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citations used are taken from the NLM database and are in the public domain.
LESSON ONE. WHY DOES MY BABY HAVE DOWN SYNDROME
GENE MUTATIONS AND FAULTY EGG DIVISION
In 1998 I was collecting family history data on the maternal line in children with Down syndrome. I was extremely curious about the apparent high number of identical twins in these families. Jill James (research scientist, member of our Scientific Advisory Committee and folate expert) and I noticed that there was also a higher than average occurrence of Spina Bifida in the maternal line. My first thought, after looking at the compiled information, was that somehow DS pregnancies were related to MTHFR mutations. This is the same gene mutation responsible for Spina Bifida. Jill applied for funding to test this theory but as anticipated, obtaining it was difficult based solely on these data.
Fortunately, I located the results of a five year trial done in New South Wales that followed birth defects after fortifying foods with folic acid. And there it was in black and white. This study contained a table listing several birth defects, including DS, and the number of live births both prior to and after the addition of folate. Down syndrome and Spina Bifida fell in number by identical margins. This supporting information enabled us to obtain funding and a year later the results of our study were published. The incidence of MTHFR mutations in mothers of children with Down syndrome was scientifically and statistically significant. Since this, the very first work connecting DS to an actual “cause” the study has been repeated over thirty times by researchers world wide. It is clear that a maternal folate deficiency interferes with chromosome segregation during first phase (and sometimes second phase) meiosis causing the equal division of the egg to fail. The unfertilized egg containing 24 chromosomes may be viable while the egg with 22 chromosomes is not.
Recent tests of single nucleotide polymorphisms have identified two genes with mutations that may also produce the same effect, the inability of the human body to properly metabolize folate. These are MTRR and CBS mutations.
WHAT IS MEIOSIS
Meiosis I consists of four phases: prophase I, metaphase I, anaphase I, and telophase I.
To understand this for our purposes we will focus only on the division resulting in 23 chromosomes in each new egg. For further study on your own, look up the four phases of meiosis.
The human egg in the ovary is immature. It cannot be fertilized at its immature state because it contains 46 chromosomes. It must shed 1/2 of these chromosomes to allow for the 23 chromosomes contributed by sperm.
Before leaving the ovary, the egg divides once (first phase meiosis). During this phase tiny fibers called spindles fly out from the poles of the egg (the ends). Each one is responsible for locking on to the center of a specific chromosome (called the centromere) and as the egg begins to divide, drag their chromosome into the half of the egg that they originated from. You now have two eggs, each with 23 chromosomes. During meiosis, DNA is varied so that no two eggs are identical. This is why siblings are so different even though their DNA comes from the same mother and father.
This division occurs one more time resulting in four eggs capable of being fertilized known as daughters.
Human sperm also goes through phases of meiosis but in almost every case, the error of chromosome segregation takes place in the egg. We will review this later in this lesson.
During the first and sometimes the second division of the egg, a spindle breaks or fails to grab the centromere and the result is one egg with twenty four chromosomes and one with 22. The reason the spindle breaks or cannot stick to the chromosomes centromere is lack of sufficient folate. Eggs have only one method of creating daughter eggs. Only the failure of the spindle to do its job results in an extra chromosome in the egg.
Before you continue, stop and watch this video.
WHAT IS AN MTHFR MUTATION
MTHFR is a gene mapped to chromosome 1 (1p36.3). It encodes for an enzyme, 5,10-methylenetetrahydrofolate reductase. This enzyme is important in the conversion of folic acid into its active form. Until this conversion takes place the human body cannot utilize folic acid. It is also important in the process of converting homocysteine into methionine but, for this discussion, we will focus is on folate.
Folate is actually Vitamin B9. It is found in its inactive form in certain fruits and vegetables, used to fortify foods and is included in most multi vitamin supplements. Without it, DNA cannot be created or repaired and cells cannot divide. This function is targeted by many forms of chemotherapy. For instance, the drug Methotrexate, inhibits an enzyme in folate metabolism called DHFR – Dihydrofolate reductase. Inhibition of DHFR stops the folate cycle. Rapidly dividing cells such as cancer and hair cells are unable to reproduce After Methotrexate, a ‘rescue’ must be performed by providing the patient with folate or slower dividing cells would also die. Without sufficient folate, the human egg fails to properly divide during first phase meiosis and a number of anomalies can result, including the addition to an egg of an extra chromosome. This is known as nondisjunction.
Before you continue, watch the following video.
It is important that you understand two things. 1) it is not your fault that your baby was born with DS as you likely had no idea you suffer from this mutation and 2) it is not difficult to overcome it. The addition of a sufficient form of active folate, methyltetrahydrofolate and B12 will usually insure normal chromosome segregation barring anything that may interfere with absorption or the cycle itself. A natural catachin found in green and black tea and apples, epigallocatechin-3-gallate (EGCG) inhibits DHFR in dose dependent amounts much like Methotrexate and should be avoided when trying to conceive. Alcohol and even stress can interfere with folate absorption as can a lack of beneficial gut bacteria. This bacteria is destroyed by antibiotics, so the use of them while trying to conceive may be also an issue, though this is unproven.
Regardless of what you may have read elsewhere untreated hypothyroidism does NOT cause Down syndrome. It is related to a number of problems, pre-term labor, placental abruption, low birth weight, learning and developmental delay, but it does not interfere with egg division. However Hashimotos Thyroiditis is associated with MTHFR mutations so it is possible for a woman who gives birth to a child with DS to also have Hashimotos but it is not in anyway connected to faulty egg segregation. Too much folic acid does NOT cause Down syndrome unless the folate is not metabolized and becomes trapped. When that occurs the result is a folate deficiency.
While the majority of mothers of children with Down syndrome have one or more MTHFR mutations, women without them also give birth to infants with chromosome abnormalities. This is likely the result of a severe folate deficiency at the moment of first phase meiosis unassociated with gene mutation.
In rare cases, Down syndrome is inherited. This usually occurs when an egg already contains an additional section of the critical region prior to meiosis. The Down syndrome critical region (DSCR) is a portion of the p leg of the maternal half of the chromosome. This usually is attached to another chromosome. Because the entire portion of the DSCR is present, the child will be born with Down syndrome despite the absence of the complete chromosome. This is referred to as translocation.
A third form of DS is mosaicism. In mosaic Down syndrome, the child has two cell lines. One contains 46 chromosomes while the other contains 47. Mosaicism occurs when nondisjunction happens after fertilization, during mitotic cell division. Children with mosaicism can be only mildly affected even if the level of mosaic cells exceeds those of normal cells. They may also be as affected as non mosaic children. The level of function in all three forms of Down syndrome varies widely.
Why don’t all of my children have DS?
MTHFR mutations are not difficult to overcome, Despite the presence of a mutation, you may have sufficient folate available at the nano second of first phase meiosis for normal cell division. Another possibility is that although a fertilized egg containing 47 chromosomes can be viable, the incidence of viability is low. The fact that a child with Down syndrome actually comes to term is itself miraculous when you couple low egg viability with a higher than 80% loss in the first weeks of pregnancy.
Your chances of a second, full term DS pregnancy are low. However many siblings of children with Down syndrome have learning disabilities, ADHD, autism, autoimmune disorders and other disorders. It is unknown whether all are associated with an MTHFR mutation but some they may be. An MTHFR mutation should not be ignored as it results in numerous diseases, including Alzheimer’s disease and cardiovascular problems. Taking the appropriate measures to help your body overcome MTHFR mutations is the smart thing to do whether or not you are considering having more children.
Why is it rare for the father with an MTHFR mutation to contribute the extra chromosome?
Unlike the human egg, sperm are mobile. Though thousands of sperm race to compete to fertilize a ripened egg, only one succeeds. Once an egg is penetrated, the outer layer of the egg immediately repels and prevents other sperm from entering.
While men certainly can carry one or more polymorphisms that interfere with chromosome segregation at the stage of sperm meiosis, only rarely is trisomic sperm successful in fertilization. There are several theories, all of them possible. 1) as with a trisomic egg, few trisomic sperm survive meiosis. 2) Extra genetic material may effect the mobility of sperm, making it more unlikely that a trisomic sperm will be first to fertilize the egg. 3) a trisomic sperm may not be fertile.
Regardless of whether it is egg or sperm, no parent is ever at fault. Parents have no control over the mutations they inherit. Since these are silent mutations, where symptoms to the mother or father are often present but unrecognized, they simply go undiagnosed.
If you have one of these mutations, there may be ways to reduce your chances of chromosome segregation errors.
1) Give yourself three full cycles prior to attempting conception.
2) Start immediately on a multi vitamin supplement containing Methylcobalamin (methyl B12), Methyltetrahydrofolate (active folate) and Betaine (a substance present in the folate cycle. I suggest Nutrivene Full Spectrum or Thorne Methyl Guard.
3) Avoid anything containing EGCG such as green tea, black tea and apples.
4) Do not drink any alcohol.
5) Avoid excess stress.
Be comfortable with the cards life has played for you. Down syndrome is not a tragedy, it can be a blessing. With special care your baby can lead a very healthy, happy and productive life. Much research, since our efforts in the mid 1990s is now designed to improve the health and cognitive abilities of people with Down Syndrome.
Read the following studies.
MTHFR MUTATIONS AND DOWN SYNDROME PREGNANCIES
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108552
FOLATE, CHROMOSOME SEGREGATION
https://www.sciencedirect.com/science/article/pii/S1110863015000889
HYPOTHYROIDISM DURING PREGNANCY
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354841/
For further research go to pubmed.com and type “MTHFR mutation and Down syndrome” in the search field.
Read. I found this interesting for the identical twins portion as I have twin boys who they say are fraternal but could pass for identical
It is possible to have identical twins where one has DS and the other does not.
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Lido e assistido!
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This is very interesting, especially with the identical, twins part I was pregnant with identical, twins I miscarried I had a typical child, and then I had a child with down syndrome.
Lido e visto
Read…guess it’s good to know there’s a reason
I wondered if having the MTHFR mutation had anything to do with DS. What I don’t understand is I already knew I had this mutation,
and was taking the proper supplements and was avoiding food with folic acid. Now, I only found out 3-4 months before I became
pregnant so maybe that wasn’t enough time for my body?
Yes. This was my theory in 1995. I published this in 1998/99 with S. Jill James. MTHFR mutations are directly responsible for failure of egg division. Since I first published this, thirty studies have confirmed my findings. We have since identified two other gene mutations that can result in failed or disturbed division, MTRR and CBS.
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Read and watched. Very interesting
Read and watched and wow I learned some stuff. Thank you for this.
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Read and watched what amazing information
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Forgot info from hs biology. Thanks!
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Li e assisti, super interessante
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Lu et Vu
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Read 2nd time. Thank you!
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I had 5 normal pregnancies and my 6th was DS But I also had spina bifida as my father did also. No twins in our family on either side. Myself and my children had minor and major disabilities. ONe boy had 80% hearing loss and Legg Perthes disease. ONe had mild ADD, one had ADHD, my mother had multiple sclerosis, I had ADD. My DS baby didn’t sleep as a baby, developed Schizo Affective possibly a missdiagnosis for the PANS PANDAS that she was later dignosed, the HS; now we are pretty sure she has the DSRD.
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I’m finally starting to read the lessons and my mind is blown, for so many reasons! Identical twins in the maternal line? Check. My sisters are identical twins. MTHFR gene mutations in the family? Check. And I’ve been saying for a decade that my gut instinct is that MTHFR gene mutations are associated with higher incidences in a family of vaccine injury, autism, and ADHD. I had started to wonder if maybe the MTHFR gene mutation was related to DS in some way too, and I can’t believe that I just read that it IS related to DS, that at least 30 studies have been doing showing this! And yet the genetic specialists continue saying there is no known cause.
I had also noticed in the national Facebook group I’m in that many of the families, when introducing themselves, talk about having kids with autism in addition to their child with DS. I know that autism rates in general have exploded, but it just seemed like more than what you would expect and I’ve wished that I was a researcher and could study this. It’s fascinating to me that there are actual researchers who have thought there might be a connection too.
And I didn’t know Hashimotos was related to MTHFR gene mutations. Thyroid issue? Check. I did notice that it seems like quite a few of the moms of kids with DS have thyroid issues too. It’s interesting that it could be because many of us have the MTHFR gene mutations. I also didn’t know that the MTHFR gene mutation is associated with Alzheimers. My mother recently passed away from Alzheimers. I wonder if, given that she gave birth to identical twins and died of Alzheimers, if she had the MTHFR gene mutation. I just recently learned that Alzheimers is strongly linked to the amyloid precursor protein (APP) gene, which is on the 21st chromosome, and the reason why almost all people with Down syndrome end up with Alzheimers eventually. But I didn’t know about the connection to the MTHFR gene mutation. I want to know how to compensate for that to lower Alzheimers risk. So much to think about already!
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Lu et Vu.
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Vu et Lu.