I assume that "high activity" means the enzyme functions normally. "Moderate activity," a bit less so. I assume moderate activity means that you are heterozygous for the normal form of the enzyme (you have one copy of the gene that functions normally and one copy that does not).
I think it's important to realize that we are really ahead of most published research here in trying to interpret the meaning of these variations. For example, having even one copy of the mutated allele (gene) for the BRCA genes means a huge increase in the lifetime risk of cancer. Having two copies of another gene means you will have cystic fibrosis. These are clear-cut cases of causation.
But with the SNPs Yasko tests for (and also 23andme), it's much less clear, I think. There are people with CFS/autism who don't have these particular SNPs and there are healthy people that do.
All I know is that taking methylfolate has had a huge impact. But is it because of a genetic defect, or is it, as Rich would say, a functional defect?
I am compound heterozygous MTHFR 1298A/C and 677 C/T. All I know is that autistic children also have these two mutations, and my personal experience tells me that it makes fixing our methylation systems very tricky. My mother and sister very quickly made huge progress with methylation supplements, while I continue to have bad reactions to all protocols. They have not been tested, but I assume that they both have only one mutation. I haven't been tested for other mutations, but I suspect problems with COMt, VDR, and others.
It's weird that the test doesn't tell you if you have homozygous wildtype or variant or hetero. It's hard to say how they establish "activity".. there should some indication of what you have though.
If you're heterozygous even (and of course homozygous variant) you should be taking methylation supplements, methylfolate being the most important as it directly is affect by the enzyme. Hetero doesn't mean 50%.. it could mean anything from ....1% to 99% activity and efficiency.
I would like to make some general comments about the relationship between genomics and ME/CFS.
First, I think that there is good evidence that a genomic predisposition is involved in the onset of sporadic cases of ME/CFS. There are several arguments in favor of this proposition. First. nearly all disorders do have a genomic component, because they involve the response of the body to some provocation, and how the body responds to the whole variety of possible provocations, whether they be infections, toxins or traumas, is influenced by the person's individual genomics. So it would be difficult for this proposition to be wrong with regard to ME/CFS.
More specifically, there have been family tree studies showing that multiple cases of ME/CFS tend to be found in families, and even out to higher-degree relatives, as in the recent paper from researchers in Utah. There have also been twin studies that suggest a genomic component to susceptibility.
In addition, there have been studies of individual genomic polymorphisms (SNPs) that have found higher frequency of them in PWCs as compared to the general population.
So I think we can be sure that genomics is a factor in the onset of ME/CFS, at least in the sporadic cases, but perhaps less so in the epidemic (cluster) cases.
As has been pointed out, this genomic influence does not stem from a SNP or mutation in a single gene, as is true for some other diseases, such as sickle cell anemia or Down syndrome.
Rather, it seems to involve the combined effects of SNPs in enzymes and other proteins involved in entire biochemical pathways. It is sort of like straws on a camel's back, where the camel's back in this case represents an entire biochemical pathway, and each SNP is a straw. The more straws, the higher the load on the camel, and eventually his back is unfortunately broken. The broken back in this analogy would be failure of some part of the biochemistry, which would then have its effects on the entire organism.
As has also been pointed out, each individual SNP or combinations of them are not deterministic in terms of dictating that a person does or does not have ME/CFS. Rather, they increase the tendency to develop this disorder, depending on the presence of "environmental" factors, which can be nutritional deficiencies or various types of stressors (physical, chemical, biological or psychological/emotional) or some combination of them.
At this point, there has not been enough research to tell us all of the SNPs that are important in inflluencing the onset and persistence of ME/CFS. I think we do know some of them, and others can be inferred from hypotheses for the etiology (root causes) and pathogenesis (development of the disease process) of ME/CFS, but the latter have not been scientifically proven, though I think there is considerable evidence now that supports their importance.
The MTHFR SNPs are among those that do appear to be important, and tests to characterize them have been available in the more conventional medical community for a while now. However, I think these SNPs are really only the tip of the iceberg, because there are quite a few others that can impact the function of the part of the biochemistry where the MTHFR reaction is located. Amy Yasko has identified several of them and characterizes them in her nutrigenomic panel, used primarily in the treatment of autism. Her emphasis is on those that can impact individual treatment, not on determining all of them that might be involved in promoting onset of the disorder.
It's pretty clear that the MTHFR 677 SNP will hinder the synthesis of 5L-methyl tetrahydrofolate, which is needed as a reactant by the methionine synthase reaction.
It's less clear what the role of the MTHFR 1298 SNP is. It is located in the regulatory part of the enzyme, where SAMe normally binds to exercise negative feedback control. Amy Yasko has argued that this SNP influences the reverse reaction of MTHFR and thus lowers the production of tetrahydrobiopterin (BH4). She has apparently inferred this from some published papers as well as observing patterns in data from many autistic children. She suggests treatment based on the presence of this polymorphism.
I would say that the view of the general research community is that the MTHFR reaction does not reverse in vivo, and that the 1298 SNP does not impact the methylation cycle. So I view this as an unresolved issue.
I think we have a long way to go to understand all of the SNPs that are involved in predisposition toward ME/CFS. In view of my hypothesis that glutathione depletion starts it off in most cases, I would be particularly interested in finding out the impact of SNPs in the enzymes and other proteins involved in the glutathione system. There are quite a few of them, and it would take considerable work to find out which ones are really important. I should note that it's one thing to identify which SNPs impact the probability of onset, and another thing to find out which ones will influence the best way to treat an individual case. I would like to understand both! -)
I think after studying the replies that my daughter is 677CT/1298AA which as far as I understand means that there is not a big risk of folic acid getting low.
This fits with an Organix Urine test which she did when she was very ill in 2003, before she started treatment. The test showed normal FIGLU, and therefore normal Folic acid.
She now gets Folic acid in her multi vitamin, just 0,4 mg. In a blood test done in October last year, folic acid was quite high, so that I think fits well with the FIGLU in 2003 and the MTHFR test.
The Organic Urine test in 2003 also showed high Methylmalonic acid, interpreted as low B12, and low sulfate which was interpreted as low Glutathione.Since then she has been taking B12 as Hydroxocobalamin (currently injections) and Glutathione (currently Liposomal) - she tolerates both in high amounts.
I am glad to know that in her case the folic acid is not an issue. As you say, Rich, it would be great to understand more about the glutathione depletion - I`ll read up on that.