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
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 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
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
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
3. What are the risk of developing autism for my child if he carries MTHFR
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
MTHFR 677 CC,
MTHFR 677 CT,
MTHFR 677TT or
MTHFR 1298CC) in control healthy population versus case population (autistic
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
Methylated folate (a product of MTHFR activity) and methionine are essential
for nucleic acid synthesis (component of your DNA) and are required for
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
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
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
(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;
(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
(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.
(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
(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.