MTHFR

For those not suffering from infertility and not well versed in genetic disorders the title to my entry probably sounds like a really dirty sentence. As some of you might know I have consulted with SIRM and have had some blood work done. The first half of my blood work came back and I have
Compound Heterozygous MTHF. It's extremely hard to explain. Basically it means my body doesn't absorb folic acid...but it's not that simple either. Here is a blip from a web site that pretty much explains what it is: (please bare in mind that this breifly talks about men and how MTHFR effects them but none the less I still think it's quite informative.

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Fortunately, most symptoms of MTHFR are surprisingly easy to treat. All it usually takes is some extra folic acid, a common B vitamin.

Most of the studies on folic acid and the MTHFR mutation have been done in women. But at least three have been done in men. These studies are too early to be conclusive but they suggest a link between low folic acid, the MTHFR mutation and male fertility.

To understand this link, we first need to learn about MTHFR. And how low levels of folic acid can affect our DNA, fertility, and risk for miscarriage.

MTHFR is a gene that makes a protein called methylenetetrahydrofolate reductase (now you see why we call it MTHFR). The MTHFR mutation is actually just a certain version of the gene.

This version leads to a weaker MTHFR protein. And people with weak MTHFR proteins need extra folic acid.

We know that folic acid is important for all sorts of things. You’ve probably heard doctors tell women to take their B vitamins when they are pregnant. Or even thinking about getting pregnant. Lots of our foods are now fortified with these vitamins too.

These B vitamins are recommended for the reasons we talked about before. Extra folic acid can help prevent miscarriages and protect developing babies from getting birth defects. And as I said, women with the MTHFR mutation need even more.


The MTHFR protein converts something called homocysteine into methionine. When MTHFR is not working properly you can get a buildup of homocysteine in the blood and not have enough methionine.

Folic acid fits into this because MTHFR doesn’t do its job alone. It needs to work with folic acid to turn homocysteine into methionine. This is actually why folic acid can help people with weak MTHFR. Extra folic acid pushes the reaction along so that the build up of homocysteine goes away.

OK, so having a weak MTHFR protein leads to an increase in homocysteine levels and a decrease in methionine. And both of these can lead to DNA damage in different ways (click here to learn more).

** this is what you find when you "click here"***

One of the effects of increased homocysteine build up may be more lost pregnancies. One number I saw was that 21% of women with high homocysteine levels have recurrent pregnancy loss! But if this is true (and I haven't seen the hard data to confirm it), is it because of chromosomal abnormalities? Or something else?

Hard to say. There are a couple of ideas out there for how high homocysteine levels might affect a pregnancy. There is some evidence that clots form more easily in these women’s blood. Too much clotting can lead to problems like cystic hygromas which are known to affect pregnancies.

Another possible consequence of high homocysteine levels is chromosomal problems. DNA is often thought of as unchanging but it is actually pretty dynamic. While the A, G, C, and TÂ’s rarely change, something called DNA methylation can change a lot.

DNA is decorated with little chemical groups called methyls. These methyl groups can affect whether a gene is turned on or off. They can also affect whether a chromosome goes to the right place when a cell divides.

The connection here is that high homocysteine levels decrease your pool of methyl groups. What this means is that there is less methyl around so your DNA might not get enough. What folic acid does is provide extra methyl groups to the pool.

It certainly looks like women with the MTHFR mutation have more babies with Down syndrome when they don’t get extra folic acid. But, is there a connection with other chromosomal problems?

No one knows for sure. In one study, researchers failed to find a connection between the MTHFR mutation you mention and any other trisomies except, possibly trisomy 18. However, the researchers couldn’t tell from that study whether the mothers had had enough extra folic acid in their diet to overcome their mutation.

As you can probably tell, more research needs to be done. For now, no research has shown that extra folic acid can help prevent trisomies in the absence of some health problem like the MTHFR mutation.

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Here is some more information. Just for the record I'm Compound Heterozygous MTHFR for 677CT & 1298AC

MTHFR = methylenetetrahydrofolate reductase

The gene MTHFR encodes the protein/enzyme MTHFR.
Its job is to convert one form of folate (5,10-methylenetetrahydrofolate) to another form of folate (5-methyltetrahydrofolate). 5-methyltetrahydrofolate is used to convert homocysteine (a "bad" amino acid) to methionine (a "good" amino acid). Therefore, if MTHFR is not doing its job as well, homocysteine will not be converted to methionine and will be elevated in plasma. Normal plasma homocysteine levels are generally quoted as between 5 and 12 uM (uM = micromoles per litre). Elevated homocysteine has been associated with a variety of multi-factorial diseases.

Folate is a generic term referring to a family of related molecules that are interconverted between each other by a number of enzymes (including MTHFR). Folic acid is the synthetic, easily absorbed form of folate. Food has been fortified with folic acid for the past decade in North America. The recommended daily intake of folic acid is 400 ug/day (ug = micrograms). MTHFR does NOT affect how folic acid is absorbed into your body --> it affects what folate forms are in your body.

In general, if you have a mutation is a gene, there are a number of consequences.
Sometimes, the gene mutation has no effect whatsoever on the protein - therefore the protein can still do its job.
Sometimes, the gene mutation has a little effect on the protein - the protein still does its job, but not as well.
Sometimes, the gene mutation results in very very little or no protein - these are serious mutations.

The 677C-->T mutation

This mutation is an example of one that has a moderate effect on the protein. It is called a "polymorphism" which means that it is a common mutation.
The C is the normal allele (copy of the gene).
The T is the variant allele (copy of the gene).
The T mutation in the MTHFR DNA causes the MTHFR protein to be "thermolabile". This basically means that it is less stable. Folate can increase the stability of thermolabile MTHFR to a level similar to that of normal MTHFR --> that's why it is important to take a BIT extra folic acid if you are 677TT.

677CC is the "normal" or "wildtype" genotype
677TT individuals (homozygous) are said to have mild MTHFR deficiency
677CT individuals (heterozygotes) are almost the same as normal individuals because the normal MTHFR can make up for the thermolabile MTHFR.

The 1298A-->C mutation

This is also a polymorphism and has little to no affect on the protein.
The A is the "normal" or more common allele.
The C is the "variant" or less common allele.
The C mutation does not appear to affect the MTHFR protein. It does not result in thermolabile MTHFR and does not appear to affect homocysteine levels.

Compound Heterozygotes

Mutations at 677 and 1298 are both in the same gene, MTHFR. They are at different locations in the same gene. Some studies have shown that the MTHFR protein in people with the genotype 677CT 1298AC does its job a bit less well than the normal MTHFR.

MTHFR Polymorphisms & Disease

There are MANY studies associating MTHFR polymorphisms with various diseases. Sometimes one study will say one thing, another study will say another thing. It is important to remember that these problems (NTDs, miscarriages, cancer) are MULTIFACTORIAL - they have a combination of causes. MTHFR polymorphisms alone will not be the sole cause of them.

In terms of "severity" of genotype for various conditions:
677TT > compound heterozygous > every other genotype

NTDs - it is clear that folic acid deficiency increases the risk of having a baby with neural tube defects such as spina bifida.
Miscarriages - some studies have shown an association between MTHFR and miscarriages - some have not.
Cancer - 677TT genotype may help protect against colorectal cancer and some leukemias.

Severe mutations in MTHFR

These are very very rare (about 50 worldwide).
Severe mutations result in little or no MTHFR protein being produced. They are different from the above-mentioned polymorphisms.
The result in motor and gait abnormalities, mental retardation, decreased lifespan, etc.

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This effects more then just fertility. A few of the symptoms are depression, anxiety & migrain headaches. All of which I suffer from. It can also cause other problems down the road like alzheimer's, problems with your heart, clotting disorders etc. Of course the symptoms all depend on what variation of MTHFR you have. One part of the info above says mine does it's job a "bit" less well then normal MTHFR then towards the bottom in "sevarity" it is in the middle so who really knows. All I know is I'll be booking an appointment with a hematologist just to make sure we keep this under control. Since this effects my over all health I'll be making an appointment as soon as my husband and I get back from vacation.

Side note: yesterday was our 5 year anniversary and we are going on vacation from Tuesday through Saturday. I can't wait. We are doing the same thing we do every year...but it's our ritual. :) We go back to where we honey mooned. Well it's late so I should head to bed.