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
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
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.
How can FR autoantibodies (FRA) affect my child neurodevelopment while pregnant?
- 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”:
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).