Folate, or vitamin B9, plays a vital role in the functioning of the body. It is essential for the synthesis of DNA and RNA, regulates methylation, and supports normal cell growth and development. A deficiency of folate in the brain can lead to serious consequences, including cognitive and neurological disorders.
Upon consumption, folates are absorbed in the intestine and transported to various organs via the folate receptor alpha (FRα). Under normal conditions, the folate level in cerebrospinal fluid (CSF) should be 2-3 times higher than in blood. However, in some individuals, blood folate levels may remain within the normal range while the delivery of folate to the brain is inadequate.
Research shows that a deficiency of folate in the central nervous system is often associated with the presence of autoimmune antibodies to folate receptors (FRAA), which hinder their transport to the brain. This condition correlates with a number of serious disorders, such as developmental delays, autism, and depression, highlighting the importance of understanding the mechanisms involved in folate transport.
Now, let’s explore these issues in more detail.
History of Research
Research in this area has been conducted recently. Here is a brief overview of the history of studies related to folate deficiency and antibodies to folate receptors (FRAA):
- 2002 – The cerebral folate deficiency (CFD) syndrome was first identified in children, characterized by low levels of folate in the brain, which can lead to cognitive and neuropsychological disorders. This rare disease may occur more frequently than recognized, as symptoms can be masked by other conditions.
- 2005-2008 – FRAA were discovered in patients with CFD, confirming the hypothesis of possible autoimmune blockade of folate and hindrance of its normal delivery to the brain.
- 2011 – FRAA began to be associated with fertility problems and embryo implantation, indicating the impact of antibodies on women’s reproductive health.
- 2013 – A possible link between FRAA and autism in children was found, providing new grounds to suggest the influence of antibodies on neuropsychological development in early childhood.
- 2013 – In addition to a possible connection with autism, data emerged regarding the impact of FRAA on the development of PANS/PANDAS syndromes in children. These syndromes are associated with inflammatory processes in the brain that provoke behavioural and neuropsychological disorders.
- 2015-2017 – Research indicated that FRAA could be linked to depression, anxiety disorders, and other autoimmune diseases affecting mental health.
- 2020s – Recent studies have shown a connection between FRAA and dementia, as well as other neurodegenerative diseases. It is hypothesized that these antibodies may negatively affect folate metabolism in the brain, exacerbating neurodegenerative processes with age. It has also been established that the quantity of FRAA increases with age, which may lead to more frequent issues in the elderly population.
Impact of Antibodies to Folate Receptors on Health
Cerebral folate deficiency syndromes are associated with impaired folate delivery to the brain, which can occur at any age, starting from pregnancy. Let’s take a closer look at the list of potential problems linked to FRAA.
- Fertility Issues: Difficulties with conception and embryo implantation.
- Neural Tube Defects: Disorders related to neural tube formation, which are particularly significant in early pregnancy (first trimester).
- Cognitive Impairments: Developmental delays, speech delays, memory problems, brain fog, and dementia.
- Neurological Disorders: Including autism, PANS/PANDAS, epilepsy, depression, suicidal thoughts, and attention deficit hyperactivity disorder (ADHD).
- Motor Disorders: Including motor tics (involuntary, repetitive movements), dyskinesia (impaired coordination of movements), myoclonus (sudden, brief muscle jerks), and seizures.
- Psychiatric Symptoms: Anxiety and behavioural disorders.
- Physical Symptoms: Fatigue, headaches, and skin issues (eczema).
- Nutritional Problems: Decreased appetite and limited diet.
This list highlights the diversity of conditions that may be associated with disruptions in folate metabolism and the presence of FRAA. Furthermore, the issue may worsen with age, dietary changes, and other external factors. In all these cases, antibody levels may fluctuate.
Some Statistics
Research shows that FRAA are found in approximately 10-15% of the adult population as a whole. Among children with autism spectrum disorder (ASD), the prevalence of FRAA is significantly higher—around 75%. This indicates a possible connection between FRAA and autism, presumably due to impaired folate transport to the brain, which can lead to neurological problems. It has also been found that over 60% of children with PANS and PANDAS syndromes have FRAA.
Additionally, studies show that in families of children with autism, the level of FRAA is noticeably higher than in families without ASD. For instance, one study found that 26% of mothers and 18% of fathers of children with ASD have these antibodies, compared to about 3% of parents of neurotypical children. This suggests a potential genetic predisposition to producing these antibodies, which may impact fetal brain development and increase the risk of disorders associated with these antibodies.
Two Types of Antibodies to Folate Receptors
Folate receptor autoantibodies (FRAA) exist in two types:
- Blocking Antibodies: These antibodies prevent folate from binding to the receptor, disrupting the transport of folate to the brain. They are found in 60% of autistic children.
- Binding Antibodies: These antibodies attach to the receptor but do not directly block folate access. Instead, they may alter the functionality of the receptor, potentially reducing its effectiveness. They are found in 50% of autistic children.
On average, 75% of autistic children have at least one type of folate receptor antibody.
Testing Folate Receptor Antibody Levels
The FRAT® (Folate Receptor Autoantibody Test) can be conducted in an American laboratory that analyzes blood for both types of antibodies. It’s important to note that this test does not measure folate levels in cerebrospinal fluid; it only shows antibody levels.
Therefore, diagnosing issues related to low folate levels without the influence of antibodies requires performing a lumbar puncture. However, such cases are significantly less common than cases of low folate levels in cerebrospinal fluid associated with the presence of folate receptor antibodies.
Main Types of Folates Circulating in Our Bodies
Let’s clarify some terminology. You may have heard that high levels of folate can cause problems. This information actually pertains to folic acid. Now, let’s take a closer look at the various types of folates.
- FoLIC Acid: This is the synthetic form of folate used in supplements and fortified foods (most commonly containing gluten). Its conversion into active forms requires the involvement of the liver and other tissues. It’s important to note that folic acid can block the conversion of folate in the body. If too much is ingested, it can be critical for certain individuals with genetic mutations (e.g., MTHFR – methylenetetrahydrofolate reductase). Folic acid is sometimes used in small therapeutic doses to slow down the methylation process when necessary, i.e., in cases of excessive methylation.
- 5-Methyltetrahydrofolate (5-MTHF): This is the primary active form of folate in the body, involved in metabolic processes. It can cross the blood-brain barrier and plays a crucial role in DNA synthesis and methylation. This form of folate does not block folate metabolism, but it cannot cross the blood-brain barrier in the presence of FRAA.
- FoLINIC Acid: Also known as the calcium salt of 5-methyltetrahydrofolate. It is used medically to treat folate deficiency and may be more effective, especially when absorption issues arise. Folinic acid uses a different transport mechanism to enter the brain, which is not blocked by folate antibodies. Once in the brain, it is converted into 5-methyltetrahydrofolate (5-MTHF), which is particularly important for correcting folate levels in the brain in the presence of FRAA. This underscores the importance of taking folinic acid to improve neurological health in patients with FRα antibodies and symptoms of cerebral folate deficiency (CFD). Despite being better absorbed by the body, in Canada, it can only be obtained by prescription.
Connection to Other Autoimmune Disorders
The presence of FRAA may indicate a predisposition to autoimmune diseases in general, especially if other risk factors are present, such as genetic mutations or environmental exposures. This is because the immune system may attack the body’s own tissues, including folate receptors.
Dietary Influences
Dairy Products
Milk can increase levels of folate receptor antibodies (FRAA), particularly in individuals with certain genetic predispositions or autoimmune conditions. All types of milk, including sheep, goat, camel, and cow’s milk, contain proteins similar to the folate receptor, such as alpha-casein. If you have heard that a certain type of milk does not cause this issue, that is not true; all types of milk can have this effect.
In people with FRAA, these proteins can trigger an immune response, as the immune system mistakenly identifies them as threats. This can lead to elevated antibodies against the folate receptor, exacerbating folate deficiency in the brain and potentially contributing to various neurological disorders.
Breast milk, unlike cow’s milk and other types of milk, typically does not induce the formation of folate receptor antibodies (FRAA). It contains protective factors that support immunity and guard against the development of autoimmune reactions. Breast milk has immunomodulatory components, such as immunoglobulins, lactoferrin, and oligosaccharides, which promote the healthy development of the immune system in infants. This composition makes it less likely to trigger immune reactions or the formation of folate receptor antibodies.
Gluten-Fortified Foods
Folic acid and natural folates have different effects on health. Folic acid, used in supplements and fortified gluten-containing products, requires metabolism into active forms, which can be problematic for individuals with genetic mutations such as MTHFR. These mutations can hinder the conversion of folic acid, leading to the accumulation of toxic metabolites and disruption of the folate cycle.
Moreover, folic acid can block folate metabolism, especially in individuals with FRAA or gluten sensitivity, which can worsen folate deficiency in body tissues, including the spinal and brain tissues.
Therapy for Increasing Folate Levels in the Brain
Currently, the treatment of all the aforementioned issues (except for preventing neural tube closure defects in the first trimester of pregnancy) is still under investigation. Researchers are using high doses of folinic acid to saturate the blood with the active form of folate. The most commonly mentioned dose in studies is 2 mg per kilogram of body weight, but no more than 50 mg per day. This significantly exceeds the recommended intake of folate, even during pregnancy.
The therapy is conducted after testing, and researchers use the prescription medication folinic acid (Leucovorin). The dose is gradually increased over six weeks. After achieving the desired effect (which may take up to 12 weeks), the dosage can be reduced, also gradually over six weeks. Researchers ensure that the therapeutic effect can be maintained in some cases even after therapy is discontinued.
During this therapy, it may be recommended to limit the intake of dairy products and gluten-containing foods to enhance the effectiveness of the treatment. Therapy is always conducted under the supervision of qualified specialists; it has its indications, contraindications, and a range of side effects that need to be monitored and managed.
Symptoms that Therapy May Help Address
The following is a list of symptoms that may improve with folinic acid therapy in patients with autism, as well as in those with PANS/PANDAS. It is important to note that improvements in other areas may be expected for other conditions:
- Reduced Anxiety: Decrease in anxious states.
- Improved Mood: Reduction in depression and mood swings.
- Enhanced Cognitive Functions: Increased concentration and learning skills.
- Decreased Obsessive-Compulsive Symptoms: Reduction in manifestations of obsessive-compulsive disorder.
- Improved Motor Function: Decrease in motor disorders (tics, dyskinesia).
- Reduced Irritability: Decrease in aggression and overall irritability.
- Enhanced Social Skills: Increased ability to interact with others.
- Reduced Hyperactivity: Decrease in symptoms of hyperactivity and impulsivity.
- Improved Speech Skills: Increased ability to express thoughts and communicate.
- Reduced Seizures: Decrease in seizure frequency or severity.
This list includes the main symptoms that may improve as a result of therapy, but individual results may vary.
Conclusion
Folate and folate receptor antibodies (FRAA) play a significant role in neurology, affecting the metabolism and functioning of the brain. Low levels of folate are associated with an increased risk of neurological disorders, including autism, PANS/PANDAS, depression, and dementia. FRAA, in turn, may indicate immune disorders and potentially serve as markers for diagnosing other autoimmune diseases. Increasing folate levels in the body and monitoring FRAA could become an important direction for the prevention and treatment of neurological diseases in the future.
Frye RE, Slattery JC, Quadros EV. Folate metabolism abnormalities in autism: potential biomarkers. Expert Rev Mol Diagn. 2017;17(7):687-99. doi: 10.2217/bmm-2017-0109.Bobrowski-Khoury N, Ramaekers VT, Sequeira JM, Quadros EV. Folate receptor alpha autoantibodies in autism spectrum disorders: diagnosis, treatment and prevention. J Pers Med. 2021 Jul 24;11(8):710. doi: 10.3390/jpm11080710.