Insight into MTHFR polymorphism and Autism

Many patients contact us here at BRI, worried about the risk of having a child on the Autistic Spectrum because they carry one or two mutations in a gene coding for the enzyme methylenetetrahydrofolate reductase (MTHFR) involved in folate metabolism.
Some have heard that their offspring could be exposed to a 90% risk factor for developing autistic symptoms, if carrying these mutations.
I would like to address those fears by exploring some facts and statistics based on scientific, published evidence. First I want to discuss MTHFR and its role in recurrent pregnancy loss.

1. Why women experiencing recurrent pregnancy losses (RPL) are more likely to carry MTHFR mutations?

Besides its key role in DNA methylation (see our previous blog on MTHFR and Autism), MTHFR is directly involved in homocysteine regulation. Homocysteine is an amino acid derived from the metabolism of methionine, an essential amino acid.
Normal MTHFR activity is crucial to maintain normal levels of circulating folate and methionine and to prevent the accumulation of homocysteine. Hyperhomocysteinemia is observed in approximately 5% of the general population and is associated with increased risk for many inflammatory disorders including auto immune disorders (Rheumatoid Arthritis, Diabetes, Multiple Sclerosis, Systemic Lupus erythematosus, Grave disease), birth defects and adverse pregnancy outcomes (pre-eclampsia, placental abruption, spontaneous abortion, low birth weight), vascular and neurodegenerative diseases.

There are at least two functional polymorphisms for MTHFR: MTHFR polymorphism 677C>T and MTHFR polymorphism 1298A>C inducing a decrease in MTHFR activity.
MTHFR 677C>T polymorphism is associated with a 70% decrease of MTHFR enzymatic activity in homozygous ( MTHFR T/T), while the heterozygous (C/T) genotype has a 35% decreased activity. MTHFR 1298A>C polymorphism results in a slight decrease in MTHFR activity. Nevertheless, double heterozygote MTHFR 677 C/T and 1298 A/C results in the lowest MTHFR activity.

2. Do I have a higher risk of having an autistic child if I carry MTHFR mutation?

In fact this question displays two main points:

  • Does maternal MTHFR deficient activity alter fetal neurodevelopment thus leading to autism?
  • What are the chances to transmit MTHFR mutation to the offspring?

It is now well established that mothers homozygous for MTHFR 677TT have an impaired MTHFR activity and a higher risk for adverse pregnancy outcomes. Furthermore, higher prevalence of MTHFR 677T/T genotype was seen in late and early RPL, while higher prevalence of MTHFR 1298C/C genotype was only seen in early RPL.
Maternal nutritional factors such as vitamin B and folic acid intake may counteract the effects of maternal MTHFR mutation.

How can supplement folic acids (synthetic folic acid found in prenatal vitamin or dietary folic acid found in cereals) help reduce the risks of autism as maternal MTHFR is deficient and unable to metabolize it?
As a quick reminder, MTHFR induces a reaction, using 5, 10 me-THF, that will mostly produce 5-m THF (methylated folate), a substrate required to synthetize methionine from homocysteine (see figure below) and this is the only form of folate used in the central nervous system (CNS).
If MTHFR is deficient (30% activity in 677TT genotype), the mother will not produce sufficient amount of methylated folate and homocysteine will accumulate.
Nevertheless, several studies reported that MTHFR 677T has a reduced activity under low or normal folate levels but a normal activity under conditions of higher folate nutritional status (1). The authors proposed that folate itself could protect MTHFR activity by stabilizing the MTHFR protein and therefore allowing it to function normally.

Figure 1: The folate cycle and the methionine cycle are two metabolic pathways existing independently. In the folate cycle, folic acid is imported into cells and reduced to tetrahydrofolate (THF). THF is converted to 5, 10-methylene-THF (me-THF). Me-THF is then reduced to 5 methyltetrahydrofolate (mTHF) by methylenetetrahydrofolate reductase (MTHFR). 5-mTHF is demethylated to complete the folate cycle by donating a carbon into the methionine cycle through the methylation of homocysteine (hCYS) by methionine synthase and its cofactor vitamin B 12 (B12) .

Adapted from Jason W. Locasale. Nature Reviews Cancer 13, 572–583 (2013).

The Childhood Autism Risks from Genetics and the Environment (CHARGE), a recent study recruiting young children in California (24-60 months of age) who are autistic (n=517), who are developmental delayed (n=194) or healthy controls (n=350) showed a strong association between folic acid supplement (synthetic and dietary) and reduced risk of autism by a factor of 2 in offspring of mothers with MTHFR 677 T allele variant (2).
With folate supplement especially the methylated form (5m-THF), the risks linked to maternal MTHFR mutations towards autism could be minimized.

To answer the second point, let’s take four case scenarios based on MTHFR 677 polymorphism. Theoretically, if:

- You and your partner are heterozygous for MTHFR 677 (C/T): you will have 25% chances of having a child with no mutation (healthy), 25% of chance that he will be homozygous for the mutation (T/T) and 50% of chances that he will be heterozygous just like you (C/T).

- One of you is heterozygous (C/T) while the other is mutant homozygous (T/T): your child has 50% chance to be mutant homozygous (T/T) and 50% of chances to be heterozygous (C/T).

- One of you is heterozygous (C/T) while the other is non-mutant homozygous (CC): your child has 50% chance to be non-mutant homozygous (C/C) and 50% of chances to be heterozygous (C/T).

- You are mutant homozygous (TT) and your partner is non-mutant homozygous (CC): your child will be heterozygous C/T.

A recent study of n=205 north American families with one autistic child in the last three generations showed an excess transmission of the two risk alleles suggested by case-control analysis from parents to affected offspring (3).

3. What are the risk of developing autism for my child if he carries MTHFR mutations?

Studies showing a strong correlation between MTHFR polymorphism and risk of developing autism for a child only displayed the frequency of MTFHR in autistic children and compared this to the general population. This does not therefore give the risk of having a child with autism if the parents have the MTFHR mutation.

All of these studies are retrospective and report the frequency of each genotype ( MTHFR 677 CC, MTHFR 677 CT, MTHFR 677TT or MTHFR 1298AA, MTHFR 1298AC, MTHFR 1298CC) in control healthy population versus case population (autistic population).

It is important to highlight that MTHFR mutations are found mostly in the control healthy population with no autistic children. Different studies reported over 40% of those without autistic children (controls) being heterozygous C/T for MTHFR 677 and up to 15% of controls are mutant homozygous CC for MTHFR 677. In the same way, 46% of healthy controls are heterozygous A/C for MTHFR 1298 and 10% are mutant homozygous (C/C).

Despite having the lowest MTHFR activity, double heterozygous 677A/T and 1298 A/C were also found in 15% of healthy controls.

The association between a genotype (“exposure”) and its outcome (autism or healthy) is expressed by the odd ratio (OR).
(OR) represent the ratio between “I have autism and I carry mutation X/ I am healthy and I carry mutation X.

  • If OR=1, it means that the genotype does not affect odds of autism.
  • If OR<1, it means that the genotype reduces the odds of autism (protective effect of the genotype towards autism).
  • If OR>1, it means that the genotype increases the odds of autism.

A recent study showed that MTHFR 677T variant allele is present in 16.3% of autistic children versus 6.5% in the control population (4). Children having this variant allele (OR=2.8) are almost 3 times more likely to develop autism than controls. No risks were associated with MTHFR 12098 C allele. Nevertheless, children who have both MTHFR 677T and 1298C variant alleles (OR=8) are 8 times more likely to develop autism than controls (MTHFR 677CC/1298AA genotype).

Another study showed that 19% of autistic children are mutant homozygous for 677 (TT) vs. 10.7% in the control population (3).
We can conclude that MTHFR 677T showed a direct strong correlation with an increased risk for autism while MTHFR A1298C acts only additively in increasing the risk for autism.

MTHFR mutation alone does not trigger autism as a large percentage of healthy people are MTHFR mutation carriers. The occurrence of autism in these children that have MTHFR mutations therefore reveals a higher susceptibility to the effects of MTHFR mutations, in a background of an in utero inflammatory environment triggered by other existing maternal conditions. This is a very important point. There seems to be the need to have other predisposing factors that MTHFR polymorphism contributes to, and in our population of recurrent pregnancy loss patients these predisposing inflammatory conditions likely occur at much greater frequency than the general population.

What can be the contributing factors “unlocking” MTHFR mutations detrimental effects on fetal neurodevelopment?

We have to keep in mind that MTHFR is an enzyme involved in epigenetic modifications (reversible changes in gene expression mediated by methylation).
When immune system is already challenged (i.e. by inflammation, autoimmune disease, altered metabolism), MTHFR could trigger autism by modulating the expression of genes involved in brain development.

Methylated folate (a product of MTHFR activity) and methionine are essential for nucleic acid synthesis (component of your DNA) and are required for methylation reactions.
Methionine metabolism gives rise, through a complex mechanism (i.e. transmethylation and transsulfuration pathway) to glutathione that also contributes to the methylation process. Glutathione is essential for cell health, maintaining a balance (redox balance) in substances such as reactive oxygen (RO) and nitrogen species, whose dysregulation leads to oxidative stress. There is increasing evidence that autistic patients present excessive ROS production, reduced glutathione level and methylation capacity (5).

In genetically predisposed individuals, oxidative stress may play a central role in the pathogenesis of ASDs promoting neuronal damage with the cumulative influence of toxic environmental injuries (6).

How can these data relate to my risk of giving birth to an autistic child?

Several observations point that both parents and children with autism share a common metabolic phenotype with methionine and glutathione metabolism being disrupted (7) causing oxydative stress, DNA methylation impairment and inflammation. Furthermore, a deficient glutathione metabolism is also largely found in patient with autoimmune diseases (8), endometriosis (9) or suffering from reccurent pregnancy losses (10), the latter being associated with GSTT1 and GSTM1 polymorphisms, two key enzymes involved in glutathione productio (11).

These conditions increased the vulnerability to the effects of a folate and glutathione deficit, and are commonly found in our patient population at Braverman Reproductive Immunology.

Altogether these data strongly suggest that glutathione metabolism abnormalities (oxidative stress, higher toxin environment sensitivity and hypomethylation) in combination with alterations in folate and methylation pathways due to MTHFR mutations (increased inflammation, hypomethylation) could act in synergy with the patients autoimmune or inflammatory disorders to promote autism development.


At Braverman Reproductive Immunology, we are working to unravel and treat any events compromising the uterine environment to minimize the predispositions linked to MTHFR mutations in the offspring. As seen in the CHARGE study, sufficient amount of supplemental folate during the first month of pregnancy and even before conception may reduce the child’s susceptibility for ASD when carrying at least one copy of MTHFR 677T.
We strongly recommend prenatal vitamin as well as methylated folate intake (5 methyltetrahydrofolate: 5mTHF also known as active folate or folinic acid) to minimize the risk of neurodevelopment impairment. Metanx twice daily would suffice.

References

(1) Kim KN, Kim YJ, Chang N. Effects of the interaction between the C677T
	 5,10-methylenetetrahydrofolate reductase polymorphism and serum B vitamins
	 on homocysteine levels in pregnant women. Eur J Clin Nutr. 2004 Jan; 58(1):10-6.
(2) Schmidt RJ, Tancredi DJ, Ozonoff S, Hansen RL, Hartiala J, Allayee
	 H, Schmidt LC, Tassone F, Hertz-Picciotto I. Maternal periconceptional
	 folic acid intake and risk of autism spectrum disorders and developmental
	 delay in the CHARGE(CHildhood Autism Risks from Genetics and Environment)
	 case-control study. Am J Clin Nutr. 2012 Jul; 96(1):80-9.
(3) Liu X, Solehdin F, Cohen IL, Gonzalez MG, Jenkins EC, Lewis ME, Holden
	 JJ. Population- and family-based studies associate the MTHFR gene with
	 idiopathic autism in simplex families. J Autism Dev Disord. 2011 Jul;
	 41(7):938-44.
(4) Mohammad NS, Jain JM, Chintakindi KP, Singh RP, Naik U, Akella RR.
	 Aberrations in folate metabolic pathway and altered susceptibility to
	 autism. Psychiatr Genet. 2009 Aug; 19(4):171-6.
(5) Frustaci A, Neri M, Cesario A, Adams JB, Domenici E, Dalla Bernardina
	 B, Bonassi S. Oxidative stress-related biomarkers in autism: systematic
	 review and meta-analyses. Free Radic Biol Med. 2012 May 15; 52(10):2128-41.
(6) Theoharides TC, Kempuraj D, Redwood L. Autism: an emerging neuroimmune
	 disorder in search of therapy. Expert Opin Pharmacother 10:2127–2143; 2009.
(7) James SJ, Melnyk S, Jernigan S, Hubanks A, Rose S, Gaylor DW. Abnormal
	 transmethylation/transsulfuration metabolism and DNA hypomethylation among
	 parents of children with autism. J Autism Dev Disord. 2008 Nov; 38(10):1966-75.
(8) Shah D, Mahajan N, Sah S, Nath SK, Paudyal B. Oxidative stress and
	 its biomarkers in systemic lupus erythematosus. J Biomed Sci. 2014 Mar
	 17; 21:23.
(9) Dubinskaia ED, Gasparov AS, Fedorova TA, Lapteva NV. [Role of the genetic
	 factors, detoxication systems and oxidative stress in the pathogenesis
	 of endometriosis and infertility (review)]. Vestn Ross Akad Med Nauk.
	 2013; (8):14-9.
(10) Yiyenoğlu ÖB, Uğur MG, Özcan HÇ, Can G, Öztürk
	 E, Balat Ö, Erel Ö. Assessment of oxidative stress markers in
	 recurrent pregnancy loss: a prospective study. Arch Gynecol Obstet. 2014
	 Jun; 289(6):1337-40.
(11) Nair RR, Khanna A, Singh K. Association of GSTT1 and GSTM1 polymorphisms
	 with early pregnancy loss in an Indian population and a meta-analysis.
	 Reprod Biomed Online. 2013 Apr;26(4):313-22.

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