Maternal folate receptors autoantibodies: Potential factors reducing folate transport and involved in ASD development

The importance of folate intake during pregnancy has been largely described. Indeed folate is essential to multiple processes including DNA synthesis and methylation, two processes involved in the regulation of gene expression. If DNA synthesis and/or methylation (epigenetic events) are altered in utero, this could affect gene expression thus impacting fetal development and that could modulate the fetal susceptibility to various diseases.
Several studies have reported the involvement of folate metabolism and transport in ASD development (for more information, read our blog “Insight into MTHFR polymorphism and Autism“). In particular, Rett syndrome and infantile onset low-functioning autism, two autism spectrum disorders, have been characterized by a lower folate transport to the central nervous system (CNS).

1. What are the folate receptors?

Folate receptors are receptors involved in folate uptake and transport across the placental-fetal barrier (FRα and FRβ) and the blood-brain-barrier (FRα). In the central nervous system, FRα functioned as “shuttles” that bind methyl folates (folinic acid) from the plasma and release it in the spinal fluid compartment of your brain (CSF), where they are delivered to the neuronal tissue. FRα and FRβ are highly expressed in reproductive tissues (particularly in placenta) and play a similar and major role during pregnancy by delivering methyl folate from the maternal bloodstream to the embryo and the developing fetus to support its growth. In addition, several animal model studies demonstrate that FRα is also important in the repair and regeneration of the CNS after injury.

2. How can FR activity be disrupt?

The production of FR autoantibodies (FRA) in autoimmune disorders can alter FRα activity as well as FRβ activity, which are receptors limited mostly to placenta and macrophages (immune cells). In particular, reports have shown that autoantibodies produced in Rheumatoid arthritis can activate FR (FRβ) present on the surface of macrophages and lead to inflammation. Although FR autoantibodies have not been shown to be involved in pregnancy complications, low levels of FRα and FRβ have been found in placenta during pre-eclampsia.

FR autoantibodies exist in two forms:

  • Blocking autoantibodies: they can block folate transport by blocking the methyl folate binding site localized on FRα. We can compare this mechanism to a key/locker unit where your key (autoantibodies) are broken inside the locker (FRα) and prevent you (methyl folate) from getting into your home.
  • Binding autoantibodies: they bind to FR and induce an inflammatory response (antibody-mediated immune reaction).

As a result, methyl folate is not provided to the fetus and his brain during pregnancy. When present in the serum of infants, FR autoantibodies limit methyl folate access to the still developing brain.

3 . How can FR autoantibodies (FRA) affect my child neurodevelopment while pregnant?

  1. Few facts:

FR autoantibodies (FRA) were described for the first time in maternal serum during pregnancy and were associated with cerebral folate deficiency (CFD), a neuro-psychiatric disorder characterized by low levels of methyl folates in the central nervous system. Maternal FRA during pregnancy have also been associated with neural tube defects in the offspring.

2. Maternal FR autoantibodies (FRA) and ASD:

Although the causes of FRA production in mothers are still unknown, FRA autoantibodies targeting FRα could disrupt methyl folate transport to the developing fetus.
Because cerebral folate deficiency have symptoms similar to those associated with ASD, several studies have looked at FRA in autistic children and their mothers. FR blocking autoantibodies have been detected in up to 76% of children with low functioning autism compared to 10% in the control population. In addition to confirming the high prevalence of FRA in autistic children (with no CFD or significant neurological abnormalities), other studies found a direct correlation between FR blocking autoantibodies and lower methyl folate levels in American autistic children’s cerebral spinal fluid (CSF). Finally, maternal FRA have been linked with an increased risk of infantile autism in the offspring. The prevalence of maternal blocking FRA (60%) was much higher in mothers of autistic children than that reported in the control population of women (estimated to be 10-15% in the USA).

Folate-related abnormalities are common in children with ASD and have been largely described in the literature. Maternal FRA during pregnancy may disrupt folate metabolism therefore limiting its transport across the placenta and the fetus blood-brain barrier.
Irrespective of the presence of FRAs, children with ASD may be genetically predisposed to abnormalities in the transport of folates (for more information, read our section on “on RFC genetic variants associated with ASD: /Autism-Education/Environmental-Triggers-to-Autism.aspx ” and our blog “Insight into MTHFR polymorphism and Autism”: /Blog-Latest-News-Updates/2015/March/Insight-into-MTHFR-polymorphism-and-Autism.aspx). Therefore FRA are one of the causes leading to reduced methyl folate levels playing a key role in ASD development.
The presence of FRA can be tested in women or their children. But because these tests measure the binding of external FRα and radiolabelled folinic acid in presence of your serum that potentially contained FRA, patients should not be taken any dietary folate supplement prior to the test. As dietary folate intake is strongly recommended to pregnant women or women planning to conceive, these tests should be done at least three month prior to the first attempt of getting pregnant.

At Braverman Reproductive Immunology, we are currently working at developing FRA screening test for women highly susceptible to have an autistic child (genetic predisposition or women who already had an autistic child).

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