Binding Folate Receptor Alpha Autoantibody Is a Biomarker for Leucovorin Treatment Response in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) affects up to 1 in 36 children in the United States. It is a heterogeneous neurodevelopmental disorder with life-long consequences. Patients with ASD and folate pathway abnormalities have demonstrated improved symptoms after treatment with leucovorin (folinic acid), a reduced form of folate.

FTY720 requires vitamin B-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis.

Vitamin B (B) deficiency causes neurological manifestations resembling multiple sclerosis (MS); however, a molecular explanation for the similarity is unknown. FTY720 (fingolimod) is a sphingosine 1-phosphate (S1P) receptor modulator and sphingosine analog approved for MS therapy that can functionally antagonize S1P. Here, we report that FTY720 suppresses neuroinflammation by functionally and physically regulating the B pathways.

Folate and Other B Vitamins in Brain Health and Disease.

B vitamins as a group play essential roles in a multitude of metabolic reactions involved in cellular replication, energy production, the synthesis of intermediary compounds, and neurotransmitters [...

Transcobalamin receptor gene polymorphisms and mutation in an elderly population.

Background & Aims: Cellular uptake of the essential nutrient vitamin B12 (cobalamin) occurs via the transcobalamin receptor (TCblR/CD320), a ubiquitous membrane receptor. Polymorphisms in the receptor exist, though the effect of such variants across patient populations is unknown.

Methods: We determined CD320 genotype in 377 randomly selected elderly individuals.

Brain Uptake of Folate Forms in the Presence of Folate Receptor Alpha Antibodies in Young Rats: Folate and Antibody Distribution.

In a rat model, following exposure to rat folate receptor alpha antibodies (FRαAb) during gestation, FRαAb accumulates in the placenta and the fetus and blocks folate transport to the fetal brain and produces behavioral deficits in the offspring. These deficits could be prevented with folinic acid. Therefore, we sought to evaluate folate transport to the brain in young rat pups and determine what effect FRαAb has on this process, to better understand the folate receptor autoimmune disorder associated with cerebral folate deficiency (CFD) in autism spectrum disorders (ASD).

The Soluble Folate Receptor in Autism Spectrum Disorder: Relation to Autism Severity and Leucovorin Treatment.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with life-long consequences that affects up to 1 in 44 children. Treatment with leucovorin (folinic acid), a reduced form of folate, has been shown to improve symptoms in those with ASD and folate pathway abnormalities in controlled clinical trials. Although soluble folate binding proteins (sFBPs) have been observed in the serum of some patients with ASD, the significance of this finding has not been studied.

The environmental monitoring of air pollution in the Santa Cruz industrial district of Rio de Janeiro using a plant fertility model.

In 2010, a steel company was established in Santa Cruz, Rio de Janeiro. In 2012, silver rain raised concerns about human and environmental impacts. In 2013, the steel company signed an Adjustment of Conduct Term (ACT).

Cerebral Folate Deficiency Syndrome: Early Diagnosis, Intervention and Treatment Strategies.

Cerebral folate deficiency syndrome (CFDS) is defined as any neuropsychiatric or developmental disorder characterized by decreased CSF folate levels in the presence of normal folate status outside the nervous system. The specific clinical profile appears to be largely determined by the presence or absence of intrauterine folate deficiency as well as postnatal age at which cerebral folate deficiency occurs. The primary cause of CFDS is identified as the presence of serum folate receptor-alpha (FRα) autoantibodies impairing folate transport across the choroid plexus to the brain whereas, in a minority of cases, mitochondrial disorders, inborn errors of metabolism and loss of function mutations of the FRα () gene are identified.

Absorption and Tissue Distribution of Folate Forms in Rats: Indications for Specific Folate Form Supplementation during Pregnancy.

Food fortification and folic acid supplementation during pregnancy have been implemented as strategies to prevent fetal malformations during pregnancy. However, with the emergence of conditions where folate metabolism and transport are disrupted, such as folate receptor alpha autoantibody (FRαAb)-induced folate deficiency, it is critical to find a folate form that is effective and safe for pharmacologic dosing for prolonged periods. Therefore, in this study, we explored the absorption and tissue distribution of folic acid (PGA), 5-methyl-tetrahydrofolate (MTHF), l-folinic acid (levofolinate), and d,l-folinic acid (Leucovorin) in adult rats.

Socioeconomic inequalities in the consumption of minimally processed and ultra-processed foods in Brazilian adolescents.

In this study, we evaluated socioeconomic inequalities in the consumption of in natura/minimally processed and ultra-processed foods among adolescents. We used data from the Brazilian National Survey of School Health (PeNSE), 2015. According to the self-reported consumption of beans, vegetables and fruits, a score of in natura/minimally processed foods was generated (0-21 points).

Behavioral profile of vitamin B deficiency: A reflection of impaired brain development, neuronal stress and altered neuroplasticity.

Our understanding of brain biology and function is one of the least characterized and therefore, there are no effective treatments for most of neurological disorders. The influence of vitamins, and particularly vitamin B, in neurodegenerative disease is demonstrated but largely unresolved. Behaviors are often quantified to attest brain dysfunction alone or in parallel with neuro-imaging to identify regions involved.

Generation of nanobodies targeting the human, transcobalamin-mediated vitamin B uptake route.

Cellular uptake of vitamin B in humans is mediated by the endocytosis of the B carrier protein transcobalamin (TC) via its cognate cell surface receptor TCblR, encoded by the CD320 gene. Because CD320 expression is associated with the cell cycle and upregulated in highly proliferating cells including cancer cells, this uptake route is a potential target for cancer therapy. We developed and characterized four camelid nanobodies that bind holo-TC (TC in complex with B ) or the interface of the human holo-TC:TCblR complex with nanomolar affinities.

Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorders: Diagnosis, Treatment and Prevention.

Folate deficiency and folate receptor autoimmune disorder are major contributors to infertility, pregnancy related complications and abnormal fetal development including structural and functional abnormalities of the brain. Food fortification and prenatal folic acid supplementation has reduced the incidence of neural tube defect (NTD) pregnancies but is unlikely to prevent pregnancy-related complications in the presence of folate receptor autoantibodies (FRAb). In pregnancy, these autoantibodies can block folate transport to the fetus and in young children, folate transport to the brain.

Physical activity and sedentary behavior as multimorbidity discriminators among elderly Brazilians: a cross-sectional study.

Background: Associations between behaviors and individual chronic diseases have been demonstrated. However, the relationship between time spent on sedentary behavior and multimorbidity remains less clear.

Objective: To identify the predictive power of various intensities of physical activity versus sedentary behavior, as discriminatory factors for cardiometabolic multimorbidity (cardiovascular diseases and diabetes) in the elderly.

Elevated sperm DNA fragmentation does not predict recurrent implantation failure.

In this study, we sought to determine whether sperm DNA fragmentation (DFI%) and high DNA stainability (HDS%) evaluated by sperm chromatin structure assay (SCSA) predict recurrent implantation failure (RIF) or pregnancy rate. A retrospective study was performed of consecutive cycles of ICSI treatment from 2009 to 2018. A total of 386 couples that underwent 1,216 frozen embryo transfer (FET) cycles were analysed.

Oxidative Stress, Folate Receptor Autoimmunity, and CSF Findings in Severe Infantile Autism.

Background: Biomarkers such as oxidative stress, folate receptor alpha (FR) autoimmunity, and abnormal brain serotonin turnover are common in autism.

Methods: Oxidative stress biomarkers with pro- and antioxidants were measured in the severe form of infantile autism ( = 38) and controls ( = 24). Children and parents had repeated testing for serum FR autoantibodies, spinal fluid dopamine and serotonin metabolites, pterins, and N-methyltetrahydrofolate (MTHF).

Glucocorticoid Receptor Activation Restores Learning Memory by Modulating Hippocampal Plasticity in a Mouse Model of Brain Vitamin B Deficiency.

Cobalamin (Cbl, vitamin B) deficiency or inborn errors of Cbl metabolism can produce neurologic disorders resistant to therapies, including cognitive dysfunction, mild mental retardation, memory impairment, and confusion. We used Cd320 KO mouse as a model for studying the pathological mechanisms of these disorders. Cd320 encodes the receptor (TCblR) needed for the cellular uptake of Cbl in the brain.

Cellular uptake of vitamin B: Role and fate of TCblR/CD320, the transcobalamin receptor.

Cellular uptake of vitamin B (cobalamin, Cbl) is mediated by a cell surface receptor (TCblR/CD320) that binds transcobalamin (TC) saturated with Cbl. TC is secreted by the vascular endothelium, has a relatively short half-life, binds Cbl with high affinity and presents the vitamin to the receptor for cellular uptake. Here we show binding and internalization of the TC-Cbl complex along with its' receptor (TCblR) in several human cell lines.

Treatment of Folate Metabolism Abnormalities in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that currently has no approved medical therapy to address core symptoms or underling pathophysiological processes. Several compounds are under development that address both underlying pathophysiological abnormalities and core ASD symptoms. This article reviews one of these treatments, d,l-leucovorin calcium (also known as folinic acid) for treatment of folate pathway abnormalities in children with ASD.

Folinic acid improves the score of Autism in the EFFET placebo-controlled randomized trial.

Autism spectrum disorders (ASD) are influenced by interacting maternal and environmental risk factors. High-dose folinic acid has shown improvement in verbal communication in ASD children. The EFFET randomized placebo-controlled trial (NCT02551380) aimed to evaluate the efficacy of folinic acid (FOLINORAL®) at a lower dose of 5 mg twice daily.

Improving Outcome in Infantile Autism with Folate Receptor Autoimmunity and Nutritional Derangements: A Self-Controlled Trial.

Background: In contrast to multiple rare monogenetic abnormalities, a common biomarker among children with infantile autism and their parents is the discovery of serum autoantibodies directed to the folate receptor alpha (FR) localized at blood-brain and placental barriers, impairing physiologic folate transfer to the brain and fetus. Since outcome after behavioral intervention remains poor, a trial was designed to treat folate receptor alpha (FR) autoimmunity combined with correction of deficient nutrients due to abnormal feeding habits.

Methods: All participants with nonsyndromic infantile autism underwent a routine protocol measuring CBC, iron, vitamins, coenzyme Q10, metals, and trace elements.

Geospatial intelligence and health analitycs: Its application and utility in a city with high tuberculosis incidence in Brazil.

Background: Geospatial Intelligence and Health Analysis have been used to identify tuberculosis (TB) hotspots and to better understand their relationship to social and economic factors. The purpose of this study was to use geospatial intelligence to assess the distribution of TB and its correlations with Human Development Index (HDI) in a city with high TB incidence in Brazil.

Methods: We conducted an ecological study, using National System of Information on Noticeable Disease (SINAN) to identify TB cases.

N-homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia.

The pathomechanisms that associate a deficit in folate and/or vitamin B12 and the subsequent hyperhomocysteinemia with pathological brain ageing are unclear. We investigated the homocysteinylation of microtubule-associated proteins (MAPs) in brains of patients with Alzheimer's disease or vascular dementia, and in rats depleted in folate and vitamin B12, Cd320 KO mice with selective B12 brain deficiency and H19-7 neuroprogenitors lacking folate. Compared with controls, N-homocysteinylated tau and MAP1 were increased and accumulated in protein aggregates and tangles in the cortex, hippocampus and cerebellum of patients and animals.