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ObjectiveNeural tube defects (NTDs) are a preventable folate deficiency disorder; increasing folic acid intake through food fortification increases serum and red blood cell folate and reduces the risk of an NTD pregnancy. There is controversy over the blood folate level needed to achieve the full preventive effect because of discrepant study conclusions.MethodsResults from two published studies were used to determine the relationship between serum folate and NTD risk which was compared with the observed result in a randomised trial of folic acid that increased serum folate from 5 ng/mL to 44 ng/mL among women who took a 4 mg daily periconceptional folic acid supplement.ResultsBoth studies showed a proportional (logarithmic) relationship between serum folate and NTD risk without evidence of a folate threshold above which there is no further NTD risk reduction. The suggestion of a threshold is due to the incorrect interpretation of the folate-NTD risk association when plotted on arithmetic scales, which conceals the proportional relationship between the two. Also, both studies accurately estimated the observed result from the randomised trial that achieved a median serum folate level of 44 ng/mL and an 83% preventive effect. This is much higher than has been achieved with current levels of folic acid fortification with serum folate between 10 and 16 ng/mL, resulting in an approximate 20% preventive effect.ConclusionTo achieve fully effective fortification, median population serum folate levels need to be about 44 ng/mL, which would globally prevent about 250 000 NTD cases every year.

Folate (vitamin B9) plays a crucial role in fundamental cellular processes, including nucleic acid biosynthesis, methyl group biogenesis and amino acid metabolism. The detection and correction of folate deficiency prevents megaloblastic anaemia and reduces the risk of neural tube defects. Coexisting deficiencies of folate and vitamin B12 are associated with cognitive decline, depression and neuropathy. Folate deficiency and excess has also been implicated in some cancers. Excessive exposure to folic acid, a synthetic compound used in supplements and fortified foods, has also been linked to adverse health effects. Of at least three distinct laboratory markers of folate status, it is the total abundance of folate in serum/plasma that is used by the majority of laboratories. The analysis of folate in red cells is also commonly performed. Since the folate content of red cells is fixed during erythropoiesis, this marker is indicative of folate status over the preceding ~4 months. Poor stability, variation in polyglutamate chain length and unreliable extraction from red cells are factors that make the analysis of folate challenging. The clinical use of measuring specific folate species has also been explored. 5-Methyltetrahydrofolate, the main form of folate found in blood, is essential for the vitamin B12-dependent methionine synthase mediated remethylation of homocysteine to methionine. As such, homocysteine measurement reflects cellular folate and vitamin B12 use. When interpreting homocysteine results, age, sex and pregnancy, specific reference ranges should be applied. The evaluation of folate status using combined markers of abundance and cellular use has been adopted by some laboratories. In the presence of discordance between laboratory results and strong clinical features of deficiency, treatment should not be delayed. High folate status should be followed up with the assessment of vitamin B12 status, a review of previous results and reassessment of folic acid supplementation regime.

Neural tube defects, such as spina bifida, remain remarkably common, despite widespread efforts to prevent them through supplementing maternal diets with folic acid. Surgery early in development has seen some success, but problems often remain. Wallingford et al. ( 10.1126/science.1222002 ) review normal and abnormal neural tube development and suggest that discovering the genetic risk factors for these serious birth defects could provide ways to prevent and treat neural tube defects. Human birth defects are a major public health burden: The Center for Disease Control estimates that 1 of every 33 United States newborns presents with a birth defect, and worldwide the estimate approaches 6% of all births. Among the most common and debilitating of human birth defects are those affecting the formation of the neural tube, the precursor to the central nervous system. Neural tube defects (NTDs) arise from a complex combination of genetic and environmental interactions. Although substantial advances have been made in the prevention and treatment of these malformations, NTDs remain a substantial public health problem, and we are only now beginning to understand their etiology. Here, we review the process of neural tube development and how defects in this process lead to NTDs, both in humans and in the animal models that serve to inform our understanding of these processes. The insights we are gaining will help generate new intervention strategies to tackle the clinical challenges and to alleviate the personal and societal burdens that accompany these defects.

Background: Inflammatory bowel disease (IBD) patients may be at risk of vitamin B12 and folate insufficiencies, as these micronutrients are absorbed in the small intestine, which is affected by IBD. However, a consensus has not been reached on the association between IBD and serum folate and vitamin B12 concentrations. Methods: In this study, a comprehensive search of multiple databases was performed to identify studies focused on the association between IBD and serum folate and vitamin B12 concentrations. Studies that compared serum folate and vitamin B12 concentrations between IBD and control patients were selected for inclusion in the meta-analysis. Results: The main outcome was the mean difference in serum folate and vitamin B12 concentrations between IBD and control patients. Our findings indicated that the average serum folate concentration in IBD patients was significantly lower than that in control patients, whereas the mean serum vitamin B12 concentration did not differ between IBD patients and controls. In addition, the average serum folate concentration in patients with ulcerative colitis (UC) but not Crohn’s disease (CD) was significantly lower than that in controls. This meta-analysis identified a significant relationship between low serum folate concentration and IBD. Conclusions: Our findings suggest IBD may be linked with folate deficiency, although the results do not indicate causation. Thus, providing supplements of folate and vitamin B12 to IBD patients may improve their nutritional status and prevent other diseases.

Vitamins B9 (folate) and B12 are essential water-soluble vitamins that play a crucial role in the maintenance of one-carbon metabolism: a set of interconnected biochemical pathways driven by folate and methionine to generate methyl groups for use in DNA synthesis, amino acid homeostasis, antioxidant generation, and epigenetic regulation. Dietary deficiencies in B9 and B12, or genetic polymorphisms that influence the activity of enzymes involved in the folate or methionine cycles, are known to cause developmental defects, impair cognitive function, or block normal blood production. Nutritional deficiencies have historically been treated with dietary supplementation or high-dose parenteral administration that can reverse symptoms in the majority of cases. Elevated levels of these vitamins have more recently been shown to correlate with immune dysfunction, cancer, and increased mortality. Therapies that specifically target one-carbon metabolism are therefore currently being explored for the treatment of immune disorders and cancer. In this review, we will highlight recent studies aimed at elucidating the role of folate, B12, and methionine in one-carbon metabolism during normal cellular processes and in the context of disease progression.

There is a large body of evidence to suggest that improving periconceptional folate status reduces the risk of neonatal neural tube defects. Thus increased folate intake is now recommended before and during the early stages of pregnancy, through folic acid supplements or fortified foods. Furthermore, there is growing evidence that folic acid may have a role in the prevention of other diseases, including dementia and certain types of cancer. Folic acid is a synthetic form of the vitamin, which is only found in fortified foods, supplements and pharmaceuticals. It lacks coenzyme activity and must be reduced to the metabolically active tetrahydrofolate form within the cell. L-5-methyl-tetrahydrofolate (L-5-methyl-THF) is the predominant form of dietary folate and the only species normally found in the circulation, and hence it is the folate that is normally transported into peripheral tissues to be used for cellular metabolism. L-5-methyl-THF is also available commercially as a crystalline form of the calcium salt (Metafolin®), which has the stability required for use as a supplement. Studies comparing L-5-methyl-THF and folic acid have found that the two compounds have comparable physiological activity, bioavailability and absorption at equimolar doses. Bioavailability studies have provided strong evidence that L-5-methyl-THF is at least as effective as folic acid in improving folate status, as measured by blood concentrations of folate and by functional indicators of folate status, such as plasma homocysteine. Intake of L-5-methyl-THF may have advantages over intake of folic acid. First, the potential for masking the haematological symptoms of vitamin B 12 deficiency may be reduced with L-5-methyl-THF. Second, L-5-methyl-THF may be associated with a reduced interaction with drugs that inhibit dihydrofolate reductase.

Sperm DNA injury is one of the common causes of male infertility. Folic acid deficiency would increase the methylation level of the important genes, including those involved in DNA double‐strand break (DSB) repair pathway. In the early stages, we analysed the correlation between seminal plasma folic acid concentration and semen parameters in 157 infertility patients and 91 sperm donor volunteers, and found that there was a significant negative correlation between seminal folic acid concentration and sperm DNA Fragmentation Index (DFI; r = −0.495, p < 0.01). Then through reduced representation bisulphite sequencing, global DNA methylation of sperm of patients in the low folic acid group and the high folic acid group was analysed, it was found that the methylation level in Rad54 promoter region increased in the folic acid deficiency group compared with the normal folic acid group. Meanwhile, the results of animal model and spermatocyte line (GC‐2) also found that folic acid deficiency can increase the methylation level in Rad54 promoter region, increased sperm DFI in mice, increased the expression of γ‐H2AX, that is, DNA injury marker protein, and increased sensitivity of GC‐2 to external damage and stimulation. The study indicates that the expression of Rad54 is downregulated by folic acid deficiency via DNA methylation. This may be one of the mechanisms of sperm DNA damage caused by folate deficiency.

This study aimed to evaluate the utility of serum folic acid testing in children and adolescents in a developed country without mandatory folic acid food fortification and to identify patients at risk for folic acid deficiency. In this cross-sectional study, records from primary care and hospitals were reviewed for patients aged 0–18 years who underwent serum folic acid testing. Data were retrieved from the Leumit-Health-Services database over a ten-year period (January 2008 to December 2018). Clinical and laboratory data were compared between patients with folic acid deficiency to those with normal levels. Among 20,411 pediatric patients tested, 884 (4.3%) had folic acid deficiency, of whom only 26.3% had anemia. Only two patients (0.2%) had megaloblastic anemia. Multivariate analysis showed that male gender (odds ratio(OR)1.6, 95% CI 1.22–2.12), older age (OR 1.32, 95% CI 1.26–1.39), higher BMI percentile (OR 1.01, 95% CI 1–1.01), antipsychotic treatment (OR 3.23, 95% CI 1.52–6.84), celiac (OR 2.97, 95% CI 1.66–5.34), and Attention-Deficit-and-Hyperactivity-Disease (ADHD) treated with psychostimulants (OR 2.21, 95% CI 1.56–3.12) were associated with folic acid deficiency (all p  <  0.01). Lower hemoglobin levels were independently associated with increased OR of folic acid deficiency (OR 0.77, 95% CI 0.66–0.90, p  =  0.001 ), but anemia as a diagnosis was not. Conclusion : Pediatric folic acid deficiency rates were low in this nationwide cohort and not linked to megaloblastic anemia, likely due to concomitant iron deficiency anemia. Although retrospective, this might suggest low utility for routine serum folic acid testing in healthy children in developed countries, except in cases of celiac disease or specific medication use such psychostimulants or antipsychotics. What is Known: • Folic acid deficiency is common among children in developing countries, causing megaloblastic anemia, growth delays, and cognitive impairments. In developed countries, the prevalence is considered low. What is New: • Of 20,411 pediatric patients tested for serum folate, in a developed country, only 4.3% had folate deficiency. • Risk factors for deficiency included celiac, antipsychotics, and psychostimulant treatment for ADHD. • Routine folate testing in developed countries may have limited utility; Targeted screening is recommended.

Micronutrients are essential to sustain life and for optimal physiological function. Widespread global micronutrient deficiencies (MNDs) exist, with pregnant women and their children under 5 years at the highest risk. Iron, iodine, folate, vitamin A, and zinc deficiencies are the most widespread MNDs, and all these MNDs are common contributors to poor growth, intellectual impairments, perinatal complications, and increased risk of morbidity and mortality. Iron deficiency is the most common MND worldwide and leads to microcytic anemia, decreased capacity for work, as well as impaired immune and endocrine function. Iodine deficiency disorder is also widespread and results in goiter, mental retardation, or reduced cognitive function. Adequate zinc is necessary for optimal immune function, and deficiency is associated with an increased incidence of diarrhea and acute respiratory infections, major causes of death in those <5 years of age. Folic acid taken in early pregnancy can prevent neural tube defects. Folate is essential for DNA synthesis and repair, and deficiency results in macrocytic anemia. Vitamin A deficiency is the leading cause of blindness worldwide and also impairs immune function and cell differentiation. Single MNDs rarely occur alone; often, multiple MNDs coexist. The long-term consequences of MNDs are not only seen at the individual level but also have deleterious impacts on the economic development and human capital at the country level. Perhaps of greatest concern is the cycle of MNDs that persists over generations and the intergenerational consequences of MNDs that we are only beginning to understand. Prevention of MNDs is critical and traditionally has been accomplished through supplementation, fortification, and food-based approaches including diversification. It is widely accepted that intervention in the first 1,000 days is critical to break the cycle of malnutrition; however, a coordinated, sustainable commitment to scaling up nutrition at the global level is still needed. Understanding the epidemiology of MNDs is critical to understand what intervention strategies will work best under different conditions.

Antigen-presenting molecules, encoded by the major histocompatibility complex (MHC) and CD1 family, bind peptide- and lipid-based antigens, respectively, for recognition by T cells. Mucosal-associated invariant T (MAIT) cells are an abundant population of innate-like T cells in humans that are activated by an antigen(s) bound to the MHC class I-like molecule MR1. Although the identity of MR1-restricted antigen(s) is unknown, it is present in numerous bacteria and yeast. Here we show that the structure and chemistry within the antigen-binding cleft of MR1 is distinct from the MHC and CD1 families. MR1 is ideally suited to bind ligands originating from vitamin metabolites. The structure of MR1 in complex with 6-formyl pterin, a folic acid (vitamin B9) metabolite, shows the pterin ring sequestered within MR1. Furthermore, we characterize related MR1-restricted vitamin derivatives, originating from the bacterial riboflavin (vitamin B2) biosynthetic pathway, which specifically and potently activate MAIT cells. Accordingly, we show that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance. As many vitamin biosynthetic pathways are unique to bacteria and yeast, our data suggest that MAIT cells use these metabolites to detect microbial infection. The structure of the major histocompatibility complex (MHC)-class-I-like molecule MR1 in complex with a vitamin B9 derivative is determined; metabolites of vitamin B2 are shown to activate MR1-restricted mucosal-associated invariant T cells, implicating them in microbial immunosurveillance. Immune surveillance role for MAIT cells Although mucosal-associated invariant T (MAIT) cells comprise up to 10% of the human T-cell population, surprisingly little is known about their role in physiology and pathology. This is in large part because the identity of the antigen or antigens recognized by MAIT cells in an MR1-restricted manner is unknown. This study reports the structure of the MHC-like molecule MR1 in complex with the vitamin B9-like protein pterin. Bacterial vitamin B derivatives are shown to activate MAIT cells, suggesting that the elusive antigens for MAIT cells are microbial vitamin metabolites and that the physiological role of these cells is to detect microbial infections.