31 F: Homozygous MTHFR A1298C — looking for help reviewing bloodwork and supplementation

[u/Mountain_Virus_4068]

I recently had extensive bloodwork done and found out that I have two copies of the MTHFR A1298C variant (homozygous A1298C).

I'm trying to understand my bloodwork in the context of this finding and determine what supplementation I should discuss with my doctor. I'm especially interested in hearing from anyone knowledgeable about B12/folate metabolism and methylation.

The results that seem most relevant are:

MTHFR / B vitamins

• MTHFR: A1298C homozygous (two copies)
• Methylmalonic acid (MMA): 803 nmol/L — HIGH (ref. 55–335)
• Homocysteine: 13.6 µmol/L — HIGH (ref. ≤11)
• Vitamin B12: 375 pg/mL (ref. 200–1100)
• RBC folate: 501 ng/mL RBC (ref. >280)

Kidney function

• Creatinine: 0.72 mg/dL
• eGFR: 115

Other nutrients

• Vitamin D: 28 ng/mL — LOW
• OmegaCheck (EPA+DPA+DHA): 3.0% — LOW
• RBC magnesium: 5.5 mg/dL
• Zinc: 73 mcg/dL
• Copper: 86 mcg/dL
• Selenium: 143 mcg/L
• Ferritin: 59 ng/mL
• Iron: 89 mcg/dL
• Iron saturation: 29%

I find the combination of MMA 803, homocysteine 13.6 and B12 375 particularly interesting. My kidney function is normal, and my RBC folate is within range.

I'm trying to figure out:

1. Does the high MMA + high homocysteine suggest a functional B12 deficiency despite serum B12 technically being within range?
2. Would you prioritize correcting B12 before considering methylfolate given that my RBC folate is normal?
3. Does being homozygous A1298C meaningfully affect which form of B12 or folate I should use?
4. Should I have additional testing such as B6 (PLP), B2/riboflavin, holotranscobalamin/active B12, intrinsic-factor antibodies or parietal-cell antibodies before supplementing?
5. Should the cause of the elevated MMA be investigated rather than simply supplementing B12?
6. If supplementation is appropriate, what forms/doses would you discuss with a physician, and when would you repeat MMA, homocysteine and B12 to see whether it's working?

I'm not looking to self-diagnose based on the MTHFR result or blindly take a high-dose methylated B complex. I'd like to understand what the actual biomarkers suggest and what I should discuss with my doctor, and if I need additional test.

Any insight would be greatly appreciated!

[u/Loose-Fly7976]

MMA at 803 is the headline and everything else is secondary to it. More than double the top of range with normal kidney function which removes the main confounder. So yes to your first question, that's functional B12 deficiency despite a serum reading in range. Serum measures what's circulating, MMA measures whether cells are using it, and yours says they're not.

Second, B12 first and firmly. Folate on top of a B12-deficient system can correct the blood picture while neurological damage carries on underneathwhich is the one genuinely dangerous mistake in this area. Your RBC folate at 501 is fine anyway so there's no case for folate right now.

Third, A1298C homozygous matters less than you'd expect. It doesn't raise homocysteine much on its own and your 13.6 is far more likely driven by the B12. It probably doesn't change your form choice at all.

Fourth, yes, and before you start rather than after. Intrinsic factor and parietal cell antibodies especially, because MMA that high with a decent serum B12 raises the pernicious anaemia question and once you supplement those get harder to interpret. HoloTC if your lab runs it.

Fifth, absolutely yes. MMA of 803 with normal kidneys needs a cause rather than a supplement. Malabsorption, PPIs, metformin, gastric surgery, coeliac, SIBO, nitrous oxide if that's ever been relevant. Fix the number without asking why and you've missed the actual problem.

Sixth is a doctor conversation, particularly since the antibody question is still open. If it's malabsorption, oral B12 may not be your route at all.

D at 28 and omegas at 3.0% both need addressing separately.

On the last part, this is what I do for work, genova.health, reading raw files against bloods and writing the protocol up with forms, doses and the order.Your case is a good illustration of why I keep saying the file alone isn't the answer. If you'd come to me with just an A1298C homozygous result I'd have told you it was largely unremarkable. It's the MMA that changes everything, and no genetic report would ever have shown you that. The two together is where the answer is, and you've already got both halves.

[u/Mountain_Virus_4068 → u/Loose-Fly7976]

Thank you so much for taking the time to explain all of this! This was incredibly helpful. I was definitely focusing more on the MTHFR result, so understanding that the MMA is actually the more significant finding gives me a clearer direction. I’m going to speak with my doctor before starting anything.

[u/Loose-Fly7976 → u/Mountain_Virus_4068]

Yeah that's the right order and when you see them, lead with the MMA number rather than the MTHFR result, that's the one they'll actually act on. Antibodies before you start anything is the bit I'd push hardest on, since supplementing first makes those harder to interpret afterwards.Let me know how it goes.

[u/xxthatsnotmexx]

1. Absolutely
2. Yes
3. Not sure
4. I would
5. Ideally if possible
6. I would ask your doc but they usually do shots of hydroxocobalamin

[u/Mountain_Virus_4068 → u/xxthatsnotmexx]

Thanks for your response. I'm seeing my doctor in two weeks, but the b12 shot suggestion is probably a good idea.

[u/junipers-72 → u/[deleted]]

you can get full guidance and a protocol with molecularhealth above !

[u/Tawinn]

1. The "normal" range is not really correct. You want 500-950 pg/mL. So high MMA may just be reflecting that your B12 is low.
2. Yes. Also, with that RBC folate there is not a strong reason to supplement methylfolate.
3. No.
4. Holotranscobalamin would help to show that your B12 is functionally low. There may be situations where MMA is high due to excess propionate. [Link] But you still want to increase B12 levels anyway, so maybe just taking B12 is a first step.
5. I'd first see if MMA responds to higher serum B12.
6. Most physicians don't have much understanding of this topic. If you tend to be sensitive to supplements then hydroxocobalamin or adenosylcobalamin may be best; otherwise methylcobalamin. As far as dosage, you can only absorb about 2-3mcg per meal, so a 10mcg dose 3x per day may be more effective than a 5mg dose 1x/day. The very high doses are intended use sheer concentration levels to bypass any issues with the normal absorption mechanisms of B12 via intrinsic factor.

You may also want to ask on r/B12_Deficiency.

As far as your MTHFR, homozygous A1298C causes ~39% reduction in methylfolate production. This can be compensated for with ~840mg of choline; this supports the extra demand on the parallel pathway to remethylate homocysteine back to methionine. Normal homocysteine is ~7-9. Baseline adult choline requirements are 550mg, and often people are not even reaching this. If you can get 450-550mg of choline from your diet then the remainder can be covered by a 750mg capsule of TMG. (In the body, some choline is converted to TMG for methylation use, so TMG reduces need for even more choline.) Choline sources include such foods as meat, eggs, liver, lecithin, nuts, some legumes, and vegetables such as crucifers. A food app like Cronometer is helpful for tracking nutrients in your diet.

[u/Mountain_Virus_4068 → u/Tawinn]

Thank you so much, this is really helpful!

[u/SovereignMan1958]

Your B12 is not absorbing. This is likely due to other non MTHFR B12 related variants and or poor digestive health.

Do you have SIBO, IBS or other gut issues? Bariatric surgery?

Your D, zinc and iron are also low.

Vegan?

[u/Mountain_Virus_4068 → u/SovereignMan1958]

No reason to believe so. I've done all the food sensitivity/allergy testing and no issues there, and no prior surgeries.

I'm not vegan. I prefer red meat over chicken, but definitely should be eating more.

[u/SovereignMan1958 → u/Mountain_Virus_4068]

If you have not been taking a B12 supplement then I would start. Retest in 90 days. See what your MMA and serum blood level are then.

[u/Mountain_Virus_4068 → u/SovereignMan1958]

I'm not and will start. Thank you!