What is the role of Vitamin B9 variants in Child Development and their link to ASD?

Vitamin B9, also known as Folate, is a water-soluble B-vitamin that is essential for various bodily functions, including DNA synthesis, cell division, and amino acid metabolism. It plays a crucial role in the production of red blood cells and in the synthesis of DNA and RNA.

Folate is particularly important during periods of rapid cell division and growth, such as pregnancy and infancy. Adequate folate intake is essential for preventing neural tube defects in developing fetuses.

Folate is a natural compound found in many foods, particularly in leafy green vegetables, legumes, fruits, and fortified grains. It is naturally occurring in these foods and is essential for various biological functions in the body. The folate name is derived from the Latin word “folium,” which means leaf.

So, in essence, Folate is a generic name for a group of related compounds with similar nutritional properties. While folate occurs naturally in foods, its synthetic form, folic acid, is also commonly used in dietary supplements and fortified foods to help prevent deficiencies.

Before entering your bloodstream, your digestive system converts folate to the biologically active form of vitamin B9 ⁠— 5-MTHF (5-methyltetrahydrofolate). The active form of vitamin B9 is a type of folate known as levomefolic acid or
5-methyltetrahydrofolate (5-MTHF). Again, different names for the same substance. Who wouldn’t get confused!

Again, “technically” Folate and folic acid are different forms of vitamin B9. While there’s a distinct difference between the two, their names have often been mixed together garnering confusion.

Low levels of vitamin B9 have been associated with an increased risk of several health conditions, including:

• Birth defects: Low folate levels in pregnant women have been linked to birth abnormalities, such as neural tube defects.
• Megaloblastic Anemia: Folate deficiency can lead to the production of large, immature red blood cells, resulting in symptoms of anemia such as fatigue, weakness, pale skin, shortness of breath, and dizziness.
• Gastrointestinal Symptoms: Individuals with folate deficiency may experience gastrointestinal symptoms such as diarrhea, loss of appetite, and weight loss.
• Neurological Symptoms: Folate plays a role in nerve function, and deficiency can lead to neurological symptoms such as irritability, forgetfulness, confusion, depression, and in severe cases, peripheral neuropathy (nerve damage) characterized by tingling or numbness in the hands and feet.
• Tongue and Mouth Changes: Folate deficiency may cause changes in the tongue, such as a swollen, red, or smooth appearance. Mouth sores or ulcers may also occur.
• Poor Growth in Infants and Children: In infants and children, folate deficiency can lead to poor growth and delayed development.
• Increased Susceptibility to Infections: Folate deficiency may weaken the immune system, leading to an increased susceptibility to infections.
• Elevated Homocysteine Levels: Folate deficiency can result in elevated levels of homocysteine, an amino acid associated with an increased risk of cardiovascular disease.

For these reasons, supplementing with a vitamin B9 known as folic acid is common. Fortifying food with this nutrient in an effort to prevent neural tube defects has been mandatory in many countries, including the United States and Canada

In order for your body to use folic acid, however, it must first be converted into an active form with the help of an enzyme (DHFR). From there, it’ll need to further convert into methylfolate (via enzyme MTHFR) before finally being used by the body. This is a long process that for most won’t even convert all the folic acid you consumed into the form your body needs to function, L-Methylfolate.

Unlike folate, not all of the folic acid you consume is converted into the active form of vitamin B9 — 5-MTHF — in your digestive system. Instead, it needs to be converted in your liver or other tissues. This process is slow and inefficient in some people. After consuming folic acid, it takes time for your body to convert all of it to 5-MTHF. Even a small dose, such as 200 to 400 mcg per day, may not be completely metabolized until the next dose is taken. This problem may become worse when fortified foods are consumed in addition to taking folic acid supplements. As a result, unmetabolized folic acid is commonly detected in people’s bloodstreams. We do not know the long-term effects of this, which may be a cause for concern, as high levels of unmetabolized folic acid have been associated with several health problems. Further studies are necessary to determine whether there are definite health implications with respect to this.

As mentioned prior, folate, or folic acid, needs to be reduced to its bioavailable equivalent, which is 5-mthf. While folic acid supplementation hasn’t been established for children, the National Institutes of Health does have a recommended amount for children above the age of one. For any child aged one to three, they should be getting 300mcg per day. This number will jump up to 400mcg from the age of four to eight, and then 600mcg from age 9-13. As a parent, you’ll have to ensure your toddler/child is receiving enough folate in their diet. Of course, the best way to do this will be through a healthy diet and healthy eating habits.

Upon consumption and conversion, the reduced folate (5-methyltetrahydrofolate) needs to be transported into the various tissues and cells that require and demand it. This is very important, as reduced folate needs to reach its final destination for proper use and biological function. Folate receptor alpha is one of the most important transporters of reduced folate into the brain.

Folate receptor alpha (FRα) is involved in transporting 5-methyltetrahydrofolate (5-MTHF), the active form of folate, across the blood-brain barrier into the brain with great efficiency. The blood-brain barrier is a selectively permeable membrane that separates the bloodstream from the brain and central nervous system, regulating the passage of substances between the two. FRα is expressed on the surface of cells in the blood-brain barrier, particularly on endothelial cells that line the capillaries supplying the brain. FRα binds specifically to folate molecules, mostly 5-MTHF, and facilitates their transport from the bloodstream into the brain. Once inside the brain, 5-MTHF is utilized in various biochemical processes, including the synthesis of neurotransmitters and DNA repair, which are essential for proper neurological function.

This mechanism ensures that the brain receives an adequate supply of folate for its metabolic needs, contributing to neurological health and function. This is critical.

However, can there be an instance where such folate transport is inhibited and has detrimental effects? Remarkably, it was discovered that there exist autoantibodies to this main folate transporter (folate receptor alpha) that block the transport of 5-mthf into and across the blood barrier. In such cases, it is assumed that reduced folate cannot get into the brain. And, even more remarkably, studies have shown that a significant percentage of children that are on the autism spectrum (well over 55%) have tested positive for these autoantibodies (folate receptor autoantibodies). Can it be that in these cases, folate receptor autoantibodies impede the proper transport into the brain, affecting children with ASD? Many studies have now been pointing to this. Folate is so critical, and if folate cannot get into the brain, then there is no doubt that neurological issues can and will arise. Although young children may be consuming the recommended among of folate, it may be that this folate cannot be distributed into the brain properly because of the presence of folate receptor autoantibodies, that impede its transport. In these instances, a new medical condition has been identified and termed Cerebral Folate Deficiency Syndrome. This all-important folate is clearly not able to cross into the brain, resulting in deleterious effects.

A test termed FRAT^® is available to screen for these folate receptor autoantibodies. Interestingly, once these autoantibodies have been identified, folinic acid is prescribed and subsequent results have been very promising. Children with ASD have shown marked improvement in language and communication skills. It seems that folinic acid is able to bypass the blocked folate receptor and enter the brain though another receptor known as the reduced folate character. Results have been very promising thus far.