Heterozygosity for Homocystinuria and Heterotaxia Syndromes?

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

Labels: congenital heart defects, heterotaxia syndromes, homocystinuria, MTHFR

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Recurrent Early Pregnancy Loss: To Treat or Not to Treat...

The readers who sent in the comments below related to recurrent early pregnancy loss (RPL) have what we could consider to be 'borderline' indications for 'treatment' and several questions related to their therapy. But, the fact remains, they have both repeatedly lost babies early. Many of you with with RPL have or will find yourself in similar situations and will be likely to have similar concerns. In my responses, I express my approach to their management given the circumstances detailed in their comments. Let me remind you up front, there is no 'right' (or proven and agreed upon) and no 'wrong' way to manage their care. Under these circumstances, you could put two Maternal-Fetal Medicine or REI physicians in the same room and come up with 10 different approaches!

• At Thu Nov 29, 06:12:00 AM 2007, Anonymous said…
Doctor,

I have written in the past about 2 miscarriages I had this year...and now I'm having my 3rd. I have a single mutation C677T MTFHR. My LMP (last menstrual period) was 10/12 and I was tested positive for hCG around 11/7 and my doctor prescribed 40mg of Lovenox. I was also taking Advanced natalcare prenatal vitamin. On 11/21 my doctor did an US and did not see anything in sac. The doctor said to not be concerned yet since I could have my dates wrong, but I know I conceived on 10/25 using fertility monitor. On 11/21 I was started on 200mg of prometrium. 11/28 they did another ultrasound and still no embryo, just empty sac. Do you have any advice you can give me for a future successful pregnancy? Who should I see next as a specialist? Are there anymore tests I need to get done? My doctor did bloodwork and found no issues except the MTFHR mutation which he said may not even be a cause.

I have had D&Cs in March and July of this year following the loss of my other two pregnancies. My doctor wants to see me again to confirm this loss on 12/6. Should I have another D&C? I find it mentally helps me get over it faster than waiting for it to happen naturally, but have concerns what a third D&C will affect the uterus and future pregnancies...Please help...I'm so desperate to find hope and a cause.

• At Sun Dec 02, 08:25:00 AM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

To Anonymous Nov 29: I am so sorry again for your losses. I am also sorry that I have no way to easily find your earlier correspondence to me or my responses. That's one disadvantage of the way this blog is set up.

I will be honest with you, it is highly unlikely the single MTHFR C677T polymorphism alone is causing your miscarriages this early, although I don't disagree with the attempt at 'empiric therapy' either. I generally will start the prometrium in mid-luteal phase after ovulation (even before conception is confirmed)rather than at '4 weeks' into the pregnancy and then continue it until 8-12 weeks after confirming a viable embryo. Refresh my memory if you can on what other tests have been done and then I will be in a better position to tell you what could be done. Are you seeing any sort of specialist at this point?

As far as the D&C goes, I have mixed emotions. It is a natural response to just want to get this over and move on, but I sometimes wonder if there might not be some advantage to future pregnancies from an 'immunologic response' standpoint until waiting until your body begins to reject the current pregnancy and you start bleeding. You are at very low risk for complications at this point and might consider that.

Repeated D&Cs can cause damage to the cervix at its internal opening and that could increase your risk for cervical incompetence when you finally do successfully get through first trimester. D&Cs can also cause damage to the lining of the uterus (the endometrium) resulting in scarring and adhesion formation that can also impair fertility. In its most severe form (Asherman’s syndrome), this scarring can cause your endometrium to stop cycling so that you don’t even have periods even if you are ovulating normally. However, the endometrium is also very resilient and it is unusual for this to happen in the absence of infection. To reduce the risk of infection with early miscarriages, I usually suggest having either a medical evacuation of the uterus (using misoprostol) or a D&C if you haven’t completed the miscarriage spontaneously within 48-72 hours after starting to bleed and cramp.

Thanks again for reading and feel free to get back to me with your answers to my questions.
Dr T

• At Thu Nov 29, 03:41:00 PM 2007, Sarah said…

I've had three early miscarriages and I tested positive for two copies of MTHFR A1298C. I have also tested borderline positive for anticardiolipin anitibodies. I have seen a hematologist who thought that my miscarriages would not have been caused by that. However a fertility doctor does think so. I am taking folic acid, vitamin B6, vitamin B12, low-dose heparin from cycle day 5, low-dose aspirin, and 10 mg prednisone. I am feeling very anxious because of the disagreement between the two doctors and I just wondered if the things I have tested positive for could have caused the miscarriagess at 5-6 weeks. Or am I taking all of this medication for no reason?

Thanks Sarah •

At Sun Dec 02, 08:45:00 AM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

To Sarah Nov 29: The honest answer is WE DON'T KNOW! That's the usual cause of disagreement between 'experts.' We don't know if your losses are the result of the individual factors for which you have screened 'positive', the combination of the individual factors, or something else entirely different (or combined with those other factors!) for which you have not yet been tested! The important fact is that you have lost 3 pregnancies very early and the 'empiric therapy' upon which you have been placed is relatively low risk to a developing baby.

But, I would suggest, in the absence of any other history or 'risk factors', if you successfully get through the first trimester on the current treatment regimen that your doctor consider getting you off the prednisone and the heparin by 20 weeks. Any beneficial effect on the development of the baby’s placenta should have been accomplished by that time and prednisone increases your risk for other complications in pregnancy such as gestational diabetes, premature rupture of membranes, and early delivery as a consequence of the latter. If your baby is showing normal growth at 26-28 weeks by ultrasound and is having no trouble pushing blood through the placenta as determined by Doppler flow studies, you are probably well on your way to a successful outcome. By the way, are you seeing the REI doctor for any reasons other than your miscarriages? Best of luck to you, thanks for reading, and let us know how things turn out!

Dr T

Labels: MTHFR, recurrent pregnancy loss, RPL

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Tales of Two Thrombophilias

Although we strive to practice “evidence-based medicine” when the evidence is good and the practice is sensible, there are many times when personal experience still plays a role in patient care activities. Nowhere does this seem to be more true in obstetrics than in situations where “thromophilias” potentially place a pregnant woman at risk or might be a contributing factor in recurrent pregnancy loss. Under those circumstances we must carefully weigh the risks and benefits of therapy vs. no therapy, and we must include in those equations a broader perspective, the emotional turmoil of pregnancy loss or the potential loss of a mother who has recently given birth to a child. The comments from the two readers below (my apologies to them for the modifications for the sake of clarity) and my responses may help put these thoughts into a better perspective, because my answers many not be what either expected, but they illustrate the various factors that must be considered when confronted by these sorts of issues.

• At Tue Nov 20, 12:48:00 PM 2007, Amber said…
I have factor V Leiden (heterozygote) and had one normal pregnancy without knowing that I had it. With my current pregnancy the doctors started me on Lovenox. My original doctor said that I would be switched from Lovenox at 36 weeks and induced at about 38 weeks. Because I am military, I don't really have the luxury of seeing the same doctor because of duty station changes, etc. At my most recent appointment, the doctor I spoke with said they weren't going to change me to heparin until 38 weeks and that they would not induce early. My son was 3 weeks early, so if this pregnancy chances to follow suit, shouldn't they change me to the heparin at 36 weeks like my original doctor advised? And is being induced 2 weeks early normal? I tend to believe my original doctor because the other one changes his mind constantly about even the littlest things. Thank you…

• At Mon Nov 26, 06:58:00 PM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…
To Amber Nov 20: Sorry for the delay in responding but I just got your comment in my mailbox today. I need to have the answer to one VERY important question, before I can answer any of yours properly. What led to you finding out that you were a factor V Leiden heterozygote? Those tests usually don't get done on any routine basis! Anyway, personally, I would switch you to heparin at 36 weeks, especially if you delivered early before (and why was that delivery early? - another important question!) because if there is nothing else I have learned in this business, it is that obstetrical history tends to repeat itself. The reason for switching you is to decrease your risk of bleeding and anesthetic complications (bleeding at the site of an epidural or spinal) around the time of delivery. Most anesthesiologists would prefer that Lovenox be out of your system for 48-72 hours before you have a regional block performed. Heparin can be reversed easily with protamine sulfate, even if you present in labor just having taken a dose, whereas Lovenox cannot be reliably. Let me know the answers and I will see if I have any other thoughts. Thanks for reading! Dr T

To which Amber responded...

• At Tue Nov 27, 12:36:00 PM 2007, amber said…
I found out because my grandmother has had clots her entire life, and was finally tested a couple years ago. She had clots after all of her pregnancies and was found to be a factor V Leiden heterozygote. My uncle had a pulmonary embolism in ‘91, and so he tested as well, and was positive. My mother has had some minor clots, and tested positive for it too and told me about it. She said it was genetic, so I requested to be tested because I had been on birth control and I have heard that hormonal birth control can add to the risk. I haven't had any problems with clotting thus far, it probably helps that I am military and usually fairly active. I was not aware of this family history until after my first child. My son was early naturally and I didn’t have any complications with him thankfully.

• At Thu Nov 29, 11:05:00 AM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…
To Amber Nov 27: Thanks for your answers. I figured there was more to the story! My first answer stands. Based on your family history and your previous early delivery, I would switch you to heparin at 36 weeks. However, if the baby is growing well, has normal fluid, normal nonstress tests, and normal Doppler flow studies, and you are not having any complications yourself, I would not deliver you before 39 weeks unless I first documented fetal lung maturity with an amniocentesis. This is the current recommendation of the American College of Obstetricians and Gynecologists. Late preterm delivery is now the number one cause of premature delivery and there is an increased risk of morbidity for both you and the baby if induced early when there is no good medical indication. After delivery, I would place you on Lovenox, starting 12-24 hours after having the baby, continuing that until at least 6 weeks postpartum. After that, you might consider taking one baby aspirin (81 mg) per day for the rest of your life in view of your very strong family history! Good luck my friend and let us know how things turn out! Dr T

The second patient was diagnosed with a different “thrombophilia” as the result of a workup for recurrent miscarriages, but otherwise has no medical history, family history, or past obstetrical history that would appear to place her at “high risk” for complications, or even necessarily implicate her thrombophilia as a cause of her recurrent early pregnancy loss…

• At Sat Nov 24, 11:06:00 AM 2007, Anonymous said…
Dr. Trofatter,
I was just diagnosed with 2 copies of the MTHFR C677T
mutation (homozygous). I am 38 years old, have a healthy 2 year old boy and have had 3 miscarriages this year, all pregnancies with the same father. We are meeting with a genetic counselor next week. I am having several tests done and have gotten the MTHFR result so far. I miscarried at 8 wks, 11 wks, and 5 wks. No testing was done prior to the 3rd miscarriage. I have gotten pregnant each time I have tried, though my doctor is still going to test my estradial and FSH. Do you think this is neccessary?

Here is my question- I have done a ton of research and have a basic grasp of the blood disorder but am wondering what actually stops the baby from surviving? Is it always that there is a defect because of the lack of folate and vitamins B getting to the fetus? Or is it that there is blood clotting and the baby isn't getting what it needs? I also want to know, and I know the geneticist will tell us more once she has mine and my husband’s results, but should we NOT try for another? This year has been gut-wrenching and I selfishly want another child, not just for me but for my son. I always wanted more than one child but is it too risky??? I am on Vitamin B12, B6, 5 mg of folic acid and 81 mg of baby aspirin. I 'm assuming I will get my homocysteine levels checked before I get the green light to conceive? I don't want to wait much longer because I am 39 years old in March. Thank you for any and all information regarding these questions.

• At Thu Nov 29, 05:16:00 PM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous Nov 24: You were homozygous for C677T when you had your first child and you did just fine. The presence of this homozygous MTHFR polymorphism only modestly increases your “risk” so that should only be a minor consideration with regard to your decisions regarding another pregnancy. To answer your questions, these polymorphisms may put you at slightly greater risk for clotting problems, particularly if you have other risk factors, but they are probably not a major cause of recurrent early pregnancy loss, especially once you have started supplemental folic acid. That probably also reduces the risk of having a baby with a neural tube defect or congenital heart disease as well.

First let me review why folate metabolism and the methylenetetrahydrofolate reductase (MTHFR) gene are important. 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. As we discussed in a previous post, when this occurs in a developing embryo as the result of either folate deficiency or certain mutations in the MTHFR gene, this may have a ‘toxic’ effect, increasing the risk for neural tube defects and certain cardiovascular abnormalities. This same biochemical pathway is also essential for the production of a substance called S-adeneosyl methionine that is an essential intermediate in pathways that 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. The MTHFR C677T polymorphism is associated with a reduced efficiency of these metabolic pathways, but this deficiency can be overcome by loading up on folic acid as you have done.

But, all that said and done, I would wager that your primary problems are more 'age-related' than anything else. Fertility drops with age for reasons that are not completely understood. Part of the contribution may be the increased risk for having a chromosomally abnormal fetus; part may be other medical problems such as diabetes, obesity, thyroid disease, autoimmune disorders, hypercholesterolemia, and hypertension; part can be anatomical changes within the uterus that impair implantation, such as fibroids, endometriosis, or endometrial polyps; part is simply that your body's ability to hormonally support an early pregnancy might not quite be what it was when you had your son.

Ovulation induction and progesterone support may be all that you need, but I would suggest you find a Reproductive Endocrinologist (if you haven't already) since he/she will be in the best position to move you through a thorough evaluation and treatment regimen, even if that ends up being just empiric therapy. As you are well aware, at your age, efficient and experienced medical care is very important if you hope to have another baby. Good luck to you and thanks for reading. Dr T

Labels: factor V Leiden, MTHFR, recurrent pregnancy loss

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Retinal Arteriole Occlusion in Early Pregnancy

The comment below was left on a recent post regarding "Readers' Questions Related to MTHFR Polymorphisms." The reader presents a very unusual complication early in her first pregnancy - retinal arteriole occlusion - and the response to her query does not have a ready answer, but it sure was fun to try to come up with one!

I'm now pregnant with my first child. At 9 weeks I developed an arteriole occlusion in the retina of my right eye with some vision loss. My OB did quite a lot of testing and I was found to be positive for homozygous MTHFR. My homocysteine level (not fasting) was normal and my doc doesn't think I need Lovenox or Heparin. I'm on baby aspirin alone but questioning if I should be on additional therapy or seek a second opinion. Any suggestions? Of note, I'm an otherwise healthy 29 year old with no history of lost pregnancies or other clotting problems.

One of the hardest things about responding to a question like this from afar is inadequate information and the inability to question the patient in person and to perform an adequate examination. The obvious concern is why did a “healthy 29 year old” pregnant woman develop occlusion of a retinal arteriole to begin with. We are told that she had “quite a lot of testing done” but without knowing what tests were done, it is hard to know what other tests should be done so that our reader’s question might be best answered.

Retinal arteriole occlusions are most common in older individuals, typically in their 70’s, and in that group, they are usually the result of embolic events – most often cholesterol emboli from atherosclerotic disease in the aorta or carotid arteries, calcific emboli from valvular disease in the heart or atheromatous plaques, and platelet/fibrin emboli from foci of thrombosus in the heart or vascular tree. It has been estimated that less than 1 in 50,000 patient visits to an ophthalmologist will be for the indication of retinal arteriole occlusion in someone less than 30 years of age (Greven, et al., Am J Ophthalmol. 1995;120:776-83).

Indeed, causes of retinal arteriolar occlusion in younger folks are typically NOT related to embolic events, although there are still circumstances when they still can be. Conditions that may increase the risk in this age group include sickle cell hemoglobinopathies, smoking, diabetes, hypertension, genetic and acquired thrombophilias (e.g., antiphospholipid antibodies, lupus anticoagulant, anti-β-2-glycoprotein-1, factor V Leiden, antithrombin III deficiency, protein C and S deficiencies, prothrombin mutation, hyperhomocysteinemia, and, perhaps MTHFR polymorphisms and plasminogen-activator-inhibitor-1), hyperlipidemia, cocaine and IV drug use, cardiac arrhythmias (e.g. atrial flutter) and valvular disease (e.g., bacterial endocarditis), hyperviscosity syndromes, as well as pregnancy and use of hormonal contraceptives. Other conditions that should also be considered are HIV infection, use of certain herbal products and prescription medications such as sildenafil citrate (Viagra) to increase libido, Behcet’s disease, and a host of less common infectious/inflammatory diseases. A history of migraine headaches is also very common among younger women who develop retinal arteriole occlusion.

So the first thing we need from our reader is a very good history, including family, dietary, and social, to query for risk factors and to select for further evaluation from the myriad of possible causes for this condition in women of her age detailed above. She needs a thorough physical exam with blood pressure, cardiac, vascular, and ophthalmologic evaluation, the latter of which she most likely has already had. Serious consideration should be given to both an electrocardiogram (or Holter monitoring) and an echocardiogram to evaluate the rhythm and structure of her heart. Unless some other physical finding such as carotid bruits dictate, carotid Doppler studies are probably unnecessary at her age. Consideration should be given to screens for syphilis (remember, false-positive results are associated with thrombophilias), general autoimmune disease (e.g., ANA, rheumatoid factor), selected genetic and acquired thrombophilias (choose from above!), homocysteine (although if she is on supplemental folic acid, or was at the time her initial homocysteine level was performed, this will probably be 'normal'), complete blood count with platelet count, hemoglobin electrophoresis, diabetes, lipid profile, HIV, and perhaps even blood cultures for bacteria that might be associated with endocarditis and valvular disease.

Interestingly, despite the association of the thrombophilias with venous and arterial thromboembolic disease, I am not aware of any good study that has correlated MTHFR polymorphisms (even in the homozygous state) with retinal arteriole occlusion. Lowenstein and colleagues (Am J Ophthalmol. 1997;124:840-41) were the first to demonstrate the presence of the MTHFR C677T polymorphism in a patient who presented with retinal vein occlusion. In a subsequent study (Ophthalmology 1999;106:1817-20) they reported that among 59 patients with retinal vein occlusions, 44% were heterozygous and 11% were homozygous for the same polymorphism. Around the same time, Saloman and colleagues (Blood Coagul Fibrinolysis 1998;9:617-622) reported an association between MTHFR C677T homozygosity and retinal vein occlusion in 102 patients (OR 1.9; 95% CI 0.95-3.81). However, a retrospective study of 174 patients in Ireland demonstrated no association between MTHFR homozygosity and either retinal vein or arterial occlusive disease (Cahill, et al., Br J Ophthalmol 2001;85:88-90). I am also unaware of any studies that indicate elevated homocysteine levels are associated with retinal arterial occlusion. Indeed, one study from Scandinavia found no association of either the MTHFR C677T polymorphism or homocysteine levels among 116 patients even with retinal vein occlusion (Larrson, et al., Acta Ophthalmol Scand 2000;78:340-343.

So, how do we counsel our reader. I suppose if nothing other than the homozygous MTHFR C677T polymorphism is found, most likely the baby aspirin, supplemental folic acid and prenatal vitamins may be adequate therapy. If some other risk factor is found upon subsequent evaluation, then her treatment should be adjusted accordingly. Admitting our limitations in current medical understanding due to the ‘unknowns’ that might have led to her retinal arteriole occlusion, and since this is such an unusual condition in young women, her pregnancy should be followed very carefully for evidence of complications related to abnormalities of placentation. Remember, thrombophilias in particular are associated with intrauterine growth restriction, fetal loss, pregnancy-induced hypertensive disorders, and early delivery.

I would suggest she have maternal serum screening done at 16 weeks, a ‘targeted sonogram’ at about 20 weeks, and a follow-up assessment of fetal growth and Doppler flow studies at 26-28 weeks. Understand, there is no standard of care here, but such an approach might help anticipate fetal complications and, thereby, allow for antepartum testing that might reduce her risks for an untoward outcome. She must also be made aware that retinal arteriole occlusion is associated with long-term risks for both cardiovascular disease and stroke and if she does have an underlying thrombophilia as the cause, other thromboembolic complications.

Thanks to our reader for sharing her story and for a most challenging question!
Dr T

Labels: MTHFR, retinal arteriole occlusion, thrombophilias

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MTHFR Polymorphisms and Schizophrenia?

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

Labels: congenital heart defects, Down syndrome, folic acid, MTHFR, neural tube defects, recurrent pregnancy loss, schizophrenia, spina bifida

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Readers' Questions Related to MTHFR Polymorphisms

Several recent comments on my post "MTHFR Mutations and Congenital Heart Defects" worthy of a general response for our readers:

Anonymous said Sept 02, 09:30:00 PM 2007...
My daughter was diagnosed with MTHFR gene mutation during a blood test before putting her on birth control because of family history of blood clotting disorders (I have anitphospholipid antibody syndrome), lupus, and have had three strokes, 1 miscarriage, and I also almost lost her because of huge blood clots in the womb during pregnancy..My question is will she need to take foltex for the rest of her life (she is 18)... also, if she decided in the future to have children should she see a specialist?

Kenneth F. Trofatter, Jr., MD, PhD said...
To Anonymous Sept 2: Having the antiphospholipid antibody syndrome is MUCH different, and MUCH more serious than having a MTHFR mutation. YOU need to be on anticoaguation therapy the rest of your life. If your daughter was worked up because of your history, and the ONLY thing found at this point is a MTHFR polymorphism, she is probably at fairly low risk for the sort of complications you have had. I will caution you though, autoimmune conditions also run in families!

By the way, do you know if she had one or two MTHFR mutations? Many people carry one and have a low risk for problems, even on oral contraceptives. Also, do you know if they checked a homocysteine level on her? If that is also normal, again her risk for problems related to thrombosis and complications during pregnancy is probably no higher than the general population. Regardless, there is probably no harm taking the foltex. I wish more young women were on supplemental folic acid before they thought about getting pregnant.

Tell her to relax, and if you want a good 'second opinion' regarding her risks, find a local hematologist. She probably will not need to see a Maternal-Fetal Medicine specialist during pregnancy unless she develops complications. Women with single MTHFR polymorphisms do not need special treatment unless they have pregnancy problems that seem to be related to this. Thanks for reading!
Dr T


Phuong said Tue Sep 04, 08:06:00 PM 2007...
I had 2 miscarriages in 6 months (7 wks, and 8 weeks with 2 normal periods in between). I was told I was heterozygous C677T MTHFR...no elevated homocysteine level which I didn't test after fasting...doctor did not seem too concerned about preparing for my next pregnancy..did not advise to take baby aspirin, extra folic acid, or prenatal vitamins...he just said to do Lovenox injections daily once I find out I'm pregnant...should I take baby aspirin, extra folic acid, or prenatal vitamins as a precautionary thing prior to conceiving...I'd like to get pregnant in the next 2 months???


Kenneth F. Trofatter, Jr., MD, PhD said...
To Phuong Sept 4: I don't like to second guess your doctor under these circumstances. He/she may know more about you than you have told me (or they have told you). If you have been thoroughly worked up and no other risk factors were found except the single MTHFR polymorphism, and you were one of my patients, I would probably place you on the baby aspirin, prenatal vitamin, and extra folic acid (2-4 mg daily)BEFORE conception and ask you to consider trying a pregnancy on that alone. But, that therapy is purely empiric at this point and there is no evidence-based standard of care in that regard. Lovenox is VERY expensive! If you lost another pregnancy early, you could undergo a work-up for other 'risk factors' for which you have not yet been evaluated or simply add the Lovenox (or heparin - much less expensive)to the treatment regimen above and try again. Thanks for reading and for a good question. Best of luck to you next time!
Dr T

Labels: MTHFR

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Another Late Midtrimester Pregnancy Loss

Soumya has left a new comment on your post "Recurrent Early Pregnancy Loss - 6 - A Special Pat..." (I have modified/revised her comment somewhat to the best of my understanding of her concerns)...


Hi I lost my pregnancy at 24 weeks on July 17. Actually I didn't have any complications during pregnancy. When I didn't feel any movements for 5 days, I went to the hospital and they didn't find my baby's heartbeat. My doctor said that blood results are showing protien C and protien S deficiencies and an MTHFR abnormality. She told me that perhaps these abnormalities caused the blood to clot in the placenta and that I should see a high risk specialist before another pregnancy so that he can give me treatment to help overcome these problems. She also said that after delivery protein C and protein S generally will be reduced.... When I lost my baby I didnt have any other symptoms like bleeding or stomach pain except when the baby moved. There is no family history of blood clotting problems. Can you tell me what would be the reason and if so what will be the treatments for blood clotting? Should I start the medication before another pregnancy or only after getting pregnant?
Fri Aug 10, 11:14:00 PM 2007

Kenneth F. Trofatter, Jr., MD, PhD said...

To Soumya: I am sorry for your loss. The most common causes of late midtrimester fetal demise are fetal chromosomal abnormalities (and, less commonly, genetic abnormalities), infection, congenital birth defects, and abnormalities of placentation (that may be associated with "blood clots," sterile inflammatory changes, and fetal growth restriction). The latter are also often associated with maternal pregnancy-related hypertensive disorders and premature placental separation (abruption).

Usually during pregnancy, protein S levels decrease and protein C levels remain the same or are only slightly lower, so from what you have told me, I cannot be sure the results you describe above are actually 'abnormal' or simply related to the pregnancy itself. It would help me if I knew what tests were done to measure protein S and protein C, the actual test results, and the 'normal' range of test results in the laboratory that did the studies. It would also be helpful if you could give me more specific information regarding the MTHFR abnormality (the specific 'polymorphism(s)' and whether this is heterozygous (one dose), homozygous (two doses), or complex heterozygous (two different abnormal genes)).

Now that you are no longer pregnant, you should go to the specialist BEFORE you get pregnant again to be tested for these and other factors that are associated with pregnancy losses and increased risk for blood clots. The best way to test for protein C and protein S deficiencies is to have a test for "functional protein C and S activity" (don't ask me to explain that here!) BEFORE you get pregnant again. Other studies that can be done to look for autoimmune or genetic thrombophilias (factors that increase your risk for either making blood clots or not breaking them down efficiently) include: antiphospholipid antibodies; lupus anticoagulant; antithrombin III levels; factor V Leiden mutation; factor II (prothrombin) G20210A mutation; and homocysteine levels. On rare occasions, mutations in the plasminogen activator inhibitor-1 (4G/4G) are also associated with increased risk for blood clot formation and pregnancy losses.

Ask the doctor who delivered your baby if the placental pathology showed any specific evidence of infection or blood clot formation (either placental abruption or evidence of vascular abnormalities or inflammatory changes). Without abdominal pain or bleeding, it is unlikely that you had a placental abruption. Was the placenta normal size? Did the baby appear normal and was it a normal size for 23-24 weeks (i.e., what did the baby weigh)? Was there any evidence of the baby having a chromosomal abnormality (and were chromosomal studies sent) or an infection (bacterial, viral, or parasitic)? Did you have any evidence of infection when you were admitted to the hospital (high white blood cell count, fever, bladder infection)? Did you have cultures sent for Group B Streptococcus? Were you or the baby tested for cytomegalovirus or toxoplasmosis infections or other organisms that are known to cause problems in your country?

If any blood clotting problems are found, a specialist in high risk obstetrics or hematology can counsel you regarding the best ways to reduce the risk for a pregnancy complications for both you and the baby. Sometimes this means simply having to take extra folic acid (2-4 mg per day) and/or a baby aspirin (81 mg). In other situations, it may be best to treat you with either prophylactic or even therapeutic levels of anticoagulation therapy (by self-injection of heparin or low-molecular weight heparin) for part or all of the pregnancy. Before you get pregnant again, you might also consider sitting down and talking with a genetic counselor who might help identify risks that may not be so obvious and help you to better understand some of your risks based on the findings of your doctors. I do hope things turn out better for you the next time. Let me know, okay? Thanks for reading and for the good question! Dr T
Fri Aug 17, 12:26:00 PM 2007

Labels: MTHFR, pregnancy loss, thrombophilias

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Down Syndrome and Folate Metabolism

The other day I received a comment from Sheila on my post related to MTHFR mutations and fetal cardiovascular malformations. She reported that she had had a history of recurrent pregnancy losses (x 4) and during her ‘work-up’ for the same was found to have a low-positive level of IgM anticardiolipin antibodies and was also found to be homozygous (two copies) for the C677T MTHFR mutation. Her “homocysteine levels are normal” (but I am not told if these were done before or after she began folic acid supplementation) and karyotyping (presumably hers and her partners) “also came back normal.” She finally succeeded in carrying a pregnancy, after being treated with Foltex, prenatal vitamins, and Lovenox, only to deliver a baby at term with Down syndrome (trisomy 21). She notes that the baby “has no cardiac problems and is actually developing very well.” Her primary question to me was “Are these blood disorders (MTHFR mutation and Down syndrome) related?”

Well, Sheila, thanks for writing and you get the prize for the most intriguing question of the month! First let me review why folate metabolism and the methylenetetrahydrofolate reductase (MTHFR) gene are important. 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. As we briefly discussed in that previous post, when this occurs in a developing embryo as the result of either folate deficiency or certain mutations in the MTHFR gene, this may have a ‘toxic’ effect, increasing the risk for neural tube defects and certain cardiovascular abnormalities. This same biochemical pathway is also essential for the production of a substance called S-adeneosyl methionine that is an essential intermediate in pathways that 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.

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. This produces one egg (ova) that has 24 chromosomes (22 different chromosomes + 2 copies of chromosome 21) and one egg that has only 22 chromosomes (with no copies of chromosome 21). If the first egg is fertilized by a normal sperm containing 23 different chromosomes, we end up with a baby that has 47 chromosomes rather than 46, and in this case Down syndrome. If the second egg is fertilized, the embryo that is produced has only 45 chromosomes and is nonviable if it has only one copy of chromosome 21 (from the father). Although the risk for trisomy 21 increases with maternal age, most children with Down syndrome are actually born to women less than 30 years of age.

“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. In this study, they evaluated the frequency of the C677T mutation, plasma homocysteine levels, and lymphocyte methotrexate cytotoxicity as indicators of functional folate status in 57 mothers of Down syndrome children and 50 matched controls. Findings of significantly higher levels of plasma homocysteine and increased sensitivity of lymphocytes to methotrexate cytotocity in the women with Down syndrome babies supported their hypothesis that abnormal folate and methyl metabolism might contribute to the risk for trisomy 21. 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.

A subsequent study published by Hobbs and colleagues the next year (Am J Hum Genet 2000;67:623-30) confirmed the preliminary results above. In a cohort of 157 women with Down syndrome babies and 150 matched controls, these investigators not only looked at the prevalence of the C677T MTHFR mutation (technically ‘polymorphism’), but also the prevalence of a common mutation (A66G) in the methionine synthase reductase (MTRR) gene, another enzyme essential for normal folate metabolism. The presence of the C677T MTHFR mutation was associated with a 1.9-fold greater risk, the presence of the homozygous A66G MTRR mutation a 2.57-fold risk, and the presence of both polymorphisms a 4.08-fold risk for having a baby with Down syndrome….(to be continued)

Labels: Down syndrome, folate metabolism, folic acid, MTHFR, nondisjunction, trisomy 21

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