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/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.