sueami
Senior Member
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I am heterozygous for MTR A2756G and homozygous for MTRR A664A. Not sure how to interpret that. I've tried fairly high doses of b12 before but not sure if it helped very much. How much methylb12 (sublingually) would I need to take to help mitigate that mutation? I know this is all very complicated but I have been trying very hard for a very long time to resolve this issue without any results to show for it.
MTR is an upregulation that makes you use up a lot more methyl groups and MTRR homozygous means you are not recycling methyl groups well at all. This is Heartfixer's take on it:
"MTR combines 5-methyl folate and homocysteine to form methionine and tetrahydrofolate (THF). More specifically, MTR removes a methyl group from 5-methyl folate, then tacks it on to homocysteine to form methionine. In the process 5-methyl folate is converted back to THF.
The MTR A2756G defect is an up regulation. The enzyme is always on, grabbing every homocysteine and 5-methyl folate molecule that it can get its hands on, processing them to methionine and THF. Methyl-B12 is required for normal function of MTR, and with each spin of the MTR enzyme, one molecule of methyl-B12 is degraded.
MTRR (Methionine Synthase Reductase) serves the needs of MTR, regenerating methyl-B12 from available methyl donors and B12. Without methyl-B12, MTR cannot convert homocysteine in to methionine. Needed downstream methyl donors such as SAMe will not be generated. Methylation fails, so does your biochemistry, and there goes your health.
When the MTR A2756G defect is present, MTR is always on, using up methyl-B12 faster than MTRR can regenerate it. The consequence is deficient methyl-B12. B12 blood levels may be normal, but as levels of methyl-B12 will be low, normal B12 physiology cannot be carried out. Homocysteine levels will typically be elevated. SAMe generation and methylation in general will be compromised. We can treat the MTR up regulation by:
a. Supplementing you with methyl-B12.
b. Measures designed to increase formation of methyl-B12.
c. We can also bypass the dysfunctional MTR step by stimulating the “backdoor” BHMT reaction, which converts homocysteine directly in to methionine (more on this approach later).
d. When we do not need to limit sulfur intake (CBS normal or under control with low urine sulfate readings) we can simply supplement you with SAMe, our most important methyl donor, which is otherwise formed from the methionine generated by the MTR/MTRR reaction. "
Without knowing your COMT status or CBS status, hard to know your best avenue to proceed. Have you posted your full snps here anywhere?
If you are CBS clean you can do his SAMe backdoor fix. If you are not (like me) you will need to push on other methyl donors, like MB12, I would think.
If you have significant COMT snps, you may have some anxiety/dopamine issues that get triggered in trying to work this out.
On the face of it, MB12 supplementation should be needed in spades, especially if you are trying to push methylfolate dosages (and you might not want to do that right now, given your MTRR/MTR status. I don't know enough to say.)
I found that I needed the MB12 shots at 1 mg every other day to start to feel better from Freddd's protocol. I was going downhill on it for the first two months because I was pushing folate higher and higher without getting enough methyl groups in. I'm backing down on my folate right now, to 1.6 mg or maybe even lower, depending on how slippery my neurotransmitter situation continues to be (I can feel normal one day and anxious the next. I want to be more stable than that.)
fwiw,
Sue