Vitamin B9, It’s importance and relevance in Autism

Vitamin B9, otherwise referred to as folate, is essential for several critical biological processes in the human body. The word “folate” is derived from the Latin word “folium,” which means “leaf.” This etymology reflects the fact that folate is abundant in leafy green vegetables. Folate is very important as is tied to many roles that are vital for human biology. Some of these roles are related to:

• Cell Growth and Division: Folate is crucial for the synthesis of nucleotides, the building blocks of DNA and RNA. This makes it vital for cell division and growth, particularly during periods of rapid growth such as pregnancy, infancy, and adolescence.
• DNA Repair: Folate is involved in the repair of DNA, helping to maintain the integrity of genetic material.

• Neural Tube Defects: Adequate folate intake before and during early pregnancy is crucial for preventing neural tube defects (NTDs) in the developing fetus, such as spina bifida and anencephaly.
• Brain Development: Folate is important for proper brain development and function, making it essential during fetal development and early childhood.

• Epigenetic Regulation: Folate is a donor of methyl groups used in various methylation reactions that regulate gene expression and epigenetic modifications. These processes are essential for normal development and cellular function.

• Amino Acid Synthesis: Folate is required for the metabolism of amino acids, which are the building blocks of proteins. This is vital for overall growth, repair, and maintenance of body tissues.

• Cardiovascular Health: Folate helps convert homocysteine, an amino acid that can be harmful at high levels, into methionine, another amino acid. Elevated homocysteine levels are associated with an increased risk of cardiovascular diseases, so adequate folate intake can help reduce this risk.

• Preventing Anemia: Folate is necessary for the production and maturation of red blood cells. A deficiency in folate can lead to megaloblastic anemia, characterized by the production of abnormally large and immature red blood cells.

• Mood Regulation: Folate is involved in the production of neurotransmitters like serotonin, which regulate mood. Low levels of folate have been linked to depression and other mood disorders.
• Cognitive Function: Folate plays a role in cognitive functions, and its deficiency has been associated with cognitive decline and an increased risk of dementia.

As seen in the above-mentioned roles, Vitamin B9 (folate) is indispensable for numerous bodily functions. Ensuring adequate intake of this vitamin is crucial for maintaining overall health and preventing various health conditions. Vitamin B9 is a water-soluble vitamin and can be found in a few different sources. These sources include:

Natural Food Sources: Leafy green vegetables (like spinach and kale), fruits (like oranges and bananas), nuts, beans, peas, and dairy products.

Fortified Foods: Many cereals and grain products are fortified with folic acid, which is a synthetic, non-natural, form. Folic acid is readily available and cheap.

Supplements: Available in tablet form, often included in multivitamins and prenatal vitamins. There are a few other forms of folate found is supplement form that include folic.

• Adults: 400 micrograms (mcg) of dietary folate equivalents (DFE) per day.
• Pregnant Women: 600 mcg DFE per day.
• Breastfeeding Women: 500 mcg DFE per day.

Ensuring adequate intake of Vitamin B9 through a balanced diet or supplements is important for overall health and well-being.

Vitamin B9 is transported into the body through a series of processes that involve digestion, absorption, and cellular uptake. In general, the following steps are involved:

1. Dietary Folate:
   • Folate from food is present as polyglutamates, which need to be converted to monoglutamates before absorption.
   • Enzymes in the small intestine, particularly in the jejunum, break down polyglutamates to monoglutamates.
2. Folic Acid (Supplement Form):
   • Folic acid in supplements and fortified foods is already in monoglutamate form, which is readily absorbed.
3. Absorption Mechanism:
   • The monoglutamate form of folate is absorbed primarily in the upper part of the small intestine (duodenum and jejunum).
   • Transport occurs through a proton-coupled folate transporter (PCFT) located in the intestinal cells’ apical membrane.

• Once inside the intestinal cells, folate is converted to 5-methyltetrahydrofolate (5-MTHF), the primary form of folate circulating in the blood.
• 5-MTHF is then released into the bloodstream and transported to various tissues.

• Folate receptors on the surface of cells recognize and bind to 5-MTHF.
• The folate-receptor complex is internalized by receptor-mediated endocytosis.
• Inside the cell, folate is released from the receptor and utilized for various cellular functions, including DNA synthesis and repair.

• Once inside the cell, 5-MTHF can be converted to other folate forms that participate in various metabolic pathways.
• Folate is essential for the synthesis of nucleotides and amino acids, and for the methylation of homocysteine to methionine.

• The liver stores a significant amount of folate and regulates its release into the bloodstream.
• Excess folate is excreted in the urine, ensuring that the body maintains adequate levels.

The major transporters of folate are Proton-Coupled Folate Transporter (PCFT), Reduced Folate Carrier (RFC), and Folate Receptor Alpha (Fra).

1. Proton-Coupled Folate Transporter (PCFT)
   • PCFT is the primary transporter responsible for the absorption of folate in the small intestine and its transport into cells.
   • It functions optimally in an acidic environment, which is typically found in the intestines.
   • PCFT transports folate across the cell membrane by coupling its transport to the inward movement of protons (H+ ions).
2. Reduced Folate Carrier (RFC)
   • RFC is another important transporter for folate uptake into cells, especially at physiological pH.
   • It facilitates the bidirectional transport of reduced folates, including 5-methyltetrahydrofolate (5-MTHF), across cell membranes.
   • RFC operates via an anion exchange mechanism, often exchanging folate with organic anions like phosphate.
3. Folate Receptors (FRs)
   • Folate receptors are high-affinity receptors located on the cell surface, particularly in tissues with high folate demand, such as the brain, the placenta, kidneys, and the thyroid.
   • FRs bind folate and folate conjugates with high affinity.
   • After binding folate, the receptor-folate complex is internalized into the cell via receptor-mediated endocytosis.

About a decade ago a specific autoantibody was discovered that targeted the Folate Receptor Alpha. Such an autoantibody was found to block the function of folate receptor alpha, meaning that it could not bind and transport folate.

Folate receptor autoantibodies (FRAAs) have significant implications for health, particularly concerning conditions related to folate transport and utilization. These autoantibodies are immune system proteins that mistakenly target and bind to the body’s own folate receptors, potentially disrupting normal folate function.

Research has found a much higher prevalence of FRAAs in children with Autism Spectrum Disorder. The presence of these autoantibodies can interfere with folate transport across the blood-brain barrier, potentially contributing to neurological development issues such as Autism.

It is thought that FRAAs can block folate receptors in the brain, leading to symptoms like Autism Spectrum Disorder, developmental delays, irritability, movement disorders, and seizures. This condition is characterized by low levels of folate in the brain despite normal blood folate levels.

There is also emerging evidence linking FRAAs to various neuropsychiatric conditions, including depression and schizophrenia, potentially due to disrupted folate metabolism in the brain.

In cases where FRAAs are detected, high-dose folate supplements (such as folinic acid) may be recommended to bypass the blocked receptors and ensure adequate folate reaches the brain and other tissues. In fact, previous clinical trials have shown marked improvement in children with ASD that were positive for folate receptor autoantibodies and treated with high dose folinic acid. This is a very promising development. Although further trials may be necessary to confirm and elucidate the actual mechanisms behind this, it is thought that folinic acid is able to bypass the dysfunctional folate receptor alpha and enter the brain via the reduced folate carrier. Indeed, promising research and studies!