Folate receptor autoantibodies in pregnancy related complications

Shapira, Iuliana; Sequeira, Jeffrey M.; Quadros, Edward V.

doi:10.1002/bdra.23436

Cited by 17 publications

(21 citation statements)

References 17 publications

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“…Maternal folate deficiency increases the risk not only for NTD, but also for autism spectrum disorders (ASD) [7, 8]. Even in the presence of a normal maternal folate status, maternal serum FR α autoantibodies directed against the FR α localized at the placental barrier were shown to block adequate folate delivery across the placenta, predisposing to intrauterine folate deficiency with consequent congenital malformations or autism spectrum disorders [9–13]. Postnatal development of serum FR α -autoantibodies directed against the FR α attached to the choroid plexus epithelial cells at the blood-brain barrier causes the so-called infantile-onset cerebral folate deficiency (CFD) syndrome associated with autism in about 1/3 of cases.…”

Section: Introductionmentioning

confidence: 99%

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

Ramaekers¹,

Sequeira

DiDuca³

et al. 2019

Autism Research and Treatment

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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 (FRα) 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 (FRα) 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. Serum FRα autoantibodies were assessed in patients, their parents, and healthy controls. A self-controlled therapeutic trial treated nutritional derangements with addition of high-dose folinic acid if FRα autoantibodies tested positive. The Childhood Autism Rating Scale (CARS) monitored at baseline and following 2 years of treatment was compared to the CARS of untreated autistic children serving as a reference. Results. In this self-controlled trial (82 children; mean age ± SD: 4.4 ± 2.3 years; male:female ratio: 4.8:1), FRα autoantibodies were found in 75.6 % of the children, 34.1 % of mothers, and 29.4 % of fathers versus 3.3 % in healthy controls. Compared to untreated patients with autism (n=84) whose CARS score remained unchanged, a 2-year treatment decreased the initial CARS score from severe (mean ± SD: 41.34 ± 6.47) to moderate or mild autism (mean ± SD: 34.35 ± 6.25; paired t-test p<0.0001), achieving complete recovery in 17/82 children (20.7 %). Prognosis became less favorable with the finding of higher FRα autoantibody titers, positive maternal FRα autoantibodies, or FRα antibodies in both parents. Conclusions. Correction of nutritional deficiencies combined with high-dose folinic acid improved outcome for autism, although the trend of a poor prognosis due to maternal FRα antibodies or FRα antibodies in both parents may warrant folinic acid intervention before conception and during pregnancy.

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Section: Introductionmentioning

confidence: 99%

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

Ramaekers¹,

Sequeira

DiDuca³

et al. 2019

Autism Research and Treatment

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“…Then she was on the diary‐free diet and took certain medications including folic acid. Eventually, the antibody titer dropped to an undetectable level and a healthy baby was delivered, suggesting that FR autoimmunity can have adverse effects on the pregnancy outcomes, which can be prevented by systematically lowering the antibody levels (Shapira et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Then she was on the diary-free diet and took certain medications including folic acid. Eventually, the antibody titer dropped to an undetectable level and a healthy baby was delivered, suggesting that FR autoimmunity can have adverse effects on the pregnancy outcomes, which can be prevented by systematically lowering the antibody levels (Shapira et al, 2015). Denny and colleagues (2015) used a folate-deficient diet in pregnant mice to demonstrate that there is a highly significant correlation between serum homocysteine levels and titers of autoantibodies directed against homocysteinylated proteins, in this case, against the FR.…”

Section: Discussionmentioning

confidence: 99%

Levels of folate receptor autoantibodies in maternal and cord blood and risk of neural tube defects in a Chinese population

Yang

Wang

Finnell

et al. 2016

Birth Defects Research

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Background After years of periconceptional folic acid supplementation, the prevalence of neural tube defects (NTDs) remains stable following the remarkable reduction observed immediately after the fortification practice. There is accumulating evidence that folate receptor (FR) autoimmunity may play a role in the etiology of folate-sensitive NTDs. Methods From 2011 to 2013, 118 NTD cases and 242 healthy controls were recruited from a population-based birth defects surveillance system in Northern China. Enzyme-linked immunosorbent assay was used to measure FR autoantibodies in maternal and cord blood. Logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (95% CI). Results Plasma FR autoantibodies levels were significantly elevated in mothers of infants with NTDs compared with mothers of healthy controls. Using the lowest tertile as the referent group, 2.20-fold (95% CI, 0.71–6.80) and 5.53-fold increased odds (95% CI, 1.90–16.08) of NTDs were observed for the second and third tertile of immunoglobulin G (IgG), respectively, and the odds of NTDs for each successive tertile of IgM was 0.98 (95% CI, 0.35–2.75) and 3.49 (95% CI, 1.45–8.39), respectively. A dose–response relationship was found between FR autoantibodies levels and risk of NTDs (P < 0.001 for IgG, P = 0.002 for IgM). The same pattern was observed in both subtypes of spina bifida and anencephaly. No significant difference in levels of cord blood FR autoantibodies was observed. Conclusion Higher levels of FR autoimmunity in maternal plasma are associated with elevated risk of NTDs in a dose–response manner.

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“…The identification of high titers of FR autoantibodies in clinical samples with gene interactions associated with NTD risk provides strengthening support for the biological significance of autoantibodies beyond mere association. Managing FR autoimmunity can potentially influence the management of human fertility and pregnancy (Shapira, Sequeira, & Quadros, ). These data also support additional testing of the proposed mechanisms involving post‐translational modification of FR and opens the possibility of developing intervention strategies that reduce FR autoantibodies before and during critical stages of development.…”

Section: Discussionmentioning

confidence: 99%

Gene variants in the folate pathway are associated with increased levels of folate receptor autoantibodies

Dong

Wang

Lei

et al. 2018

Birth Defects Research

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Background: Folate receptors (FRs) facilitate embryonic uptake of folates and are important for proper early embryonic development. There is accumulating evidence that blocking FR autoantibodies contribute to developmental diseases. However, genetic factors associated with the expression of FR autoantibodies remain unknown. Objective: We investigated the effects of genetic polymorphisms in folate pathway genes on FR autoantibody titers in women. Methods: We recruited 302 pregnant women in China. The FR antigen-down immunoassay was used to measure levels of FR autoantibodies including human immunoglobulin G (IgG) and immunoglobulin M (IgM) in maternal plasma. Genotypes were identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry and polymerase chain reaction methods. General linear model was used to analyze the effects of genetic variants on FR autoantibody levels. Results: Significant associations were observed between genotypic variations and levels of FR autoantibodies. Plasma levels of FR autoantibodies in women with the TT genotype at MTHFR rs1801133 were significantly higher than those of women with the CC genotype (IgG: β = 0.62, 95% CI 0.21–1.04; IgM: β = 0.42, 95% CI 0.12–0.72). For DNMT3A rs7560488, the level of FR autoantibody IgG significantly increased in the TT genotype compared with CC genotype (β = 0.90, 95% CI 0.20–1.59). For MTHFD2 rs828903, genotype GG was associated with elevated levels of FR autoantibody IgM compared to the AA genotype (β = 0.60, 95% CI 0.10–1.10). No association was detected between genetic variants of the DHFR gene with FR autoantibodies levels. Conclusion: Genetic variations in MTHFR, DNMT3A, and MTHFD2 genes were associated with elevated plasma levels of FR autoantibodies.

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Folate receptor autoantibodies in pregnancy related complications

Abstract: This long-term follow up of a subject with folate receptor autoantibodies is a first report of its kind and describes treatment strategy to prevent pregnancy related complications due to folate receptor autoantibodies.

Cited by 17 publications

References 17 publications

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

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

Levels of folate receptor autoantibodies in maternal and cord blood and risk of neural tube defects in a Chinese population

Gene variants in the folate pathway are associated with increased levels of folate receptor autoantibodies

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