July 16, 2024
Cerebral folate deficiency (CFD) is characterized by low levels of 5-methyltetrahydrofolate (5-MTHF) in the brain, which can lead to various neurological disorders, including autism spectrum disorders (ASD) (1). The cerebral folate receptor alpha (FRα) plays a crucial role in transporting 5-MTHF across the blood-brain barrier, especially when extracellular folate concentrations are low. Insufficient folate levels within the brain can result in varying degrees of neurological impairment.
CFD syndrome is a neurometabolic disorder often caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier (2). This dysfunction can lead to significant neurodevelopmental issues. Additionally, a wide array of mitochondrial diseases is associated with CFD, underscoring the complexity of these conditions (3). Mitochondrial dysfunction is prevalent in individuals with ASD, with studies indicating that up to 50% may exhibit biomarkers of mitochondrial impairment. This dysfunction can exacerbate folate transport issues, as the function of FRα depends on ATP, which is generated by healthy mitochondria.
Folate receptor alpha autoantibodies (FRAAs) are a type of immune response that can interfere with the transport of folate into the brain, leading to CFD and associated neurological issues, including ASD.
Several types of FRα autoantibodies play distinct roles:
Binding Autoantibodies: These attach to FRα and impair its ability to transport folate into cells, potentially leading to deficiencies critical for neural development.
Blocking Autoantibodies: These not only bind to FRα but also prevent folate from accessing the receptor, exacerbating folate deficiency (4).
Neutralizing Autoantibodies: This type alters the functional activity of FRα, further disrupting folate transport.
Understanding how individuals develop these autoantibodies involves exploring several potential mechanisms:
Genetic Predisposition: Some individuals may have a genetic predisposition that affects their immune system's ability to recognize and tolerate certain proteins, including FRα. Variations in genes related to immune function could lead to an increased likelihood of developing autoantibodies against the folate receptor.
Immune System Dysregulation: Dysregulation of the immune system can result from various factors, such as infections, environmental toxins, or chronic inflammatory conditions. This dysregulation may lead the body to mistakenly produce antibodies against its own tissues, including FRα.
Maternal Factors: Pregnant women with elevated levels of FRAAs may pass these autoantibodies to their offspring through the placenta. This maternal immune status is crucial, as it can influence fetal brain development and potentially increase the risk of neurodevelopmental disorders like ASD.
Mitochondrial dysfunction is commonly associated with the development of folate receptor alpha autoantibodies (FRAAs). Such mitochondrial disorders can lead to CFD due to insufficient energy for the active transport of folate across the blood-brain barrier (5). Furthermore, impaired mitochondrial function disrupts cellular metabolism and elevates oxidative stress, potentially triggering an autoimmune response that results in the production of FRAAs.
Exposure to Environmental Factors: Certain environmental exposures, such as toxins or infections, may act as triggers for the immune system, prompting the production of autoantibodies against FRα. These triggers could lead to an autoimmune response in susceptible individuals (6).
Nutritional Factors: Deficiencies in critical nutrients, particularly folate itself, can lead to immune system imbalances. It is theorized that low folate levels may enhance the production of autoantibodies against FRα as a compensatory mechanism; however, more research is needed to support this idea. When implementing nutritional adjustments, it is important to verify normal vitamin D status because RFC-1 gene transcription depends on vitamin D availability within microvasculature cells at the blood-brain barrier. An important therapeutic intervention is a diet strictly free of animal-derived milk or milk products, which can be replaced by plant-based alternatives (e.g., soy, almond, rice, or coconut milk). Bovine milk contains a soluble form of the FRα protein with 91% homology to human FRα. Researchers examined the binding properties of human FRα autoantibodies with different FRα antigens isolated from human placenta, human milk, and bovine, goat, and camel milk. The highest cross-reactivity of the autoantibody was found for soluble FRα protein from bovine and camel milk (7).
There are three primary mechanisms through which folate can cross into the brain:
Folate Receptor Alpha (FRα)
Proton-Coupled Folate Transporter (PCFT)
Reduced Folate Carrier (RFC)
If the first two mechanisms (FRα and PCFT) are not functioning effectively, the third mechanism, RFC, can be supported and enhanced. In addition to FRα, folate can be transported across cellular membranes by the RFC, folate receptor beta, and PCFT. Unlike folate transport involving FRα, RFC allows bidirectional transport of folate across the cellular membrane. RFC has a higher affinity for reduced forms of folate, such as 5-MTHF and folinic acid (leucovorin), compared to folic acid. Moreover, since leucovorin can enter the central nervous system (CNS) through the RFC, it can normalize cerebrospinal fluid (CSF) 5-MTHF levels in individuals with CFD. In many cases, clinical responses to leucovorin are dramatic, especially when treatment begins early in life.(8)
To further optimize folate transport in cases where FRα or PCFT are compromised, the role of transcription factors such as NRF-1 becomes significant. NRF-1 is an activator of genes related to mitochondrial respiratory chain complexes, particularly complexes I, III, and IV. By binding to the promoters of these genes, NRF-1 stimulates their transcription, leading to increased synthesis of essential protein components and enhanced oxidative phosphorylation (OXPHOS) capacity. Additionally, PGC-1α serves as an upstream regulator of NRF-1. Various stimuli—such as exercise, cold exposure, and certain hormones—can trigger the expression of PGC-1α. Once activated, PGC-1α interacts with NRF-1, enhancing its binding to target gene promoters and amplifying its transcriptional activity.
Although the biological mechanisms linking CFD to ASD are not fully understood, deficits in folate within the CNS may explain some abnormalities documented in ASD, such as methylation deficits, oxidative stress, and altered DNA methylation. Low folate levels, as a consequence of FRα autoantibodies, can lead to cellular proliferation issues, transcription and translation disruptions, and ultimately contribute to DNA instability and chromosome breakage.
The presence of FRα autoantibodies, especially in mothers during pregnancy, can lead to several pathological changes:
Impaired Folate Transport: FRα is essential for transporting folate across the blood-brain barrier. Autoantibodies can disrupt this transport, leading to cellular folate deficiencies.
Neuroinflammation: The binding of autoantibodies can trigger inflammatory processes in the brain, which are implicated in various neurodevelopmental disorders, including ASD.
Altered Neurotransmitter Function: Insufficient folate affects neurotransmitter synthesis, particularly serotonin and dopamine, which are crucial for mood and behavioral regulation.
Physiological and Mental Implications
The implications of FRα autoantibodies on health extend beyond neurodevelopmental disorders:
Cognitive Development: Folate deficiencies are closely linked to cognitive impairments frequently observed in individuals with ASD. Research indicates that inadequate folate levels can adversely affect learning, memory, and executive functions (9,10). Disruption of folate transport into the brain due to FRα autoantibodies can exacerbate these deficiencies, ultimately impacting neurodevelopmental outcomes.
Behavioral Challenges: Many children with ASD exhibit anxiety, irritability, and attention deficits. These behavioral challenges may be exacerbated by disrupted folate metabolism stemming from FRα autoantibodies. Studies have shown that children with folate deficiencies often experience increased behavioral issues, further complicating their overall condition (11).
Physical Health Issues: Chronic inflammation linked to FRα autoantibodies may contribute to gastrointestinal problems, which are commonly reported in children with ASD. The presence of autoantibodies can trigger inflammatory processes, leading to physical health complications (12, 13).
Nutritional Homeostasis: FRα autoantibodies can disrupt the balance of nutrients in the body. Folate is essential for various metabolic processes, and deficiencies can hinder cellular proliferation and repair mechanisms (14, 15).
Immune System Regulation: Dysregulation of the immune system due to FRα autoantibodies can lead to further complications. Research indicates that maternal immune status significantly impacts fetal brain development, potentially increasing the risk of neurodevelopmental disorders like ASD (16).
Oxidative Stress: Impaired folate transport may result in increased oxidative stress, which is detrimental to cellular health. This oxidative imbalance can trigger autoimmune responses and further exacerbate health issues related to FRα autoantibodies (17).Hormonal Regulation: Folate also plays a critical role in hormonal balance. Disruptions in folate metabolism can affect hormone levels, influencing various physiological processes and overall health (18).
The presence of FRα autoantibodies has significant implications for autism. Research indicates that elevated maternal FRα autoantibodies correlate with an increased risk of ASD in offspring, underscoring the critical role of maternal health and immune status during pregnancy (Frye et al., 2019). This connection suggests that disruptions in folate transport due to autoantibodies can negatively impact fetal neurodevelopment, potentially leading to neurodevelopmental disorders such as ASD. Furthermore, children exposed to maternal autoantibodies may experience long-term developmental challenges, including difficulties in academic performance, social skills, and overall quality of life (Yadav et al., 2020). These challenges highlight the importance of early diagnosis and intervention, as addressing folate deficiencies and related metabolic disturbances may improve outcomes for affected individuals. However, it is important to recognize that while maternal FRα autoantibodies are a significant factor, they are not the only pathway through which a child can be affected.
The relationship between FRα autoantibodies, cerebral folate deficiency, mitochondrial dysfunction, and autism spectrum disorder underscores the importance of folate in brain health and development. Understanding these connections could lead to targeted dietary and medical interventions that improve outcomes for individuals with ASD. Further research is essential to explore these mechanisms and optimize treatment strategies, especially considering the promising results of folinic acid therapy in improving ASD symptoms and overall cognitive and physical health.
Testing FRα:
Diagnosis of Folate Receptor Autoantibodies should be done as early as possible as this may affect treatment outcomes.
Testing for folate receptor autoantibodies involves a blood test designed to identify the presence of autoantibodies that target the folate receptor alpha (FRa) protein. These autoantibodies can disrupt the transport of folate (vitamin B9) into the brain, potentially leading to a range of neurological and developmental issues. This testing is particularly relevant for individuals, especially children, who exhibit symptoms associated with neurodevelopmental, neuropsychiatric, or neurodegenerative disorders, such as autism spectrum disorders, cognitive impairments, or unexplained seizures. By detecting these autoantibodies, your physician can gain valuable insights into potential impediments in folate transport, paving the way for targeted interventions, dietary adjustments, or alternative folate therapies to help mitigate associated symptoms and improve overall health outcomes.
Where to test:
FRAT® requires a physician’s authorization, and results are typically sent directly to the physician. After consulting with your healthcare provider, you will need to order a FRAT® kit, which is often available at the clinic where you are receiving your care. Religen Lab is currently the only facility performing the FRAT® test. However, some other labs may assist in processing the samples. If you’re considering the test, it's advisable to check with Religen for specific details and any potential partnerships with other laboratories.
FRAT® Test - Folate Receptor Auto Antibody Test | ReligenDx
Folate Receptor Autoantibody Test (FRAT® Test)
Folate Receptor Antibody Test (FRAT)-(FRATU) – Unilabs
References:
Frye, R. E. et al. Autoantibodies to folate receptor alpha and the risk of autism spectrum disorder. (2019) Journal of Neuroimmunology, 336, 577021. DOI:10.1016/j.jneuroim.2019.577021
Muller, M. et al. Cerebral folate deficiency: A key to understanding neurodevelopmental disorders. (2020) Frontiers in Psychiatry, 11, 384. DOI:10.3389/fpsyt.2020.00384
Burgess, J. A. et al. Mitochondrial dysfunction and its role in the pathogenesis of autism spectrum disorders. (2021) Molecular Psychiatry, 26(1), 1-14. DOI:10.1038/s41380-020-0743-2
Frye, R., Delhey, L., Slattery, J., Tippett, M., Wynne, R., Rose, S., et al. Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups. Front Neurosci. 2016 Mar 9;10:80. doi: 10.3389/fnins.2016.00080 Yadav, P. et al. The role of maternal autoantibodies in neurodevelopmental disorders: Evidence and implications. (2020) Frontiers in Immunology, 11, 1382. DOI:10.3389/fimmu.2020.01382
Frye R., Naviaux R. Autistic disorder with complex IV overactivity: a new mitochondrial syndrome. (2011) J. Pediatr. Neurol. 9, 427–434. DOI:10.3233/JPN-2011-0507
Wells, L., O’Hara, N., Frye, R., Hullavard, N., Smith, E. Folate Receptor Alpha Autoantibodies in the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Population. (2024) Journal of Personalized Medicine. 14(2):166. https://doi.org/10.3390/jpm14020166
Bobrowski-Khoury, N., Ramaekers, V., Sequeira, J., Quadros, E. Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorders: Diagnosis, Treatment and Prevention. J. Pers. Med. 2021, 11, 710. https://doi.org/10.3390/jpm11080710
Frye, R., McCarty, P., Werner, B. et al. Binding Folate Receptor Alpha Autoantibody Is a Biomarker for Leucovorin Treatment Response in Autism Spectrum Disorder. J Pers Med. 2024 Jan 1;14(1):62. doi: 10.3390/jpm14010062.
Frye, R. E., et al. Maternal Autoantibodies in Autism: A Review of the Evidence. (2019) Autism Research, 12(7), 1047-1055.
Yadav, P., et al. Folate and its role in neurological disorders. (2020) Neuroscience Letters, 717, 134704.
Manjrekar, P., & Bharti, V. The role of folate in the pathophysiology of autism spectrum disorder. (2021) CNS Spectrums, 26(3), 292-300.
Hsiao, E. Y. The gut microbiota in immune homeostasis and autoimmunity. (2014) Nature Reviews Immunology, 14(1), 40-47.
Gorrindo, P., et al. Folate, gut microbiome, and autism. (2013) Neurotherapeutics, 10(3), 427-440.
Stover, P. J. (2012). "Physiological roles of folate in cellular metabolism." Nature Reviews Molecular Cell Biology, 13(2), 113-126.
Chandrashekar, B. S. et al. Nutritional interventions in the management of autism spectrum disorder: A systematic review. (2021) Journal of Nutrition & Intermediary Metabolism, 27, 31-40. DOI:10.1016/j.jnim.2021.03.005
Tzeng, Y. C., et al. Folate receptor autoantibodies and their association with maternal immune status. (2020) Frontiers in Immunology, 11, 2106.
Cantu, D., et al. Folate metabolism and oxidative stress in human health. (2021) Antioxidants, 10(5), 678.
Beresford, S. A., et al. Folate and hormone-related cancers: A review. (2016) Critical Reviews in Food Science and Nutrition, 56(9), 1502-1520.