Cerebral folate deficiency (CFD) results from inadequate folate transport across the blood-brain barrier and is associated with various folate-deficiency pathologies. Cerebral folate deficiency is believed to be most often caused by folate-receptor-alpha blocking and binding autoantibodies that block folate receptor alpha. Incidence of folate receptor antibodies is increased in some people with autism spectrum disorder and schizophrenia.
Cerebral Folate Receptor Antibodies in Autism Spectrum Disorders and Schizophrenia
Evidence suggests a surprisingly large proportion (60%) of children with ASD have folate receptor antibodies resulting in cerebral folate deficiency. Only 4-15% of the general population has blocking antibodies (Frye et al., 2013). Additionally, tetrahydrobiopterin (BH4) levels are decreased in cerebrospinal fluid of autistic individuals. BH4 is produced through utilization of folate, and the reduced BH4 production is theorized to result from reduced folate in the CNS (Tani et al., 1994). In schizophrenia patients, folate receptor antibodies are more prevalent, BH4 is lower, and positive and negative symptoms respond to CFD treatment (V. T. Ramaekers et al., 2014). (See treatments section below.)
Symptoms of Cerebral Folate Deficiency
Cerebral folate deficiency manifests most commonly around 4-6 months of age and results in the following symptoms (Gordon, 2009):
- Delayed development
- Developmental regression
- Deceleration of head growth
- Hypotonia
- Ataxia
- and in 1/3 of children:
- Dyskinesia
- Spasticity
- Speech difficulties
- Epilepsy
- Neural tube defects (when maternal folate receptor antibodies are present in utero)
Folate receptor-alpha is an energy-dependent transporter that forces folate into the central nervous system against a concentration gradient even when serum folate levels are low. Its functioning is essential for adequate folate levels in the brain and for proper brain development.
Causes of Cerebral Folate Deficiency
In cerebral folate deficiency, the most common proximate cause is the presence of autoantibodies that block folate receptor alpha, impeding folate transport into the central nervous system. Impaired mitochondrial function (and resultant ATP insufficiency impairing folate transport into the CNS) is another posited cause of cerebral folate deficiency, along with certain metabolic abnormalities.
Immune Reaction to Dairy
Humoral antibody response to dairy proteins (specifically soluble folate receptors) is the probable upstream cause of most autoantibody development and CFD in general. This autoantibody formation is most likely to develop in the context of intestinal hyperpermeability (Vincent T. Ramaekers et al., 2008).
Fumonisin Exposure from Moldy Corn
Other potential causes include fumonisin toxins from moldy corn. Fumonisins have been found in association with neural tube defects and folate receptor autoantibodies (Gelineau-van Waes et al., 2009; Vojdani, 2008).
Food Fortification with Folic Acid
Conflicting evidence points at increased risk of ASD development from excessive folic acid intake due to industrial fortification of food. Folic acid is a form of folate that under extreme conditions may actually cause aberrant folate uptake into the CNS. How this may relate to cerebral folate levels and CFD during development is not yet clear (Wiens & DeSoto, 2017).
Assessment
History
Symptoms History
Patients presenting with or reporting history of neurological problems, including the symptoms listed above, should be considered at risk of CFD. In one study, 60% of ASD patients were found to have folate-blocking antibodies. Thus, anyone with an ASD diagnosis should be considered as possibly having folate receptor autoantibodies.
Autoimmunity
Interestingly, the existence of folate receptor antibodies in one study was actually negatively correlated with family history of autoimmunity and autoimmune comorbidity. This is in contrast to the fact that ASD development is associated with increased autoimmunity in probands and relatives.
Dairy-free Diet Trial
Parent report of improvement after a dairy-free diet trial may indicate possible folate receptor antibody involvement.
Environmental Exposures
Obtaining an environmental toxin exposure history may prove helpful in ascertaining potential mitochondrial toxins, fumonisin, or other molds or heavy metals.
Laboratory Assessments
Because the problem in CFD involves CNS folate transport, blood levels of folate or other methylation parameters are not useful in diagnosing CFD. Affirmative diagnosis of CFD requires lumbar puncture to ascertain CSF folate levels, but this procedure is not without risk and should be considered carefully against those risks. Since CFD correlates strongly with serum FR-alpha antibodies, however, Frye and Rossignol (2013) recommend that serum folate receptor antibody testing be considered on all ASD patients due to its high likelihood of benefit and lower risk of side effects from lumbar puncture.
Treatment
Treatment of CFD primarily involves folinic acid supplementation and a dairy-free diet.
Folinic acid (aka Leucovorin calcium) supplementation
Normally, folate enters the CNS via active transport through folate receptor alpha. Passive transport of folate into the CNS can occur through the reduced folate carrier even when the alpha receptor is blocked, but only when serum folate levels are high and a concentration gradient favors movement of folate into the CNS. This requires supplemental folate. Folinic acid (Leucovorin calcium; not folic acid) is the form studied in research investigating cerebral folate deficiency, and is thus the form that should be used according to evidence. For CFD, Hansen FJ used 0.5 to 1mg/kg/day DL-folinic acid (half this dose if using L-folinic acid). Frye and Rossignol used leucovorin calcium 2mg/kg/day in ASD patients, with a maximum dose of 50mg per day. It takes an average of 1-3 years to treat CFD, but improvements have been reported after 4 months. These dosages resulted in substantial clinical improvement (Frye et al., 2013).
A pilot study in autistic children with folate receptor antibodies treated with folinic acid reported improvements in communication, social interaction, attention, and stereotypical behavior. Two-thirds of those treated saw some improvement while one-third of patients reported moderate to high improvement in functioning. Some reported dramatic improvement, including complete reversal of autism and CFD symptoms.
Folinic acid should perhaps be avoided or used cautiously in those with aggressive behavior and/or using risperidone because treatment was associated with increased aggression in a small study.
Dairy-free Diet
Strict avoidance of dairy results in reduction of folate receptor autoantibodies. Additionally, many parents of autistic children, in general, report improvement in autistic symptoms when a milk-free diet is implemented (Vincent T. Ramaekers et al., 2008).
Theoretical treatments
Additional approaches may include supplementation for mitochondrial support, environmental detoxification, and GI support including gut barrier healing and microbiome support.
References
Frye, R. E., Sequeira, J. M., Quadros, E. V., James, S. J., & Rossignol, D. A. (2013). Cerebral folate receptor autoantibodies in autism spectrum disorder. Molecular Psychiatry, 18(3), 369–381. https://doi.org/10.1038/mp.2011.175
Gelineau-van Waes, J., Voss, K. A., Stevens, V. L., & Speer, M. C. (2009). Maternal fumonisin exposure as a risk factor for neural tube defects. Advances in Food and Nutrition Research, 56, 145.
Gordon, N. (2009). Cerebral folate deficiency. Developmental Medicine & Child Neurology, 51(3), 180–182. https://doi.org/10.1111/j.1469-8749.2008.03185.x
Ramaekers, V. T., Thöny, B., Sequeira, J. M., Ansseau, M., Philippe, P., Boemer, F., Bours, V., & Quadros, E. V. (2014). Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies. Molecular Genetics and Metabolism, 113(4), 307–314. https://doi.org/10.1016/j.ymgme.2014.10.002
Ramaekers, Vincent T., Sequeira, J. M., Blau, N., & Quadros, E. V. (2008). A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Developmental Medicine & Child Neurology, 50(5), 346–352. https://doi.org/10.1111/j.1469-8749.2008.02053.x
Tani, Y., Fernell, E., Watanabe, Y., Kanai, T., & Långström, B. (1994). Decrease in 6R-5,6,7,8-tetrahydrobiopterin content in cerebrospinal fluid of autistic patients. Neuroscience Letters, 181(1–2), 169–172. https://doi.org/10.1016/0304-3940(94)90586-X
Vojdani, A. (2008). Antibodies as Predictors of Complex Autoimmune Diseases and Cancer. International Journal of Immunopathology and Pharmacology, 21(3), 553–566. https://doi.org/10.1177/039463200802100308
Wiens, D., & DeSoto, M. C. (2017). Is High Folic Acid Intake a Risk Factor for Autism?—A Review. Brain Sciences, 7(11). https://doi.org/10.3390/brainsci7110149
