Blood Tests, SAM Cycle, Folate, and Leukemia
The Wipers on the Bus Go Trap, Trap, Trap
by Ginger Houston-Ludlam
For some time I have been e-chatting with another mom about life and biochemistry. She is very knowledgeable about the folate/SAM cycle because her little girl has leukemia, and is having to take methotrexate, which is bad news for people with Down Syndrome. (Their folate/SAM cycle is already messed up, and this drug damages it further.) I finally met her at a recent NDSS conference. Some of the things she said to me have encouraged me to revisit the whole issue again publicly. She encouraged me to share the technical details she has learned in the hopes that even one person could be spared the journey she has had.
I also learned a tremendous amount from this gal. She has had to get smart about this stuff in a hurry to understand her daughter’s treatment and to beat the doctors over the head with research articles when they made decisions which would be fine for most folks, but not for someone with a Down Syndrome biochemistry.
One of the most interesting things she told me is that her daughter was showing some interesting blood chemistry anomalies before being diagnosed with leukemia, including a rising MCV (Mean Corpuscular Volume, or relative size of blood cells.) However, when the doctors would run blood tests, her “vitamin levels” would be fine. It was only when she began studying what was going on after the diagnosis that she began to realize what the problems were with the doctor’s tests.
I am going to try to explain this stuff in as close to English as I can manage, but the bottom line is this: high MCV is a big-time indicator of folate imbalance. Trimethyl Glycine (TMG, also called Betaine) is one way to begin to fix that. However she is also giving her daughter increased folic acid and methyl-B12 to further normalize this cycle. Dr. Leichtman has suggested that we all add 500 mg per day of TMG to our kids’ protocols. [The current version of Nutrivene reflects this.--Editor, August, 2002] I guess I’m saying that if we don’t make an effort to normalize this stuff, it can lead to very serious consequences. But we must proceed with caution, because methyl-B12 can disrupt other cycles in the body because it is used in so many places.
The following documents the essence of our discussion on the subject. This is a combination of her reading of the medical literature, her discussions with various doctors and scientists, and her theories derived from all that. I am bringing this all up because I mentioned that Carmen’s MCV was a little high, and I have received several private posts asking what this all means because other kids’ MCV are high as well. I want to assure everybody that just because your kid has a high MCV does not mean they are necessarily getting leukemia. But if left to go way out of whack, it is possible that leukemia is one outcome. Support for that statement follows, and I will try very hard not to lose people in the biochemical weeds. Several people have asked me recently if this can all be explained in English, and I am going to attempt to do so in this article.
The problem in Down Syndrome relating to the folate/SAM cycles has to do with triplication of two genes: CBS and GART.
Let’s start with the folic acid cycle. I am going to steal and expand Dr. Jill James’ analogy when she described this to me, because I think it is a good one. Think of this folate cycle as a bus route with four “stations.” The “bus” is a molecule of folate. At each station, some things get on or off the bus, depending on what chemical reactions happen at that station. So, under normal circumstances, the busses will whiz around their circuit, stopping at each station, letting passengers on and off, and then moving on to the next station. The idea of stations matches the enzymes and vitamins that do the work within the folate cycle. Some of those are familiar: there is a B12 and B6 station in the folate cycle. (There is also a MTHFR station about which some of us moms have learned we have mutations.) At each station, the bus changes the label on the front. So when the bus comes into the B12 station, for example, it is labeled Methyl-THF (“methyltetrahydrofolate” for you diehards like me!) If the names confound you, forget about what the labels mean. It’s just a name on the bus. The chemistry is not important for the purpose of this description. At the B12 station, the methyl group gets off, and the bus changes its name to THF.
At the B12 station, the folate bus line connects with the SAM bus line (Figure 4). Passengers (“methyl groups” in this case) get off the folate bus line and transfer to the SAM bus line. The methyl groups get onto a bus labeled “Homocysteine,” at which point it changes its name to “Methionine.” The methionine bus then goes to the station where it becomes “SAM.” The methyl groups get off the bus at the SAM station and go on to do a lot of very important stuff in the body, such as methylating DNA. Methylating DNA means attaching a methyl group to DNA. Remember that, because it is important in the discussion of the possible connection between this cycle and leukemia.
Here’s the problem in Down syndrome. The homocysteine busses have two possible routes they can take, one goes back up into the SAM cycle B12 station, and the other goes out of the SAM cycle to the CBS station (the triplicated one!) In Down Syndrome, the homocysteine busses are being hijacked to the CBS station because CBS is triplicated, and so there are no busses available to pick up the methyl groups who are milling around grumbling at the B12 station waiting to get on the homocysteine bus. Because there are no homocysteine busses available to take the methyl groups around to the SAM station, the chemicals (like DNA) waiting for the methyl groups at the SAM station can’t go about their business either. The methyl-folate is “trapped” there. Remember the term folate trapping? That is what is happening. The folate molecule (the bus) with the methyl group attached is trapped waiting for a homocysteine to pass its methyl group to.
So, let’s say your kid has this problem. If a doctor does a blood test to measure folate, they will find that there is plenty of folate. The problem is that the folate is trapped and not able to do what it needs to. So you can have a functional folate deficiency in the presence of tons of folate in the system! (And this can lead to high MCV.) Unfortunately doctors don’t measure all the different forms of folate. If they did they’d find that the trapped form is off the scale, and the other forms are way low. The same thing can be true of B12. If you don’t have the particular version that is active in the cycle I’ve just described above, your overall B12 levels can measure just fine, but there isn’t enough of the right kind to do this job. So if your doctor even notices the high MCV, and tests for a folate deficiency, he will likely stop worrying about it because folate will measure fine. Of course, things are not fine at this point.
Which brings me to the possible leukemia connection. Cancer is the uncontrolled growth of cells of a particular type. It is controlled by something called “oncogenes” on the DNA for the cell. If the oncogenes are turned on, the cell will grow rapidly. If they are turned off, the cell will divide at a much slower rate. One of the mechanisms for turning these oncogenes off is having them “covered” by methyl groups, kind of like a chemical blanket. For some kinds of cancer, if the oncogene is exposed, then the cancer grows. If the oncogene is covered, the cell behaves normally. The methylation of the DNA happens at the SAM bus station. If there are no methyl groups arriving there because the busses have all been hijacked, then the oncogene can’t be covered, and leukemia can erupt if this problem is left untreated over time.
I have to tell you that this explanation is a compelling one to me, certainly compelling enough to put this whole MCV thing in the “watch closely” category. I’m sure that my regular pediatrician (who knows better than to fight me too hard on reasonable requests, like checking blood levels of things that have been high) will work with Dr. Leichtman and I to tinker with Carmen’s protocol. If not, it’s probably time for those thigh-high boots again!
That being said, I have to tell you that while this explanation makes sense to me, I have done absolutely no investigation into the leukemia literature, and could not produce a single medical article or piece of hard evidence to defend it if challenged. This mother whom I refer to has read the leukemia literature extensively, and is living with it on a day-to-day basis. The rest of it (the cycles, the fact that SAM mediates DNA methylation and that some oncogenes are turned off by methylation) I could defend.
So there you have it. Again, I am not trying to scare anybody, just to encourage you to be vigilant. Demand personal copies of your kids’ lab reports and read them. If you are doing it for the first time, go get a medical dictionary out of the library to help decipher it. Most of the reports have methods of highlighting anything out of range to make it easier for the doctor to read. The normal ranges are also usually listed. Don’t just take your doctor’s word that everything is OK. They may not want to scare “hysterical” females (like us) with information. Information is power. And an ounce of prevention is worth a pound of cure.