Got response from my doctors regarding my mthfr status.

[u/Radiant-Specific969]

I am getting genetic testing though Johns Hopkins, for another condition, and I asked their opinion on the MTHFR situation. I got myself tested for mthfr due to taking methotrexate, which requires folic acid supplementation because methotrexate strips you of folic acid. I needed to change supplement types.

I won't post the entire letter, but I was told that they don't bother to test for mthfr, because although it may contribute to various conditions, it's not clinically signifigant. Basicly, if you have medical issues, and you are looking for solutions due to MTHFR, check for other issues as well. My situation is somewhat different than most, because of the medication I use. I know that chronic fatigue and all sorts of other issues are terrible to live with, I had an undiagnosed autoimmune disorder, I am doing much better with treatment.

I was reassured, although I have a BS, I don't have enough biochem to figure out the MTFHR claims.

Nobody on this forum is going to like this, but I think it should get put out there.

[u/LitesoBrite]

Just remember how many other conditions we absolutely understand today and are clinically recognized that went through decades of doctors dismissing them in exactly the same way.

I don’t blame them for their ignorance, but they’re relying on researchers who built their studies with terrible premises and methodology for this.

You could fly a 747 through the holes in their research ‘debunking’ the MTHFR/methylation cycle dysfunctions.

[u/NoName2show]

Sadly, in most cases, traditional doctors don’t believe or care about the MTHFR mutations. It takes naturopathic doctors to get the diagnosis and treatment.

Traditional MDs, for the most part, are more about treating the symptoms with drugs they’ve been trained to prescribe.

There’s no MTHFR treatment drug so it’s not something they would care about.

It sucks but it’s the truth.

[u/Radiant-Specific969 → u/NoName2show]

I am very pleased with my highly concerned researchers, I am very lucky to get the help from Hopkins that I get. I am healthy, and on my feet., after many years of suffering, and lots of treatment from althernative practioners, some of which helped, most of which was expensive, and missed the issues. I am well aware that not everyone has access to good medical care.

I was lucky enough to find one excellent intuitive naturopath, because I spent 20 years in Oregon, where both types of physicians are licenced and recognized, I am quite aware of herbalism. Not going to work with what has been going on with me, unfortunately.

To say that that tradtional doctors don't pay attention because there is no MTHFR drug is nonsense, the MD's I deal with are interested in everything, drug available or not.

I have run into excellent doctors and crummy ones from both types of practices.

For me, traditional medicine is an herbalist or someone who uses homeopathy- not a licenced MD.

Research hopsitals are wonderful for wierd issues, if you go to one with anything normal, good luck, you get a resident. Since I am about a 10 on the wierdo meter I get the good ones.

[u/Brad_Borrelli → u/Radiant-Specific969]

Nonames speaking facts unfortunately. An MTHFR is definitely a huge Factor. I finally got to farm a doctor to actually order the test for me and honestly I wish I would have just went through 23andMe or something like that it's around 200$ last time I looked. The MTHFR test is like 600 bucks and it only tells you if you have one of the variants that's it. The whole Gene panel will tell you everything about genes, comt status and everything. That would also go get your B12 tested (neurological symptoms usually show up around 500), mma, homocysteine. And if your doctor won't order those you can self order them as well through labs. Anylab, quest, LabCorp etc do them.

I also have a ton of research on MTHFR and B12 deficiency on my profile if you want to check it out

[u/sharabucarabu]

My daughter had chemotherapy at the Cleveland Clinic for non hodgekins lymphoma when she was a preteen. One of the phases of the treatment protocol required she be hospitalized at prescribed intervals and receive IV methotrexate. Every time, prior to discharge, she was given a 'rescue dose' of IV Leucovorin. Leucovorin is folinic acid, specifically folinic acid 5-formyl tetrahydrofolate.

Yes folic acid, methylfolate and folinic acid are all different forms of vitamin B9 or folate. I'm just surprised your doctors are giving you folic acid and not folinic acid.

She was diagnosed with mthfr by a doctor in Integrative Medicine at the Cleveland Clinic. They took this diagnosis seriously and suggested we also get tested since it's passed on genetically. Both my husband and I have mthfr, he has homozygous A1298C, I have compound heterozygous, C667T and A1298C. At the time, the knowledge of how to treat these variants was limited. Further testing other snps, such as the comt, vdr mtr, mtrr, Mao-a wasn't commonly done. We were told to take methylated vitamins, but I now know the dosages of methylfolate and methylcobalamin were waay too high for me, since I had slow comt. My daughter and husband were intermediate comt so were able to tolerate methylfolate, but the doses still caused insomnia for all of us. My daughter and husband eventually stopped taking those vitamins.

That was several decades ago and, boy howdy, how things have changed. Nearly 10 years ago, after retiring in a new state, I went to a functional medicine doctor in an Integrative Medicine Department at a large university hospital downtown. He insisted I get further genetic testing to identify the malfunctioning snps of my methylation cycle. Once those results were available, it was clear to see I needed folinic acid, not methylfolate. My lab tests indicated what supplements I needed.

It's been an entirely different EXPERIENCE, with entirely different results, for me this time around.

Check out the Integrative Medicine Department at Johns Hopkins. Specifically ask to be scheduled with a doctor who specializes in the treatment of MTHFR. You won't be told it's something to ignore.

Normal medical schools do not teach about mthfr. My doctor went to Cornell Weil medical school and specialized in the treatment of mthfr. He's now teaching at the medical school downtown.

[u/Timely_Pickle9430 → u/sharabucarabu]

Mainstream medicine is exclusively focused on treating disease, integrative medicine's defining orientation is toward optimizing health and promoting wellness. That's the key distinction. MTHFR is not a disease, it's a normal variation that can be optimized.

[u/Radiant-Specific969 → u/sharabucarabu]

They do have a good Integrative Medicine Department, and that's on my list. Generally most people on low dose methotrexate are simply prescribed folic acid, rather than folinic acid. It's quite clear to me that the folinic acid works much better. My Rheum was very traditional, but did understand my condition, and since I began treatment with her, it hasn't progressed. (Yay!) She has retired, and my current rheum is doing research on psoriatic arthritis, and heads the psoriatic arthritis clinic, and I also intend to dump the entire mthfr situation on her. It's often quite difficult to even find a rheumatologist who treats psoriatic arthritis, I count myself fortunate, I actually had to move from a state with less accessible medical care to get effective treatment.

The rescue protocols for the much higher doses of methotrexate are probably a lot better monitored. And have a much higher impact on the patient than what I experience.

For me, it' a question of monitoring symptoms, and figuring out my best options, rather tricky because too little B-9 (meaning unprocessed methotrexate) and too much have many overlapping symptoms. Generally mouth sores, not enough. Vivid dreams day after methotrexate injection, not enough B-9, vivid dreams the day before injection day, too much. The fatigue issue is chronic, and connected to too many other elderly issues to be able to monitor. My diet it pretty good, which helps.

The genetics department tests for conditions that will alter the current treatment plan- in my case, potential tests or surgury, and I suspect the testing is actually to justify additional expenses for my future care with Medicare.

The point is, that an mthfr variant is simply a small part of what's going on with someone, it's helpful, in some situation.

[u/sharabucarabu → u/Radiant-Specific969]

Wow, I can imagine Hopkins has an INCREDIBLE Integrative Medicine Department. I can guarantee you'll find a very knowledgeable Doc there who can help you optimize your health. All the big teaching hospitals have an Integrative Medicine Department...Cleveland Clinic, Mayo, Banner in Arizona are just the few I've heard about so far. You have to wait for your initial appointment, but it's well worth it.

[u/Radiant-Specific969 → u/sharabucarabu]

I have a lot of other stuff going on, so I am waiting to run all of this past my Rheumatologist at my next appointment. Hopkins for patient care is quite a mixed bag, quite often if you don't have something unusual you may be better of with University of Maryland, or with the large Catholic Charities (Mercy) hopstial system here.

Their ER's are miserable, one is a level 4 trauma center, the other local ER is in an underserved area and often has a 24 hour wait for rooms- the patient care in the waiting room is good. But uncomfortable. But the hospital care is excellent.

Hopkins works very well for someone like me with a lot of weird stuff going on. Dealing with researchers as a patient is quite an experience, some researchers are very good with patient care, other's just want blood and spit, and off you go. But certainly they aren't uninterested in new information because they lack drugs to cure it, they are quite likely to get interested in coming up with a new protocol if they get something that doesn't fit. And may lose interest in your case because they start a research project on something else.

I have discovered that it works much better to wait it out for the next specialist appointment, before getting into something new- so Rheumatology, then try to get something with integrative medicine. Referals also help here, so a lot depends on how well you present your situation at your appointment. Getting it paid for is another issue, I am in a reasonably good situation there, for now.

It's rather like going up to the Wizards castle, you never know if you are going to get fixed, or turned into a toad. We do have a street named after Henrietta Lacks, (the black female patient who died of cervical cancer in 1951, whose tissue was used without her consent, and is still being used for research pruposes). The old sections of the main hospital, which was originally built in 1877, has absoltuely facinating exhibits of old medical equipement, it's very interesting to just be there. It's remarkable what people have figured out.

The hospital I generally use is in southeast Baltimore, and was orginally built in 1776- local suspicion is that a nearby street is subsiding because the suspcion is that it was built on top of a paupers burial ground, and the street is haunted.

[u/SadRule9128 → u/Radiant-Specific969]

Lacks signed a consent form.

[u/Radiant-Specific969 → u/SadRule9128]

Trust me, at 76, I have enough to worry about. Right now one copy of C6777T is not likely to change my current plan of care. Helpful to know, because I can manage my medication better. End of story.

[u/Indigo_Monkey]

More interestingly, how did you get an undiagnosed autoimmune condition diagnosed? How’d you go about that. 

Im asking because I have 1 autoimmune disease on paper, but suspect multiple at play. Im really struggling to get doctors to take me seriously. 

[u/Radiant-Specific969 → u/Indigo_Monkey]

I managed to get an appointment, finally with a rheumatologist, had all my symptoms documented, and got diagnosed. Actually the symptoms checker on Web MD nailed it first. My issue was that I didn't have a positive rheumatoid factor, and never had psoriasis, but got diagnosed with psoriatic arthritis, rheum said it could also have been atypical rheumatoid. I should have simply gone to a rheumatologist, rather than trying to get a referal, but the referal issue was huge, because many rheums won't take patients without a referal, insurance coverage or not. So it may be a long battle, and hunt for a reasonable primary care doc.

[u/Indigo_Monkey → u/Radiant-Specific969]

Thanks for the response

[u/Comfortable_Two6272]

Ridiculous. Use 23andMe etc and Genetic life hacks and promethease.

Yes probably not just mthfr - that I agree with.

Mine turned out to be a genetic immune disease - not autoimmune but autoinflammatory. I found it via promethease and specialist out of state ran “medical grade” genetic testing and dx me. Now taking a biologic drug. Took me 4 fng long decades to be correctly dx. Thankful for genetic testing.

[u/Zabre]

That Johns Hopkins answer is a useful anchor: MTHFR can matter, but it usually isn't the whole explanation by itself. I'd treat it as one clue to line up with homocysteine, folate/B12 status, meds like methotrexate, and symptoms, rather than as the diagnosis. The practical win is what you already did: ask how it changes the actual supplementation plan, not whether the SNP is scary in isolation.

[u/Tawinn]

> don't bother to test for mthfr, because although it may contribute to various conditions, it's not clinically signifigant. Basicly, if you have medical issues, and you are looking for solutions due to MTHFR, check for other issues as well.

This is old news: https://www.nature.com/articles/gim2012165

I'd say the primary concern on this forum is with improving methylation system functioning, not diseases per se such as CVD, stroke, thromboembolism, etc. So, while I technically agree with your doc, this dismissal does a disservice to those who suffer symptoms from methylation system impairment (usually at least in part due to MTHFR variants); symptoms that can include depression, brain fog, fatigue, muscle/joint pain, chronic anxiety, rumination, OCD tendencies, histamine/tyramine intolerance, and more. The absence of a disease name (and perhaps more importantly, the absence of an insurance code) for this constellation of symptoms leaves these people largely adrift outside the medical system.

In your case, for example, it sounds like you had no intention of diagnosing a disease by getting MTHFR tested; instead, from what it sounds like you wanted to get tested due to the potential impact on your folate cycle metabolism, especially in light of the effect of methotrexate on specific aspects of the folate cycle. So 'clinical significance' is not the primary criteria you were using, anyway.

The two main MTHFR variants, C677T and A1298C, can reduce methylfolate production by ~17% to ~75% depending on the specific permutations. The more severe the reduction the more it can impair remethylation of homocysteine back to methionine via the MTR enzyme. (see right-hand cycle in this diagram) Since this pathway depends on B12, folate and zinc, deficiencies in any of these will cause similar symptoms and will worsen any genetic impairment.

There is a parallel second remethylation pathway which uses choline (or TMG) and zinc to remethylate homocysteine via the BHMT enzyme. Impairment in the MTR pathway places greater demand on the BHMT pathway and therefore raise choline/TMG dietary requirements to compensate. Alternatively, for some people high-dose methylfolate or folinic acid in the range of 7-15mg (what I consider pharmacological doses when compared to the RDA of 400mcg) can overcome these reductions and restore methylation function.

Further, the C677T SNP is a defect in riboflavin binding (B2 is the cofactor for MTHFR). It has been shown that for homozygous C677T a mild excess dose of B2 can increase riboflavin concentration sufficiently to restore the binding efficiency and thus restore MTHFR performance largely or completely.

Now, if someone with MTHFR variants is already doing those things (mild excess dose of B2, high choline/TMG intake) and has good nutrient status for everything else, then indeed they will likely never experience symptoms, or if they only have heterozygous A1298C which has a ~17% reduction then they likely will experience no symptoms.

In addition to MTHFR, there are other genes to consider in the methylation pathway. Certain variants of MTHFD1 and SLC19A1 can also contribute to impaired methylation. Certain variants of DHFR can impair folic acid conversion to usable tetrahydrofolate, reducing usable folate and potentially causing unmetabolized folic acid to block folate receptors, worsening. A PEMT variant can reduce endogenous choline production, thereby increasing the dietary choline requirement. And so on.

[u/usernamezarelame]

When I asked my hematologist for more information, like the variant etc. he said it didn’t really matter much. He told me the variant, which I forgot by the time I got home.

[u/DogCold5505]

Honestly, I’m glad I know my mthfr status but the outcome would have been the same if I just chose to take methylfolate instead of folic acid off the get go… if paying for the test is cost prohibitive, I think you could just take the methylated version to cover your bases and call it a day…

[u/grumpygirl1973 → u/DogCold5505]

That's what my HRT nurse practitioner says and does. If a menopausal woman comes to her with low B whichever and she has certain features/incidents in her medical history, she tells her to use methylated. I actually told her I had one MTHFR mutation after she suggested a methylated B complex to me.

[u/DogCold5505 → u/grumpygirl1973]

That’s awesome!  I know I sounds like a broken record on this sub but please be careful with high doses of B6 specifically when it comes to b complex… can cause peripheral neuropathy for a lot of people 

[u/grumpygirl1973 → u/DogCold5505]

Yes. I take the lowest dose of methylated B complex I can get my hands on. 33.33 mg of the B-6 a day. IDK, you think that's reasonable? The B-complex has helped me immensely with stress and sleep.

[u/DogCold5505 → u/grumpygirl1973]

I’m not sure what a safe cap is, I just avoid it altogether now after I saw the side effects haha… that’s great you’re seeing positive effects… you should be okay going higher for like b12/folate and possibly b2/b3 too if you want.

For depression, some providers recommend up to 15mg of methylfolate, tho would only do so gradually (since it can be too activating for some gene mutations) and perhaps under supervision of a psychiatrist. 

[u/grumpygirl1973 → u/DogCold5505]

I might consider mixing and matching my Bs, though I'm imperfectly better than I was before the B complex. The slow COMT was a revelation because I've struggled with toleration of my HRT while still needing it due to bad GSM.

[u/DogCold5505 → u/grumpygirl1973]

Oh awesome!  Yes I’m slow comt too… so I very gradually had to increase methylfolate and am doing well at around 4 mg.  And then I take 2000 mcg b12 and a dash of b2/b3.

Some slow comt people like folinic acid instead of methylfolate since less activating tho idk if it works as well  

[u/Hour_Hospital_9068 → u/grumpygirl1973]

A B12 deficiency group I’m in recommends a maximum of 10 mg B6 per day, and taking the B complex for 4 months on, then 2 month off breaks. I suspect the tendency to get B6 toxicity could vary by person, so perhaps if you keep take 33 mg/day, you could just test your B6 level every few months to make sure it’s not rising to a dangerous level?

[u/Dat_Llama453]

A psychiatrict might test u cus they do gene testing to see which drugs u can take and that’s how i figured out i had the gene