Folate (5-MTHF)

Folate deficiency among women of reproductive age in Ethiopia: A systematic review and meta-analysis.

Gebremichael B, Roba HS, Getachew A, Tesfaye D, Asmerom H · PloS one · 2023

Folate deficiency (FD) can cause adverse health outcomes of public health significance. Although FD is a significant micronutrient deficiency in Ethiopia, concrete evidence is limited. Therefore, this systematic review and meta-analysis was designed to estimate the pooled prevalence of FD among women of reproductive age (WRA). A systematic literature search was performed using MEDLINE, Embase, CINAHL, Google Scholar, African Journals Online (AJOL), The Vitamin and Mineral Nutrition Information System (VMNIS) of the World Health Organization (WHO), Global Health Data Exchange (GHDx), and institutional repositories of major universities and research centers. Additionally, we scanned the reference lists of relevant articles. Two authors independently selected the studies, extracted the data, and the study risk of bias. Heterogeneity was assessed using the I2 statistic. We used a random-effects model to estimate the pooled mean serum/plasma folate and the pooled prevalence of FD. Begg's a

Correction: Rossignol, D.A.; Frye, R.E. Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis. J. Pers. Med. 2021, 11, 1141.

Rossignol DA, Frye RE · Journal of personalized medicine · 2022

In the original publication [...].

Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis.

Rossignol DA, Frye RE · Journal of personalized medicine · 2021

The cerebral folate receptor alpha (FRα) transports 5-methyltetrahydrofolate (5-MTHF) into the brain; low 5-MTHF in the brain causes cerebral folate deficiency (CFD). CFD has been associated with autism spectrum disorders (ASD) and is treated with d,l-leucovorin (folinic acid). One cause of CFD is an autoantibody that interferes with the function of the FRα. FRα autoantibodies (FRAAs) have been reported in ASD. A systematic review was performed to identify studies reporting FRAAs in association with ASD, or the use of d,l-leucovorin in the treatment of ASD. A meta-analysis examined the prevalence of FRAAs in ASD. The pooled prevalence of ASD in individuals with CFD was 44%, while the pooled prevalence of CFD in ASD was 38% (with a significant variation across studies due to heterogeneity). The etiology of CFD in ASD was attributed to FRAAs in 83% of the cases (with consistency across studies) and mitochondrial dysfunction in 43%. A significant inverse correlation was

Toward an optimal use of folic acid: an advisory report of the Health Council of the Netherlands.

Weggemans RM, Schaafsma G, Kromhout D, Health Council of the Netherlands · European journal of clinical nutrition · 2009

In this report, benefits (preventing neural tube defects and folate deficiency), risks (masking vitamin B(12) deficiency), and uncertain effects (risk of colon cancer) of folic acid supplementation and fortification have been weighted. On the basis of the available evidence, the Health Council of the Netherlands advises the Dutch government to improve the use of folic acid approximately at the time of conception by increased education and the implementation of preconception care. It further recommends considering fortifying staple foods, provided that voluntary fortification of specific foods is banned, as otherwise children are at risk of having an excessively high intake of folic acid. Policy making in relation to fortification should take into account all possible health effects, even if the evidence is not strong.

Cerebral folate receptor autoantibodies in autism spectrum disorder.

Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA · Molecular psychiatry · 2013

Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg(-1) per day; maximum 50 mg per day). Treatment response was measured and compared with a wai

Clinical concerns and considerations for leucovorin use in autism spectrum disorder.

Howard C, Mekhail J, Ravikoff LM, Milanaik R · Current opinion in pediatrics · 2026

To provide pediatric clinicians with an overview of current research on leucovorin use in children with autism spectrum disorder (ASD) and a guide to patient evaluation and treatment. An association between cerebral folate deficiency (CFD) and ASD has been suggested in some studies. Autoantibodies that block folate entry into the brain are a cause of CFD and have been detected in 71% of patients with ASD. Leucovorin is a synthetic drug that increases folate concentrations in the brain despite the presence of autoantibodies. Certain studies have indicated reductions in communication deficits in nonverbal children with ASD, particularly those with these autoantibodies, following consistent leucovorin use. However, other studies have found no change in symptoms despite leucovorin intake. The American Academy of Pediatrics (AAP) currently does not recommend use of leucovorin in children with ASD. Due to recent popularity among policymakers and on social media, many pediatricians have rep

New Insights into Folate-Vitamin B(12) Interactions.

Castillo LF, Pelletier CM, Heyden KE, Field MS · Annual review of nutrition · 2025

Folate and vitamin B12 (B12) are essential cofactors in folate-mediated one-carbon metabolism (FOCM). FOCM includes a series of methyl transfer reactions for methionine regeneration and de novo synthesis of nucleotides, including thymidylate. Deficiency in either folate or B12 can result in negative health outcomes including megaloblastic anemia, with additional neurocognitive impairments observed as a result of B12 deficiency. While folate deficiency is not common in the United States due to mandatory folic acid fortification, B12 deficiency is observed more frequently, particularly in certain subpopulations such as vegetarians/vegans and older adults. Fortification of the food supply with folic acid has been effective to increase folate status and reduce the incidence of birth defects. However, consumption of fortified foods and use of dietary supplements containing folic acid have led to an increase in the proportion of individuals exceeding the tolerable upper intake level of folic

Folic acid and plasma lipids: Interactions and effect of folate supplementation.

Fogacci F, Pizzi C, Bergamaschi L, Di Micoli V, Cicero AFG · Current problems in cardiology · 2024

Dyslipidaemia and hyperhomocysteinemia are known risk factors for cardiovascular disease. While it is evident that optimization of plasma lipid is associated with low risk of cardiovascular disease in the general population, it is not yet fully clear whether reduction of homocysteinemia is associated with an improvement in risk in all subjects. The aim of our narrative review is to highlight eventual effects of folate supplementation on LDL-C levels, LDL-C oxidation and atherosclerosis-related complications. A comprehensive literature search was done in electronic database, including PubMed, Web of Science, Cochrane, and Scopus from inception up to January 2024. Based on the available evidence, epidemiological data, pathophysiological observations and meta-analyses of randomized clinical trials suggest that folic acid supplementation may modestly but significantly improve plasma lipid levels, lipid atherogenicity, and atherosclerosis-related early vascular damage, and that folic acid s

Vitamin B12 or folate deficiency anaemia

National Health Service (NHS)

This NHS page details the causes, symptoms, diagnosis, and treatment of vitamin B12 and folate deficiency anaemia, offering patient-friendly information.

Randomized Clinical Trial of Folate Therapy/Placebo for Reduction of Homocysteine Serum Levels in Uremic Patients and Influence on Cardiovascular Mortality

n=186 · NCT00317005 · COMPLETED · COMPLETED

Homocysteine recently gained access to the category of risk factor for the development of atherosclerotic cardiovascular disease in the general population. Chronic renal failure patients, even before being introduced to dialysis therapy have almost universal elevation of serum homocysteine; when on dialysis their mortality is above 50% related to cardiovascular disease that we might now speculate, with a contribution of potentially toxic levels of the aminoacid homocysteine.

Profound Cerebral Folate Deficiency as a Clinical Model for Identification of MRI and Biochemical Signatures of Choroid Plexus Dysfunction

n=65 · NCT06403189 · RECRUITING · RECRUITING

Cerebral folate deficiency (CFD), a partially treatable condition defined by a low folate cerebrospinal fluid (CSF) concentration, can be linked to genetic defects of folate metabolism or be secondary to various diseases without clear causal link. The team identified a neurological syndrome (named LHIPFOLFD) characterized by deep CFD and a specific leukoencephalopathy, related to several possible gene defects never involving folate metabolism. The team hypothesize that CFD in LHIPFOLD is due to a Choroid Plexus (CP) dysfunction, a brain organ that expresses transporters regulating flux between blood and CSF of numerous metabolites (including folate), and secretes CSF and specific proteins. Consequently, other potentially treatable biochemical abnormalities due to PC dysfunction may exist in LHIPFOLD, beyond CFD. Currently, there is no available clinical explorations to evaluate CP functions, whereas the team consider LHIPFOLD a very useful model to validate the capacity of some relevant diagnostic tools to do so. The objectives are to identify a CP-related MRI and biochemical signature in LHIPFOLD patients, using morphological and functional imaging (CP capillary permeability and CP macrovascular perfusion), and metabolomics/proteomics approaches (untargeted then targeted validation of candidate biomarkers related to CP physiology); and to set-up imaging and biochemical diagnostic tests for clinical practice. For this, brain MRI data and blood/CSF samples will be collected during 2 years from LHIPFOLD patients and controls. Some experimental data indicate that the innovative concept of generalized PC dysfunction as part of a more global pathophysiology has the potential to be applied to other neurological diseases like Alzheimer's disease. Therefore, efficient diagnostic tools exploring CP function will be of great utility not only in LHIPFOLD but also in more common neurological diseases, potentially leading to original therapeutic approaches.

A Randomized Controlled Trial to Study the Effect of Folic Acid Supplementation in Pregnant Women Having Thalassaemia Trait

n=270 · NCT04310059 · NOT_YET_RECRUITING · NOT_YET_RECRUITING

Folic acid supplementation has been recommended for prevention of neural tube defects in pregnancy when taken periconceptionally up to 12 weeks of gestation. A daily dose of 0.4mg has been endorsed by World Health Organisation to achieve a Red blood cell (RBC) folate level of 906nmol/L (400ng/mL) for reduction of neural tube defect. Hong Kong has no policy on food fortification. Research data conducted in countries with food fortification may not be applicable. It is therefore essential to study the baseline folate status in pregnant women locally. For pregnant women with thalassaemia, they are believed to have a higher risk of folate deficiency because of an increased rate of erythropoiesis and chronic haemolysis. However, information on folate level of thalassaemia trait in pregnancy is scanty. Unmetabolized folic acid has been detected in maternal and fetal blood when daily dosage greater than 0.8-1mg was taken. In term of the dosage and duration of folic acid supplementation after 12 weeks of gestation, the practice varies widely among public hospitals and Maternity \& Child Health Care centres. It is therefore essential to study the optimal dosage of folic acid supplementation in women with thalassaemia.