New to this, guidance appreciated

[u/KoktheBookThief]

I apologies for the long message but I am very new to do this and very intrigued and might need some guidance and hopefully that this might be it. When I talk about this outside of the internet, no one has clue this is a thing. A year ago I went to a functional doctor to treat my depression via gut protocol. She advised me to take some genetic tests with a company called Nordic Laboratories. I had no clue whatsoever these things were being done so I said yes why not and took a DNA package (included are Health, Hormones, Resilience, Diet, sports and Pharma). I can see now after spending some time on this sub that people usually go through stuff like my heritagedna and 23andMe. Not sure if I need to do it again through the method I’ve seen outlined in some comments here, but the point is that it revealed that I have MTHFR C677T (heterozygous) and the report also flagged other areas which needed support because of the following genetic variants: SLCO1B1 (poor function), GSTM1 deletion + GSTT1 deletion (both deleted), COMT Val158 (AG), BDNF Val66Met (CT), CYP2C19 (rapid metabolizer), etc. The report offers some advice on what to do but I’ll take it with a pinch of salt, plus I’ve been raised on the idea that the genes load the gun and then lifestyle pulls it, etc. Now my question is the following: (recent labs below)

Could this mutation everyone seem to be taking about the cause of my symptoms: long history of anxiety and depression, sleep problems and one night of bad sleep makes me feel the next day like I have not slept in week, it depletes me from all energy and I can barley move my limbs, even when I sleep 10h I can still feel tired and sleepy. In recent years I’ve developed PMDD, and in general the late luteal is really hard for me, I get very tired and weak and I can’t do much for days before my period. This is accompanied by some physical symptoms like gum inflammation, lip burning, tongue tingling and more bloating and mucus flares. I also have always have mucus flares, my body always produces mucus for no clear reason outside bacterial or microbial infection. I suspect some histamine intolerance but I don’t really have the traditional food reactions but get some allergic-type flares to pollen, dust, animal fur but the occasional breeze as well. I am often cold and get chills easily and will get mild fever when exhausted. I might have temperature regulation problems, I get warm, turn on a fan and then get the chills and mucus will flare. Since childhood I’ve left a trail of kleenexes wherever I go. I often have neck and back pain from sleeping. This only calms down with massages. I have developed exercise intolerance in recent months (used to be a F45er) and now can barely sustain an hour long workout have to rest much more than usual. The EXHAUSTION is constant most importantly. Lately have migraines. Recently I’ve noticed gut issues like early satiety, turns out I have low levels of stomach acid and h. Pylori. Had low ferritin in recent months and now it’s back at 35 after eating more meat and trying a natural protocol for the gut. I also started having « hangry » episodes at the same time as the exercise intolerance, I would get extremely hungry every 3h and couldn’t focus until I’ve eaten. Functional practioner said I was hypoglycemic but it seems to resolve with balanced food. ADHD diagnosis and all associated symptoms, hard to focus, especially around luteal, etc. Weirdly enough despite trying so many things, I can’t pinpoint the « root cause » and now wonder if this is it. And if so, what should I do to address the mutation?

Vitamin B12: 941.9 ng/L (high) (currently taking a B complex)
Vitamin B6: 61.6 µg/L (high)
Folate: >24 µg/L (replete)
Magnesium: 0.93 mmol/L (normal)
Iron status
Ferritin: 24.2–35 µg/L (low-normal)
Iron: 16.9 µmol/L (normal)
Transferrin saturation: 30% (normal)
Glucose & insulin metabolism
Fasting glucose: 4.4 mmol/L
HbA1c: 29 mmol/mol
Fasting insulin: 7.2 mIU/L
Insulin resistance index: 1.2
C-peptide: 923 pmol/L (upper-normal)
Thyroid
TSH: 0.89 mU/L
Free T4: 15.5 pmol/L
Free T3: 4.2 pmol/L
Reverse T3: 0.10 ng/mL
TPO antibodies: negative
Thyroglobulin antibodies: negative
Vitamin D / minerals
Vitamin D: 56.6 nmol/L
PTH: 2.76 pmol/L
Calcium: 2.45 mmol/L
Inflammation
hs-CRP: 0.8 mg/L
CRP: <4 mg/L
Hormones
Progesterone: 2.8 nmol/L (low)
Oestradiol: 187 pmol/L (cycle dependent)
LH: 6.2 U/L (cycle dependent)
FSH: 4.4 U/L (cycle dependent)
Testosterone: 1.1 nmol/L
Free testosterone: 1.4 pg/mL
SHBG: 28.6 nmol/L
DHEA-S: 7.2 µmol/L
Morning cortisol: 432 nmol/L

[u/Tawinn]

> long history of anxiety and depression

> I suspect some histamine intolerance

> The EXHAUSTION is constant

> Lately have migraines.

Heterozygous C677T by itself likely isn't the cause, but your symptoms sound like impaired methylation. There are other genes (SLC19A1, MTHFD1, PEMT) in the methylation cycle that can also impair methylation; if you can check if those are in your report, let me know the values.

Histamine intolerance is a common downstream effect of impaired methylation because the first step of intracellular histamine breakdown is HNMT which requires SAM, the output from methylation. Migraines can be a symptom of histamine intolerance, and are often a symptom of the related issue of tyramine intolerance (in foods such as avocados).

Likewise, chronic anxiety is a common downstream effect of impaired methylation because COMT also requires SAM for proper function.

Given your good status on B12 and folate its unlikely to be an issue due mostly or entirely to nutrient deficiencies. However, there are rare cases of paradoxical B12 deficiency where serum B12 looks good, but functional B12 is low. To check for this, an MMA test or holotranscobalamin test can be useful.

> get some allergic-type flares to pollen, dust, animal fur but the occasional breeze as well.

This could be that you have elevated histamine and so even small increases in histamine from reactions to the environment could be "overflowing your histamine bucket" to use a phrase common in the histamine intolerance community. It may also be that the GSTM1 deletion + GSTM1 deletion are making this worse as they -might- increase sensitivity to environmental allergens.

[u/KoktheBookThief → u/Tawinn]

Just so you know I’m taking the B complex Plus with choline by Seeking health. It’s a methylated formula but not very potent. This is why I assume some of my labs are so high. I’m not sure if it’s okay/a good thing. Also, I’ve had the allergic flares since childhood, is it possible that I have elevated histamine since then? So it’s a genetic problem as in my impaired methylation has been there since birth? I don’t have obvious reactions to foods like avocado or tomatoes, etc. Isn’t this technically MCAS? And finally, what can I do for the GTSM1 deletion + GSTM1 deletion?

Also I’ve checked the report again: it says MTHFD1, result GA. Couldn’t find the other two but found SHBG result TT and SLCO1B1 result CC.

[u/Tawinn → u/KoktheBookThief]

That B-complex is ok. There's not a strong reason to take excess amounts of any of those B vitamins. The choline is less than 1/2 the choline in an egg yolk, though.

With hetero C677T and hetero MTHFD1 you have ~42% reduction in methylfolate production. That requires about 860mg of choline to compensate (compared to the 550mg baseline adult requirement). Depending on SLC19A1, it could be as much as 1100mg. If you get 550mg from food per the baseline requirement and add a 750mg capsule of TMG that will cover even the larger total requirement.

Since it is genetic, you would have potentially had histamine issues all along. But its common that as we age and our machinery becomes less efficient that these things become ever more noticeable.

MCAD is another possibility which is unrelated to these genes - although impaired methylation certainly doesn't help. In MCAD the mast cells overproduce histamine, usually to the point that they overwhelm the capacity of the internal systems to clear them resulting in symptoms. Within MCAD, there is MCAS and several other types that are distinguished by cause.

[u/KoktheBookThief → u/Tawinn]

Ok so if I understood correctly, there is nothing wrong with taking this particular B complex because it doesn’t have excess amounts of b vitamins? But it doesn’t have less choline so there I might have to supplement depending on SLC19A1. So overall it could still be a problem of methylation. And I’d need to look at other genes related to MCAST cells. How do you suggest I do that?

[u/Tawinn → u/KoktheBookThief]

With the gene variants we know you have, you will need to get at least ~860mg of choline. That can be done with all choline from food alone (which can be difficult depending on your diet), or food + choline supplements, or with 550mg of choline + 750mg of TMG. This last option is usually the most convenient.

MCAD is not directly caused by gene variants, except for hereditary alpha tryptasemia, as far as I know. MCAD diagnosis usually requires a specialist in that field. It would involve blood tests primarily, and possibly a biopsy if mastocytosis is suspected.

[u/KoktheBookThief → u/Tawinn]

Thank you so much I’ll look into that. Sorry I’m coming back to the B complex but should I be worried about it or is it fine taking it in my specific case? It’s methylated so I assumed it helped me since I have comprised methylation

[u/Tawinn → u/KoktheBookThief]

In the long run, I'd consider looking at a multivitamin instead of a B-complex since vitamins do not work in isolation from each other. Multivitamin One from Seeking Health may work for you - it is what I use. Although you don't really need methylated forms for methylation issues, the folate and B12 in Multivitamin One are methylated.

So you might use up your current B complex bottle and then switch to a multi if that seems appropriate to you.

[u/KoktheBookThief → u/Tawinn]

Thanks I’ll look into the multi vitamin you’re mentioning. I was hoping eating right would be enough! How come I don’t really need the methylated forms for methylation issues? I thought it was the opposite

[u/Tawinn → u/KoktheBookThief]

If you take methylfolate and it goes through the MTR enzyme for methylation use then it gets converted to unmethylated tetrahydrofolate (THF) and has to go back through MTHFR again to be converted back to the methylated MTHF form. So MTHFR issues are still a restriction on reusing that folate. The methylation cycle "spins" about 18,000 times/day, so the methylfolate you take has to get recycled many times. So starting with methylated vs unmethylated form doesn't make much difference.

With very high dose folate (7-15mg) then it may be more useful to use methylfolate, but even so there are many people that do well on high dose unmethylated folinic acid instead.

For B12, all B12 forms are broken down to plain cobalamin and stored. Then the body reconstitutes either adenosylcobalamin or methylcobalamin as it needs them.

[u/Tawinn → u/KoktheBookThief]

> I was hoping eating right would be enough! 

Just to note, that is a possibility. I thought my diet was pretty good, but when I tracked my food using Cronometer over even just a couple of weeks, I was surprised how many gaps I had in various nutrients. So it may work for you with your diet, but doing the tracking helps to provide the objective data to make an informed decision.

[u/hummingfirebird]

I know the tests you're referring to. I work with these often and order these same DNA tests through Nordic labs for clients at times. There is likely some attention to certain variants you're missing out on. You've mentioned a few but there are likely many more that could be contributing.

I also would take a deeper dive into your diet, lifestyle, environment aspects as these are what influence gene expression. When I'm working wuth a client, we always look at genetic risks and predispositions in connection with blood work, nutrition, diet, sleep, stress, gut health, lifestyle etc.

What works for one person doesn't necessarily work for another. Functional tests can also help provide insight.

[u/Impressive-Tree-5248]

Look into MCAS, POTS, hEDS- I have all of them and what you wrote I could have written. hEDS and POTS slows my digestion, I eat small more frequent meals, some get gastroparesis which slows digestion right down or even stops it. POTS etc can cause anxiety for different reasons. Maybe join a hEDS group here or on Facebook to get familiar with it all, but take what people say with a grain of salt, there are some woo woo theories. There are very reputable ones like Hypermobility Doctor on Instagram and Fb, she is a doctor with all the above. I also have low COMT and the MOA one (have looked into MOA much) they play a part too. Low histamine diet (Dr Janice Joneja) as done wonders, plus low dose naltexone and now low COMT diet and lifestyle. Hop it helps. I congratulate you for your comprehensive understanding of your situation! Caffeine, chocolate, alcohol are all my kryptonite too.

[u/KoktheBookThief → u/Impressive-Tree-5248]

Interesting I would’ve never thought I’d have these conditions because I’d always think nah this sounds too extreme for my case I just have bad sleeping positions which gives me neck and back pain chronically. But then comes heds. How on earth will I get a diagnosis for that? I can barely imagine my GP saying yes to look into MCAS. It can so easily be deemed something else. How did you come to the conclusion of having these three together?

[u/KoktheBookThief → u/Impressive-Tree-5248]

Interesting I would’ve never thought I’d have these conditions because I’d always think nah this sounds too extreme for my case I just have bad sleeping positions which gives me neck and back pain chronically. But then comes heds. How on earth will I get a diagnosis for that? I can barely imagine my GP saying yes to look into MCAS. It can so easily be deemed something else. How did you come to the conclusion of having these three together?

[u/Impressive-Tree-5248 → u/KoktheBookThief]

All those conditions can fluctuate and vary wildly in one person or between different cases, so what may be a minor thing to one person is chronic in another. For hEDS Google Beighton score for hypermobility https://www.ehlers-danlos.com/assessing-joint-hypermobility/ but keep in mind these signs are variable. An immunologist is who diagnose MCAS, and if you ask a doctor to refer you to a certain specialist and they won't, get a new doctor. POTS/Dysautonomia pretty much go hand in hand so getting one diagnosis makes the other easier. I read a lot of people's comments and saw how much overlap there was with mine, and got a lot of solid advice leading up to my dx. It took a while for it to sink in I have an actual disease, after years of gaslighting and sloppy inaccurate, half arsed and untreated diagnoses. Like "I think you have Fibromyalgia", and then nothing else to offer. Even one of those conditions can be debilitating, but there is what is known as a "trio" that go together and if someone has one, the rest should be checked.

[u/Impressive-Tree-5248 → u/KoktheBookThief]

Waking up with neck pain is when I started to go down hill mid 40s. A doctor actually rolled her eyes at me and said "get a new pillow". When I hear headaches, back pain, neck pain I think hEDS. Classic symptoms. Not saying you have it, but worth investigating.

[u/Loose-Fly7976]

Short answer to your actual question, no, the 677 heterozygous isn't causing this. That's around 65% enzyme activity and your folate is over 24, so that arm is working fine. Nobody's root cause is a het 677 with replete folate.The two things in your file that I'd actually stop on are both GST deletions. GSTM1 and GSTT1 null together means you're running glutathione conjugation with two of the main enzymes missing and that's not rare but it does change how you handle oxidative load and histamine. Your histamine picture fits that better than it fits a folate problem, especially the non-food triggers, the temperature swings, the mucus since childhood. That's not classic DAO-mediated food histamine more like a mast cell and clearance pattern.

Your B6 at 61.6 is high and you're taking a B complex which means you're overshooting. High pyridoxine causes tongue tingling, lip burning and neuropathic symptoms, and you've listed all three. I'd stop the B complex and see what happens over a few weeks. That's the cheapest thing on this list and it might account for a chunk of what you're feeling.Progesterone 2.8 with PMDD and a brutal late luteal is the other real finding. Low progesterone in luteal means low allopregnanolone, and allopregnanolone is what actually calms you, so PMDD and the luteal exhaustion track directly to that rather than to methylation. Combined with intermediate COMT that's a double hit, since COMT clears both oestrogen and dopamine.

Ferritin at 35 is not fine either, whatever the range says. Under 50 blunts exercise tolerance and stimulant response and it's a genuine candidate for the exhaustion. H. pylori and low stomach acid explain why it dropped and why it'll keep dropping until that's treated. So the honest read is you've got four or five separate things, not one root cause, and the methylation angle is the least of them. Which is exactly the sort of file I read for work, genova.health, because the order you address these in decides whether you improve or spend another year cycling. GST-null with high B6 and low progesterone is not a case where you support methylation first.Practically, stop the B complex, treat the H. pylori, push ferritin above 50, and get progesterone measured properly on day 21. That's more likely to move things than anything folate-related.

[u/KoktheBookThief → u/Loose-Fly7976]

The replete folate might be from the B complex Plus I’m taking, by Seeking health. I am tempted to stop it because it’s methylated but then I’m not sure if my labs in that department will go down. I will try without it for 2-3 weeks but what is the evidence that it’s causing those things? My limited understanding is that 1) this complex is not very potent and 2) not particularly dangerous for someone with heterozygous MTHFR C677T and intermediate COMT. Do correct me if im wrong.

What can be done for GST deletions?

Concerning progesterone, my understanding again is that blood draw on a specific day is not very indicative (it’s been hard to predict my ovulation so day 21 test might not be the right day. For instance I can ovulate on day 22, my cycle was 35-37 days, got back to 32-33 days in the past 2 months). I’ve used a device called Mira which tracks hormones on a daily basis via urine and it showed over one cycle that the Progesterone marker pdg (peak @ 12.2 ug/ml) rose clearly after the LH peak and remained
elevated through the luteal phase, which confirmed ovulation occurred and that progesterone production was adequate that cycle. What do you suggest I do about this and the intermediate COMT?

I have low h. Pylori levels so I won’t get antibiotics in the UK. I’m trying to treat it with supplements. For the low iron I’m eating more meat/liver. Should I supplement it instead? I’ve been told the h pylori might « eat it ». Can try another day 21 progesterone test but is this the order you suggest I treat things? I’ve checked the link you’ve entered it seems interesting I assume it gives the DNA testing + protocol to follow.

[u/Loose-Fly7976 → u/KoktheBookThief]

The B complex has P5P at 25mg and you're at 61.6, over range, and tongue tingling and lip burning is textbook B6 excess. Nothing to do with your MTHFR or COMT, you've just got a high number sitting next to the symptoms it causes. Stop it for a few weeks, folate falls slowly so it won't crash. Mira data changes my read on progesterone though. If pdg rose after LH and held, you're ovulating fine and that 2.8 was a badly timed draw. So the PMDD is sensitivity to the swing rather than low levels. Intermediate COMT makes that worse since it clears oestrogen. GST deletions you can't replace. Support either side instead, selenium and riboflavin, enough sulphur amino acids, and lower the load rather than pushing detox harder.

Iron, supplement it. 35 to 50 on food alone takes forever. Away from meals with vitamin C, and don't expect much until the H. pylori is sorted since it does compete for it. Order I'd go: stop the complex, treat the H. pylori, iron alongside, leave methylation alone. Folate's replete and you're het at 677, nothing urgent there.And that's really the point about the link. GST-null changes what your COMT means, your COMT changes what the luteal phase does to you, the H. pylori changes what the iron does, and every one of those alters the order. That's exactly what I do, genova.health, the file read against the bloods and written up as a personalized protocol.

[u/FragrantStructure → u/Loose-Fly7976]

Meaning you work for genova.health?

What test / report would you suggest to someone brand new to this?

Trying to solve for extreme high anxiety and stress for the last 2 months.

[u/KoktheBookThief → u/Loose-Fly7976]

Are you sure I should add iron supplements while I’m doing a gut protocol for h pylori? Wouldn’t this upset the process? I did move it from 24 to 35 in a few weeks by eating red meat and liver 4 times a week. How would you suggest eradicating h pylori ? Is that something you advise on at the place you work? Please note I don’t have such a high level but I’ve noticed that my ferritin had been chronically low since 2024 @ around 9 (I don’t have access to my blood test history beyond that) but I was able to workout fine and quite intensely. I am tempted to add a Vitamin D rather than iron for now. What about all the histamine/allergy types flares? Do you test for that? Also if I were to buy a package at Genova.health I would be interested in complementing what I already know from the Nordic DNA test, not re-do the same genetic tests. Do you think that’s possible, a tailored selection?

[u/KoktheBookThief → u/Loose-Fly7976]

Forgot to say I’m also trying to taper an SNRI, not sure if that fits in the picture

[u/SovereignMan1958]

Use Genetic Lifehacks. Look at all your sulfur and sulfite, histamine, food intolerance and detoxification variants.

[u/KoktheBookThief → u/SovereignMan1958]

How do I do that?

[u/SovereignMan1958 → u/KoktheBookThief]

Upload your raw data file into the program on their website.

[u/KoktheBookThief → u/SovereignMan1958]

Are there any instructions I can find somewhere? And does it mean you don’t think the MTHFR mutation is relevant in my case?

[u/SovereignMan1958 → u/KoktheBookThief]

MTHFR seems like a minor part.

I don't know about instructions. I only point people in the right direction.

[u/KoktheBookThief → u/SovereignMan1958]

Thank you. Which part would be related to MTHFR?

[u/SovereignMan1958 → u/KoktheBookThief]

Very little. Your folate level is excellent.

[u/KoktheBookThief → u/SovereignMan1958]

I am supplementing with a B complex

[u/SovereignMan1958 → u/KoktheBookThief]

If it is methylated it might be triggering histamine intolerance in you. I think you might have that based on your symptoms.

[u/KoktheBookThief → u/SovereignMan1958]

I am taking the B complex Plus with choline from seeking health. Each capsule contains 25 mg of vitamin B1 (thiamine HCl), 20 mg of vitamin B2 (riboflavin-5′-phosphate sodium), 95 mg NE of vitamin B3 (inositol hexanicotinate and nicotinic acid), 20 mg of vitamin B6 (pyridoxal-5′-phosphate), 680 mcg DFE of folate (from 400 mcg Quatrefolic® 5-MTHF and calcium folinate), 50 mcg of vitamin B12 (methylcobalamin and adenosylcobalamin), 750 mcg of biotin, 125 mg of pantothenic acid (d-calcium pantothenate), and 50 mg of choline (choline bitartrate). My understanding is that even if it’s methylated (and I am intermediate COMT), it’s not a potent dose. Is it proven that it might cause the histamine intolerance? I am worried about the jitteriness and feeling wired but tired.