysteine Research Articles

The concept of folic acid supplementation and its role in prevention of neural tube defect among pregnant women: PRISMA.

Folic acid is the synthetic form of vitamin B9, found in supplements and fortified foods, while folate occurs naturally in foods. Folic acid and its derivatives are extremely important in the synthesis of nucleic acids (DNA and ribose nucleic acid [RNA]) and different proteins. It acts as a coenzyme for the transfer of 1 carbon in the biosynthesis of purine, pyrimidine, and amino acids. Folic acid is critically important in rapidly proliferating tissues, including fetus and trophoblastic tissue to prevent neural tube defect (NTD). The main objective of this review is to identify the role of folic acid to prevent NTD among pregnancy mothers. Electronic databases including Web of Science, Google Scholar, MEDLINE, Scopus, and Cochrane library used to systematically search without limitation of publication date and status. In pregnancy, the first trimester is a significant time for neural tube closure. Decreased blood folic acid levels inhibit DNA replication, repair, RNA synthesis, histone and DNA methylation, methionine production, and homocysteine remethylation reactions that cause NTDs in pregnancy. Therefore, folic acid supplementation is critically important for childbearing mothers before conception and in the first trimester pregnancy. As a result, women are recommended to take 400 microgram FA/day from preconception until the end of the first trimester to prevent NTD-affected pregnancies. This allows the developing neural tissue to acquire critical mass and provides the preferred rostrocaudal orientation so that these divisions contribute to the elongation of the developing neural tube in embryos.

The effect of methionine and folic acid administered in ovo on the blood biochemical parameters of chickens (Gallus gallus domesticus)

Methionine is one of the most frequently supplemented amino acids in raising of poultry. However, an overdose of methionine can cause hyperhomocysteinemia. Folic acid, taking part in the process of homocysteine remethylation, is a factor affecting the reduction of the concentration of this amino acid. The study was carried out in 2 stages. The experiment of step I was to investigate the effect of methionine and/or folic acid administration in ovo in the early stage of embryogenesis (E4), and the experiment of the second stage - in the late stage of embryogenesis (E17) on the following biochemical parameters of chicken blood: glucose concentration in whole blood and concentration of homocysteine and uric acid in plasma of domestic chickens (Gallus gallus domesticus). Our results confirm that methionine supplementation may increase the concentration of uric acid and homocysteine. Moreover, we demonstrated that folic acid administered during embryogenesis decreased homocysteine concentration, also in groups simultaneously supplemented with methionine, especially in the initial stage of postnatal life of the bird.

Unusual presentation of acute psychosis in a Child

Background: Psychosis is often solely described as a psychiatric presentation; however, it is vital that organic causes are eliminated, especially in children. Case presentation: We report the case of a 14yr old girl who presented two months history of self-neglect, poor school performance and a week history of mutism. At initial presentation, her neurological examination was normal except for expressive aphasia, and occasional inappropriate laughing. First line investigations showed low vitamin B12 and folate and normal MRI. She was planned for follow up with psychiatrists. She presented about a week later with worsening symptoms. She had further investigations which revealed high homocysteine, in keeping with homocysteine remethylation disorder. She started betaine therapy after which she had a significant improvement in her symptoms. Conclusion: This case emphasizes the importance of thorough investigations of children with acute psychosis before making an assumption of a psychiatric cause, as reversible causes have better outcomes.

Cerebellar stroke in a young female associated with elevated homocysteine levels and heterozygous MTHFR <em style="mso-bidi-font-style: normal;">C677T</em> gene:  A case report.

Homocysteine is an amino acid, which is an intermediate in the metabolism of methionine and cysteine. Elevated homocysteine levels are recognized as a cause for both arterial and venous thrombotic phenomena. Methylenetetrahydrofolatereductase -encoded by MTHFR gene- is the rate-limiting enzyme of the remethylation of homocysteine to methionine. Homozygous MTHFR T677T gene mutation can independently cause raised homocysteine levels and increase the risk of thrombosis whereas heterozygous MTHFR C677T gene mutation usually does with an acquired cause such as folate or vitamin B12 deficiency, and is with lesser risk for thrombosis. We report a case of a previously healthy 23-year-old female, who was excluded from other inherited and acquired thrombophilic conditions, but was found to be having heterozygous MTHFR C677T gene mutation and elevated level of homocysteine presented late with right cerebellar stroke. Therefore, when young patients present with thrombotic phenomena, homocysteine levels should be assessed in the absence of other common thrombophilic conditions.

The Implication of a Polymorphism in the Methylenetetrahydrofolate Reductase Gene in Homocysteine Metabolism and Related Civilisation Diseases.

Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in the one-carbon cycle. This enzyme is essential for the metabolism of methionine, folate, and RNA, as well as for the production of proteins, DNA, and RNA. MTHFR catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to its active form, 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Numerous variants of the MTHFR gene have been recognised, among which the C677T variant is the most extensively studied. The C677T polymorphism, which results in the conversion of valine to alanine at codon 222, is associated with reduced activity and an increased thermolability of the enzyme. Impaired MTHFR efficiency is associated with increased levels of homocysteine, which can contribute to increased production of reactive oxygen species and the development of oxidative stress. Homocysteine is acknowledged as an independent risk factor for cardiovascular disease, while chronic inflammation serves as the common underlying factor among these issues. Many studies have been conducted to determine whether there is an association between the C677T polymorphism and an increased risk of cardiovascular disease, hypertension, diabetes, and overweight/obesity. There is substantial evidence supporting this association, although several studies have concluded that the polymorphism cannot be reliably used for prediction. This review examines the latest research on MTHFR polymorphisms and their correlation with cardiovascular disease, obesity, and epigenetic regulation.

Methionine sources at different dietary levels alters the growth and expression of genes related to homocysteine remethylation in the jejunum of broilers.

Sulfur amino acids are essential for the proper development of broilers and are required throughout the bird's life to perform important physiological functions. Studies that seek to understand the actions of sulfur amino acids in the body of birds are essential. The present study evaluated the influence of sulfur amino acid supplementation using DL-Methionine (DL-Met) and DL-Methionine hydroxy analogue (DL-HMTBA), on the performance and expression of genes related to methionine metabolism, in the jejunum of broilers. Four hundred and fifty male broilers (Cobb-700 slow feathering) were distributed in a completely randomized design, in a factorial scheme (2x3), with two sources of methionine (DL-Met and DL-HMTBA) and three levels of methionine (deficiency, requirement and excess). The mRNA expression of the MAT1, MTR, BHMT, MTRR, CBG and GSS genes, and performance data such as feed intake, weight gain, and feed conversion were evaluated. DL-HMTBA increased the expression of BHMT (p = 0.0072) and MTRR (p = 0.0003) in the jejunum of the birds. Methionine deficiency increased the expression of BHMT (p = 0.0805) and MTRR (p = 0.0018). Higher expression of GSS was observed in birds that were supplemented with DL-HMTBA (p = 0.0672). Analyzing our results, it is preferable to supplement sulfur amino acids with DL-Met at the requirement level. Birds fed with DL-HMTBA showed worse weight gain (p = 0.0117) and higher feed conversion (p = 0.0170); methionine deficiency resulted in higher feed intake (p = 0.0214), lower weight gain (p<0.0001) and consequently higher feed conversion (p<0.0001). Based on the information found in this work, it is recommended to supplement sulfur amino acids with DL-Met at the level of compliance with the requirement.

Intermediate metabolites and molecular correlates of one‑carbon and nutrient metabolism differ in tissues from Holstein fetuses

Methionine and folate cycles along with transsulfuration comprise the one‑carbon metabolism (OCM) pathway. Amino acids and other nutrients feed into OCM, which is central to cellular function. mRNA abundance, proteins (Western blotting), and metabolites (GC-MC) associated with OCM were used to characterize these mechanisms in fetal tissues. Liver, whole intestine, and semitendinosus muscle were harvested from fetuses in 6 multiparous Holstein cows (37 kg milk/d, 100 d gestation). Data were analyzed using PROC MIXED (SAS 9.4). Protein abundance of BHMT was greatest (P < 0.01) in liver suggesting active remethylation of homocysteine to methionine. This idea was supported by the greater (P < 0.05) mRNA of CBS, BHMT, MTR, SHMT1, and MAT1A (encoding OCM enzymes) in liver. The antioxidant protein GPX3 had greatest (P < 0.05) abundance in liver, whereas the glutathione-transferase GSTM1 was 5-fold greater (P < 0.05) in intestine than liver and muscle. Greatest concentrations of glycine, serine, and taurine along with lower cysteine underscored the relevance of OCM in fetal liver. Phosphoethanolamine concentration was greatest (4-fold, P < 0.05) in intestine and along with the greatest (P < 0.05) mRNA of SLC44A1 (choline transporter), CHKA, and CEPT1 underscored the importance of the CDP-choline pathway. Greatest (P < 0.05) mRNA of PPARA, CPT1A, and HMGCS2 along with lower PCK1 in liver highlighted a potential reliance on fatty acid oxidation. In contrast, greater (P < 0.05) concentration of myo-inositol in muscle and intestine suggested both tissues rely on glucose as main source of energy. Future research should address how environmental inputs such as maternal nutrition alter these pathways in fetal tissues and their phenotypic outcomes.

Influence of Cobalt Source, Folic Acid, and Rumen-Protected Methionine on Performance, Metabolism, and Liver Tissue One-Carbon Metabolism Biomarkers in Peripartal Holstein Cows.

Vitamin B12 plays a role in the remethylation of homocysteine to Met, which then serves as a substrate for Met adenosyltransferase (MAT) to synthesize S-adenosylmethionine (SAM). We investigated effects of feeding two cobalt sources [Co-glucoheptonate (CoPro) or CoPectin, Zinpro Corp.], an experimental ruminally-available source of folic acid (FOA), and rumen-protected Met (RPM) on performance and hepatic one-carbon metabolism in peripartal Holstein cows. From -30 to 30 d around calving, 72 multiparous cows were randomly allocated to: CoPro, CoPro + FOA, CoPectin + FOA, or CoPectin + FOA + RPM. The Co treatments delivered 1 mg Co/kg of DM (CoPro or CoPectin), each FOA group received 50 mg/d FOA, and RPM was fed at 0.09% of DM intake (DMI). Milk yield and DMI were not affected. Compared with other groups, the percentage of milk protein was greater after the second week of lactation in CoPectin + FOA + RPM. Compared with CoPro or CoPro + FOA, feeding CoPectin + FOA or CoPectin + FOA + RPM led to a greater activity of MAT at 7 to 15 d postcalving. For betaine-homocysteine S-methyltransferase, CoPro together with CoPectin + FOA + RPM cows had greater activity at 7 and 15 d than CoPro + FOA. Overall, supplying FOA with CoPectin or CoPectin plus RPM may enhance S-adenosylmethionine synthesis via MAT in the liver after parturition. As such, these nutrients may impact methylation reactions and liver function.

DNA methylation as a biomarker for cardiometabolic disease risk

Abstract Funding Acknowledgements Type of funding sources: None. Cardiovascular disease (CVD) is the leading cause of death in most countries [1]. Risk factors known to predispose to the development of CVD include increasing age, male gender, diabetes mellitus, high blood cholesterol, tobacco smoking, high blood pressure (hypertension), obesity, physical inactivity, and family history [2]. Elevated plasma homocysteine is also an independent risk factor for CVD [2,3]. The mechanism by which elevated homocysteine contributes to CVD risk is not well understood, but it is well-established that dietary folate and vitamin B supplementation can reduce serum homocysteine levels by facilitating remethylation of homocysteine to methionine [4]. DNA methylation can modulate gene expression in response to exposure to various substances, such as nutrients, smoking, and environmental chemicals.Variation in healthy aging and lifespan is ascribed more to various non-genetic factors than to inherited genetic determinants, and a major goal in aging research is to reveal the epigenetic basis of aging. The remethylation cycle is essential for the systemic methyl donor supply, which is used for important biological processes, such as cytosine-5 methylation of genomic DNA, an epigenetic modification that plays an important role in maintaining genomic stability, chromatin structure, and in controlling transcriptional capacity [2,4]. Methodology/Principal Findings In this prospective study, we examined both gender patients, aged 40-50 years. Relationship between prevalence of Cardiometabolic risk factors (metabolic syndrome, oxidative stress and arterial hypertension) or its predisposing conditions (hypertrigliceridemia, dislipedimia, inusline resistance, D vitamin hipovitaminosis)) and DNA hydroximethylation was investigated. Hydroxymethylation measurement was done using a gold standard technique (liquid chromatography + mass spectrometry), the biological age equivalent was calculated by LC-MS in laboratories Reunis, to verify the potential value of DNA methylation as a CVD biomarker. Results Generally, 296 both gender patients were analyzed regarding metabolic syndrome and oxidative stress, age group 40-50 years (Me=47,1). MethylAge (DNA-hydroxymethylation) in analyzed group has average age 40,1 years old. DNA Hydroxymethylation is higher in those individuals, who has increased waist circumference, as well as, statistically significant correlation was observed between MethylAge waist circumference, metabolic syndrome and hypertriglyceridemia (p&amp;lt;0,05). Conclusion The evidence that the age-related changes in DNA methylation play a role in aging comes from studies of anti-aging interventions (e.g., caloric restriction, iron deficiency, dyslipidemia). Our data showed a link between premature biological ageing and waist circumference, hypertrigliceridimia. Hydroxymethylation of DNA is a good epigenetic marker for aging and risk assessment, especially in alliance with AGEs and oxidative stress research.

Abstract P6-11-03: Lipid-rich environment induces epigenetic reprogramming in non-transformed breast epithelial cells enhancing a mammary cell plasticity

Abstract Introduction. The identification of women specifically at risk for estrogen receptor negative breast cancer (ER- BC) and the targeted treatment of this disease are significantly unmet clinical needs. We analyzed the gene expression profiles of epithelial cells from the contralateral unaffected breasts (CUBs) of BC patients and identified a lipid metabolism gene signature enriched in the CUBs of women with ER- BC (PMID: 28263391). Subsequently, we observed that exposure of non-transformed breast epithelial cells to lipids results in significant changes in gene expression and histone posttranslational modifications; and increased flux through multiple metabolic reactions, including those of serine and methionine (PMID: 35508495). Interestingly, the upregulated genes are involved in neural development, axon guidance, neural crest pathways and stemness. Neural genes are highly expressed in Triple Negative Breast Cancers (TNBCs) especially in the C2 cluster. Given that mammary stem/progenitor cells have distinct metabolic properties compared to other mammary cell subsets, we hypothesized that upon lipid exposure, stem-like cells have a survival advantage, and that lipid induces epigenetic reprogramming into neural-like cells which may foster a malignant transformation. Methods. To interrogate potential mechanisms linking lipids and epigenetic reprogramming, we performed CUT&amp;RUN for H3K4me3 and H3K27me3 in non-transformed, estrogen and progesterone receptor negative MCF-10A cells cells exposed to vehicle or octanoic acid (OA) for 24 hrs. Peaks were called using MACS2 and differential peaks identified with DiffBind. Differentially expressed genes affected by OA (PMID: 28263391) were compared with target genes from the CUT&amp;RUN. To determine the contribution in OA exposed cells of serine and methionine metabolism to S-adenosyl methionine (SAM), 13C-glucose tracing was performed. The Aldefluour assay was used to identify stem-like (ALDH+) cells in lipid-exposed MCF-10A cells. To determine if lipid-exposed cells adopt a neural-like phenotype, MCF-10A cells were grown on Poly-D-Lysine/Laminin (PDL/LM) coated plates. Results. A total of 661 differential peaks were identified for H3K4me3 (FDR &amp;lt; 0.05) encompassing TNBC C2 markers (NRTN, CHRM3) and genes involved in neuron differentiation, axonogenesis (NGFR, NGF, FOXA2), neural crest migration (NTRK2, MMP2) and EMT (DLL4, MMP15). Approximately 73% of H3K4me3 OA-associated peaks encompass regulatory regions of genes that experienced a significant increase in gene expression with OA exposure (FDR &amp;lt; 0.01), including NGFR (log2 FC = 11.7), FOXA2 (log2 FC = 11.6), NGF (log2 FC = 8). Twelve H3K27me3 peaks were significantly enriched in vehicle (FDR &amp;lt; 0.05) and associated with increased gene expression in OA, among them were the stem cell markers LGR6 (log2 FC = 1.9) and PLAG1 (log2 FC = 2.8). 13C stable isotope tracing revealed that in presence of OA, glucose contributes to increased fractional abundance of the SAM M+1 isotopologue (adj p = 0.003) indicating that carbons derived from the serine synthesis pathway are used for re-methylation of homocysteine to methionine. Vehicle treated cells growing on PDL/LM plates assumed an epithelial phenotype while OA-treated cells adopted a neurite-like phenotype. Upon OA treatment the percentage of ALDH+ cells increased by a minimum of 10%. Conclusions. The increase of fractional abundance of SAM and the upregulation of neural genes regulated by H3K4me3 as well as the enrichment of ALDH+ cells and the development of a neural-like phenotype in a rich lipid environment, suggests that lipid exposure affects the production of SAM, which results in epigenetic fostered plasticity, leading to reprogramming/selecting cells with a multi-potential embryonic or stem-like state and/or differentiation to a neural/neural crest-like state. Citation Format: Mariana Bustamante Eduardo, Gannon Cottone, Seema Khan, Susan Clare. Lipid-rich environment induces epigenetic reprogramming in non-transformed breast epithelial cells enhancing a mammary cell plasticity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-03.

Association between folate and non-alcoholic fatty liver disease among US adults: a nationwide cross-sectional analysis.

Association between folate and non-alcoholic fatty liver disease among US adults: a nationwide cross-sectional analysis.

식이제한이 마우스 신장의 글루타치온 대사과정에 미치는 영향

Various benefits for the maintenance of metabolic homeostasis can be obtained through dietary restriction. Short-term fasting of mice may induce systemic metabolic remodeling, which may have a significant effect on the level of endogenous metabolites. This study was conducted to examine metabolic changes of sulfur-containing substances in the kidneys of fasted mice over 48 h. No change in the concentration of renal methionine was observed over 48 h; however, significant decreases in the concentrations of S-adenosylmethionine and S-adenosylhomocysteine were observed at both 24 and 48 h after fasting. A significant decrease in the concentration of renal cysteine was observed from 24 h, and this was maintained at 48 h. A significant decrease in the concentration of glutathione (GSH) was observed in the kidney at 48 h, whereas increased concentrations of taurine were observed 48 h after fasting. Although significantly increased expression levels of BHMT were observed, markedly decreased expression levels of CβS were observed at 48 h after fasting, indicating activated generation of methionine, but downregulation of cysteine synthesis. The expression level of γ-GCL was not altered by fasting for 48 h; however, a significant increase of cysteine sulfinate decarboxylase mediating the taurine synthesis was observed. Significantly decreased protein expression levels of solute carrier family 7 member 11, which imports extracellular cystine, were observed at 48 h. These results suggest that the renal methionine concentration was maintained during short-term fasting through an increase in the re-methylation of homocysteine. Moreover, a reduction in the concentration of cysteine was the result of an increase in the synthesis of taurine and a decrease in the uptake of extracellular cystine, which may result in a decreased concentration of renal GSH.

Efficacy and pharmacokinetics of betaine in CBS and cblC deficiencies: a cross-over randomized controlled trial

BackgroundBetaine is an “alternate” methyl donor for homocysteine remethylation catalyzed by betaine homocysteine methyltransferase (BHMT), an enzyme mainly expressed in the liver and kidney. Betaine has been used for more than 30 years in pyridoxine non-responsive cystathionine beta-synthase (pnrCBS) and cobalamin C (cblC) deficiencies to lower the hyperhomocysteinemia, although little is known about the optimal therapeutic dosage and its pharmacokinetic in these patients.AimsWe compared 2 betaine doses (100 mg/kg/day vs. 250 mg/kg/day) in children affected by pnrCBS or cblC deficiencies. We also measured the pharmacokinetics parameters after a single dose of betaine (100 or 250 mg/kg) in these patients.MethodsWe conducted a prospective, randomized, crossover clinical trial with blinded evaluation. The primary outcome was the equivalence of total plasma homocysteine (tHcy) concentrations upon one-month oral treatment with betaine at 100 versus 250 mg/kg/day.ResultsEleven patients completed the study (5 pnrCBS and 6 cblC). tHcy concentrations were equivalent after a one-month treatment period for the two betaine dosages. Multivariate analysis showed a significant effect of betaine dose on methionine (Met) (p = 0.01) and S-adenosylmethionine (SAM) concentrations (p = 0.006).ConclusionsOur analysis shows that there is no overt benefit to increasing betaine dosage higher than 100 mg/kg/day to lower tHcy concentrations in pnrCBS and cblC deficiencies. However, increasing betaine up to 250 mg/kg/d could benefit cblC patients through the increase of methionine and SAM concentrations, as low Met and SAM concentrations are involved in the pathophysiology of this disease. In contrast, in pnrCBS deficiency, betaine doses higher than 100 mg/kg/day could be harmful to these patients with pre-existing hypermethioninemia.Trial registration: Clinical Trials, NCT02404337. Registered 23 May 2015—prospectively registered, https://clinicaltrials.gov.

Effect of guanidinoacetic acid supplementation on nitrogen retention and methionine methyl group flux in growing steers fed corn-based diets.

Six ruminally cannulated Holstein steers (256 ± 14 kg) were used in a 6 × 6 Latin square design to assess effects of guanidinoacetic acid (GAA) supplementation on N retention and methionine (Met) methyl group flux in growing cattle fed corn-based diets. Factorial treatments were two levels of Met (0 or 5 g/d) and three levels of GAA (0, 7.5, or 15 g/d) delivered by continuous abomasal infusion. Periods were 10 d in length and included 6 d of treatment adaptation, 3 d for total fecal and urine collections, and 1 d for blood sampling and flux measurements. Urinary N linearly increased (P < 0.01) with GAA supplementation and decreased (P < 0.05) with Met supplementation. Fecal N excretion was unaffected (P ≥ 0.42) by treatment. Retained N was not affected by GAA supplementation, but it was increased (P < 0.01) by Met supplementation. Use of methionine for transmethylation reactions, as well remethylation of homocysteine, was not affected by GAA supplementation when Met was not supplemented, but tended to be linearly increased by GAA supplementation when Met was supplemented (GAA-linear × Met interaction; P = 0.07), with the increases matching the amount of GAA provided. This response suggests that methylation reactions for compounds other than GAA were reduced by GAA supplementation when Met supply was deficient. Plasma concentrations and urinary excretion of creatine increased linearly (P = 0.03 and P = 0.06, respectively) when GAA was supplemented. There was a linear increase (P < 0.01) in urinary GAA excretion with GAA supplementation. Neither plasma concentration nor urinary excretion of creatinine was affected (P ≥ 0.17) by treatment. No treatment differences (P ≥ 0.13) were observed for plasma haptoglobin concentrations. Plasma urea-N linearly increased (P < 0.05) with GAA supplementation. Concentrations of Met and taurine increased (P < 0.05) when Met was supplemented. Plasma arginine was greatest at the intermediate level of supplemental GAA (quadratic, P < 0.05). The increase in N retention when Met was supplemented demonstrates Met was limiting in the corn-based diet. Supplementation of GAA alone or with Met as a methyl donor did not increase N retention in growing steers, perhaps because creatine production was favored over protein deposition as a use for Met.

Role of choline in ruminant nutrition: a detailed review

Recent studies designate feed additives, such as rumen-protected choline (RPC), were seen decreasing the health disorders and upsurges the milk yield. Choline is an endogenous agent and the insufficiency of choline is very problematic. The deficiency has been documented in ruminants for a while. The scale of choline production is affected by administered dose, lactation stage, and basal diet composition. Endogenous synthesis through a pathway (PEMT) signifies a precarious source of choline. High occurrence of fatty liver disease happens in the dairy cows during lactation especially in the periparturient period and to lessen such incident high supply of choline is necessary. This supply is known to decrease the chances of hepatic fatty infiltration and upsurge the countenance of genes tangled in the transport of VLDL (very low-density lipoprotein). RPC typically provided as choline chloride is covered inside a shield of the fatty acid matrix. Therefore, to continue choline susceptibility on important mechanisms, like sparing of a methyl group (–CH3), supporting of animal metabolism, and remethylation of homocysteine via metabolite of betaine; choline must be provided in the rumen-protected form in the ration of dairy cows. Precisely concerning lactation, it is important to note that rumen-protected choline positively affects the performance of animals during the lactation period especially when supplementation started before calving and continues throughout the early lactation. But the difference of commercial products of rumen-protected choline in their rumen degradability and choline content is one of the big problems yet to be resolved.

Homocysteine Metabolism in Pregnancy and Developmental Impacts.

Homocysteine is a metabolite generated by methionine cycle metabolism, comprising the demethylated derivative of methionine. Homocysteine can be metabolised by the transsulphuration pathway to cystathionine, which requires vitamin B6, or can undergo remethylation to methionine. Homocysteine remethylation to methionine is catalysed by methionine synthase activity which requires vitamin B12, regenerating methionine to allow synthesis of the universal methyl donor S-adenosylmethionine required for methylation and gene transcription regulation. The methyl-group donated for homocysteine remethylation comes from 5-methyltetrahydrofolate generated by the folate cycle, which allows tetrahydrofolate to be returned to the active folate pool for nucleotide biosynthesis. Therefore the integrated actions of the methionine and folate cycles, required to metabolise homocysteine, also perpetuate methylation and nucleotide synthesis, vitally important to support embryonic growth, proliferation and development. Dysregulated activities of these two interdependent metabolic cycles, arising from maternal suboptimal intake of nutrient co-factors such as folate and vitamin B12 or gene polymorphisms resulting in reduced enzymatic activity, leads to inefficient homocysteine metabolic conversion causing elevated concentrations, known as hyperhomocysteinemia. This condition is associated with multiple adverse pregnancy outcomes including neural tube defects (NTDs). Raised homocysteine is damaging to cellular function, binding to proteins thereby impairing their function, with perturbed homocysteine metabolism impacting negatively on embryonic development. This review discusses the “cross-talk” of maternal-fetal homocysteine interrelationships, describes the placental transport of homocysteine, homocysteine impacts on pregnancy outcomes, homocysteine and methylation effects linking to NTD risk and proposes a putative pathway for embryonic provision of folate and vitamin B12, homocysteine-modulating nutrients that ameliorate NTD risk.

Association of Plasma Folate, Vitamin B12, and Betaine With Total Homocysteine in Pregnancy, and Effect Modification Due to Folic Acid Versus Natural Folate Supplementation

ObjectivesElevated circulating total homocysteine (tHcy) is associated with numerous pregnancy complications. Determinants of circulating tHcy include folate, vitamin B12, and betaine status, which catalyze the remethylation of homocysteine to methionine. In countries with folic acid food fortification, vitamin B12 and betaine are reported as stronger predictors of tHcy than folate. We evaluated the association between plasma folate, vitamin B12, and betaine with plasma tHcy in pregnancy, and any effect modification due to supplementation with folic acid versus 5-methyltetrahydrofolate (natural folate; 5-MTHF).MethodsPregnant women (n = 60) in Vancouver, BC, were randomized to 0.6 mg folic acid or 5-MTHF for 16 weeks, starting at 8–21 weeks gestation. Dietary folate intake was recorded at baseline. A 3-hour fasting blood sample was collected at baseline and endline for quantification of plasma folate (LC-MSMS), vitamin B12 (immunoanalyzer), betaine and tHcy (HPLC-MSMS). Linear regression was used to assess the association of endline plasma folate, vitamin B12, and betaine with endline tHcy, with folate group as an interaction term, adjusting for baseline tHcy, weeks gestation, and dietary folate intake. As the trial is not yet unblinded, groups are presented as “A” and “B”.ResultsThe median [IQR] concentrations of plasma analytes at endline in groups “A” and “B” were: folate 58 [54, 65] and 66 [61, 82] nmol/L; vitamin B12 204 [159,239] and 206 [166,300] pmol/L; betaine 15 [13, 16] and 14 [12, 17] µmol/L; tHcy 4.9 [4.5, 5.6] and 5.2 [4.7, 5.8] µmol/L, respectively. Folate group did not significantly modify the association of tHcy with folate (p = 0.39), vitamin B12 (p = 0.42), or betaine (p = 0.56). Overall, there was no association (β, 95% CI) of endline plasma folate, vitamin B12, or betaine with the outcome tHcy (µmol/L): folate −0.002 (−0.01 to 0.009); tB12 −0.0005 (−0.002 to 0.0005); betaine 0.02 (−0.04 to 0.07). Baseline tHcy was the most significant predictor of endline tHcy in each model (β = 0.8, 95% CI 0.6 to 1.0).ConclusionsFolate, vitamin B12, and betaine concentrations were not associated with tHcy, nor was the effect modified by supplementation with folic acid versus 5-MTHF. In this group of n = 60 healthy pregnant women, baseline tHcy was the most important predictor of tHcy in later pregnancy.Funding SourcesHealthy Starts Catalyst Grant (BCCHR).

Genetic origin of patients having spastic paraplegia with or without other neurologic manifestations

BackgroundHereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases characterized by lower-limb spastic paraplegia with highly genetic and clinical heterogeneity. However, the clinical sign of spastic paraplegia can also be seen in a variety of hereditary neurologic diseases with bilateral corticospinal tract impairment. The purpose of this study is to identify the disease spectrum of spastic paraplegia, and to broaden the coverage of genetic testing and recognize clinical, laboratorial, electrophysiological and radiological characteristics to increase the positive rate of diagnosis.MethodsTwenty-seven cases were screened out to have definite or suspected pathogenic variants from clinically suspected HSP pedigrees through HSP-associated sequencing and/or expanded genetic testing. One case was performed for enzyme detection of leukodystrophy without next-generation sequencing. In addition, detailed clinical, laboratorial, electrophysiological and radiological characteristics of the 28 patients were presented.ResultsA total of five types of hereditary neurological disorders were identified in 28 patients, including HSP (15/28), leukodystrophy (5/28), hereditary ataxia (2/28), methylmalonic acidemia/methylenetetrahydrofolate reductase deficiency (5/28), and Charcot-Marie-tooth atrophy (1/28). Patients in the HSP group had chronic courses, most of whom were lower limbs spasticity, mainly with axonal neuropathy, and thinning corpus callosum, white matter lesions and cerebellar atrophy in brain MRI. In the non-HSP groups, upper and lower limbs both involvement was more common. Patients with homocysteine remethylation disorders or Krabbe’s disease or autosomal recessive spastic ataxia of Charlevoix-Saguenay had diagnostic results in laboratory or imaging examination. A total of 12 new variants were obtained.ConclusionsHSP had widespread clinical and genetic heterogeneity, and leukodystrophy, hereditary ataxia, Charcot-Marie-Tooth atrophy and homocysteine remethylation disorders accounted for a significant proportion of the proposed HSP. These diseases had different characteristics in clinical, laboratorial, electrophysiological, and radiological aspects, which could help differential diagnosis. Genetic analysis could ultimately provide a clear diagnosis, and broadening the scope of genetic testing could improve the positive rate of diagnosis.

Influence of early identification and therapy on long-term outcomes in early-onset MTHFR deficiency.

MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early-onset patients mostly exhibit a life-threatening acute neurologic deterioration. Furthermore, data on early-onset patients' long-term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early-onset MTHFR-deficient patients (i.e., ≤3months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR-deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early-onset MTHFR deficiency were described at time of diagnosis and at the last follow-up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non-early-onset MTHFR deficiency. The majority of early-onset MTHFR-deficient patients (n=32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow-up visit (median follow-up time of 8.1 years), 76% of treated early-onset patients (n=29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre-symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002-0.232]; p= 0.003). This study provides evidence for benefits of pre-symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre-symptomatic treatment that may improve outcome.

The Effects MTHFR Gene Mutations on Vitamin B12 Concentration in the Blood; Bioinformatics Approach – A Review

Introduction: The protein encoded by MTHFR gene catalyzes the conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease; neural tube defects, colon cancer and acute leukemia. Also, mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.&#x0D; Methods: NCBI bioinformatics database application was used to search for MTHFR gene. Protein sequences were converted into DNA and mRNA. Protein sequences were analysed into DNA and mRNA. It includes information about the accession number, the number of amino acids in the protein product, the number of exons and the length of nucleotide. Also, nucleotide sequences and mRNA were included in FASTA format. Additionally, basic local alignment search tool (BLAST) was used to compare the sequences of this gene in humans with other organisms like mouse.&#x0D; Results: Human MTHFR gene can be studied through [Pan Troglodytes (chimpanzee)]. Hyperhomocysteinemia leads to several health problems including cardiovascular disease, deep vein thrombosis (DVT), pulmonary embolism (PE) and pregnancy complications.&#x0D; Conclusion: There is a relationship between MTHFR gene and vitamin B12 levels. Mutation in MTHFR gene has negatively impact vitamin B12 levels and methylation pathway, which affects the conversion process of homocysteine to methionine. Therefore, several health complications are caused by the observed increases in the levels of homocysteine.