MTHFR Gene Mutation and The Potential Association With PMDD


The Chemistry of Your Body

There is a very important and complex biochemical process in your body that is responsible for converting an amino acid called methionine into homocysteine and then back again to methionine. 

Methionine is an essential amino acid meaning that your body cannot produce it so you must get it in your diet. Once you have methionine in your body it gets converted into homocysteine that is then used by your body for:

1. Cysteine production

Homocysteine is then converted into cysteine a biochemical process that is facilitated by Vit B6. This happens in your liver. Cysteine is an important protein in your body that promotes cellular health and acts as an antioxidant that is important for your immune system.

2. Methionine rescue 

Homocysteine is also converted back to methionine. This conversion process requires another substance called methylated folate. Your body makes methylated folate from the folate in your diet. To do this your body uses the enzyme produced by the MTHFR gene. Vit B12 also plays a role in this process.

If you have a mutation of the MTHFR gene you cannot properly methylate your folate because your MTHFR enzyme is defective and your body cannot properly run the biochemical process of rescuing methionine.  The result is that you have a build up of homocysteine and an overall decrease in methionine because it is not able to be recycled from homocysteine.

Elevated homocysteine levels are thought to be associated with increased risk of heart attack, stroke, blood clots, and dementia.

If you have an elevation of your homocysteine levels due to a MTHFR gene mutation you most certainly have a relative methionine deficiency.

Methionine is required for your body to make many other important compounds in your body including the amino acid S-adenosylmethionine or SAM-e. 

If you have PMDD you already have a luteal phase disruption in your brain chemicals likely caused by how you genetically process the normal cyclic changes in your hormone levels. 
— Andrea Chisholm, MD

SAM-e is the PMDD connection

SAM-e runs many biochemical processes in your body. It plays important roles in your immune system, maintaining cellular health, and regulating the production and breakdown of several brain chemicals or neurotransmitters including serotonin.

If you have PMDD you already have a luteal phase disruption in your brain chemicals likely caused by how you genetically process the normal cyclic changes in your hormone levels. Exactly how this happens is an area of active investigation.

Although we don’t understand the exact connection it makes sense that an underlying condition that decreases your body’s production of SAM-e could worsen the neurotransmitter imbalance.

For instance, one of the potential causes of PMDD is the relative decrease in estradiol in the luteal phase. It is thought that in some women this drop causes an exaggerated response in serotonin decreasing its availability to your brain. Serotonin is responsible for maintaining your mood and a general sense of wellbeing. If your serotonin concentration is already relatively low due to a decrease in your SAM-e levels it makes sense that your luteal phase changes may worsen this relative serotonin deficit. 

About MTHFR gene mutation

MTHFR gene mutation is fairly common in the general population. You get one copy of this gene from each of your parents. The two most common mutations are the C677T and the A1298C mutation. 

About 33 % of Americans have one copy of either of these mutations. That means you got a MTHFR gene mutation from one parent and a normal MTHFR gene from another parent.  Having one copy of a mutation or being heterozygous for the MTHFR gene does not appear to cause significant health risks.  However, when you are one of the 11% of Americans who have two copies of the C677T mutation (homozygous) or you have one copy of C677T and one copy of A1298C mutation (compound heterozygous) you are at an increased risk of significant health problems.

When talking about the health risks of MTHFR gene mutation much of the research is looking at the effect of elevated homocysteine levels.  Elevated homocysteine levels have been shown to increase your risk of heart attack or stroke. Some studies also suggest that it can increase your risk of blood clots or certain pregnancy related complications like preeclampsia, placental abruption, and recurrent miscarriages.

However, it is not the increase in homocysteine levels caused by the MTHFR gene mutation that is associated with the depressive symptoms of PMDD. It is the relative decrease in methionine levels causing a relative decrease in SAM-e that is likely the culprit. We really don’t know what impact the milder forms of the gene mutation could have or not have on your mental health. (Want to learn more about your mental health and PMDD? Attend our 3rd Annual Conference →)

Checking Your Homocysteine Level

That being said, your homocysteine level is an indirect marker of whether or not you may have a significant MTHFR gene mutation.

Although the exact value may vary between labs a normal homocysteine level is considered to be less than13 mmol/L. A value of greater than 60 mmol/L is considered to be severely elevated and more than likely associated with a homozygous or compound heterozygous MTHFR gene mutation. 

At this time, no clinical guidelines support the routine testing of homocysteine levels in women with PMDD. However, it is a test that you could consider discussing with your healthcare provider.

If you have a severely elevated homocysteine level > 60 mmo/L it is highly likely that you have a MTHFR gene mutation and you should consider discussing genetic testing with your doctor.

If you have an elevated homocysteine level >13 mmolL but <60 mmol/L it is possible that you may have a MTHFR gene mutation. 

However, it is also possible that you may have a B complex vitamin deficiency that is blocking your otherwise normal enzyme from doing its job.

B Complex Vitamins

Folate or folic acid, which is also Vitamin B9, and Vitamin B12 are needed for the MTHFR enzyme to run the biochemical process of converting homocysteine back to methionine. If your diet significantly lacks adequate folate and or Vitamin B12 you could end up with an elevated homocysteine level and a relative deficiency in methionine. 

Vitamin B6 is needed to help make SAM-e from methionine and to make cysteine from homocysteine.

And remember to begin this important biochemical process you have to get methionine into your body through your diet. So, if your diet is also significantly lacking in methionine rich foods you are giving yourself a double whammy. 


Andrea Chisholm, MD is a Board Certified Obstetrician and Gynecologist practicing in Cambridge, Massachusetts. She is an Assistant Clinical Professor of Obstetrics and Gynecology at Tufts University School of Medicine and a Clinical Instructor of Obstetrics and Gynecology at Harvard Medical School. Dr. Chisholm is currently Clinical Advisory Board Chair for Gia Allemand Foundation.