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Fruit of the Womb
Fruit of the Womb

MTHFR Mutations and Congenital Heart Defects

This afternoon, I attended a ‘focus group’ devoted to congenital heart disease and fetal cardiology. As we have discussed on other occasions, fetal heart defects are the most common abnormalities a baby can have, affecting about 1% of all pregnancies, but more than 60% of these are not detected until after the baby is born. The cause of congenital heart defects is thought to be ‘multifactorial’ in many cases, involving some degree of underlying ‘genetic predisposition’ and certain ‘environmental factors.’ This is similar to the situation with neural tube defects (abnormalities in closure of the spine).

Dr. Katharine Wenstrom from Vanderbilt University School of Medicine presented a wonderful talk during this session on “MTHFR mutation and risk of congenital heart defect.” She pointed out that certain congenital heart defects, particularly those involving abnormalities of the great vessels (e.g. aorta; aortic valve; pulmonary artery; pulmonic valve) can have very high rates of recurrence. This same group of fetal heart abnormalities are also found in the offspring of women who have mutations in the MTHFR (methylenetetrahydrofolate reductase) gene. This particular gene requires folic acid to convert homocysteine to methionine (an important amino acid) and when this does not occur, homocysteine can accumulate and may have toxicity for the developing embryo. This same biochemical pathway is also essential for the production of a substance called S-adeneosyl 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.

Interestingly, it has clearly been shown in animal experiments that the normal development of the fetal heart requires proper migration of ‘neural crest cells,’ the same types of cells that must move normally to close the spine and abnormalities in MTHFR function increase the risk of heart defects. (Neural tube defects are also more common in babies of women that have MTHFR deficiencies and elevated levels of homocysteine). Dr. Wenstrom also presented evidence that babies with a certain severe cardiac malformation, hypoplastic left heart syndrome, have heart tissue that is clearly not as well ‘methylated’ as that seen in the hearts of normal babies. Therefore, impaired neural crest cell migration and impaired nucleic acid methylation may both play a role in the etiology of these heart abnormalities.

The most common gene mutation in MTHFR (C677T) does not completely inactivate the gene, but reduces 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. 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 prior to conception and during early pregnancy, 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.
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