MTHFR Gene Mutation

Written By Brittyn Coleman, MS, RDN/LD

What is the MTHFR Mutation?

  • MTHFR stands for MethyleneTetraHydrofolate Reductase and it is an enzyme that is vital for a pathway in a process called methylation.

    • In the fewest words, methylation is a process of adding/donating a “methyl group” (CH3) from one substance in the body to another.

    • The MTHFR enzyme is important for the folate metabolism pathway, which both methylates or “activates” the inactive form of folic acid into the active form methylfolate (read more in the folate note!).

      • The folate metabolism pathway is important for DNA, RNA, and protein methylation [1]

    • MTHFR also helps inactivate homocysteine (high levels are a risk factor for heart disease) and turn it into methionine. [2]

  • When methylation happens correctly, it has a significantly positive effect on many biochemical reactions in the body such as:

  • When methylation happens incorrectly, it can be related to major health concerns (see “Signs and Symptoms” below)

  • There is varying information about prevalence, but overall we can see that C677T has the highest significance and prevalence within ASD. Some studies show a very strong connection. More research needs to be done on A1298C. Ethnicity or cultural norms (diet, environment, etc.) could potentially be a risk factor. [3-8]

Types of MTHFR Mutations

We have two main MTHFR variants:

  • MTHFR C677T

  • MTHFR A1298C

For each MTHFR variant (either C677T or A1298C), each person has a set of two genes, which are either + (mutated) or - (typical, or “wild”). You receive one gene each parent. This means that for each variant, you can be:

  • Homozygous wild, or -/-

    • This means that there is no mutation and the gene is working properly

  • Heterozygous, or +/-

    • This means that one of the variants is mutated, yet the other is working properly

  • Homozygous mutant, or +/+

    • This means that both genes are mutated

There may possibly be 10+ other MTHFR genes that we just don’t know much about. Most of the research on MTHFR is focused on C677T, more research needs to be done on A1298C and other MTHFR variants.

Important Nutrients

There are many nutrients needed for proper methylation function including (but not limited to):

 
 

Signs & Symptoms

Symptoms of the MTHFR gene vary from person to person and vary depending on the variant mutation (C677T or A1298C). Some people can be completely asymptomatic and will not know that they have the mutation unless they test for it. MTHFR may play a role in: [1, 2]

  • Anxiety

  • Depression

  • Cardiovascular disease

  • Recurrent pregnancy loss & infertility

  • Neural tube defects (like spina bifida or anencephaly)

  • Congenital anomalies

  • Neurodevelopmental disorders

  • Psychiatric diseases

    • Includes autism, ADHD, schizophrenia, bipolar disorder, and depression

  • Certain cancers

  • Some people will claim that the following are also signs of MTHFR, but to our knowledge, these have not been confirmed in any research studies.

    • Stork bites

    • Sacral dimples

    • Sugar bugs (a prominent blue vein found on the nose)

    • Tongue ties

Next Steps

Diet

  • Get tested for the MTHFR Gene Mutation if testing hasn’t been done yet. You can ask your physician for a buccal (cheek) swab or blood test. Buccal swabs are the least invasive and the quality will be the same as a blood panel.

    • If you have done 23andMe or Ancestry.com, your MTHFR data can be found in your Raw Data. Find directions on how to download your raw data on their websites.

  • Consume a nutrient-dense diet, especially packed with folate, vitamin B12, vitamin B6, and choline.

    • NOTE: Those with MTHFR should avoid the inactivated, synthetic folic acid and B12 (found in many fortified breads, pastas, and grains) and should only consume the active form of folate, found in specific supplements and found naturally-occuring in food. See each respective nutrient note for the correct form that should be consumed.

    • If your child is a picky eater, work on expanding the diet. See the picky eating note for more guidance.

  • Improve gut health to increase absorption of B vitamins in the diet and through supplements. Take a look at the gastrointestinal issues note for more guidance.

  • Choose organic produce to reduce intake of pesticides like glyphosate, which may be difficult to detox for those with MTHFR

  • Address underlying sources of inflammation, such as food reactions

  • Test for nutrient deficiencies, especially folate, vitamin B12, vitamin B6, and choline.

    • NOTE: if someone isn’t methylating appropriately, it is possible that their serum nutrient levels are severely elevated, not deficient. If high levels are detected, it could either be due to under-methylation (the body is not methylating well) or excessive intake of a certain nutrient either through diet or supplements.

  • Test homocysteine levels. High homocysteine levels (caused by poor methylation) can increase risk of chronic disease, especially cardiovascular disease.

  • Reducing artificial ingredients and chemicals in the diet, such as food dyes and artificial sweeteners, may be beneficial.

  • Some information suggests avoiding Acetaminophen for those with an MTHFR gene mutation, as Acetaminophen may deplete glutathione levels [14]. Discuss which alternatives are appropriate with your healthcare provider.

Supplements

  • Supplement with methylated B vitamins.

  • Consider other methylation support supplements such as:

    • SAM-E (stands for S-adenosyl-L-methionine) and is a great methyl donor!

    • TMG (trimethylglycine - may also be listed as betaine) or DMG (dimethylglycine) are both great methyl donors. Some suggest that TMG is better for those with elevated homocysteine while DMG is better for those needing support with folate metabolism. Consult your healthcare provider for guidance on which is best for your child.

    • Glutathione to re-build glutathione levels that are potentially depleted due to poor methylation

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.

Lifestyle

  • Get sufficient exercise each day (60 minutes for children) to reduce homocysteine levels, even if preventatively.

  • Low Toxin Lifestyle. See: Toxic Load.

 

MTHFR & Autism in the Research

Prevalence of MTHFR in Autism

There is varying information about prevalence, but overall we can see that C677T has the highest significance and prevalence with ASD, while more research needs to be done on A1298C. Ethnicity or cultural norms (diet, environment, etc.) could potentially be a risk factor.

  • A meta-analysis in 2019 revealed that the MTHFR C677T polymorphism may be associated with increased risk of autism overall, while MTHFR A1298C was reported to be significantly associated with the risk of autism only in Caucasians. [3]

    • Another study showed similar findings, that the C677T polymorphism is a risk factor for ASD, but A1298C polymorphism is not. [4]

  • Another meta-analysis in 2016 confirmed that the association between C677T polymorphism and autism was significant in both Caucasian and Asian populations. [5]

  • There is a significant association between severity and occurrence of autism with MTHFR gene polymorphisms C677T and A1298C [6-7]

  • One study found that MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%), but it was not found to be statistically significant. [8]

Homocysteine in Autism

  • Metabolic and genetic differences may vary depending on the subtypes of ASD (such as autistic disorder, Asperger’s syndrome, and PDD-NOS). [9]

  • In children with ASD and the C677T MTHFR polymorphism, levels of plasma methionine, plasma cysteine, and total blood glutathione were reduced. Plasma levels of homocysteine and cystathione were not significantly different. [9]

  • Hyperhomocysteinemia and the MTHFR C677T gene have been identified as risk factors for autism worldwide. [7]

Maternal Folate and B12 Levels

  • Extremely high maternal plasma folate and B12 levels at birth were associated with ASD risk. [10]

    • “This hypothesis-generating study does not question the importance of consuming adequate folic acid and vitamin B12 during pregnancy; rather, raises new questions about the impact of extremely elevated levels of plasma folate and B12 exposure in-utero on early brain development.”

    • This re-iterates that “too much of a good thing” may not be beneficial, and even detrimental.

    • Under-methylation may cause elevated serum levels of both folate and B12, which may be relevant in this study.

Improvements in ASD with Methylation Support

  • A case study (n=1) showed that L-methylfolate supplementation improved symptoms of aggression and disruptive behavior in a child with autism who tested positive for the C677TT allele of the methyltetrahydrofolate reductase enzyme gene. [11]

  • Two studies done on mice (not humans), they suggested that MTHFR deficiency can increase the risk of ASD-like behavior in mice and that prenatal dietary intervention focused on MTHFR genotypes can reduce the risk of ASD-like behavior. [12, 13]

  • Another mouse study revealed that supplementation with choline to adult offspring who had mothers positive for MTHFR for 14 days counteracted characteristics related to repetitive behavior and anxiety both in males and in females and improved social behavior solely in male mice. Choline treatment also normalized deviant cortical levels of the autophagy markers measured in male mice. [15]

  • [1] Liew SC, Gupta ED. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Genet. 2015 Jan;58(1):1-10. doi: 10.1016/j.ejmg.2014.10.004. Epub 2014 Nov 4. PMID: 25449138.

    [2] Levin BL, Varga E. MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence-Based Literature. J Genet Couns. 2016 Oct;25(5):901-11. doi: 10.1007/s10897-016-9956-7. Epub 2016 Apr 30. PMID: 27130656.

    [3] Sadeghiyeh T, Dastgheib SA, Mirzaee-Khoramabadi K, Morovati-Sharifabad M, Akbarian-Bafghi MJ, Poursharif Z, Mirjalili SR, Neamatzadeh H. Association of MTHFR 677C>T and 1298A>C polymorphisms with susceptibility to autism: A systematic review and meta-analysis. Asian J Psychiatr. 2019 Dec;46:54-61. doi: 10.1016/j.ajp.2019.09.016. Epub 2019 Sep 23. PMID: 31614268.

    [4] Li Y, Qiu S, Shi J, Guo Y, Li Z, Cheng Y, Liu Y. Association between MTHFR C677T/A1298C and susceptibility to autism spectrum disorders: a meta-analysis. BMC Pediatr. 2020 Sep 24;20(1):449. doi: 10.1186/s12887-020-02330-3. PMID: 32972375; PMCID: PMC7517654.

    [5] Rai V. Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: evidence of genetic susceptibility. Metab Brain Dis. 2016 Aug;31(4):727-35. doi: 10.1007/s11011-016-9815-0. Epub 2016 Mar 8. PMID: 26956130.

    [6] El-Baz F, El-Aal MA, Kamal TM, Sadek AA, Othman AA. Study of the C677T and 1298AC polymorphic genotypes of MTHFR Gene in autism spectrum disorder. Electron Physician. 2017 Sep 25;9(9):5287-5293. doi: 10.19082/5287. PMID: 29038711; PMCID: PMC5633227.

    [7] Shaik Mohammad N, Sai Shruti P, Bharathi V, Krishna Prasad C, Hussain T, Alrokayan SA, Naik U, Radha Rama Devi A. Clinical utility of folate pathway genetic polymorphisms in the diagnosis of autism spectrum disorders. Psychiatr Genet. 2016 Dec;26(6):281-286. doi: 10.1097/YPG.0000000000000152. PMID: 27755291.

    [8] Sener EF, Oztop DB, Ozkul Y. MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders. Genet Res Int. 2014;2014:698574. doi: 10.1155/2014/698574. Epub 2014 Nov 6. PMID: 25431675; PMCID: PMC4241316.

    [9] Paşca SP, Dronca E, Kaucsár T, Craciun EC, Endreffy E, Ferencz BK, Iftene F, Benga I, Cornean R, Banerjee R, Dronca M. One carbon metabolism disturbances and the C677T MTHFR gene polymorphism in children with autism spectrum disorders. J Cell Mol Med. 2009 Oct;13(10):4229-38. doi: 10.1111/j.1582-4934.2008.00463.x. PMID: 19267885; PMCID: PMC4496129.

    [10] Raghavan R, Riley AW, Volk H, Caruso D, Hironaka L, Sices L, Hong X, Wang G, Ji Y, Brucato M, Wahl A, Stivers T, Pearson C, Zuckerman B, Stuart EA, Landa R, Fallin MD, Wang X. Maternal Multivitamin Intake, Plasma Folate and Vitamin B12 Levels and Autism Spectrum Disorder Risk in Offspring. Paediatr Perinat Epidemiol. 2018 Jan;32(1):100-111. doi: 10.1111/ppe.12414. Epub 2017 Oct 6. PMID: 28984369; PMCID: PMC5796848.

    [11] Siscoe KS, Lohr WD. L-Methylfolate supplementation in a child with autism and methyltetrahydrofolate reductase, enzyme gene C677TT allele. Psychiatr Genet. 2017 Jun;27(3):116-119. doi: 10.1097/YPG.0000000000000170. PMID: 28272116.

    [12] Orenbuch A, Fortis K, Taesuwan S, Yaffe R, Caudill MA, Golan HM. Prenatal Nutritional Intervention Reduces Autistic-Like Behavior Rates Among Mthfr-Deficient Mice. Front Neurosci. 2019 May 2;13:383. doi: 10.3389/fnins.2019.00383. PMID: 31133774; PMCID: PMC6511811.

    [13] Sadigurschi N, Golan HM. Maternal and offspring methylenetetrahydrofolate-reductase genotypes interact in a mouse model to induce autism spectrum disorder-like behavior. Genes Brain Behav. 2019 Jan;18(1):e12547. doi: 10.1111/gbb.12547. PMID: 30552741.

    [14] McGill MR, Jaeschke H. Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharm Res. 2013 Sep;30(9):2174-87. doi: 10.1007/s11095-013-1007-6. Epub 2013 Mar 6. PMID: 23462933; PMCID: PMC3709007.

    [15] Agam G, Taylor Z, Vainer E, Golan HM. The influence of choline treatment on behavioral and neurochemical autistic-like phenotype in Mthfr-deficient mice. Transl Psychiatry. 2020 Sep 18;10(1):316. doi: 10.1038/s41398-020-01002-1. PMID: 32948746.

Brittyn Coleman, MS, RDN/LD https://www.autismdietitian.com
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