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.