MTHFR mutations

shijing

The Living Force
monotonic said:
Thanks. I hope it does calm down over time because it can be dangerous. It's one of those deceptive states of mind where you feel great and it just seems like everyone else is an idiot and you need to start breaking things and you have bizarre fantasies. And after it has passed the feeling good part seems to persist without the irritation. I'll reduce the dose, and maybe some NAC will also help.

When I first started taking methylcobalamin, I did experience intermittent bouts of anxiety, which may or may not have been related to either it or to the experience you're describing. I was supplementing with S-acetyl glutathione (mentioned in the excerpt RedFox posted above) at the same time, so this may have blunted the effects if they were related to the B12 (so NAC here would be good). It eventually calmed down, and I noticed real progress after doing a heavy metal detox for awhile. I don't really notice any difference at this point and I still take it regularly, although I do agree with LQB that it's better to take it in the morning rather than before bed. If this is your first time taking it, I agree it's good to reduce the dose for now and supplement with anything that will bolster your detox pathways. Also try to read (and/or watch videos) as much as you can about the body chemistry involved and possible side effects -- not everyone responds the same way to methylcobalamin, and the same person can be affected in different ways at different times depending on the circumstances.
 

Keyhole

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monotonic said:
We were at our local health market today and we found the Mercola B12 and vitamin D sprays on clearance, so we decided to try them out. The B12 spray uses methylcobolamin. After using it I experienced a strange mental state of being extremely irritated at every little annoyance. It reminded me of times in my childhood when I would explode with rage, times when I also could have been taking B vitamins. Not sure what to think of this?

I notice a lot of other people have noticed a similar problem:

http://www.health24.com/Experts/Question/vitamin-b-makes-me-angry-and-violent-20090319
Monotonic, have you had your B12 status tested?
 

Keyhole

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monotonic said:
So why have you been taking it then? If you haven't had any testing done, then taking methylB12 is a pretty naive thing to do and could have some consequences down the road. Methylation is not something to play around with. Supplementing a methyl donor essentially throws every other methylation process out of balance.
Really, unless you have the details of what your body is deficient in, then all of this is really just expensive guess work.

Honestly, I don't think it is wise for anyone to mess around with methyl donors unless they are under strict supervision and monitoring by a trained clinician. If you are genuinely interested in understanding the details of your body, save up and get some functional testing done. Otherwise, its probably best to steer clear from specialised supplementation like methyl donors.
 

climmm1

A Disturbance in the Force
Re: Hi Shijing, thanks for posting this as I hadn't connected it to Endothelial dysfunction before.
I did a genetic test at the end of last year and got my results back in January. I have a similar mutation 677CT/1298CA - 2 heterozygous mutations (compound heterozygous) gs192.

Where can you get the genetic test done for the MTHFR mutation at a reasonable cost? Also is there a saliva test available?

Thanks!
 

shijing

The Living Force
Hi climmm1,

climmm1 said:
I did a genetic test at the end of last year and got my results back in January. I have a similar mutation 677CT/1298CA - 2 heterozygous mutations (compound heterozygous) gs192.

Where can you get the genetic test done for the MTHFR mutation at a reasonable cost? Also is there a saliva test available?

I assume you're asking for someone else, since you already know your own polymorphisms, right? I'm not sure if there's a really cheap test available -- it's possible to do a saliva test through 23andme.com for the equivalent of about $180 USD, and run your returned data through Genetic Genie for free (or for a donation if you can afford it). For an additional $45, you can also submit it to StrateGene, which is discussed by Ben Lynch on his helpful resources page.

Also, I see this is your first post -- if you take a look around the forum and decide you'd like to participate more broadly, feel free to write a short introduction for yourself on the Newbies Forum.

I hope this is helpful to you, and good luck learning about MTHFR -- it's a very interesting topic, and if you have the polymorphisms there's a lot you can do for yourself which will improve and/or maintain your health.
 

trendsetter37

The Living Force
I'm a little out of my depth here but have recently had genetic testing done. Long story short It seems that I have the homozygous MTHFR A1298C (C1298C) mutation.

From GeneticGenie

First we'll look at a few of your MTHFR mutations. According to research, these mutations are important and can be
implicated in various disease states.

You have 1 homozygous (red) mutation(s). These are the worst type of mutations. They include:

MTHFR A1298C

MTHFR A1298C

MTHFR A1298C is involved in converting 5-methylfolate (5MTHF) to tetrahydrofolate (THF). Unlike MTHFR C677T,
the A1298C mutation does not lead to elevated homocysteine levels. This reaction helps generate BH4. BH4 is
important for the detoxification of ammonia. The gene is compromised about 70% in MTHFR A1298C (+/+)
individuals,
and about 30% in people with a heterozygous (+/-) mutation.

BH4 acts as a rate limiting factor for the production of neurotransmitters and catecholamines including serotonin,
melatonin, dopamine, norepinephrine, and epinephrine. A MTHFR A1298C + status may cause a decrease in any of
these neurotransmitters or catecholamines.
BH4 is also a cofactor in the production of nitric oxide. A dysfunctional
BH4 enzyme may lead to mental/emotional and/or physical symptoms.
Mercury, lead, and aluminum may act as a
drain on BH4

At this point in my reading, it seems that It'd be prudent to supplement with a good b vitamin from Jarrow. Thoughts?
 

Foxx

The Living Force
At this point in my reading, it seems that It'd be prudent to supplement with a good b vitamin from Jarrow. Thoughts?

It'd probably be good I think and as the theory goes that B vitamins are water soluble, there's probably not much of a potential down side. I suspect I have some kind of MTHFR variant and I know I've had severe folate deficiencies at times. FWIW I'm taking this one (2 at night, though I was taking 5mg daily for a while not too long ago to correct the deficiency):

https://www.amazon.com/Research-Methylfolate-Activated-Methylcobalamin-Homeocysteine/dp/B07DCM9Z81/

It's a pricier, but I think higher quality, brand than Jarrow.
 

Turgon

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At this point in my reading, it seems that It'd be prudent to supplement with a good b vitamin from Jarrow. Thoughts?

Correct me if I'm wrong, but I was under the impression that you could have the mutations but not have them active, so it depends. I got checked and had several myself, which isn't surprising. It probably won't hurt to supplement with B Vitamins as long as its methylated although you should be getting quite a bit from eating red meats. Dr. Ben Lynch had mentioned before that when taking some methylated B vitamins, start off small and work your way up with dosage because depending on your needs, it caused unnecessary aggression in some of his patients when they took too much, in particular methylcobalamin (B12). Jack Kruse talked about how doing cold therapy and making sure to get your vitamin D from sunlight and grounding in the morning, avoiding blue light at night and making sure your sleeping at the right times 10-6 ideally, are some of the best ways of eliminating concerns for MTHFR mutations, and Dr. Andrew Rostenberg said supplementing with digestive enzymes and eating lots of green leafy vegetables is another key component. Ben Lynch says the same thing about the green leafies.
 

trendsetter37

The Living Force
It'd probably be good I think and as the theory goes that B vitamins are water soluble, there's probably not much of a potential down side. I suspect I have some kind of MTHFR variant and I know I've had severe folate deficiencies at times. FWIW I'm taking this one (2 at night, though I was taking 5mg daily for a while not too long ago to correct the deficiency):

https://www.amazon.com/Research-Methylfolate-Activated-Methylcobalamin-Homeocysteine/dp/B07DCM9Z81/

It's a pricier, but I think higher quality, brand than Jarrow.

Thanks for the suggestion; I will definitely be giving this a try. Regarding downsides, I agree that there's probably little to speak of here but I did stop taking my b-complex (probably much lower quality than what you've suggested) because it caused a bit of anxiety shortly after taking it. This all began around April or May of this year and didn't happen consistently. It may be that I don't need to supplement daily but we'll see.


Correct me if I'm wrong, but I was under the impression that you could have the mutations but not have them active, so it depends.

I agree. Just wanted to cover all the bases really. If I'm honest I did see some things in the "what happens when BH4 production is compromised" that could potentially apply to myself but the symptoms listed were vague and could be caused by a number of issues. So no cigar either way.

Jack Kruse talked about how doing cold therapy and making sure to get your vitamin D from sunlight and grounding in the morning, avoiding blue light at night and making sure your sleeping at the right times 10-6 ideally, are some of the best ways of eliminating concerns for MTHFR mutations, and Dr. Andrew Rostenberg said supplementing with digestive enzymes and eating lots of green leafy vegetables is another key component. Ben Lynch says the same thing about the green leafies.

These are all good preventive measure I can work towards. Thanks for the reminder here!
 

dugdeep

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Chris Masterjohn just posted this article about MTHFR mutations and it's very interesting indeed!

Your “MTHFR” Is Just a Riboflavin Deficiency

[...]
I just got done doing a TON of research into riboflavin. I recorded a podcast on it with Alex Leaf of Examine.Com, where I focused on the basic science and Alex focused on the outcomes of supplementation studies. You can find that here.

One of the fascinating things we stumbled on is the possibility that the famous MTHFR polymorphisms — variations in the gene that uses riboflavin to make the methyl group of methylfolate — only decrease MTHFR activity because most people in whom the activity has been measured have mediocre riboflavin status.

Alex found some key studies supporting this and blogged about them here.

Here are the key findings:
  • Using experiments in bacteria, where the part of the MTHFR enzyme that binds riboflavin is similar to humans and other animals, the reason that the polymorphisms decrease enzyme activity is because they make the enzyme bind to riboflavin more weakly. At low riboflavin concentrations, the enzyme has poorer activity. However, at high enough riboflavin concentrations, enzymatic activity is restored to normal.
  • In humans who have the MTHFR C667T polymorphism, all of the elevated homocysteine is concentrated among people who have poor riboflavin status.
  • 1.6 milligrams of riboflavin per day decreases homocysteine, and this decrease is highly concentrated among people with the C677T MTHFR polymorphisms who also have poor riboflavin status. In them, 1.6 milligrams of riboflavin decreases homocysteine a whopping 40%!
And how many people have poor riboflavin status? It’s generally assumed that riboflavin deficiency is rare in the developed world. Only 10% of Americans consume less than the RDA and clinical deficiency is rarely reported. But rarely does anyone study whether people have biochemical evidence of poor riboflavin status. A recent study in the UK found that a whopping 75% of boys, 87% of girls, and 41% of adults had blood markers of poor riboflavin status.

Why?

Because the best source of riboflavin is liver, and we don’t eat liver any more. Because the next best sources of riboflavin are heart, kidney, and almonds. We don’t eat heart or kidney and few people make large amounts of almonds a daily staple. The next best sources are red meat, cheese, eggs, salmon, mushrooms, seaweed, sesame, wheat germ, and wheat bran. But you have to eat lots of these foods to get enough riboflavin and most people don’t. They are either demonized (red meat, cheese, and in some circles eggs) or they are used once or twice a week at most (salmon) or as minor portions of dishes (everything else in the list, if they are used at all). And while some people do load up on red meat and cheese, often the rest of their diet is rather terrible because they are not health-conscious.

Another reason might be that poor magnesium status and any kind of problem with energy metabolism — like hypothyroidism, adrenal stress, or insulin resistance — hurts riboflavin retention. So we have worse food selection riding on top of poor metabolic health and poor magnesium status. Less riboflavin is coming it, and more is going out. We’re left with a double-whammy on our riboflavin status.

If suboptimal riboflavin status is truly widespread, and if that is the reason why the C667T and the A1298C polymorphisms lower MTHFR activity, it suggests that riboflavin should really be central to our thinking of how to deal with methylation issues.

But it also helps explain something else: why almost everyone has at least one of these genetic variations. Only about 10-15% of the population doesn’t have either one! In fact, they are combined in such a way that there is almost an even spread across the population. There are six possible combinations of the different MTHFR alleles, producing a continuous gradation of MTHFR activity from 100% of full activity in the best case to 25% of full activity in the worst. Roughly 15% or so of people fall into each one of the six combinations, leading to an even spread of MTHFR activity across the population.

This distribution is compatible with a tradeoff, as if both low methylfolate and high methylfolate levels had equal advantages and disadvantages. That’s conceivable.

But if these variations in enzyme activity are just a result of having crappy riboflavin status, then another explanation emerges: from an evolutionary perspective, these variations proliferated because they just didn’t matter. Our ancestors had better riboflavin status than we did. They ate more riboflavin. They ate more magnesium and peed out less of it. They held on to their riboflavin better because they had better magnesium status and better metabolic health. They could get away with MTHFRs that didn’t bind riboflavin as tightly because they had so much riboflavin around.

So, what do we do about this?

First, I have revised my MTHFR protocol. My MTHFR protocol is laid out on my Start Here for Methylation page. While that page has always mentioned riboflavin, until now it had given riboflavin a back-seat consideration. I have now moved riboflavin to the driver’s seat. The first point in the MTHFR protocol is to aim for 3 milligrams of riboflavin per day.

Here’s how I suggest doing that:

On one or two days a week, eat four ounces of liver, ideally from beef, bison, or lamb. On the other days, consume one “liver equivalent,” mixed and matched from the following foods. These foods supply 1/2 of a liver equivalent: kidney, heart, and almonds. These foods provide 1/6 of a liver equivalent: red meat, cheese, eggs, salmon, mushrooms, seaweed, sesame, wheat germ, and wheat bran. On days that you cannot meet the food requirement for a liver equivalent, take a low-dose riboflavin supplement or B complex providing 3-5 milligrams of riboflavin. For example, you could use a half a dropper of this liquid riboflavin supplement.

It’s important to note that endurance exercise, weight loss, high-fat diets, and sunlight exposure all increase your riboflavin requirement substantially. If two or more of these apply to you and you have low MTHFR activity, your riboflavin requirement could be closer to 5 milligrams per day.

It’s also important to note that we don’t know yet just how close to maximal the extra riboflavin can get your MTHFR working. It might be the case that enough riboflavin completely normalizes the MTHFR enzyme.

Since we don’t know for sure, my recommendation isn’t to get extra riboflavin and then forget everything else. Rather, I recommend getting enough riboflavin first and foremost, and then still engaging the rest of the protocol by increasing choline, getting enough folate and protein, and considering supplementation with creatine and either collagen or glycine on an as-needed basis.

Think how different this is than trying to make up for low MTHFR activity by taking extra methylfolate. One methylfolate molecule goes into your body, stays inside your cells for 200 days, and every day has 18,000 methyl groups added to it using MTHFR. If you have a 75% decrease in that, you’re losing 13,500 of those recycling events. You can’t take 13,500 times the normal dose of methylfolate. I have no idea what it would do but I know it’s not safe. Methylfolate is one of the primary normal food forms of folate, and I think it’s great. You need to get enough folate, so getting normal, reasonable doses of methylfolate into your diet makes complete sense. But adding more to make up for low MTHFR activity is ludicrous.

Doubling your riboflavin intake from 1.5 mg to 3 mg may normalize MTHFR activity, or get close. You help the enzyme work right, and then those 13,500 lost recycling events are suddenly recovered.

Taking riboflavin to support the enzyme is high-impact. Loading up on methylfolate is not.

[...]

It seems to make a lot of sense - given the wide prevalence of MTHFR mutations, it wouldn't have been a big deal had people been getting enough riboflavin. It's just now, with crappy diets when we're all deficient in riboflavin, that the mutations start to become a hindrance. So maybe everyone with this mutation simply needs to start eating more liver rather than getting into a complicated supplement routine. It's worth a try.
 

Keyhole

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Chris Masterjohn just posted this article about MTHFR mutations and it's very interesting indeed!

It seems to make a lot of sense - given the wide prevalence of MTHFR mutations, it wouldn't have been a big deal had people been getting enough riboflavin. It's just now, with crappy diets when we're all deficient in riboflavin, that the mutations start to become a hindrance. So maybe everyone with this mutation simply needs to start eating more liver rather than getting into a complicated supplement routine. It's worth a try.
Thanks for posting this up, as it was posted on his newsletter this morning. I am a massive fan of Chris Masterjohn, since his strategies make so much sense. Instead of supplementing really high doses of folate, you bypass the issue with 4 main nutrients: ribioflavin, choline, creatine, and glycine!

Where do we find those in abundance? Animal products! Hence, I don't buy the idea that we need to eat plenty of greens for folate. Chris is basically saying that as long as we are eating enough riboflavin, then boom - the enzyme starts working better. More organs!
 

Turgon

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Dr. Ben Lynch recently came out with the book Dirty Genes which is a culmination of his research on genetic SNP's and mutations in genes, among them MTHFR. He essentially picked 7 of what he considers the main culprits as far as genetic mutations that can cause all sorts of health problems and targets each in their own section. They are:
  • MTHFR: The Methylation Master
  • COMT: Focus and Buoyancy, or Mellowness and Calm
  • DAO: Over-sensitivity to foods
  • MAOA: Mood Swings and Carb Cravings
  • GST/GPX: Detox Dilemmas
  • NOS3: Heart Issues
  • PEMT: Cell Membrane and Liver Problems
He talks about how there are two main issues here. Some genes can act dirty while others are born that way. So for example, if you took the 23andme or other genetic tests and ended up getting the results where you have heterozygous or homozygous mutations (so those genes may not be working properly leading to all sorts of problems) that could be a problem. On the other side of the coin, due to lifestyle or other factors, you may not have those variations in your tests but still suffer from the symptoms. Also, if you do have a variant in one area, for example I have issues with MAOA, that can effect other areas, such as COMT and GST/GPX where I apparently am totally fine according but after reading his descriptions, show signs of them acting 'dirty'.

Rather than getting expensive tests done, which he doesn't recommend unless absolutely necessary, he has a series of questionnaire's on each of the 7 to determine what areas you need to focus on the most. Some, like MAOA and COMT have fast and slow symptoms and questionnaires. They are very specific. With MAOA, you can either burn through dopamine and other neurotransmitters very fast or very slow and each comes with it's own sets of issues and lifestyle changes and specific ways of supplementing to help with that.

What he reiterates the most is lifestyle, perspective and diet changes! So a lot of the information presented in this book has already been said somewhere or another on the forum and through the recommending reading. Although he does not seem to recommend eating a lot of fat and advocates for what seems like a paleo-ish diet of lots of veggies, meat, and whole foods. Unless I've misunderstood, the information keyhole has brought up seems to indicate we can pretty much skip out on the green leafies that have high oxalate content and focus on organ meats to get those same nutrients!

He breaks his protocol down to the Soak and Scrub phase, which is essentially getting ALL of your genes to work effectively - although this has already been reiterated on the forum. Eat the 'right' foods, when you do eat, don't rush but relax and enjoy your meal - preferably with people, work on your emotions, get to sleep by 10:30, don't use wifi or your cellphones before bed, meditate, take vacations depending on which variant you have, and keep track of your moods, how you feel, and make determinations on what you should and shouldn't eat and whether you should be taking supplements and what kinds to take.

Then there's the Spot Clean Phase - which is more refined. He doesn't recommend taking a lot of supplements at one time, but testing out one at a time based on how you did on the symptoms quizzes and only taking the supplement until you feel better, and once you do, stopping - up until you start to feel worse again. If you keep taking supplements past the point of feeling better or seeing symptoms that you have subside, it may have the potential of making things worse. He calls that the Pulse Method and this part of the process relies on listening to your body to give you the signals of when enough is enough.

He does recommend everyone take these 3 supplements regardless:
  • A multivitamin/multimineral without folic acid - choose one that's with methylfolate and folinic acid and ideally without iron - although only take it if your tired or have brain fog, and take 1/4 to 1/2 the suggested daily dose in the morning, and again during lunch if you need to but never in the evening or before going to bed
  • Electrolytes - if you have muscle contractions, fatigue, feeling dizzy or not sweating well get an electrolyte supplement that contains at a minimum potassium, magnesium, chloride, sodium, taurine and take it before exercise or when you wake up - I figure Quinton plasma water would do the trick but he suggests if your constipated either drink more water or skip a day
  • Adaptogens - like Ashwaganda, rhodiola, siberian ginseng, and passionflower. Vit B5 and Vit C count too. This helps a lot with resiliency and dealing with stress and he recommends taking it daily
That's the basic premise and breakdown of the book and I'd recommend reading this book if you think you suffer from some sort of mutation or are having issues on the diet that you just can't solve or figure out no matter what you do. Or curious! If that's the case, doing the quizzes and narrowing things down might go a long way. He goes into details on each, what specific foods to eat, what to avoid. Also what supplements you might need to take for different scenarios and issues you have, which ones go well together and which don't, what to look out for and what symptoms to keep an eye on in case something your taking isn't helping.

It's pretty detailed in that regard.
 
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