Vitamin B9 (Folate)
What is Vitamin B9 (Folate)?
Folate is a water-soluble vitamin, and was formerly known as vitamin B9. Folate is one of the most studied vitamins in relation to autism. Research shows that folate levels are often abnormal and folate receptors may be faulty in those with ASD. The MTHFR gene mutation and the microbiome both play important roles in folate status.
Folate is the name of the naturally-occurring B vitamin found in foods, while folic acid is the name of the synthetic form found in dietary supplements and fortified foods.
Ranked from the least bioavailable (hardest to absorb) to the most bioavailable (east to absorb) the forms of folate are as follows: folic acid → dihydrofolate → tetrahydrofolate (THF) → folinic acid (5, 10 methylene THF)→ methylfolate (L-5-MTHF).
Some people who struggle with a process called methylation or have the MTHFR gene mutation have a hard time activating folic acid and should take it in a more active form, such as methylfolate.
Folate levels in children with autism are found to be significantly lower than those of typically developing children. [1-4]
Folate is also made by the bacteria that live in the large intestine. Bacteria that produces folate within the gut is less abundant in children with ASD. [14]
Folate helps the body produce DNA and RNA and helps break down amino acids (part of proteins). Folate is also crucial for cell division, so if folate is not available it can lead to a specific type of anemia called megaloblastic anemia, which can cause neural tube defects (like spina bifida) during gestation.
Food Sources of Folate
Folate can be found in a variety of foods, especially dark leafy green vegetables. In 1998, The U.S. Food and Drug Administration required folic acid to be enriched into a variety of grain products to reduce risks of neural tube defects in infants. Soon after many other countries established the same guidelines to improve folic acid intake.
Since folic acid is not easily absorbed for some people, and contraindicated for those with the MTHFR gene mutation, avoiding foods fortified with folic acid and consuming fruits and vegetables with naturally-occurring folate may be advised.
Recommended Intake
These recommendations are based on the Recommended Dietary Allowance (RDA), which is the average daily level of intake sufficient to meet the nutrient recommendations of nearly all (97-98%) of healthy individuals.
RDA for Males & Females
o-6 months: 65 mcg/d
7-12 months: 80 mcg/d
1-3 years: 150 mcg/d
4-8 years: 200 mcg/d
9-13 years: 300 mcg/d
14-18 years: 400 mcg/d
Pregnancy: 800 mcg/d
19-50+ years: 400 mcg/d
Folate Deficiency
Folate deficiency rarely occurs alone and is typically paired with other nutrient deficiencies associated with certain lifestyles like restricted eating, poor methylation, or absorption issues.
Symptoms of deficiency include:
Sores on the tongue and in the mouth
Changes in skin, hair or fingernails
Gastrointestinal issues
Elevated homocysteine blood levels
Folate deficiency (and B12 deficiency) can cause megaloblastic anemia. This kind of anemia causes your red blood cells to become larger than usual and impair their ability to transport oxygen around the body.
Symptoms of megaloblastic anemia include:
Weakness
Fatigue
Difficulty concentrating
Irritability
Headache
Heart palpitations
Shortness of breath
Folate Deficiency During Pregnancy increases risk for the child having neural tube defects. Low folate status during pregnancy is also associated with low birth weights, preterm babies, and fetal growth retardation for the child. Emerging evidence shows a reduction in risk of autism in children when peri-conceptional folic acid supplementation is used. The exact reason for this is still being researched, but the belief is that it is due to folate’s role in DNA methylation and how that affects neurodevelopment.
Individuals at Risk of Folate Deficiency:
Restricted diets or poor eaters
Alcohol dependency
Women of childbearing age
Pregnant women
Absorption issues such as celiac disease and inflammatory bowel disease
Toxicity
Supplementation or large amounts of folate have been found to be helpful in treating anemia from B12 deficiency, but don’t treat the neurologic damage that occurred from B12 deficiency. Some professionals are worried that large doses of folate have the ability to mask B12 deficiency so that the symptoms do not appear but the neurologic damage from long-term deficiency will still occur.
Chronic large doses of folate been linked to certain health issues including:
Increased risk of colorectal cancer and other cancers
When used during the periconceptual period, increases risk of cognitive development impairment in the child.
Impaired immune system
Cognitive impairment in older adults
Tolerable Upper Intake Level (UL)
Upper limits for folic acid intake from supplements and fortified foods only have been established, as excessive intake of folate from foods alone has not been shown to cause toxicity. The Tolerable Upper Intake Level (UL) is the maximum daily intake unlikely to cause adverse health effects.
UL for Males & Females
o-6 months: Not Determined
7-12 months: Not Determined
1-3 years: 300 mcg/d
4-8 years: 400 mcg/d
9-13 years: 600 mcg/d
14-18 years: 800 mcg/d
19-50+ years: 1,000 mcg/d
Supplements
Folate can be found in dietary supplements like multivitamins, a B-Complex, or on it’s own. The amount given in the vitamin varies between supplements. Most conventional supplements will include folate in the form of folic acid because it is cheaper to produce, but it is often hard to absorb for children with ASD (often due to methylation issues). Supplements containing L-5-MTHF (methylfolate) are available and are in an easier form to absorb. This can be a better choice for certain people such as those with MTHFR polymorphism.
Leucovorin (folinic acid) is a medication that is often prescribed to children with ASD. Some children will do well with this form of folate, but for those who have issues with methylation, methylfolate (L-5-MTHF) may be a better option.
Examples
Note: All supplements are linked to Amazon for convenience, however, buying supplements on Amazon does not guarantee quality, as there are many “unverified resellers” selling nutrition supplements. To buy supplements that are verified to be sent directly to the consumer, you can create an account on the Autism Dietitian FullScript and search for the respective supplement under “Catalog”.
DISCLAIMER: Before starting any supplement or medication, always consult with your healthcare provider to ensure it is a good fit for your child. Dosage can vary based on age, weight, gender, and current diet.
Folate & Autism in the Research
Folate Levels
Folate levels in children with autism are found to be significantly lower than those of typically developing children. [1-4]
Folate insufficiency can affect cellular function including methylation and redox homeostasis, which contribute to ASD pathology. [4]
Several chemical exposures such as air pollution, pesticides, BPA, phthalates, mercury or lead, and nutrition deficiencies such as folic acid, vitamin D, or fatty acid are possibly associated with the onset of ASD, whereas other traditional risk factors such as smoke/tobacco, alcohol, or PCB are less likely to be associated with ASD. [5]
Folate Receptors
Transportation of folate to the central nervous system is reduced in individuals with certain types of autism spectrum disorders such as Rett syndrome and infantile low-functioning autism with neurologic abnormalities. [6]
Casein can lead to the development of antibodies that inhibit folate absorption in the body. [7]
Children with autism have higher levels of folate receptor autoantibodies that interfere with folate transport to the brain than individuals without autism. [8]
Supplementation
Children with autism and cerebral folate deficiency (CFD), where folate is impaired in its ability to be transported to the brain, have been reported to benefit from leucovorin (folinic acid) supplementation. [8]
Supplementation of folinic acid can help with CSF abnormalities. [9]
Maternal Folate Levels
Some research shows that an above average folic acid intake in a pregnant mother who is also exposed to pesticides has a protective feature for reducing risk of the child developing autism. [10]
Research shows that mothers who were taking anti-epileptic medication during pregnancy, without folic acid supplementation paired with it, were more likely to have a child that showed autism traits within 1 ½ years after birth. [11]
Research does say that mothers need to be mindful, in that too much or too little folate and B12 in the blood can be linked to having a child with autism spectrum disorder. [12]
Methylation + MTHFR
Children with autism are more likely to have specific gene mutations that are linked to problems in the MTHFR enzyme that is crucial for methylation of folate. [13]
For more information, see the MTHFR note
Microbiome and Folate
The microbiome within our gut plays a major role in vitamin synthesis, immune regulation and metabolism. The microbiome within a child with ASD is typically less diverse, lacking the abundance of certain bacteria that help with these functions. Specifically, bacteria that produces folate within the gut is less abundant in children with ASD. [14]
-
[1] Guo M, Li L, Zhang Q, et al. Vitamin and mineral status of children with autism spectrum disorder in Hainan Province of China: associations with symptoms. Nutr Neurosci. 10.1080/1028415X.2018.1558762
[2] Altun H, Kurutaş EB, Şahin N, Güngör O, Fındıklı E. The Levels of Vitamin D, Vitamin D Receptor, Homocysteine and Complex B Vitamin in Children with Autism Spectrum Disorders. Clin Psychopharmacol Neurosci. 2018;16(4):383-90.
[3] Al-Farsi YM, Waly MI, Deth RC, et al. Low folate and vitamin B12 nourishment is common in Omani children with newly diagnosed autism. Nutrition. 2013;29(3):537-41.
[4] Mattson MP, Shea TB. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci. 2003;26(3):137-46.
[5] Fujiwara T, Morisaki N, Honda Y, Sampei M, Tani Y. Chemicals, Nutrition, and Autism Spectrum Disorder: A Mini-Review. Front Neurosci. 2016;10:174.
[6] Ramaekers VT, Blau N, Sequeira JM, Nassogne MC, Quadros EV. Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits. Neuropediatrics. 2007;38(6):276-81.
[7] Compart PJ. The pathophysiology of autism. Glob Adv Health Med. 2013;2(6):32-7.
[8] Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol Psychiatry. 2013;18(3):369-81.
[9] Moretti P, Sahoo T, Hyland K, et al. Cerebral folate deficiency with developmental delay, autism, and response to folinic acid. Neurology. 2005;64(6):1088-90.
[10] Schmidt RJ, Kogan V, Shelton JF, et al. Combined Prenatal Pesticide Exposure and Folic Acid Intake in Relation to Autism Spectrum Disorder. Environ Health Perspect. 2017;125(9):097007.
[11] Bjørk M, Riedel B, Spigset O, et al. Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero. JAMA Neurol. 2018;75(2):160-8.
[12] Raghavan R, Riley AW, Volk H, et al. Maternal Multivitamin Intake, Plasma Folate and Vitamin B12 Levels and Autism Spectrum Disorder Risk in Offspring. Paediatr Perinat Epidemiol. 2018;32(1):100-11.
[13] Boris M, Goldblatt A, Galanko J, James J. Association of MTHFR Gene Variants with Autism. Journal of American Physicians and Surgeons. 2004;9(4):106–8.
[14] Frye RE, Slattery JC, Quadros EV. Folate metabolism abnormalities in autism: potential biomarkers. Biomark Med. 2017;11(8):687-99.
