Fruit of the Womb
Fruit of the Womb

MTHFR Polymorphisms and Schizophrenia?

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The other day, tjtiger left a new comment on my post "MTHFR Mutations and Congenital Heart Defects". Her many questions made her comment worthy of a post of their own and the query related to the possible assocation of MTHFR polymorhisms and schizophrenia is not only quite intriguing, but taught me something new as well. That's what I love about this work!

Hi, I found out yesterday that I am heterozygous for the C677T and A1298C gene mutations. I had a baby girl last August and three days after I left the hospital my blood pressure spiked and I had massive swelling in my legs. My OB put me in the hospital and ordered an EKG and Sonogram of my heart. They ran a zillion different blood tests but could find nothing. The OB said I was just exhausted from having a new baby and was doing too much. Several months later at a check up with my family doctor I told him about the incident and he said it sounded like MTHFR. He said most doctors don't know about it and that it wouldn't just show up in the Cardiologist's tests. He ordered a full set of labs including the MTHFR test and it came back positive. I actually have a copy of all the labs but I don't quite understand all of this and have a few questions...

Kenneth F Trofatter, Jr., MD, PhD. Said…
Hi tj, thanks for writing. First of all, I doubt very much that your compound heterozygous state for those MTHFR polymorphisms caused your blood pressure problems and swelling after delivery of your baby girl. It sounds like you simply developed preeclampsia following delivery. About one-third of women will not show evidence of preeclampsia until after they have had their babies. In my reading of the current literature, there is at best a very weak, if any, association between MTHFR polymorphisms and preeclampsia. However, I would be curious to know about the other complications you had during your pregnancy, your gestational age at delivery, the size of your baby at delivery, and any problems the baby might have had after birth. I would also be very curious to see the results of the other laboratory tests done by your family physician. If you would like to send them to me privately, write through the ‘Heathline Feedback’ link and they will send them to my email address. Now, let me try to address some of your questions, because they are good ones…

1. Where can I find more information about MTHFR?

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that requires folic acid to convert homocysteine to methionine (an important amino acid) and when this does not occur, homocysteine can accumulate. This same biochemical pathway is also essential for the production of a substance called S-adenosyl methionine that is an essential intermediate required to add methyl (CH3) groups to nucleic acids (DNA; RNA), proteins, neurotransmitters, and phospholipids, a process that plays an important regulatory role in the biological functions of each of these.

Nutritional deficiencies of folic acid and/or mutations (polymorphisms) of the
MTHFR genes decrease the efficiency of these enzymatic pathways and increase the risk of accumulating homocysteine. Elevated levels of homocysteine and decreased production of methionine and S-adenosyl methionine may have toxicity for the developing embryo, resulting in increased risk for early pregnancy loss, congenital heart defects (particularly those involving the great vessels), and neural tube defects (e.g., spina bifida and anencephaly).

MTHFR polymorphisms are also included among the ‘genetic thrombophilias’ that place individuals at increased risk for developing vascular thrombosis (blood clots) and thromobembolic complications such as pulmonary emboli because they have either an increased propensity for developing clots or a decreased ability to break them down (fibrinolysis). The greatest risks for these complications are in individuals who not only have the gene mutation(s), but also have elevated homocysteine levels and/or other ‘risk factors’ such as smoking, use of estrogen-containing contraceptives, and other genetic or autoimmune thrombophilias.

As I have also discussed in another series of posts, there also appears to be an association between Down syndrome and MTHFR polymorphisms. Down syndrome results from the presence of 3 copies of chromosome 21. In 90-95% of cases, the extra chromosome is maternal in origin and results from a failure of normal chromosomal segregation (nondisjunction) during meiosis. “On the basis of evidence that abnormal folate and methyl metabolism can lead to DNA hypomethylation and abnormal chromosomal segregation,” James and colleagues (Am J Clin Nutr 1999;70:429-30) hypothesized in 1999 that young women with the most common MTHFR mutation (C677T) might be at greater risk for having a baby with Down syndrome than their peers who do not have the mutation. Indeed, the women with the C677T MTHFR mutation in this small study had a 2.6-fold higher risk for having a baby with Down syndrome than those who did not.

With the growing evidence of the importance of folic acid in the development of the fetal heart as well, and the high prevalence of the MTHFR gene mutation among women that may put their babies at risk, it appears we now have another good reason for insuring an adequate intake of folic acid, and may well be able to reduce the risk of specific, severe fetal heart malformations. One might also make the case for routine screening of women for elevated levels of homocysteine, prior to, or early in, pregnancy to identify those women who may be at increased risk, take steps to reduce their risk, and plan for proper evaluation of their babies during pregnancy.

2. I have several brothers, sisters and half brothers and sisters. Should they all get tested. Can this affect their children?

There is not an easy answer to this question. Many more individuals carry MTHFR polymorphisms than ever have complications related to the same. Indeed, the detection of your genetic state probably had nothing to do with the post-partum pregnancy complications you had as I have already pointed out. The most common gene mutations in MTHFR (C677T and A1298C) do not completely inactivate the gene, but reduce its efficiency in catalyzing the biochemical reactions of importance. We know that this deficiency can be overcome by supplementation with folic acid (hence ‘genetic predisposition’ and ‘environmental factors’) and greatly reduces the rates of neural tube defects and perhaps early pregnancy loss and congenital heart defects as well. I suppose, my suggestion for your family members would be to have their homocysteine levels checked, eat healthy foods containing folic acid and B vitamins, and for the women anticipating pregnancy, begin supplemental folic acid (1 to 4 mg daily) prior to conception and during early pregnancy to reduce the risk of embryotoxicity and congenital birth defects.

3. I have a 14 month old daughter, should I have her tested? Can this condition cause any health problems for a baby so young?

I am honestly not aware of any, but I think you should discuss this with your pediatrician – ask about testing, diet, and folic acid supplementation. Ditto to my comments above when she starts thinking about having your grandchildren!

4. Is there a possibility that I could also have Factor V Leiden? I don't know if that is a separate test or not.

The test for Factor V Leiden (G1691A) is a separate test for another of the gene mutations considered to be a genetic thrombophilia. Others include the prothrombin (Factor II) mutation (G20210A), protein C, protein S, and antithrombin III deficiencies, plasminogen activator inhibitor (PAI)-1 (4G/4G), and excess Factor VIII production. Autoimmune thrombophilias are associated with antiphospholipid antibodies and lupus anticoagulants.

5. Is there any link between MTHFR and Paranoid Schizophrenia? My father has Schizophrenia and I am wondering if maybe the underlying cause is this genetic condition.

This is a GREAT question and the answer appears to be YES! Although the world literature has shown some differences in results, a meta-analysis published by Gilbody and colleagues (Am J Epidemiol. 2007;165:1-13) demonstrated an association between the MTHFR C677T polymorphism and depression, schizophrenia, and bipolar disorder. The risk seems to be correlated with elevated homocysteine levels (Muntjewerff, et al., Mol Psychiatry. 2006;11:143-9). Male carriers of the MTHFR C677T and A1298C polymorphism may be at somewhat greater risk than women for schizophrenia (Sazci, et al., Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:1113-23) and women may be at greater risk for bipolar disorders (Kempisty, et al., Eur Psychiatry. 2007;22:39-43).

6. My family doctor said I should consider not having any more children until this condition has been studied more. Is this condition so severe I should consider not having anymore children? I had a very hard pregnancy and was put on bed rest several times. I am diabetic and had to take insulin injections while pregnant.

I am afraid I have to disagree with your family doctor on this point. Your diabetes probably is a greater risk factor than your MTHFR status although the two could certainly act together to increase your risk for pregnancy complications. If you supplement your diet with folic acid and tighten your diabetic control prior to conception, you should be able to minimize risks for both fetal and maternal problems during pregnancy. On the other hand, if your diabetes is NOT in good control during the critical stages of embryologic development, your risks will be increased for fetal abnormalities, especially neural tube defects and congenital heart defects that are, as we have pointed out earlier, also associated with MTHFR polymorphisms.

Well, tj, thank you again for writing and for the great questions. I hope I have answered most of them in a way that you feel they’ve been answered. Best wishes to you and your family.
Dr T
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About the Author

Dr. Trofatter is an expert on maternal-fetal medicine.

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