Fruit of the Womb
Fruit of the Womb

Heterozygosity for Homocystinuria and Heterotaxia Syndromes?

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Although I have had a hard time keeping up with new posts lately because of added responsibilities at the job that feeds my family, I have tried to keep up with my responses to the many comments I have received.. However, today I opened my mailbox and found that I had fallen behind about 60 in the last 3-4 days. OUCH! Double-OUCH because I leave for a long overdue vacation at the end of this week and will not have internet access for the week I am gone. Anyway, as I have done before, occasionally, I generate fresh posts from interesting questions that make me think or dig into the medical literature. (Sorry, I am the first to admit that I can’t answer all your questions off the top of my head). The comment below from Talya is one of those questions…

Talya has left a new comment on your post "MTHFR Mutations and Congenital Heart Defects":

Hi, my name is Talya. I have a 16 year old son with homocystinuria. I have a 12 year old daughter who was born with a unique congenital heart defect - isolated ventricular inversion. She also has heterotaxia. I was religious about taking my prenatal vitamins before and during my pregnancies, which included folic acid. Early on in my pregnancy with my daughter the doctor recommended that I take high doses of vitamin B6. I do not have an elevated level of homocysteine although I am a carrier of homocystinuria. I would like to know whether my daughter’s heart defect may be related to folic acid/homocysteine.


Talya’s questions appeared under a post from about a year ago in which we reviewed a presentation by Dr. Katharine Wenstrom from Vanderbilt University School of Medicine regarding the association of fetal heart malformations with genetic defects (polymorphisms) in methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in folic acid metabolism. MTHFR 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-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.

Dr. Wenstrom pointed out that certain complex 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 is also found in the offspring of women who have mutations in the MTHFR gene. It was also pointed out 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. (Neural tube defects are also more common in babies of women that have MTHFR deficiencies and elevated levels of homocysteine). To support the importance of these biochemical pathways in the normal development of the fetal heart, Dr. Wenstrom 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 complex heart abnormalities.

It is clear from the above that the buzz words of homocysteine and folic acid metabolism, combined with the complications of her children (one with homocystinuria and one with a complex and rare congenital heart defect), led Talya to consider an association that might be a common explanation for their problems. And, I am sure she took hope in the possibility that dietary supplementation with folic acid can often overcome the partial enzymatic defects associated with certain MTHFR polymorphisms. In her case, although the possibility of an association is intriguing, and cannot be entirely ruled out, there really may not be a relationship.

Homocystinuria is an autosomal recessive defect (requires one bad gene from Mom and one from Dad) in methionine metabolism that is caused by a deficiency in cystathionine synthase. It is a rare condition affecting about 1 in 300,000 children born worldwide with higher frequencies in certain countries such as Ireland and Denmark. The rarity of the condition increases the likelihood of consanguinity (known or unsuspected) in couples who end up with children that have homocystinuria.

This condition is associated with an accumulation of homocysteine in the serum and an increased excretion of homocysteine in the urine. Children born with homocystinuria often appear normal at birth, but generally will become “failure to thrive” and develop a very characteristic appearance similar to Marfan syndrome: tall, thin build: long arms and legs; nearsightedness; high-arched feet; knock-knees; depressed sternum (pectus excavatum); and varying degrees of mental and neurological impairment. If homocysteine levels cannot be normalized by therapy and diet, there is an increased risk for problems related to blood clots, atheroscerotic cardiovascular disease, and damage to connective tissue over time, however, for purposes of our discussion here, as far as I am aware, there is no significant increase in risk for congenital heart defects in children born with homocystinuria.

Talya’s other child had ‘heterotaxia’ and an unusual congenital heart defect. She does not have homocystinuria (but I do not know her 'carrier' status). But, the question remains, could maternal heterozygosity for the gene defect associated with homocystinuria (and perhaps a heterozygous state in the daughter) have contributed to her daughter’s conditions. Here I cannot be so sure whether or not there is a relationship! In reviewing the literature, I could find no association between heterotaxia (a condition characterized by cardiovascular malformations and intestinal rotation abnormalities – situs inversus (a mirror image of normal orientation of the stomach and intestines)) and elevated homocysteine levels or homocystinuria. But based on the suspected effects of abnormalities of the same folic acid/vitamin B12-dependent pathways noted above, as well as the observations on defective methylation and abnormal neural crest cell migration that appear to be present in congenital heart defects accompanying MTHFR polymorphisms, I am not closing the door on the possibility of an association that has not yet been recognized! However, there is also known familial predilection for heterotaxia syndromes and for certain types of congenital heart defects, so my greater concern in Talya’s case is that she and her husband may share more ‘bad genes’ than just those associated with homocystinuria!

Thanks for your question Talya. It really is a great one! For the time being, keep taking your folic acid and B12 and if you get pregnant again, let us know the outcome!
Dr T
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About the Author

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

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