I think I am finally starting to really get a handle on this issue. Dr. William Walsh says that all the mutations a person has creates a type of tug of war, so no one mutation will tell you if you are over or under methylated (assuming you are one or the other and not in a normal state). Photo from the Walsh Research Institute.
So maybe if you have an MTHFR mutation, another mutation that slows down GAMT might counteract it. It is the sum of the effects of a person's mutations which gives them a tendency to over vs. under methylation.
Here is a diagram showing a mathematical model of the MTHFR 677TT mutation (double). On the right side of the diagram you can see the DNA methylation has been weakened. On the left all the other folate reactions have been strengthened. This includes folate reactions which are not generally shown on the diagrams which change epigenetics such as LSD1, which uses THF. Here is my chart which shows LSD1, which we can presume only occurs in the nucleus.
Since 677TT increases the steady state of THF, the activity of LSD1 would be increased and the histones would be less methylated. I would think that the body would compensate by making less of the enzyme, but I have found from experience that whatever is happening, the compensation isn't enough. I don't know whether this is the enzyme causing the problems or not, it's just an example of something it could be. Epigenetics is so new and so little is known we may discover more enzymes involved in genetic expression that are influenced by levels of folate.
So now we have more demethylation going on and less methylation. Undermethylation is happening. (Keep in mind that this is simplified, in real life the person could have other mutations to make the whole thing go the other way.) How can we change the inputs to achieve balance? By increasing the input of methionine (METin in the diagram in the link above) we can increase the levels of SAMe and compensate to some degree. But wait - we have undermethylators in our family and I tried that and it didn't work. Why didn't it work? Because the intake of folate was too high. We have to not only stop taking any folate supplements, but we have to lower our intake of natural folate. Here is the diagram showing the effects of folate deficiency.
Somewhere between the first and the second charts (from the links) there is a place where the folate is neither too high nor too low, but of course extra input of methionine is needed to make up for the loss of SAMe in an undermethylated person since both MTHFR mutations and folate deficiency decrease SAMe levels.
This is why Dr. Walsh's protocol for undermethylated people calls for low folate which seems the opposite of what you would expect. My son with depression finally started remembering his dreams recently after we lowered the amount of folate in his diet. Up till now I couldn't get him to remember his dreams except for a day or two after raising his dose of B6 (as high as 300 mg P5P a day with no dream recall!) I think we have his folate intake in the range of 200 mcg a day now, which in some places (UK) is considered the average needed. When I looked at the folate content of what he was eating I realized that he probably averaged at least 800 mcg a day, even though he doesn't eat processed, fortified foods. I had noticed previously that when he was taking folate supplements and I dropped the amount of folate, his depression improved to a new level about 3 weeks after each drop and that he got worse a while after I tried to put it back in.
On the other hand at one point he was on a vegan (low methionine) diet and his folate was insufficient due to extremely low zinc, which we didn't realize until later, and he was depressed until he started eating meat again, so we know that just low folate isn't enough for him. He has to have both low folate intake and methionine intake (which can be from meat). He still isn't completely back to normal as far as the depression is concerned, but he is close. It will probably take 3 weeks to evaluate whether the folate intake is low enough.
Another interesting point - Dr. Walsh says that a sign of overmethylation is high blood histamine and my son gets completely knocked out by Claritin, an antihistamine which is not supposed to cause drowsiness. Even a half dose makes him very sleepy. I assume that this is because his body has compensated for the high histamine by lowering the number of receptors or increasing the transporters and that he is more sensitive to blocking of the receptors because of this. I don't know if this would be the case for all undermethylators, though.
Overmthylation would be the opposite situation. I am writing from the point of view that I have experience with. I hope this has helped to clear things up and not made them more confusing.
Dr. Walsh says that if a person does not suffer from inadequate serotonin, even if they are undermethylators, then they don't need to have low folate. But I question whether there might not be other unhealthy effects from this undermethylation of histones which do not involve any "mental" symptoms. Anyone have any thoughts about this?
By the way, what many people refer to as overmethylation may sometimes be the opposite, in my opinion, because it is based on what happens soon after a person takes a folate supplement. If the symptoms take a few days or even weeks to appear it is more likely to be true overmethylation, in my opinion, and the treatment is to take folate along with niacinamide, according to Dr. Walsh. Probably the whole blood histamine or SAM/SAH ratio that Dr. Walsh recommends is the most accurate way to diagnose this.
So maybe if you have an MTHFR mutation, another mutation that slows down GAMT might counteract it. It is the sum of the effects of a person's mutations which gives them a tendency to over vs. under methylation.
Here is a diagram showing a mathematical model of the MTHFR 677TT mutation (double). On the right side of the diagram you can see the DNA methylation has been weakened. On the left all the other folate reactions have been strengthened. This includes folate reactions which are not generally shown on the diagrams which change epigenetics such as LSD1, which uses THF. Here is my chart which shows LSD1, which we can presume only occurs in the nucleus.
Since 677TT increases the steady state of THF, the activity of LSD1 would be increased and the histones would be less methylated. I would think that the body would compensate by making less of the enzyme, but I have found from experience that whatever is happening, the compensation isn't enough. I don't know whether this is the enzyme causing the problems or not, it's just an example of something it could be. Epigenetics is so new and so little is known we may discover more enzymes involved in genetic expression that are influenced by levels of folate.
So now we have more demethylation going on and less methylation. Undermethylation is happening. (Keep in mind that this is simplified, in real life the person could have other mutations to make the whole thing go the other way.) How can we change the inputs to achieve balance? By increasing the input of methionine (METin in the diagram in the link above) we can increase the levels of SAMe and compensate to some degree. But wait - we have undermethylators in our family and I tried that and it didn't work. Why didn't it work? Because the intake of folate was too high. We have to not only stop taking any folate supplements, but we have to lower our intake of natural folate. Here is the diagram showing the effects of folate deficiency.
Somewhere between the first and the second charts (from the links) there is a place where the folate is neither too high nor too low, but of course extra input of methionine is needed to make up for the loss of SAMe in an undermethylated person since both MTHFR mutations and folate deficiency decrease SAMe levels.
This is why Dr. Walsh's protocol for undermethylated people calls for low folate which seems the opposite of what you would expect. My son with depression finally started remembering his dreams recently after we lowered the amount of folate in his diet. Up till now I couldn't get him to remember his dreams except for a day or two after raising his dose of B6 (as high as 300 mg P5P a day with no dream recall!) I think we have his folate intake in the range of 200 mcg a day now, which in some places (UK) is considered the average needed. When I looked at the folate content of what he was eating I realized that he probably averaged at least 800 mcg a day, even though he doesn't eat processed, fortified foods. I had noticed previously that when he was taking folate supplements and I dropped the amount of folate, his depression improved to a new level about 3 weeks after each drop and that he got worse a while after I tried to put it back in.
On the other hand at one point he was on a vegan (low methionine) diet and his folate was insufficient due to extremely low zinc, which we didn't realize until later, and he was depressed until he started eating meat again, so we know that just low folate isn't enough for him. He has to have both low folate intake and methionine intake (which can be from meat). He still isn't completely back to normal as far as the depression is concerned, but he is close. It will probably take 3 weeks to evaluate whether the folate intake is low enough.
Another interesting point - Dr. Walsh says that a sign of overmethylation is high blood histamine and my son gets completely knocked out by Claritin, an antihistamine which is not supposed to cause drowsiness. Even a half dose makes him very sleepy. I assume that this is because his body has compensated for the high histamine by lowering the number of receptors or increasing the transporters and that he is more sensitive to blocking of the receptors because of this. I don't know if this would be the case for all undermethylators, though.
Overmthylation would be the opposite situation. I am writing from the point of view that I have experience with. I hope this has helped to clear things up and not made them more confusing.
Dr. Walsh says that if a person does not suffer from inadequate serotonin, even if they are undermethylators, then they don't need to have low folate. But I question whether there might not be other unhealthy effects from this undermethylation of histones which do not involve any "mental" symptoms. Anyone have any thoughts about this?
By the way, what many people refer to as overmethylation may sometimes be the opposite, in my opinion, because it is based on what happens soon after a person takes a folate supplement. If the symptoms take a few days or even weeks to appear it is more likely to be true overmethylation, in my opinion, and the treatment is to take folate along with niacinamide, according to Dr. Walsh. Probably the whole blood histamine or SAM/SAH ratio that Dr. Walsh recommends is the most accurate way to diagnose this.