Illustration showing the impact of folinic acid supplementation and folate receptor autoantibodies on neurodevelopmental and autism spectrum disorders.

Vitamin B9, also known as folate, is an essential vitamin for several important functions in the body.

  • Prevention of Neural Tube Defects: Adequate folate intake is crucial for pregnant women to prevent neural tube defects in the developing fetus. Neural tube defects are serious birth defects affecting the brain and spinal cord.
  • Cell Division and DNA Synthesis: Folate is crucial for cell division and the synthesis of DNA. It plays a vital role in the formation of new cells, especially during periods of rapid growth, such as pregnancy and infancy.
  • Methylation Reactions: Folate is involved in various methylation reactions in the body, which are essential for the synthesis of neurotransmitters, DNA repair, and the regulation of gene expression. This is important for many neurological functions.
  • Immune System Function: Folate is necessary for the proper functioning of the immune system, helping the body defend against infections and diseases.
  • Supports Cognitive Function: Adequate levels of folate are important for maintaining cognitive function and may play a role in preventing cognitive decline associated with aging.
  • Homocysteine Regulation: Folate, along with vitamins B6 and B12, helps regulate the levels of homocysteine in the blood. Elevated homocysteine levels are associated with an increased risk of cardiovascular diseases and cerebral vascular disorders, which may lead to neurodevelopmental delays and associated issues.
  • Detoxification: Folate is involved in detoxification processes in the liver, helping the body eliminate certain toxins.
  • Red Blood Cell Formation: Folate is involved in the production of red blood cells. It helps prevent anemia by supporting the maturation of red blood cells in the bone marrow.

As seen in the above, highlighting the many aspects of how folate affects the body, it is exceedingly important to obtain sufficient folate through diet or supplements. If folate is not adequate, cellular metabolism and replication is interrupted. This is most critical during fetal and neonatal development because inadequate folate during this period can result in interruptions in brain development leading to structural abnormalities that produce functional deficits of what is now termed CFD (Cerebral Folate Deficiency) syndrome.

Folate is metabolized in the body and transported to individual cells through various folate receptors/transporters. The primary receptors involved in folate uptake include:

  • Folate Receptor Alpha (FRα):
    • FRα is a glycosylphosphatidylinositol (GPI)-anchored protein expressed on the cell surface. It has a high affinity for 5-methyltetrahydrofolate (5-MTHF), the active form of folate. FRα is involved in the endocytosis of folate, allowing its internalization into the cell.
  • Reduced Folate Carrier (RFC):
    • RFC is a transmembrane protein that transports various forms of folate, including folic acid and reduced folates, across the cell membrane. RFC is found in many cell types and is responsible for the uptake of folate into cells, where it can undergo intracellular conversion to active forms like 5-MTHF.
  • Proton Coupled Folate Transporter (PCFT):
    • Proton Coupled Folate Transporter facilitates the uptake of folates, including folic acid and reduced folates, across the cell membrane. It is particularly important in the acidic environment of the proximal small intestine.

These receptors play a crucial role in the regulation of folate homeostasis within the body. The presence of specific receptors allows for targeted uptake of folate into cells with varying folate needs, ensuring that the vitamin is efficiently delivered to tissues where it is required for processes such as DNA synthesis, cell division, and methylation reactions. The diversity of folate receptors enables the uptake of folate in different cell types and physiological conditions. One of the most important folate transport receptors to the brain and choroid plexus is the Folate Receptor Alpha.

More recently, researchers have discovered specific autoantibodies (folate receptor autoantibodies) that attack folate receptor alpha and hinder it dysfunctional. In other words, these autoantibodies (and there are 2 distinct types – blocking and binding) affect the function of the folate receptor alpha by either completely blocking it (blocking autoantibodies) or clogging it (binding autoantibodies). In both cases, the folate receptor alpha becomes inhibited thereby not being able to properly transport folate into the surrounding cells. This certainly becomes a problem.

Interestingly, many children with autism spectrum disorders have tested positive for folate receptor autoantibodies. With this in mind, it may be assumed that in these cases (positive for folate receptor autoantibodies) not enough folate is being delivered into the brain. Even more interesting is that research and several trials have shown that the administration of folinic acid has greatly improved speech and communication skills and some behaviors in children that have tested positive for the autoantibodies. It is thought that in these cases, folinic acid – a reduced folate – is able to bypass the blocked folate receptor alpha and be transported into the brain through another receptor, notably the reduced folate carrier. More research is needed to validate this strategy, but it seems to be a very good start! The results have been very positive.

It is strongly recommended that the testing for folate receptor autoantibodies be done as soon as possible, once any neurodevelopmental, neuropsychiatric disorder may be suspected. The reasoning here, and evidenced in many cases, is that early detection will allow for early intervention when brain plasticity is still amenable to changes. Generally, younger children that have participated in earlier intervention with folinic acid have made greater improvements. Because of this reasoning, early testing is highly stressed. The FRAT® test will screen for both blocking and binding antibodies.

As with any medical condition a physician’s participation is required. Please consult your medical professional for further information.

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