Extra or Missing Chromosomes

I have heard that the MTHFR mutation can affect whether a woman has a baby with Down syndrome or not. I have also heard that taking folic acid can help. Does the MTHFR mutation also affect men? Can they benefit from extra folic acid as well?

-A curious adult from Malta

July 19, 2007

The MTHFR mutation you are talking about is likely to cause problems for pregnant women. You mention Down syndrome.

But it can also lead to an increased risk of miscarriage. And it can also be an increased risk for having kids with birth defects that involve the brain and/or spine.

Now before you get too worried, it is important to mention that this MTHFR mutation is actually pretty common. A person from Europe has a 1 out of 10 chance of having the more severe form of the MTHFR condition. That is the same chance of being born with blue eyes!

Fortunately, most symptoms of MTHFR are surprisingly easy to treat. All it usually takes is some L-methylfolate.

Most of the studies on L-methylfolate 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 can't easily process 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. 

What most people don't know is that folic acid is important for men's fertility too. For example, men who don't have enough folic acid have a lower sperm count.

So it kind of makes sense that men with a bum MTHFR might have poor sperm. We know that men who have low levels of folic acid have decreased fertility. And we know there is a link between MTHFR and folic acid levels. But can we say for sure that men with weak MTHFR have trouble with fertility? Yes and no.

Not surprisingly, it looks like it might depend on how much folic acid a man has in his diet.

There have been at least 3 different studies that try to answer whether the MTHFR mutation affects male fertility. The first two studies looked at only western European males. The third looked at men from India.

The results were mixed in these studies. In one study the researchers said that MTHFR condition did not cause a decrease in male fertility.

In the second study the researchers said that they could not tell if there was a difference. They found that men with the MTHFR condition were twice as likely to be in the infertile group as the fertile group. But because the groups were so small, the researchers couldn't say for sure that weak MTHFR leads to infertility.

The third study that was done in India had much more conclusive results. The researchers found that men with the MTHFR condition did show a significant decrease in fertility. Now why are European males with this mutation not strongly affected and Indian males are?

One guess is that it has to do with diet. See, the Indian diet tends to have less folate than does the European one. The idea is that the lower levels of folate made these folks more susceptible to their MTHFR mutation. In other words, by having extra folate, Europeans were able to mask their MTHFR mutation.

The lower sperm count in the men in India may be due to damage in the DNA of the sperm. How does the MTHFR mutation lead to DNA damage?

To understand this, we need to finally dig down and learn what MTHFR does A big part of MTHFR's job is to make an important amino acid called methionine.

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.

Folate fits into this because MTHFR doesn't do its job alone. It needs to work with folate to turn homocysteine into methionine. This is actually why L-methylfolate can help people with weak MTHFR. Extra L-methylfolate 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).

Lots of sperm with damaged DNA will die off. This may be why these men have a lower sperm count.

But some of the sperm with DNA damage may survive and pass the damage onto the man's children. This might be a way for a man's MTHFR mutation to lead to increased risk of miscarriage. (click here to learn more).

So overall we do not know exactly how the MTHFR condition affects male fertility. A lot more research needs to be done. No matter what, it does seem like getting enough folate is important for fertility regardless of how well your MTHFR works.

By Lucy Southworth, Stanford University

Folate is important for sperm health.