MTHFR Gene Defect Survey of ME patients

ME patients: Do you have a defective methylenetetrahydrofolate reductase gene (determined by test)?


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gbells

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Survey on MTHFR gene mutations for ME patients.

The methylenetetrahydrofolate reductase (MTHFR) enzyme converts synthetic folic acid and dietary folate into its active form, L-methylfolate, which plays a critical role in neurotransmitter synthesis. Some individuals carry a mutation at the C677T SNP of the MTHFR gene, which results in a 35% reduction in activity for heterozygotes (C/T) and a 70% reduction in activity for homozygotes (T/T).1,2 Individuals who carry this mutation will have a reduced capacity to create L-methylfolate.
https://genesight.com/articles/is-t...n-for-patients-with-the-mthfr-c677t-mutation/
 
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nerd

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I certainly don't have the C677T mutation, but there is a huge chunk of the MTHFR gene missing despite the 30x sequencing. So I don't really know if it's a deletion or a gap. I don't think it's a deletion though, because it's just too large of a piece. I guess something affected the MTHFR in both saliva samples.
 

gbells

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Wow, 30% of the population has this but it is very prevalent in ME patients so far. I had no idea. EBV further decreases folate metabolism and it is important for nerve cells DNA repair, depression. B12 is also involved so this explains irritability and depression also. Perhaps the nerve hypersensitivity ME patients get is related to MTFHR and folate/B12 metabolism problems that are not being addressed by MDs. The MD I saw in 2012 did the gene test but didn't prescribe active B12 so I did not get any symptomatic benefit but when I supplemented both recently I noticed a big boost in my mood, aerobic capacity and mental energy.
 

Learner1

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Wow, 30% of the population has this but it is very prevalent in ME patients so far. I had no idea. EBV further decreases folate metabolism and it is important for nerve cells DNA repair, depression. B12 is also involved so this explains irritability and depression also. Perhaps the nerve hypersensitivity ME patients get is related to MTFHR and folate/B12 metabolism problems that are not being addressed by MDs. The MD I saw in 2012 did the gene test but didn't prescribe active B12 so I did not get any symptomatic benefit but when I supplemented both recently I noticed a big boost in my mood, aerobic capacity and mental energy.
Mutations are actually more common than that. Worth knowing one should only take 5-MTHF. However, other genes and, most importantly, environmental factors can dramatically change one's need for folate and other methylation nutrients.
 

pattismith

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"rs1801133 is a SNP that is relatively common and has been studied for (relatively) a long time. Also known as C677T, Ala222Val, and A222V"

"Homozygous rs1801133(T;T) individuals have ~30% of the expected MTHFR enzyme activity, and rs1801133(C;T) heterozygotes have ~65% activity, compared to the most common genotype, rs1801133(C;C)."
 

gbells

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Here's a statistic for the percentage of EBV in ME patients, 90%.

The seroprevalence of EBV in the general population and in CFS/ME patients is ~90%. And the proportion of CFS/ME patients with EBI2 upregulation was found to be between 38 and 55% CFS/ME patients, all of whom had IgG to EBV VCA.
(Kerr JR. Epstein-Barr Virus Induced Gene-2 Upregulation Identifies a Particular Subtype of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. Front Pediatr. 2019;7:59. Published 2019 Mar 13. doi:10.3389/fped.2019.00059)

Mutations are actually more common than that. Worth knowing one should only take 5-MTHF. However, other genes and, most importantly, environmental factors can dramatically change one's need for folate and other methylation nutrients.
Learner's comment raises the question whether EBV could give a false positive for MTHFR mutation by reading methylation instead of actual DNA sequences. The lab test is not for methylation of the gene but is for the actual bad gene itself so it does not give false positives. While EBV does impact the need for folate, increasing the severity of the effect for a heterozygous MTHFR patient, it isn't going to give a false positive as it doesn't actually code for the gene, it is impairing folate metabolism downstream.

Results typically are reported as negative or positive and, if positive, the report will name the mutation(s) present. Often, an interpretation of the results is also provided.

Only a small percentage of cases of elevated homocysteine are due to an inherited cause. Of these, MTHFR C677T and A1298C mutations are among the most common.

If a person has two copies (homozygous) of MTHFR C677T, or has one copy of C677T and one of A1298C, then it is likely that elevated homocysteine levels are due to these inherited mutations, or that the mutations are contributing to them.

Two copies of A1298C are not typically associated with increased homocysteine levels.

If the MTHFR mutation test is negative, then the C677T and A1298C mutations were not detected and the tested person's elevated homocysteine level is likely due to another cause. Other, more rare MTHFR genetic mutations will not be detected with typical testing.
https://labtestsonline.org/tests/mthfr-mutation#:~:text=The methylenetetrahydrofolate reductase (MTHFR) gene,, spina bifida, and others.

So the fact that we are seeing that MTFHR mutation predisposes people for ME is important and suggests a possible explanation why two similarly infected patients would give ME symptoms for one patient but not the other. This is also important when considering that the odds ratios of dying from cancer in ME patients are much higher. So the MTHFR mutation is likely increasing the cancer deaths as folate is important for DNA repair and we may lower cancer deaths in ME patients by getting these patients the activated folic acid they need to prevent early damaged cells from progressing to cancerous ones by having their DNA repaired.

Another factor would be whether the patient was able to develop protective antibodies that would limit the spread of infected cells. Here is where infection timing becomes important.

CFS was present in 0.5% of cancer cases overall and 0.5% of controls. CFS was associated with an increased risk of non-Hodgkin lymphoma (NHL) (OR = 1.29, 95% confidence interval [CI] = 1.16-1.43, P = 1.7 × 10−6). Among NHL subtypes, CFS was associated with diffuse large B cell lymphoma (OR = 1.34, 95% CI = 1.12-1.61), marginal zone lymphoma (OR = 1.88, 95% CI = 1.38-2.57), and B cell NHL not otherwise specified (OR = 1.51, 95% CI = 1.03-2.23). CFS associations with NHL overall and NHL subtypes remained elevated after excluding patients with medical conditions related to CFS or NHL, such as autoimmune conditions. CFS was also associated, although not after multiple comparison adjustment, with cancers of the pancreas (OR = 1.25, 95% CI = 1.07-1.47), kidney (OR = 1.27, 95% CI = 1.07-1.49), breast (OR = 0.85, 95% CI = 0.74-0.98), and oral cavity and pharynx (OR = 0.70, 95% CI = 0.49-1.00). Chronic immune activation or an infection associated with CFS may play a role in explaining the increased risk of NHL. Cancer 2012.
(Chiang, C. Chronic fatigue syndrome and subsequent risk of cancer among elderly US adults. December 2012Cancer 118(23))
 
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gbells

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Just to follow up, treatment guidelines require people that use both activated B12 and activated folic acid. It is not sufficient to use folate alone. I previously treated with only activated folate and it did not help lower anxiety and improve mood (though it cured macrocytic anemia) however when I treated with both it did.

Given the high rate of ME responders if your PCP won't order the gene test you may want to just try the supplements and see if they help.
 
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Anything else beyond mB12 and a form of activated folate? I tried those for awhile and it seemed to help a bit with my fatigue and brain fog, but also potentially caused more tachycardia and less restful sleep (I took it in the mornings).
 

xebex

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no, I have the COMT ++ mutation which means I cannot take methylated b vitamins. I am taking pure encapsulations adenosyl hydroxy b12 which doesn't give me the horrendous side effects of methly b12, but I'm not sure it's doing much really. I have found eating liver helpful but it's liver and it's gross and it's hard to get hold of grass-fed beef liver all the time.
 
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I have the COMT C677T double, but I've taken methylated B vitamins in the past (maybe that was good, maybe bad). Seems like varying information on the correct way to proceed.

Have you tried dessicated grass fed liver supplements?
 

xebex

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I have the COMT C677T double, but I've taken methylated B vitamins in the past (maybe that was good, maybe bad). Seems like varying information on the correct way to proceed.

Have you tried dessicated grass fed liver supplements?
yes, I've tried them and didn't notice much from them whereas the effect from 1 oz of liver was pretty good - about an hour of cognitive clarity and a feeling of lightness - however it doesn't seem to have much of an effect nowadays I presume it boosted my b12 and I don't really need the boost anymore. Overall didn't affect my ME severity.

yes the info on COMT is very confusing - it seems that with MTHFR you MUST take methylated b vits but with COMT, you may be ok with them but might find other forms better.
 
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Learner's comment raises the question whether EBV could give a false positive for MTHFR mutation by reading methylation instead of actual DNA sequences
I made no such suggestion. What I did say is that many different factors can alter the body's need for folate. That might include viruses, bacterisk infections, physical trauma, various toxins, stress, nutrient status, gut microbiom and gut lining health, etc.

So the fact that we are seeing that MTFHR mutation predisposes people for ME is important and suggests a possible explanation why two similarly infected patients would give ME symptoms for one patient but not the other. This is also important when considering that the odds ratios of dying from cancer in ME patients are much higher. So the MTHFR mutation is likely increasing the cancer deaths as folate is important for DNA repair and we may lower cancer deaths in ME patients by getting these patients the activated folic acid they need to prevent early damaged cells from progressing to cancerous ones by having their DNA repaired.
Though MTHFR mutations are fairly common, there doesn't seem to be much evidence saying one or more predispose one to ME/CFS. There are many other factors, too.

The relationship to cancer is more complex. The attached article describes the various points in the one carbon cycle (methylation) where cancer may be triggered
Just to follow up, treatment guidelines require people that use both activated B12 and activated folic acid. It is not sufficient to use folate alone. I previously treated with only activated folate and it did not help lower anxiety and improve mood (though it cured macrocytic anemia) however when I treated with both it did.

Given the high rate of ME responders if your PCP won't order the gene test you may want to just try the supplements and see if they help.
One should take 5-methyltetrahydrafolate, not folic acid.
Anything else beyond mB12 and a form of activated folate? I tried those for awhile and it seemed to help a bit with my fatigue and brain fog, but also potentially caused more tachycardia and less restful sleep (I took it in the mornings).
Yes, other nutrients are needed, like zinc, potassium, magnesium, B2, B6, B1, molybdenum, and amino acids. Best to test and see what you need, which may very well differ from what other people need.
, I have the COMT ++ mutation which means I cannot take methylated b vitamins.
have the COMT C677T double, but I've taken methylated B vitamins in the past (maybe that was good, maybe bad). Seems like varying information on the correct way to proceed
yes the info on COMT is very confusing - it seems that with MTHFR you MUST take methylated b vits but with COMT, you may be ok with them but might find other forms better.
There is an awful lot of confusing information about COMT. I have COMT mutations and have done well with methyated B12 for years. Methylation is something everyone does every day. We need metal groups to survive. Some people need more than others. If you try taking methyl B12 when you are B12 deficient, and it works, great. Some people need to take adenosyl cobalamin and others do bell better with hydroxocobalamin, but the hydroxyl cobalamin doesn't contain methyl groups.
 

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gbells

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This is why medicine is behind the times with regards to MTHFR mutations.

MTHFR C677T and A1298C: Explained In Plain English (dietvsdisease.org)

They are only concerned with heart disease through raising homocysteine, don't consider viral inhibition and mood effects. So according to their model MTHFR treatment would not help me because I am heterozygous. However, they are wrong. Now my macrocytic anemia is corrected and anxiety much better.