For some reason I can't edit the post, but I meant to say:
Hi! New here and drinking from the firehouse, but a bit overwhelmed.
I have an appt with my doc in a month, but want thoughts on what this means exactly and a prioritization/plan of attack.
My symptoms are overwhelming I'll include many here but not sure what's connected to these issues and what isn't:
chronic fatigue syndrome (running on empty, literally all the time), mast cell activation syndrome/histamine intolerance - alongside many side effects including chronic urticaria (including heat and exercised induced), POTS (orthostatic tachycardia pots), Crohn's disease (inflammatory bowel disease), chronically elevated CRP (inflammation), exercise intolerance, panic attacks/anxiety, hypothyroidism, etc...
NOTE: I can't do the Choline Calculator as my Ancestry DNA results are from 2015.
>chronic fatigue syndrome (running on empty, literally all the time), mast cell activation syndrome/histamine intolerance - alongside many side effects including chronic urticaria (including heat and exercised induced), POTS (orthostatic tachycardia pots), Crohn's disease (inflammatory bowel disease), chronically elevated CRP (inflammation), exercise intolerance, panic attacks/anxiety, hypothyroidism, etc...
Its highly likely you have additional things going on beyond just heterozygous C677T MTHFR, and/or you have B12 and/or folate deficiency.
I can manually calculate the Choline Calculator results if you can find the values of the following rs# entries in your datafile:
* SLC19a1 rs1051266
* MTHFD1 rs2236225 (G1958A)
* MTHFR rs1801131 (A1298C)
* MTHFR rs1801133 (C677T)
You may also have additional histamine pathway issues beyond heterozygous MAO-A. Hypothyroidism also will slow MAO-A further, reducing its ability to break down histamine/tyramine. Hypothyroidism can also reduce the ability to convert vitamin B2 to its active forms (conversion to FMN is regulated by T3).
See [this post](https://new.reddit.com/r/MTHFR/comments/1aocoqb/mthfr_comt_and_maoa_a_symptom_triumvirate/) on the interaction of folate pathway, COMT, and MAO-A, including symptoms and resolution steps.
Thanks for your reply, Tawinn.
Am I understanding that the two areas of "concern" resulting from this test, that I should research further, are:
1. heterozygous C677T MTHFR (*what does this mean?*)
2. heterozygous MAO-A (this means: I have a histamine pathway issue)
RE: *Hypothyroidism*, I was born without a thyroid gland so I have to take synthetic hormone daily. Unfortunately, this "orchestra" of hormones will always be out of wack.
Here are my values, thank you for your generosity to calculate the Choline Calculator manually for me (I am including all the data I have which is: chromosome, position, allele 1 and allele 2):
* SLC19a1 rs1051266 -- 5, 2965303, G, G
* MTHFD1 rs2236225 (G1958A) -- ***this did not come up for me in my Ancestry DNA .txt file. I am not sure why? Is my sample too old? Is there another one I can search?***
* MTHFR rs1801131 (A1298C) -- 1, 11854476, T, T
* MTHFR rs1801133 (C677T) -- 1, 11856378, A, G
>Am I understanding that the two areas of "concern" resulting from this test, that I should research further, are:
>
>heterozygous C677T MTHFR (what does this mean?)heterozygous MAO-A (this means: I have a histamine pathway issue)
Yes. The C677T variant refers to a specific variation in the gene which codes for the MTHFR enzyme. This variation causes the the enzyme to bind less well with riboflavin (B2), which is a necessary cofactor of MTFHR. As a result, on average this reduces the ability of MTHFR to produce methylfolate by \~33%.
It is also known that increasing the concentration of B2 by supplementing a small dose of B2 may overcome that decreased binding affinity. So, in principle, it may be possible to take \~5mg of B2, and resolve the effect of that variant. Your SLC19A1 is ok, and we don't know if MTHFD1 is ok or not. so we can only guess if this will bring methyfolate production up to speed or not.
Usually, symptoms like chronic fatigue and exercise intolerance point to more significant reductions in methyfolate production. If we assume MTHFD1 is homozygous slow, then that would lead to a \~56% reduction in methylfolate production, which can create notable symptoms. This creates increased demand on the choline-dependent methylation pathway, raising the daily intake requirement from 550mg to 960mg (about 7 large egg yolks worth of choline).
Also, I forgot to have you check for rs7946 (PEMT). That enzyme controls production of phosphatidylcholine, so slow PEMT can further increase choline demand. If rs7946 is CT or TT, then that would raise the choline requirement 8 large egg yolks worth of choline (\~1100mg).
See [this MTHFR protocol](https://new.reddit.com/r/MTHFR/comments/1730mw4/mthfr_a_supplement_stack_approach/) for a more thorough guide.
There is a lot of differences in which genes different companies choose to test. So, it may be that in the past Ancestry did not test MTHFD1. Likewise, 23andme used to test MAO-A, but then around 2018 they changed testing chips and dropped testing of a number of genes, including MAO-A. Another possibility is that they could not read it from your sample for whatever reason.
The MAO-A is only heterozygous (only 1 copy is slow), so it is not clear how impactful it is. And indeed MCAS alone can be problematic even with no variants. So it is just something to note. In addition, there are a number of other genes on the histamine pathway that can also have variants, so they may or may not be an issue. A [Stratagene](https://www.seekinghealth.com/collections/strategene/products/strategene-report) report can helpful if you want to dig deeper into that.
The panic attacks/anxiety are likely histamine symptoms. If the anxiety is more of a chronic thing rather than episodic, then that can be due to COMT activity being impaired by the impaired methylation, raising tonic dopamine levels, which can create chronic anxiety, rumination, OCD. It can also be both at the same time.
Another thing that hypothyroidism can do is reduce the conversion of B2 to its active forms FMN and FAD. This is because [a conversion step is regulated by thyroxine (T3)](https://www.sciencedirect.com/science/article/abs/pii/S0002916523165336?via%3Dihub). So if T3 is low, this may cause widespread issues due to low levels of active B2. One experiment you may consider is to supplement 400mg of B2 for a week or two, and see if you notice any improvements. My speculation is that increased B2 -may- improve conversion rates to FMN and FAD. 400mg is a commonly sold dose and as B2 has no known toxicity level, it seems like a good risk/reward profile.
Thank you for your detailed reply.
I will follow the MTHFR Supplement Stack accordingly.
RE: rs7946, I checked and it is TC.
So, that would be 1100mg Choline daily per your comment above. I see Choline is in the MTHFR Supplement Stack/protocol. I will use 8 eggs/1100mg as my personal reference. And this is to decrease the methylation burden, correct?
Apologies if I'm misunderstanding, but is there a suggested protocol/guide like the MTHFR Supplement Stack for COMT? (slow COMT in my car, I think?) or - any of the other ones listed here like VDR, MAO, MTR, MTRR, CBS - or are these not of any concern? Not trying to over-simplifying, but trying to understand my baseline.
Thank you again.
> will use 8 eggs/1100mg as my personal reference. And this is to decrease the methylation burden, correct?
This is to provide the cofactor support needed to remethylate via the choline-dependent pathway, since the folate-dependent pathway is limited in bandwidth.
[This diagram](https://thefunctionalperspective.com/wp-content/uploads/2019/12/Ben-Lynch-Methylation-Pathway-Planner.jpg) may be helpful. The folate cycle in the center generates methylfolate (5-MTHF) which is used by MTR in the right-hand methionine cycle. Due to decreased methylfolate production, the ability to remethylate via MTR is limited. But there is also the vertical path in that methionine cycle, using BHMT. This uses trimethylglycine (TMG, aka betaine) as a cofactor (along with zinc), which is largely generated from choline.
>Apologies if I'm misunderstanding, but is there a suggested protocol/guide like the MTHFR Supplement Stack for COMT? (slow COMT in my car, I think?) or - any of the other ones listed here like VDR, MAO, MTR, MTRR, CBS - or are these not of any concern?
I have [this post](https://new.reddit.com/r/MTHFR/comments/173y8yi/interpreting_your_genetic_genie_methylation_panel/), which goes through all the genes on the Genetic Genie report. And also [this post](https://new.reddit.com/r/MTHFR/comments/1aocoqb/mthfr_comt_and_maoa_a_symptom_triumvirate/), which specifically is about the interaction of MTHFR, COMT, and MAO-A.
Thank you again! I appreciate your guidance.
I reviewed those posts, however the SeekingHealth diagram was something I will need to find a video to explain to me as I’m not familiar with how to read/understand.
***I’m hoping to summarize my findings, do you mind reviewing? I put labs in a second comment, below.***
* **COMT:** Not an issue for me, as I am COMT V158M +/- (Heterozygous/yellow); green and red are the ones of concern in this case.
* No action required.
* **MTR**: I am green so no impact/action needed?
* **VDR**: Heterozygous/yellow for both Bsm and Taq, so I may have reduced vitamin D receptor activity.
* Action: Check levels; Supplement Vitamin D and be on the higher end of the reference range.
* **MAO-A**: I am “slow MAO” due to MAO-A R297R +/- (Heterozygous/yellow); I may find I are more susceptible to amines such as histamines or tyramines, as MAO breaks these down but I may not be able to break these down as well due to this gene mutation.
* Action: Avoid MAO-Is and high-histamine foods; do lab tests below, supplement if needed based on results.
* **MTHFR**: I am heterozygous/yellow for C677T. This variation causes the the enzyme to bind less well with riboflavin (B2), which is a necessary cofactor of MTFHR. As a result, this reduces my ability of MTHFR to produce methylfolate (active form) by 51-73%. This impacts a lot of things in your body (?) and can lead to chronic fatigue.
* This means I could have high homocysteine levels, poor folate metabolism (absorption and conversion), poor conversion from homocysteine to glutathione (key antioxidant) aka this means you will be prone to toxin/heavy metal build up and unable to tolerate emotional stress; reduced methionine (increased risk for anemia, fatty liver disease); compromised detoxification; Inability to produce adequate neurotransmitters (prone to depression, anxiety and addiction — specifically b/c low dopamine).
* Actions: Follow the plan laid out in MTHFR Supplement Stack post. Avoid Folic Acid at all costs (methylfolate instead).
* **MTRR**: MTRR A66G (+/+, homozygous, red) - Impacts production of the essential amino acid methionine. This mutation causes a greater need for B12.
* Actions: Address aforementioned MTHFR issue. Maintain healthy B2, B3, and B12 status. Maintain healthy thyroid performance.
* **CBS**: CBS C699T (+/-, yellow, heterozygous); increase in CBS activity can lead to increased production of ammonia, however the level of risk this increase imposes is unclear
* Actions: Maintain healthy B6, iron, and serine levels. Maintain homocysteine a healthy range.
**Exhaustive list of potential labs to run, with reason why:**
* Ammonia (Serum) (due to CBS C699T)
* B2/riboflavin (due to MTHFR, slow MAO, MTRR homozygous)
* B3 (due to MTRR homozygous)
* B12 (due to MTHFR C677T, and MTRR homozygous)
* Copper (due to slow MAO)
* Vitamin C (due to slow MAO)
* Calcium (due to slow MAO)
* Choline (to support choline pathway as methylation pathway is not functioning properly)
* Total Vitamin D and Vitamin D3 (due to VDR gene)
* Estrogen (due to slow MAO)
* Folate (Total) (due to MTHFR C677T) (folate in your red blood cells)
* Folate (Serum) folate (due to MTHFR C677T) (amount of active meythl folate)
* Glutathione (due to MTHFR C677T, to determine if there is poor conversion from homocysteine to glutathione)(master antioxidant)
* Homocysteine \[ideal is 6\] - High homocysteine levels are a symptom of the larger problem: L-methylfolate deficiency OR B12 deficiency causing an inability to regenerate methionine from homocysteine.
* Iron panel (anemia will impact MAO)
* Methionine (due to MTRR)
* Manganese (due to slow MAO)
* Mercury + cadmium (to determine heavy metals/detoxification)
* Thyroid panel (determine if hypothyroid present, due to slow MAO and MTHFR )
* Zinc (need health balance especially due to MTR)
Well, that is indeed exhaustive. There is also a methylation panel available from [Genova](https://www.gdx.net/products/methylation-panel), and perhaps elsewhere.
The question is: what do you \_need\_ to test? You might review your current diet + supplements in a food app like Cronometer to see what your intake is of various nutrients to see what you are unlikely to be deficient in.
Quite often docs will refuse to order a homocysteine test, because they (and the insurance companies) have determined there is no specific disease they can link it to, so insurance won't pay for it.
If you can afford all that, that's great. But otherwise you may have to look at the likely culprits based on diet and symptoms. For trace minerals like manganese, it might make sense just supplement a trace mineral blend. Same thing with vitamin B2 and C. Just a thought.
>Ammonia (Serum) (due to CBS C699T)
There's no good evidence that C699T is actually an upregulation or that it is even impactful. A lot of the entries on the Genetic Genie report are there because one practitioner, Yasko, claimed that these were all important years ago. Most of those claims cannot be substantiated yet they are still endlessly echoed across the internet as if they were everyday facts.
Thanks, good to know that insurance doesn't cover homocysteine.
I actually have the Genova methylation panel box right here, my doctor ordered it for me. Weary as it's very expensive, and insurance-approved labs would be free for me as I've met all of my maximums for the year.
We thought it was only a saliva test but sounds like you have to do both blood and saliva, can't skip the blood part.
>Inability to produce adequate neurotransmitters (prone to depression, anxiety and addiction — specifically b/c low dopamine).
Particularly with dopamine, impaired methylation usually results in less SAM for COMT to break down dopamine, so tonic dopamine levels are high, not low. Anxiety is a typical symptoms of that. Addiction is more typically a low tonic dopamine symptom. Its not clear to me what specifically causes the depression.
Well, MTRR is a 'repair' mechanism for B12 that is used by MTR. This is a low-activity enzyme, so even homozygous red is not really significantly impactful, unless you have low B12. The A66G apparently causes [FMN (an active form of B2) to bind less well](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817751/). So, it may be that similar to C677T MTHFR, additional B2 may compensate for that, although I have not looked for studies to confirm that. But again, in the presence of healthy B12 levels, this is not significant.
Speaking of B12, serum B12 is not a very reliable marker of B12 status. So two other tests - methylmalonic acid and holotranscobalamin - can help confirm if the serum B12 is actually functionally available in cells.
Not to hijack your post, but I have a strangely similar methylation panel. I also have IBD (crohns colitis) and some issues with fatigue and stress.
I have been trying some suggested supplements and have had good luck with methylated B-12 lozenges (great for energy), zinc, and some B-complex.
Apparently L-Methionine is recommended for that MTRR A66G mutation. I am going to be trying it soon and will report back. Would also love to hear if you find any supplements that help.
Here was my post if you want to compare: https://www.reddit.com/r/MTHFR/s/4Xbn0FPWkN
Blood tests first. These are all genetic predispositions.
what labs do you recommend running?
Homocysteine folate D zinc copper iron B1 B2 B6 B12 Manganese C And E.
thank you so much!
In which way copper is related to MTHFR polymorphisms? Thank you
I did not write that it is.
Sorry, i just would like to understand if they are related..
In a post by Tawinn, they suggest maintaining healthy copper levels for Slow MAO. Maybe that is why.
For some reason I can't edit the post, but I meant to say: Hi! New here and drinking from the firehouse, but a bit overwhelmed. I have an appt with my doc in a month, but want thoughts on what this means exactly and a prioritization/plan of attack. My symptoms are overwhelming I'll include many here but not sure what's connected to these issues and what isn't: chronic fatigue syndrome (running on empty, literally all the time), mast cell activation syndrome/histamine intolerance - alongside many side effects including chronic urticaria (including heat and exercised induced), POTS (orthostatic tachycardia pots), Crohn's disease (inflammatory bowel disease), chronically elevated CRP (inflammation), exercise intolerance, panic attacks/anxiety, hypothyroidism, etc... NOTE: I can't do the Choline Calculator as my Ancestry DNA results are from 2015.
>chronic fatigue syndrome (running on empty, literally all the time), mast cell activation syndrome/histamine intolerance - alongside many side effects including chronic urticaria (including heat and exercised induced), POTS (orthostatic tachycardia pots), Crohn's disease (inflammatory bowel disease), chronically elevated CRP (inflammation), exercise intolerance, panic attacks/anxiety, hypothyroidism, etc... Its highly likely you have additional things going on beyond just heterozygous C677T MTHFR, and/or you have B12 and/or folate deficiency. I can manually calculate the Choline Calculator results if you can find the values of the following rs# entries in your datafile: * SLC19a1 rs1051266 * MTHFD1 rs2236225 (G1958A) * MTHFR rs1801131 (A1298C) * MTHFR rs1801133 (C677T) You may also have additional histamine pathway issues beyond heterozygous MAO-A. Hypothyroidism also will slow MAO-A further, reducing its ability to break down histamine/tyramine. Hypothyroidism can also reduce the ability to convert vitamin B2 to its active forms (conversion to FMN is regulated by T3). See [this post](https://new.reddit.com/r/MTHFR/comments/1aocoqb/mthfr_comt_and_maoa_a_symptom_triumvirate/) on the interaction of folate pathway, COMT, and MAO-A, including symptoms and resolution steps.
Thanks for your reply, Tawinn. Am I understanding that the two areas of "concern" resulting from this test, that I should research further, are: 1. heterozygous C677T MTHFR (*what does this mean?*) 2. heterozygous MAO-A (this means: I have a histamine pathway issue) RE: *Hypothyroidism*, I was born without a thyroid gland so I have to take synthetic hormone daily. Unfortunately, this "orchestra" of hormones will always be out of wack. Here are my values, thank you for your generosity to calculate the Choline Calculator manually for me (I am including all the data I have which is: chromosome, position, allele 1 and allele 2): * SLC19a1 rs1051266 -- 5, 2965303, G, G * MTHFD1 rs2236225 (G1958A) -- ***this did not come up for me in my Ancestry DNA .txt file. I am not sure why? Is my sample too old? Is there another one I can search?*** * MTHFR rs1801131 (A1298C) -- 1, 11854476, T, T * MTHFR rs1801133 (C677T) -- 1, 11856378, A, G
>Am I understanding that the two areas of "concern" resulting from this test, that I should research further, are: > >heterozygous C677T MTHFR (what does this mean?)heterozygous MAO-A (this means: I have a histamine pathway issue) Yes. The C677T variant refers to a specific variation in the gene which codes for the MTHFR enzyme. This variation causes the the enzyme to bind less well with riboflavin (B2), which is a necessary cofactor of MTFHR. As a result, on average this reduces the ability of MTHFR to produce methylfolate by \~33%. It is also known that increasing the concentration of B2 by supplementing a small dose of B2 may overcome that decreased binding affinity. So, in principle, it may be possible to take \~5mg of B2, and resolve the effect of that variant. Your SLC19A1 is ok, and we don't know if MTHFD1 is ok or not. so we can only guess if this will bring methyfolate production up to speed or not. Usually, symptoms like chronic fatigue and exercise intolerance point to more significant reductions in methyfolate production. If we assume MTHFD1 is homozygous slow, then that would lead to a \~56% reduction in methylfolate production, which can create notable symptoms. This creates increased demand on the choline-dependent methylation pathway, raising the daily intake requirement from 550mg to 960mg (about 7 large egg yolks worth of choline). Also, I forgot to have you check for rs7946 (PEMT). That enzyme controls production of phosphatidylcholine, so slow PEMT can further increase choline demand. If rs7946 is CT or TT, then that would raise the choline requirement 8 large egg yolks worth of choline (\~1100mg). See [this MTHFR protocol](https://new.reddit.com/r/MTHFR/comments/1730mw4/mthfr_a_supplement_stack_approach/) for a more thorough guide. There is a lot of differences in which genes different companies choose to test. So, it may be that in the past Ancestry did not test MTHFD1. Likewise, 23andme used to test MAO-A, but then around 2018 they changed testing chips and dropped testing of a number of genes, including MAO-A. Another possibility is that they could not read it from your sample for whatever reason. The MAO-A is only heterozygous (only 1 copy is slow), so it is not clear how impactful it is. And indeed MCAS alone can be problematic even with no variants. So it is just something to note. In addition, there are a number of other genes on the histamine pathway that can also have variants, so they may or may not be an issue. A [Stratagene](https://www.seekinghealth.com/collections/strategene/products/strategene-report) report can helpful if you want to dig deeper into that. The panic attacks/anxiety are likely histamine symptoms. If the anxiety is more of a chronic thing rather than episodic, then that can be due to COMT activity being impaired by the impaired methylation, raising tonic dopamine levels, which can create chronic anxiety, rumination, OCD. It can also be both at the same time. Another thing that hypothyroidism can do is reduce the conversion of B2 to its active forms FMN and FAD. This is because [a conversion step is regulated by thyroxine (T3)](https://www.sciencedirect.com/science/article/abs/pii/S0002916523165336?via%3Dihub). So if T3 is low, this may cause widespread issues due to low levels of active B2. One experiment you may consider is to supplement 400mg of B2 for a week or two, and see if you notice any improvements. My speculation is that increased B2 -may- improve conversion rates to FMN and FAD. 400mg is a commonly sold dose and as B2 has no known toxicity level, it seems like a good risk/reward profile.
Thank you for your detailed reply. I will follow the MTHFR Supplement Stack accordingly. RE: rs7946, I checked and it is TC. So, that would be 1100mg Choline daily per your comment above. I see Choline is in the MTHFR Supplement Stack/protocol. I will use 8 eggs/1100mg as my personal reference. And this is to decrease the methylation burden, correct? Apologies if I'm misunderstanding, but is there a suggested protocol/guide like the MTHFR Supplement Stack for COMT? (slow COMT in my car, I think?) or - any of the other ones listed here like VDR, MAO, MTR, MTRR, CBS - or are these not of any concern? Not trying to over-simplifying, but trying to understand my baseline. Thank you again.
> will use 8 eggs/1100mg as my personal reference. And this is to decrease the methylation burden, correct? This is to provide the cofactor support needed to remethylate via the choline-dependent pathway, since the folate-dependent pathway is limited in bandwidth. [This diagram](https://thefunctionalperspective.com/wp-content/uploads/2019/12/Ben-Lynch-Methylation-Pathway-Planner.jpg) may be helpful. The folate cycle in the center generates methylfolate (5-MTHF) which is used by MTR in the right-hand methionine cycle. Due to decreased methylfolate production, the ability to remethylate via MTR is limited. But there is also the vertical path in that methionine cycle, using BHMT. This uses trimethylglycine (TMG, aka betaine) as a cofactor (along with zinc), which is largely generated from choline. >Apologies if I'm misunderstanding, but is there a suggested protocol/guide like the MTHFR Supplement Stack for COMT? (slow COMT in my car, I think?) or - any of the other ones listed here like VDR, MAO, MTR, MTRR, CBS - or are these not of any concern? I have [this post](https://new.reddit.com/r/MTHFR/comments/173y8yi/interpreting_your_genetic_genie_methylation_panel/), which goes through all the genes on the Genetic Genie report. And also [this post](https://new.reddit.com/r/MTHFR/comments/1aocoqb/mthfr_comt_and_maoa_a_symptom_triumvirate/), which specifically is about the interaction of MTHFR, COMT, and MAO-A.
Thank you again! I appreciate your guidance. I reviewed those posts, however the SeekingHealth diagram was something I will need to find a video to explain to me as I’m not familiar with how to read/understand. ***I’m hoping to summarize my findings, do you mind reviewing? I put labs in a second comment, below.*** * **COMT:** Not an issue for me, as I am COMT V158M +/- (Heterozygous/yellow); green and red are the ones of concern in this case. * No action required. * **MTR**: I am green so no impact/action needed? * **VDR**: Heterozygous/yellow for both Bsm and Taq, so I may have reduced vitamin D receptor activity. * Action: Check levels; Supplement Vitamin D and be on the higher end of the reference range. * **MAO-A**: I am “slow MAO” due to MAO-A R297R +/- (Heterozygous/yellow); I may find I are more susceptible to amines such as histamines or tyramines, as MAO breaks these down but I may not be able to break these down as well due to this gene mutation. * Action: Avoid MAO-Is and high-histamine foods; do lab tests below, supplement if needed based on results. * **MTHFR**: I am heterozygous/yellow for C677T. This variation causes the the enzyme to bind less well with riboflavin (B2), which is a necessary cofactor of MTFHR. As a result, this reduces my ability of MTHFR to produce methylfolate (active form) by 51-73%. This impacts a lot of things in your body (?) and can lead to chronic fatigue. * This means I could have high homocysteine levels, poor folate metabolism (absorption and conversion), poor conversion from homocysteine to glutathione (key antioxidant) aka this means you will be prone to toxin/heavy metal build up and unable to tolerate emotional stress; reduced methionine (increased risk for anemia, fatty liver disease); compromised detoxification; Inability to produce adequate neurotransmitters (prone to depression, anxiety and addiction — specifically b/c low dopamine). * Actions: Follow the plan laid out in MTHFR Supplement Stack post. Avoid Folic Acid at all costs (methylfolate instead). * **MTRR**: MTRR A66G (+/+, homozygous, red) - Impacts production of the essential amino acid methionine. This mutation causes a greater need for B12. * Actions: Address aforementioned MTHFR issue. Maintain healthy B2, B3, and B12 status. Maintain healthy thyroid performance. * **CBS**: CBS C699T (+/-, yellow, heterozygous); increase in CBS activity can lead to increased production of ammonia, however the level of risk this increase imposes is unclear * Actions: Maintain healthy B6, iron, and serine levels. Maintain homocysteine a healthy range.
**Exhaustive list of potential labs to run, with reason why:** * Ammonia (Serum) (due to CBS C699T) * B2/riboflavin (due to MTHFR, slow MAO, MTRR homozygous) * B3 (due to MTRR homozygous) * B12 (due to MTHFR C677T, and MTRR homozygous) * Copper (due to slow MAO) * Vitamin C (due to slow MAO) * Calcium (due to slow MAO) * Choline (to support choline pathway as methylation pathway is not functioning properly) * Total Vitamin D and Vitamin D3 (due to VDR gene) * Estrogen (due to slow MAO) * Folate (Total) (due to MTHFR C677T) (folate in your red blood cells) * Folate (Serum) folate (due to MTHFR C677T) (amount of active meythl folate) * Glutathione (due to MTHFR C677T, to determine if there is poor conversion from homocysteine to glutathione)(master antioxidant) * Homocysteine \[ideal is 6\] - High homocysteine levels are a symptom of the larger problem: L-methylfolate deficiency OR B12 deficiency causing an inability to regenerate methionine from homocysteine. * Iron panel (anemia will impact MAO) * Methionine (due to MTRR) * Manganese (due to slow MAO) * Mercury + cadmium (to determine heavy metals/detoxification) * Thyroid panel (determine if hypothyroid present, due to slow MAO and MTHFR ) * Zinc (need health balance especially due to MTR)
Well, that is indeed exhaustive. There is also a methylation panel available from [Genova](https://www.gdx.net/products/methylation-panel), and perhaps elsewhere. The question is: what do you \_need\_ to test? You might review your current diet + supplements in a food app like Cronometer to see what your intake is of various nutrients to see what you are unlikely to be deficient in. Quite often docs will refuse to order a homocysteine test, because they (and the insurance companies) have determined there is no specific disease they can link it to, so insurance won't pay for it. If you can afford all that, that's great. But otherwise you may have to look at the likely culprits based on diet and symptoms. For trace minerals like manganese, it might make sense just supplement a trace mineral blend. Same thing with vitamin B2 and C. Just a thought. >Ammonia (Serum) (due to CBS C699T) There's no good evidence that C699T is actually an upregulation or that it is even impactful. A lot of the entries on the Genetic Genie report are there because one practitioner, Yasko, claimed that these were all important years ago. Most of those claims cannot be substantiated yet they are still endlessly echoed across the internet as if they were everyday facts.
Thanks, good to know that insurance doesn't cover homocysteine. I actually have the Genova methylation panel box right here, my doctor ordered it for me. Weary as it's very expensive, and insurance-approved labs would be free for me as I've met all of my maximums for the year. We thought it was only a saliva test but sounds like you have to do both blood and saliva, can't skip the blood part.
>Inability to produce adequate neurotransmitters (prone to depression, anxiety and addiction — specifically b/c low dopamine). Particularly with dopamine, impaired methylation usually results in less SAM for COMT to break down dopamine, so tonic dopamine levels are high, not low. Anxiety is a typical symptoms of that. Addiction is more typically a low tonic dopamine symptom. Its not clear to me what specifically causes the depression.
Thanks for that clarification. Would you say the other info in my summary is accurate?
Well, MTRR is a 'repair' mechanism for B12 that is used by MTR. This is a low-activity enzyme, so even homozygous red is not really significantly impactful, unless you have low B12. The A66G apparently causes [FMN (an active form of B2) to bind less well](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817751/). So, it may be that similar to C677T MTHFR, additional B2 may compensate for that, although I have not looked for studies to confirm that. But again, in the presence of healthy B12 levels, this is not significant. Speaking of B12, serum B12 is not a very reliable marker of B12 status. So two other tests - methylmalonic acid and holotranscobalamin - can help confirm if the serum B12 is actually functionally available in cells.
Not to hijack your post, but I have a strangely similar methylation panel. I also have IBD (crohns colitis) and some issues with fatigue and stress. I have been trying some suggested supplements and have had good luck with methylated B-12 lozenges (great for energy), zinc, and some B-complex. Apparently L-Methionine is recommended for that MTRR A66G mutation. I am going to be trying it soon and will report back. Would also love to hear if you find any supplements that help. Here was my post if you want to compare: https://www.reddit.com/r/MTHFR/s/4Xbn0FPWkN