Down Syndrome and Folate Metabolism
Wednesday, May 30, 2007
Kenneth F. Trofatter, Jr., MD, PhD
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
31 Comments:
At Fri Jan 18, 07:04:00 PM 2008,
RTM rachel toledo at yahoo dot com said…
I am so glad to have found your site, as I will start TTC next month and have elevated plasma homocysteine levels and am homozygous for the C677T MTHFR mutation, and protien s deficieny.
Aside from folate/folic acid, what other preventative measures can be taken?
At Wed Jan 23, 06:16:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Rachel Jan 18: Personally, I like to add a baby aspirin (81 mg) to that as well. But, ask your doctor. She/he might not like that idea! Good luck and let us know how you do! Dr T
At Tue Mar 04, 09:30:00 AM 2008,
jody said…
Dr. Trofatter,
Thank you. I am in a dilemna. I am homozygous c677t, have low progesterone, and was born with gastroschisis. After 5 years, lots of $$$, and laproscopy, d&c, and hysteroscopy in Aug 06, I am still not pregnant. I am considereing in-vitro fertilization. My question is, am I "pushing my luck" trying to have a healthy baby? I don't want to create embryos to have them attach to a womb that could possibly create Downs, heart defects, etc. What do you think? I have a 6 year old son (medical mystery) to consider and don't want to burden him with a sibling to look after his whole life.
At Tue Mar 04, 08:16:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Jody: You have had one normal baby and probably can have another. Your risks for congenital abnormalities can be minimized (but not eliminated) by supplemental folic acid and, early diagnosis of a chromosmally abnormal baby is possible, but that may not be a 'risk' you are willing to take. If you are considering some form of assisted reproductive technology, be prepared for the expense, but if that is not an issue, do what your heart tells you! Best of luck to you and thanks for reading. Dr T
At Wed Mar 05, 05:06:00 AM 2008,
jody said…
Dr. Trofatter,
Thank you so much. I have searched the internet for 3 years and your blog has
been most helpful. MTHFR is confusing to so many people (and doctors) and can
cause real heartache. My reproductive specialist, Dr. Michael Doody, had me
tested simply becuase of my family's history (my father died of premature
hardening of the arteries at age 44). Dr. Doody's care and treatment will
likely add many years to my life! I meet with him on March 19 to discuss
in-vitro and your comments make me feel much much better. I meet with an
adoption agency on March 18. I think after those two discussions I will be
ready to make a decision. I will keep reading your blog. Thank you for helping
me.
Jody
At Wed Mar 05, 05:06:00 AM 2008,
jody said…
Dr. Trofatter,
Thank you so much. I have searched the internet for 3 years and your blog has
been most helpful. MTHFR is confusing to so many people (and doctors) and can
cause real heartache. My reproductive specialist, Dr. Michael Doody, had me
tested simply becuase of my family's history (my father died of premature
hardening of the arteries at age 44). Dr. Doody's care and treatment will
likely add many years to my life! I meet with him on March 19 to discuss
in-vitro and your comments make me feel much much better. I meet with an
adoption agency on March 18. I think after those two discussions I will be
ready to make a decision. I will keep reading your blog. Thank you for helping
me.
Jody
At Wed Mar 05, 10:13:00 AM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Jody Mar 5: Good luck to you and give my regards to Dr. Doody. I have not seen him in many years, but worked with him while we were at the University of Tennessee in Knoxville! Stay in touch. Dr T
At Tue Mar 18, 06:36:00 PM 2008,
Allyson said…
Hi Dr. T,
I hope you are still answering questions in the section!
I had an early miscarriage in Oct 2007 and after a battery of tests, I was found to be homozygous MTHFR for the C677t with elevated homocysteine levels at 15.5. My RE put me on 5mg Folic Acid plus my prenatal the beginning of November.
My homocysteine levels were never rechecked and I never worried about it until now. I'm 12 weeks along and I'm just concerned that my levels may not have gone down. Are there any reasons why the folic acid would not absorb properly? My main concern is NTD, as I would not be devastated with a child with Downs Syndrome. Should I be overly concerned or should I just trust that the folic did it's job and hope and pray for the best? Thanks in advance!
At Wed Mar 19, 05:22:00 PM 2008,
jody said…
Unfortunately I won't get the chance to see. Dr. Doody has changed his billing policy and won't see patients unless they can offer a debit card or credit card to draft. Who can afford that?
So, I am left with a HUMILIATING experience at his office and likely no more children.
I wonder why his staff didn't tell me this one month ago when I set the appointment. It would have been much less embarassing and would have saved me a month of heartache, anticipation, and anxiety.
Thank you for listening to all these girls in pain. We are sooooo weary and hurt and desperate for help, healing, and hope. I give up. Good luck to everyone else. I can't take any more emotional pain.
At Thu Mar 20, 06:03:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Jody Mar 19: I am so sorry for your situation. You might consider simply this: continue on the folate supplementatikn and perhaps a baby aspirin every day. Don't think about getting pregnant. Relax and enjoy life again. And, who knows, another "miracle" might just come along! Thank you for writing back and best wishes to you! Wish I could help in other ways! Dr T
At Thu Mar 20, 07:02:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Allyson Mar 18: At this point, all you can do is trust the folic acid "did its job." If the baby has Down syndrome, a neural tube defect, or congenital heart defect, there is nothing that can be done now. But, I am putting my faith in the folic acid for you, so best of luck and let us know how things turn out. A good ultrasound 6-8 weeks down the line will probably answer all your concerns! Thanks for reading. Dr T
At Mon Mar 24, 09:08:00 AM 2008,
Allyson said…
Thanks so much for getting answering. I'm scheduled for a Level II Ultrasound at the beginning of May. What are your feelings on the Quad Screening? I originally was not going to do any testing but the level II, but I'm debating whether or not I should do the Quad. I've been reading that it can detect about 80% of NTD, which doesn't sound too statistically great. I also read that the Level II can detect upto 90%.
I'm just curious as to your thoughts on the Quad screen.
Thanks so much!
At Tue Mar 25, 05:37:00 PM 2008,
Stacy said…
Hi...I just terminated a 19 week pregnancy last week due to Down's. I am 38 years old, and am blessed to have two healthy little boys already. We are going to try again ASAP, but I am just starting to read of this correlation between folate level and T21, in addition to MTHFR mutation. I had an amnio and the Down's karyotyping came back showing that my case was random, nothing genetic...my risk for NTD according to my integrated screen was something like 1:1600, so I assumed my folate level must've been adequate. Now I'm wondering if that was not the case. And if karyotyping proved this was not genetic, is it possible I might still have a MTHFR mutation? I am really praying to have another healthy baby, and I want to have any testing necessary prior to TTCing again, to promote having a healthy child, since I will be at least 39 years old, and my eggs aren't getting any younger! I'm deathly afraid that having conceived one child with Down's, in combination with my age, that I will not be able to conceive another healthy child. Thanks so much for any info you can provide!
At Wed Mar 26, 06:14:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Stacy Mar 25: Many people carry the MTHFR polymorphisms and do not know it or ever have any complications that would lead to them finding out. I would not recommend having the testing done at this point since it could only be another source of anxiety. You have had two healthy children with uncomplicated pregnancies and the odds are in your favor that you can have more. Your age increased your risk for having a bay with Down syndrome, but the odds are in your favor the next baby will not. I would recommend combined first trimester risk assessment with any subsequent pregnancies so that you can have the diagnosis sooner than later. Best of luck to you and thanks for reading.
Dr T
At Wed Mar 26, 07:29:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Allyson Mar 24: I would encourage you to have the "quad screen" done. It not only helps to pick up neural tube defects and abdominal wall defects, it also helps reevaluate your risk for having a baby with Down syndrome and trisomy 18. If the test results are 'abnormal' but no abnormalities of the baby are found, it may indicate an abnormality of placentation that can lead to fetal growth restriction, so it helps your doctors to plan for follow-up. Again, thanks for reading and good luck! Dr T
At Fri Jun 06, 02:58:00 PM 2008,
Isidora said…
Dr. Trofatter,
I'm glad I found this site. Today we went for our 19 wk ultrasound. We were told that our baby boy has Choroid Plexus Cysts. I was told that everything else is normal and my quad test came negative. My question is...how big is the chance our baby to have a down syndrome? We made an appointment for an obstetrical ultrasound and perinatal consultation with a high risk pregnancy specialist for a second opinion. My OB/GYN who has been my doctor for the past 10 years and she delivered my two daughters said that from her experience when everything else is normal she expects by 24/wk check-up everything should be normal. What should we expect? I'm calm about it awaiting the second ultrasound, but my husband is very worried, I need more information on this.
Thank you in advance.
At Fri Jun 06, 06:39:00 PM 2008,
Brandi said…
I am so glad I found your site! I just found out yesterday I am homozygous for C577T MTHFR after 2 back to back m/c and 4 total. I have already been on progesterone suppositories for a week and now I have started the FOLTX and aspirin. However today I found I'm PG again! I'm very excited but really scared too.
My question is, my husbands aunt had down syndrome and I was wondering how high are risks are with the MTHFR? We will love the child regardless but want to do everything to give a baby a healthy life. If I am only 3 wks pregnant will the folic acid help with NTD and DS?
Thank you so much
At Sat Jun 07, 10:07:00 AM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Isidora: If your quad screen was normal, the choroid plexus cysts probably mean ABSOLUTELY NOTHING! While I was making rounds in the hospital toda, I patient's husband grabbed me to come into the room to see his wife and beautiful newborn daughter. They were in the same situation you were in - a normal looking baby, normal maternal serum screening, and the baby had choroid plexus cysts. They thanked me for having reasssured them that the baby was almost certainly going to turn out just fine and were grateful that I had put them at ease for the rest of their pregnancy. Most CPCs are simply 'normal developmental variants' and by themselves they have no long-term consequences with regard to how your baby will turn out. Best wishes and thanks for writing! Dr T
At Sat Jun 14, 10:47:00 AM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Brandi: Your risks for Down syndrome depend, among other things, upon your age and perhaps the reason your husband's aunt had Down syndrome, although that is probably very unlikely to contribute to your risks. I would suggest if you are worried, that you have combined first trimester screening done for aneuploidy at 11-12 weeks. This has about a 90% pickup rate for Down syndrome and even higher for trisomies 18 and 13 with a false positive rate of only about 5%. The actual contribution of the homozygous MTHFR polymorphism for Down's risk is not clearly defined at this point to the best of my knowledge. Best wishes and let us know how things turn! Dr T
At Wed Aug 27, 06:53:00 PM 2008,
Tina S said…
Dr T
I am 38, 39 in Dec. Am currently 15wks pregnant and have been told our bub has Downs Tris21. We are now faced with a decision to make. This is our first child together but have children from previous marriage. I have 2 others, 1 15yrs 1 is 9yrs. If I terminate how soon would I take folate or whatever and for how long do I take before trying. I desperately want us to have a child together. Babys NT fold was 4.8mm, blood PAPP-A was .38. CVS confirmed 99% T21. Please help me. I do not know what to do.
At Wed Sep 03, 06:01:00 AM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
Tina: I don't know what to do either because that is your decision to make and yours alone. You need to get some very good and balanced counseling ASAP and then in the end, you have to do what is best for YOU. am sorry I cannot be of more help because quite honestly I do not know what I would do under the circumstances. With regard to folic acid, that can be started anytime prior to conception. Kind regards, Dr T
At Sun Jan 18, 11:14:00 AM 2009,
Anonymous said…
hello, my name is mary, thank you so much for so important info. I was looking more into it and found that in methylation pathway mutations some treat them with downstream metabolites and i want to put this into your consideration to see what you think and this may be of help for polyphormism that dont respond to high doses of folic acid.
here in this link you can find a methylatin map: http://www.heartfixer.com/AMRI-Outcomes-Non-CV-Autism-Methyl%20Cycle.htm#Methyl%20Cycle%20Genomic%20Analysis%20and%20Supplementation
here a Supplementation Cycle:
www.dramyyasko.com/Diagrams_files/supplmentation.jpg
5 formyl THF=folinic acid=leucovorin
5 Methyl THF= L-methylfolate=Deplin (medical food)
Folate is one of the 13 essential vitamins. Dihydrofolate, a mixture of polyglutamates (ie, a number of glutamatic acid entities) is the form of folate obtained from dietary intake of green vegetables, yeast, liver, kidney, and egg yolk. Folic acid is the synthetic form of folate contained in over-the-counter vitamin supplements (usually mixed with several other vitamins and nutrients and present in low doses). Folic acid is also the synthetic form of folate contained in prescriptions written by a licensed practitioner in higher doses for medical use.
Dihydrofolate and folic acid are converted to monoglutamate entites by the enzyme alpha-L-glutamyl transferase in the intestinal wall as they are absorbed.47 Once absorbed, monoglutamate entities are converted to MTHF, the form of folate that passes into the brain and is utilized by trimonoamine neurons to facilitate neurotransmitter synthesis (Figures 1 and 4B). Normally, ingesting folate from dihydrofolate in the diet or from folic acid in synthetic supplements will result in adequate delivery of MTHF levels to the brain, especially in those individuals with the more efficient genotype (C677C) producing up to 100% of the enzyme methylene tetrahydrofolate reductase http://www.cnsspectrums.com/aspx/articledetail.aspx?articleid=1267
please point me out to any source or blog with more info about it. could you suggest me where to have done a genetic test for MTHFR, MTRR
and any other type of mutation that increase the risk for having babies with down syndrome? I just have one, and want to get pregnant again and try to avoid to have another one with ds.
thank you so much.
At Wed Jan 28, 04:25:00 PM 2009,
Lindsay said…
I am 16 weeks 3 days pregnant and through doing genetic testing for a different blood disorder that my grandmother had & died from, they found out that I have MTHFR. My doctor had me go back for more blood work, I'm guessing to find out what form of the mutation I have ?? It's all so confusing because I'd never heard of this disorder until a week & a half ago, and now I'm shocked and afraid. Everything I've read so far hasn't looked promising for pregnancy. I obviously wasn't taking the dose amounts of folic acid that someone with this disorder should have been. Although of course I want my baby to be born healthy & with nothing wrong, I would keep the baby no matter what. I just want to carry to full term & I'm so afraid of having a miscarriage late term. I've read that it's very common for women to have late term miscarriages, and since I haven't been aware of the disorder until now, I'm very afraid that will happen. Do you know what percentage of women have later term miscarriages??? Any answers would be nice right now. I feel so helpless and lost.
At Wed Apr 01, 09:02:00 PM 2009,
RTM said…
Following back up on my post from last year. I didn't mention at the time, but I am on daily Coumadin therapy due to history of DVT and PE (which led to MTHFR dx). I was switched to Lovenox while TTC & PG. I'm thrilled to report that with the outstanding care of my high-risk ob and my hematologist, and careful monitoring from my perinatologist, I concieved naturally within three months, carried to term with no NTD or other abnormalaties, and am now the mother of an amazing, healthy, perfect baby girl! The one complication was that after stopping anticoag therapy for a scheduled induction, we resumed it too aggressively and I hemmoraged one week postpartum. A learning opportunity for next time, to be sure. But, otherwise, complication free and extremely blessed to have had an amazing care team, and to have been well-informed and a partner in my healthcare, not a subordinate patient.
At Thu Apr 30, 01:30:00 PM 2009,
kenna's mom said…
Dr. Trofatter, its sheila from the original blog. We had baby #2 9 mos ago - she is sooooo cute. We declined the 'testing' for genetic disorders, we love Kenna so much it didn't matter. If you don't mind, I'd like to offer some insight into parenting a child w/ Down Syndrome. Its nothing like u think, NOTHING! Kenna is almost 3, potty trained & goes to a regular daycare w/ regular friends. Those of us who know her don't see a 'down syndrome child', we see kenna (I see myself in her actually). There is a book called "Common Threads" that tells many wonderful stories.... My 12 y/o step son & his friends LOVE her and fight for her attn! Bryce has also taken a young girl with Down Syndrome under his wing at school. PS the new baby doesn't have Down Syndrome, but to us she is just as perfect as Kenna! thank you Dr T :)
At Thu Apr 30, 01:36:00 PM 2009,
kenna's mom said…
Dr Trofatter, off the record some comments on this site make me very sad, my initial blog was never with the intent of abortion being a topic here.... I know that in your position you must remain neutral on the subjuct, please post my previous note to you and I pray that others find a sense of security and home with regaurd to special needs kids. At a later date I might send another post re my husbands response and love for her, very profound (in a good way) I won't use this as a forum against abortion, but I'd sure like to add some positive input re the blessings of having Kenna, thank you so much sheila
At Sun May 17, 10:30:00 AM 2009,
Amanda H. said…
Dear Dr. T.,
I am 42 and have 2 copies of MTHFR and 1 of Factor 5 Leiden. I am 19 weeks pregnant by IUI. I have had the Nuchal/First Trimester Screens which were---.
Free Beta HCG .61
Pappa A MOM 3.24
Downs Risk of 1 in 881
Trisomy 18/13 Risk of 1in 1,501
Nuchal Fold measured at 1
I have had the 19 week scan and all looked good.
During weeks 8-11 I was very sick and dehydrated with the flu. I had to be hospitalized during week 9 and 10 with strong does of z-pac (double dose IV) because of severe bronchitus, codene to control cough and related coughing up of blood (because of bleeding--I am on Lovenox 40mg 1 time daily), and also severe dehydration and electrolyte deficiencies. During this time I was unable to take any prenatal vitamins although previously before pregnancy and during the 1st month at least I took 3mg of folic acid and 1mg of B12 as well as progesterone (at double does for 6 weeks do to incorrect instructions from my fertility doctor). I wonder if you could tell me your thoughts given this picture on the amnio. Specifically-- Are these results of the 1st trimester screen good for my age? What does the 10% error rate mean--is it included in the risk calculation already? How will my illness and the lack of vitamins during those weeks affect the risk of Downs given my MTHFR? I have two uterine fibroids do they complicate the amnio?
I am agonizing about the amnio decision as I had a hard time getting pregnant and had a FSH of 26 on one test and on other 16 at age 39. I also understand that the MTHFR puts me at an increased risk of Downs? Could you offer your perspective ASAP as we are scheduled for amnio on Thursday of this week? Sorry for so many questions but this has been a complex pregnancy. Amanda H
At Fri Jul 31, 12:44:00 PM 2009,
Anonymous said…
I am very glad that I found this site !!! I have a MTHFR 677mutation but my homocysteine levels are normal... Am I in a higher risk of having a child with Down Syndrome??
At Fri Jul 31, 02:01:00 PM 2009,
Anonymous said…
This site is really helpful. I am homozygous for MTHFR 677 mutation but my homocysteine levels are normal. Am I at a higher risk of having childrem with down syndrome??? I am really anxious about this !!! If yes, how can I prevent that from happening??
Thanks, Yova
At Sat Sep 19, 04:41:00 PM 2009,
Anonymous said…
Having a child with Down syndrome is a blessing. Our daughter is healthy, smart, loving, and a pure joy to be around. That is more than i can say for some of the other typical 7 year olds i know. It makes me sad to read that some people choose to terminate their pregnancies simply because their baby isn't perfect enough for them. Be sure to get the most current info on DS before making your decision to terminate.
At Tue Sep 29, 05:03:00 PM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous sep 19: Thank you for sharing! Best wishes.
Dr T
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