MTHFR mutations

[RedFox]

Thanks Shijing and RedFox

I'm considering taking some B vitamins along with minerals and other supplements as I go through an EDTA protocol before doing the anti-evil-critters protocol. But I'm not sure if I should do this MTHFR protocol.

Given the family history you described, I agree that it's likely something is going on in this area. Ideally, it would be good for you to know your specific SNP profile, because it would help to narrow down where you have blockages and the best ways to bypass them. Are you in a position to get tested and/or do you have access to a doctor who knows something about methylation issues?

Yes, I'm planning to do a test if I can find one that isn't very expensive. I have a functional physician that I can rely on, but I don't know how much he knows about methylation issues. I'll have to ask ;)

Have you considered 23andme.com? $99(US) is all it costs to get your full genome sequenced via a postal kit.

 

[shijing]

Just a few comments to follow up on some things RedFox mentioned above:

It does seem that sublingual B12 is the best way to go, if possible. I'm picking up some Dibencozide this week, and am going to make sure it's in a sublingual form. My primary compound supplement (Methyl Protect) is in capsule form, but I sometimes open the capsule and empty it under my tongue for better absorption. The taste is ... interesting ... so if you're putting together a supplement regime from scratch, it might be best to try to make as much of it sublingual as possible at the outset. There appear to be several good options on Amazon.

Priming your system with the right kind of lithium also seems to be important -- I'm going to be doing it post hoc, but it would have been better to do it in the beginning before I started the full supplementation program. Amy Yasko focuses quite a bit on lithium deficiency in people with methylation polymorphisms, and it seems to be a pivotal issue missed by a lot of doctors who are otherwise knowledgeable about methylation defects.

One thing that RedFox mentioned in a previous post is glutathione and methyl trapping -- there seems to be a lot of contradictory information about it online, and I'm not yet sure who's correct. The idea is that glutathione binds to B12, so if you take a glutathione supplement, you run the risk of losing the majority of your supplemented B12 through excretion -- however, the catch-22 is that people with methylation blockages are generally deficient in glutathione. I've been supplementing with S-acetyl glutathione, but am going to take a break from it to see if it makes a difference one way or the other.

The thing about the mutations is that, all things being equal they don't cause a problem. It's when you get stressed/infected/full of toxins that things go out of balance, and the mutation means things Don't re-balance naturally.

That's an important point -- there are people with methylation defects who can go through life without any serious problems, and it's partly why Dr. Rostenberg has a slogan, "Genetics are your tendency, not your destiny." Problems arise when a major stressor occurs and tips you into a methylation deficit that is difficult to recover from without intervention. The probability of this happening is increasing with each generation -- it can result from a vaccine cluster, exposure to pesticides at school, acute or chronic infections, a physical trauma such as a broken leg, or an emotional trauma like a divorce, a death in the family, or even moving.

Apparently zinc is needed for B-12 absorption too [...] So as it stands, my body only needs the B-12 supplements very occasionally (once or twice a month - or when I'm under high stress). It seems to be getting enough folate from a handful of green leaves every few days. And making sure I had enough zinc and carnitine seems to be the last major adjustment needed to re-balance my system.

For whatever reason, zinc tends to be low in people with methylation blockages, and this appears to be why there's a strong tendency for them to also exhibit pyroluria (correlated with zinc and B6 deficiency, and downstream from the methylation issues). I've found that zinc is one of my indispensable supplements -- I personally take zinc picolinate.

This works best with a handful of green leaf salad. And incidentally olive oil. It seems my body needs a good quality olive oil once a week at the moment too.

Interestingly, I had noticed the same thing -- I didn't mention it in my post, but it's one of the reasons I included olive oil in my Babushka recipe. I'm currently trying the mono-food protocol, and my general regimen is bacon in the morning, eggs with butter in the afternoon and leafy greens in the evening with olive oil poured over them.

Well cooked (the longer the btter) chicken seems to be important at the moment too, due to needing a boost of tryptophan for serotonin production.

FWIW, since I still have intermittent sleep problems (usually the worst for me during the summer), I occasionally use a sleep aid called Alteril (the tablets, not the softgels). The primary ingredient is L-tryptophan, and it seems to work well for me.

I think this issues, combined with the infection-chronic disease connection is very interesting in the way that it gives a view of how many aspects of our psyche are interconnected with our bodies and it gives us some clues about how to deal with the physical aspects so that we can improve our psychological-spiritual aspects too.

Me too! I see it as a pie chart divided into four sections -- genetics, toxins, infection, and emotions. They all interact with each other, and knowledge of each area helps us to bring our whole system into better balance.

 

[RedFox]

One thing that RedFox mentioned in a previous post is glutathione and methyl trapping -- there seems to be a lot of contradictory information about it online, and I'm not yet sure who's correct. The idea is that glutathione binds to B12, so if you take a glutathione supplement, you run the risk of losing the majority of your supplemented B12 through excretion -- however, the catch-22 is that people with methylation blockages are generally deficient in glutathione. I've been supplementing with S-acetyl glutathione, but am going to take a break from it to see if it makes a difference one way or the other.

That's one thing that was bugging me about the research and testing things. Glutathione and NAC would give me a good boost, and then I'd crash.
For me it seems I had to build up the B12 reserve and daily folate levels before I could handle things. I used NAC for testing.
My best guess at the moment is it's something to do with the sulpher pathways (at least in me). Probiotics helped with this, and so did the zinc/b6/carnitine.

It was wondering how to get the glutathione levels up a few weeks back that led me back to carnitine.

http://www.life-enhancement.com/magazine/article/1730-acetyl-l-carnitine-protects-cellular-function

Two Ways to Boost Glutathione Levels

So we take antioxidant supplements, such as vitamins C and E, lipoic acid, coenzyme Q10, carotenoids (lycopene, lutein, zeaxanthin, etc.), and polyphenolics (resveratrol, quercetin, curcumin, EGCG, etc.). We do not, however, take glutathione, because it’s a tripeptide (three linked amino acids), and such compounds are degraded in the digestive tract. Fortunately, there are ways to boost our glutathione levels from within. The best way, probably, is by taking lipoic acid, which is called “the antioxidant’s antioxidant” because it’s so effective not only as an antioxidant in its own right but also in facilitating the chemical regeneration of certain other antioxidants, notably glutathione.

Another way is by taking acetyl-L-carnitine, which boosts glutathione levels via a more indirect route—in rats, at least, and presumably in humans as well. As rats grow old, their glutathione levels decline, to the detriment of their health. At the same time, their levels of oxidized glutathione (the molecular form that results from neutralizing a free radical) are elevated. Smart old rats who understood something about the role of oxidative stress in disease and aging would surely wish that their glutathione levels could be restored to those of their younger years.

ALC Upregulates Rats’ Glutathione Levels

Recently a team of Italian and American scientists obligingly tried to do that for a group of senescent (very old—28 months) rats, by adding some ALC to their chow daily for 4 months.1 In order to see whether the experiment was successful, the researchers had to kill the rats and examine their brains, which was probably not what the rats had in mind when they wished for more glutathione (they should have remembered the old saying, “Be careful what you wish for—you might get it.) As it turned out, the experiment was successful. ALC supplementation (150 mg per kg of body weight) upregulated glutathione levels in the rats’ brains to those of normal adult (12-month-old) rats, and their oxidized glutathione was brought down to normal adult levels.

ALC Upregulates Heat-Shock Proteins

ALC’s ability to restore glutathione levels has broad implications beyond the obvious antioxidant benefit. Our bodies’ glutathione status is intimately connected with the production of a special class of proteins whose function is to protect the structural and functional integrity of countless other proteins (which constitute most of the cellular machinery of life) from damage caused by such factors as excessive heat or cold, infection, inflammation, oxygen deprivation, cellular trauma, and toxic agents. The special proteins also protect against disruptions of redox homeostasis, the delicate balance between the oxidative and reductive (antioxidative) forces within our cells.

These extremely tough, versatile protein guardians of other proteins and of our redox status are called heat-shock proteins (HSPs), although their functions, as we have just seen, encompass far more than just protection from heat shock. (In recognition of that, they’re also called stress proteins.) One HSP of particular interest is heme oxygenase-1 (HO-1, also known as HSP32), an enzyme that appears to play a central role in stress tolerance in the brain, where it helps protect against oxidative injury and neurodegenerative processes. Production of HO-1 is triggered by, among other things, the presence of free radicals as well as the depletion of glutathione.

Vitagenes Control Longevity Assurance Processes

Increasingly, scientists are viewing the heat-shock response, as exemplified by HO-1 (and other HSPs, including a crucial one called HSP70), as being of fundamental importance in protecting our cells from damage associated with a variety of metabolic disturbances and injuries, including the aging process. Such protection is part of a complex network of so-called longevity assurance processes, which are under the control of a number of genes that some scientists have termed vitagenes. These genes include the ones that code for heat-shock proteins and for certain critical antioxidants, such as superoxide dismutase-2 (SOD-2).

ALC Provides Neuroprotection

Naturally, there is a strong incentive to find molecular agents that can activate this comprehensive defense mechanism, which is critical for maintaining optimal brain function. In the study mentioned above, the researchers found that ALC stimulated the heat-shock response in the brains of senescent rats—as they suspected it would, based on the glutathione results. They also found (again not to their surprise) that ALC inhibited the formation of neurotoxic compounds resulting from the oxidative degradation of lipids and proteins. This protective action was most pronounced in the hippocampus, the region of the brain most closely associated with memory and learning.

These results seem to support those of previous studies demonstrating the therapeutic role of ALC in various neurodegenerative diseases (see “Acetyl L-Carnitine Protects Memory and Intellectual Functions” in the August 2005 issue). In summarizing their results, the authors stated,

… we found that treatment of rats with acetyl-L-carnitine resulted in upregulation of protective antioxidant genes, such as HSP70, HO-1, and SOD-2, as well as prevention of age-dependent changes in mitochondrial chain respiratory complex expression. … The results from our study show for the first time that ALC treatment of aging rats induces HO-1 and HSP70 heat-shock proteins in the brain. … The data presented here are consistent with the notion that ALC plays a crucial role in the regulation of critical vitagenes (HO-1, HSPs, and SOD) …
Can We Be Civil . . . Please?

It’s noteworthy that numerous health and antiaging benefits have been ascribed both to ALC and to lipoic acid (see “Can Acetyl L-Carnitine and Lipoic Acid Slow the Aging Process?” in the October 2004 issue). Lipoic acid is an antioxidant, but ALC is not. In fact, ALC can have pro-oxidant effects (when given to old rats in large doses). Although it tends to diminish oxidative stress by stimulating antioxidant defense mechanisms, ALC also contributes to the production of reactive oxygen species by boosting cellular energy metabolism. Because of the potential for a net pro-oxidant effect, it’s advisable to take ALC together with lipoic acid, whose powerful antioxidant action can offset this effect.

It’s reassuring, in any case, to know that we have two such stalwart soldiers on the side of the Good Guys in our bodies’ internal civil war. Which, however, brings to mind George Carlin’s disarming question, “How is it possible to have a civil war?”

Adding ALA might be a good idea too - but then again maybe not.
I hadn't found the above until you mentioned the glutathione connection again - looks like ALC works via a hormetic effect. i.e. upregulating glutathione production because it's needed. That probably only works if you've got enough B12.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1135203/

Carnitine metabolism was studied in the vitamin B-12-deficient rat to define the relationship between alterations in acylcarnitine generation and the development of methylmalonic aciduria. Urinary excretion of methylmalonic acid was increased 200-fold in vitamin B-12-deficient rats as compared with controls. Urinary acylcarnitine excretion was increased in the vitamin B-12-deficient animals by 70%. This increase in urinary acylcarnitine excretion correlated with the degree of metabolic impairment as measured by the urinary methylmalonic acid elimination. [..]Thus vitamin B-12 deficiency was associated with a redistribution of carnitine towards acylcarnitines. Propionylcarnitine was a significant constituent of the acylcarnitine pool in the vitamin B-12-deficient animals. The changes in carnitine metabolism were consistent with the changes in CoA metabolism known to occur with vitamin B-12 deficiency.

So a B12 deficiency is going to remove carnitine from circulation I think.
Carnitine is needed for fat metabolism (i.e. the keto diet).

 

[shijing]

Adding ALA might be a good idea too - but then again maybe not.
I hadn't found the above until you mentioned the glutathione connection again - looks like ALC works via a hormetic effect. i.e. upregulating glutathione production because it's needed. That probably only works if you've got enough B12 [...] So a B12 deficiency is going to remove carnitine from circulation I think.

Thanks for that additional info, RedFox -- that's very helpful to know about glutathione regulation. For now, I've taken out the S-acetyl glutathione, but am continuing NAC (partly for the anti-mucolytic effect) and ALA -- I'm interested to see what the net effect will be when I add Dibencozide and lithium orotate. I'm also trying a form of liquid L-carnitine -- I'm taking it in the morning before breakfast along with liquid CoQ10 on the assumption that they'll be more readily absorbed than the capsule forms.

 

[Turgon]

Thanks for putting all this information together. I've been reading it for the last few weeks and taking notes, trying to wrap my head around exactly how MTHFR works and operates, what the different genetic mutations are, how to supplement for each, etc. I've gone cross-eyed several times on the thread but am slowly starting to understand the mechanisms a bit more.

What cinched it for me was Ben Lynch's talk where he mentioned peoples reactions to Nitrous Oxide and how if you have an MTHFR mutation, just one dose or spray of the stuff can sometimes do irreversible nerve damage and can reduce methionine synthase drastically. Several months ago, I went for my first dental surgery and I requested the Nitrous Oxide because they were going to stick a few needles in my mouth. This was my first and only experience using it and I had a very bad reaction to it. They strapped the nozzle onto my face and lying down there I became exceptionally paranoid, like I was floating out of my body and losing touch with what was happening. The entire time felt like torture. It affected me for weeks and I was very on edge and irritable, until I finally did an EE session where I focused on all the emotions and helplessness I felt lying there and it seemed like I was able to release the 'trauma' stored up from that experience.

It's interesting, because on the one hand, I do notice how susceptible I am to stressful situations which may very well be an inability to process certain nutrients into a bio-available form which is causing a backlog of toxins, yet a lot of it also seemed to be my perception of events, people and situations (I viewed the dental assistant in a negative way, so being at her 'mercy' while being in such a helpless state probably exacerbated and made worse the fact that I was inhaling a foreign substance that was causing all sorts of harmful bio-chemical reactions.) I later switched dental assistants to another person who I do get along with and even though I never asked for NOS again, the surgeries have been quick and painless since then.

But anyways, I just ordered the test kit from 23andme so I can find out what specific methylation pathways are giving me issues and am hoping to take the results to Dr. Rostenberg and book a skype session with him. The interview the Health and Wellness show had with him was very insightful and he seems like a really knowledgeable person so hopefully by working with him to make sense of the data, I can come up with a strategic supplement protocol.

 

[patty2292]

Thanks for putting all this information together. I've been reading it for the last few weeks and taking notes, trying to wrap my head around exactly how MTHFR works and operates, what the different genetic mutations are, how to supplement for each, etc. I've gone cross-eyed several times on the thread but am slowly starting to understand the mechanisms a bit more.

Same feeling for me aswell Turgon, it really is overwhelming at the start, but its great to see all the dots start to slowly connect to make a understanding of the whole picture when all the parts start coming together!

But anyways, I just ordered the test kit from 23andme so I can find out what specific methylation pathways are giving me issues and am hoping to take the results to Dr. Rostenberg and book a skype session with him. The interview the Health and Wellness show had with him was very insightful and he seems like a really knowledgeable person so hopefully by working with him to make sense of the data, I can come up with a strategic supplement protocol.

Ive gone down the same road, and messaged Dr Rostenberg's team to check on prices and to see the forms he uses etc.

Just in-case you havnt contacted them, or if anyone else is curious of the prices, the reply i got included:

''The cost of the initial initial consultation is $180. This includes a 40 minute phone consultation (also includes skype), and a follow up email in which I will personally prescribe your unique protocol for greater health and well-being. If the consultation is longer than 40 minutes, there will an additional fee of $3 per minute. Each follow up phone consultation after this will be billed at the rate of $3 per minute.

Emails will be charged a flat fee of $10 for my assistant to type and prepare your email, plus a fee of $3 per minute of my time to personally dictate/record your answers.''

So the price itself does seem on the high end, but im currently doing abit of research and prepping while i wait for my 23andME to come so that i can get the most out of the first consultation and know what direction to go in with my questions.
Ive also contacted a local natural doctor to see the price difference for what he can offer, in comparison to Rostenberg. As its safe to say id rather spend abit more, but get the best information.

 

[Yas]

On my side, I can't use 23andme kit because they don't work with my country.

The good news is that I went to visit my doctor and he is also very interested in this topic and he seems to know a lot about it. He told me there's another place where I can get the genetic profile, but I can't remember the name now. It can be a possibility for those who can't use 23andme, so I'll ask him again.

The topic is complex and I still have to read a lot more before I can understand it, but having a doctor who is researching aswell is great! :D

 

[Turgon]

Just in-case you havnt contacted them, or if anyone else is curious of the prices, the reply i got included:

''The cost of the initial initial consultation is $180. This includes a 40 minute phone consultation (also includes skype), and a follow up email in which I will personally prescribe your unique protocol for greater health and well-being. If the consultation is longer than 40 minutes, there will an additional fee of $3 per minute. Each follow up phone consultation after this will be billed at the rate of $3 per minute.

Emails will be charged a flat fee of $10 for my assistant to type and prepare your email, plus a fee of $3 per minute of my time to personally dictate/record your answers.''

So the price itself does seem on the high end, but im currently doing abit of research and prepping while i wait for my 23andME to come so that i can get the most out of the first consultation and know what direction to go in with my questions.
Ive also contacted a local natural doctor to see the price difference for what he can offer, in comparison to Rostenberg. As its safe to say id rather spend abit more, but get the best information.

Thanks for the info, Huxley. I just checked the websites of a few Naturopathic Doctors that specialize in MTHFR in the area, and I'm looking at an average of $215-$255 for a 90 minute consultation (and that's in Canadian Dollars, not US) so even without the conversion rate to US, Dr. Rostenberg charges more. But like you said, I'd rather spend some more money on someone who's knowledgeable and really knows their stuff.

 

[patty2292]

After being completely confused at all of the diagrams, even when gaining some basic knowledge of the cycles, I found a description of what's going on in each section that helped my understanding. So I thought I would share incase anyone else has the same problem:

http://resqua.com/100005927200207/is-there-a-simple-explanation-of-the-methylation-cycle-diagram

"A simple explanation of the methylation cycle diagram"

"Common Terminology:

Methyl group: A methyl group is simply a single carbon atom bonded to 3 hydrogen atoms (CH3).

Methylation: Transfer of methyl groups from one chemical to another is called methylation. Essentially any chemical compound that has a methyl group as part of its chemical structure is capable of donating it to another chemical that needs it. The chemical that receives the methyl group is "methylated". This process of moving methyl groups around is necessary for the functioning of several biochemical reactions such as DNA and RNA synthesis, creatinine generation, immune responses involved in silencing viruses etc.

Role of enzymes: Most of the biochemical reactions in the body operate as cycles that are dependent on one or more enzymes. E.g. Chemical A gets converted to Chemical B; Chemical B in turn gets converted to Chemical C. Each of those steps has an enzyme involved that aids in the actual conversion of the first chemical into the second and so on.

In terms of the various pathways that we are addressing, there are several enzymes involved. When these cycles are operating optimally, each chemical moves through the various steps continuously. It is important to remember that while it looks like each of these cycles is occurring in isolation, in reality there are several copies of each of these chemicals being converted into their respective intermediates by several copies of enzymes. It is not a single methionine molecule being converted to SAMe or a single homocysteine molecule being converted to methionine but multiple copies of each by multiple copies of the respective enzymes. I like the analogy I found on one site: start thinking of these not as single chemicals, but buckets full of each, and pumps (the enzymes) to move the chemical from one bucket to the next.

Mutations or Single Nucleotide Polymorphism (SNP): A gene mutation is a permanent change in the DNA sequence that makes up a gene. Mutations range in size from one DNA base to a large segment of a chromosome. A Single Nucleotide Polymorphism or SNP (pronounced "snip"), is a small genetic change, or variation, that can occur within a person's DNA sequence. The genetic code is specified by the four nucleotide "letters" A (adenine), C (cytosine), T (thymine), and G (guanine). SNP variation occurs when a single nucleotide, such as an A, replaces one of the other three nucleotide letters: C, G, or T.

Think of mutations in enzymes as breaks that affect the ability of the enzyme to do its job. Homozygous (++) mutations are ones where both copies of the gene are affected and heterozygous (+-) mutations are the ones where only one copy of the gene is affected. Each of us has two copies of each gene that we inherit from each parent. Some mutations speed up the activity of the enzyme (e.g. CBS upregulation) whereas others slow them down considerably (e.g. MTHFr C677T and A1298C, COMT mutations).

The "slower" mutations create a situation where the bucket cannot be filled, like trying to fill the bath tub with the faucet only open to a drip. The "faster" mutations are like having a hole in the bucket. No matter how fast or slow you fill the bucket, the faster mutations drain out all of the contents of the bucket. This is why the CBS upregulation is such an overriding factor. It will drain the bucket. If the bucket is filling via a slow drip, due to the MTHFr C677T mutation, or methioninesynthasereductase mutations, then having a hole in your bucket will be more of a problem than if you are able to easily refill your bucket because you do not have the slow mutations too.

Note: The following material is intended to be used in conjunction with the pathway diagrams that are posted.
http://www.dramyyasko.com/d...

Methylation Cycle: This is the pathway at the far right in the diagrams, it is also known as the SAM or Methionine cycle. It is so named because of the intermediates involved in the cycle and also because this is the cycle that is responsible for the process of methylation that was described above (adding or removing methyl groups to various chemicals/metabolites and/or reactions).
The intermediates or chemicals involved in this cycle are methionine, S-adenosylmethionine (SAM or SAMe), S-adenosylhomocysteine (SAH) and homocysteine. It involves the regeneration of methionine from homocysteine. This conversion of homocysteine to methionine occurs with the help of Vitamin B12 (specifically the methyl version of Vitamin b12, methylcobalamin) and 5-methyltetrahydrofolate (folapro), which is an intermediate in the folate cycle. Look at this cycle as starting with methionine, methionine then being converted into the various intermediates such as SAMe, SAH, homocysteine and then ultimately being re-converted into methionine.

Step I: This involves methionine being converted to SAMe in the presence of magnesium (Mg) and ATP (universal energy donor) by the enzyme methionineadenosyltransferase (MAT). SAMe is called the universal methyl donor as it is the primary source of methyl groups for most other biochemical reactions including methylation of DNA, RNA, proteins, creatine etc.

Step II: SAMe, once it donates its methyl group to the various reactions, gets converted to SAH.

Step III: SAH in turn is metabolized to homocysteine by the enzyme S-adenosylhomocysteinehydrogenase (SAHH). This reaction also generates a chemical called adenosine.

Step IV: There are three possible ways homocysteine is removed as an intermediate. One is a reversible reaction that converts homocysteine back to methionine and is dependent on the folate cycle. The other is an irreversible reaction that is referred to as the TransSulfuration pathway. This involves the conversion of homocysteine into cystathione and its subsequent intermediates. The third involves the methylation of homocysteine into methionine, independent of the folate cycle. Let us take a look at each of them.

a) TransSulfuration Cycle: This cycle entails the irreversible conversion of homocysteine into cystathione by the enzyme cystathione B-synthase (CBS) in the presence of Vitamin B6 and heme as cofactors. Cystathione is in turn converted to cysteine and alphaketoglutarate. The amount of cysteine generated by this process acts as the rate limiting factor for the subsequent products that are generated, i.e. taurine and/or glutathione. If there is excess cysteine generated as a result of the CBS upregulation (mutation that makes the enzyme activity faster than normal), more taurine is generated instead of glutathione. Glutathione is one of the essential antioxidants involved with detoxification in our bodies.

b) Some of the homocysteine goes back up the cycle to regenerate methionine. This process is mediated by the enzyme methionine synthase (MS aka MTR), with the aid of methylcobalamin (Vitamin B12 that has a methyl group as part of its structure). Essentially cobalamin accepts a methyl group from 5-methyltetrahydrofolate (which is an intermediate in the folate cycle) and becomes methylcobalamin. This is where the SAM and folate cycles meet. Think of each of the cycles as independent entities doing their business but each of them are dependent on one another in order to function properly.
Methylcobalamin in turn donates the methyl group it gained to homocysteine and this converts homocysteine back to methionine. Essentially, homocysteine is being re-methylated to methionine.

Once methylcobalamin donates its methyl group to methionine, it becomes cobalamin again. Some of this cobalamin is remethylated into methylcobalamin by the enzyme methioninesynthasereductase (MSR aka MS_MTRR). Think of this as a reaction that is trying to maintain the levels of methylcobalamin. The methyl group necessary for this reaction is donated by SAMe (this reaction is not indicated on the diagram, this is just FYI for those of you wondering what the role of MSR is in the pathway).
Just remember that the methyl group that is donated by methylcobalamin to convert homocysteine to methionine comes from the folate cycle (5-methyltetrahydrofolate). Once methylcobalamin donates that methyl group to homocysteine, it becomes cobalamin which in turn gains a methyl group from SAMe to regenerate some of the methylcobalamin.

c) If that wasn't complex enough, there is yet another reaction that converts homocysteine into methionine (look at the center of the methylation pathway diagram for this reaction). The enzyme involved here is betainehomocysteinemethyltransferase (BHMT). BHMT converts homocysteine into methionine in a reaction independent of the one that is mediated by MS, i.e. the one described before, which involves the transfer of a methyl group from 5-methyltetrahydrofolate to methylcobalamin and from methylcobalamin to homocysteine. Just remember that this step doesn't involve B12 or the folate cycle. In this case methionine is regenerated from homocysteine by the transfer of a methyl group from betaine (TMG or trimethylglycine) to homocysteine. Once TMG loses a methyl group to homocysteine, it gets converted to dimethylglycine (DMG). In turn homocysteine gains a methyl group and becomes methionine.

This in essence is the Methylation pathway.

Folate Cycle: This cycle involves the conversion of tetrahydrofolate (THF) into 5,10-methylenetetrahydrafolate which in turn gets converted to 5-methyltetrahydrofolate (MTHF). MTHF is then converted back into THF.

Dietary folate, or folic acid that you get from your foods, is converted into a product called dihydrafolate (DHF) in the presence of Vitamin B3. DHF is then converted to THF, also with the aid of B3. THF is converted to 5,10-methylenetetrahydrofolate with help from Vitamin B6, P5P and Serine. Essentially THF gains a "methylene" group (different from methyl group) from serine to become 5,10-methylenetetrahydrofolate.
Alternatively folinic acid (5-formyltetrahydrofolate, different from folic acid) is also converted to 5,10-methylenetetrahydrofolate in a reaction occurring simultaneously.

5,10-methylenetetrahydrofolate is then converted to 5-methyltetrahydrofolate (MTHF) aka "Folapro" by the enzyme methylenetetrahydrafolatereductase (MTHFr) with the aid of NADH, B2 and ATP.

MTHFr: The MTHFr enzyme has multiple functions. However we are concerned with two of the roles it plays with respect to autism and these pathways. The first one being its involvement in the generation of MTHF within the folate cycle and the second being its ability to drive the conversion of BH2 to BH4 (BH4 cycle). Mutations in the part of the eznyme that is involved in the folate cycle are characterized as the "C677T" mutation and this mutation slows down the activity of the enzyme. This means MTHF production will be affected. Why does the amount of MTHF (folapro) matter? Because if you remember from the previous discussion on the Methylation pathway, MTHF is the compound that donates the methyl group to cobalamin which in turn donates it to homocysteine to regenerate methionine. If we have less of the MTHF to begin with, there will be less of it to go around to regenerate THF in the folate cycle, and to transfer methyl groups to regenerate methionine in the Methylation cycle. So this will affect not only the Folate cycle but also the Methylation cycle. Remember the Folate and Methylation pathways meet to transfer methyl groups and any breaks preceding that transfer will affect the functioning of both of the pathways.

As mentioned before MTHFr has a dual role in terms of these pathways. While it is driving the folate cycle in one direction, it is also driving a reverse reaction on the other side. This reaction is the conversion of BH2 to BH4. Mutations that affect this part of the enzyme are characterized as "A1298C" mutation.

BH4 Cycle: Tetrahydrobiopterin (BH4) is essential for normal central nervous system functioning. It is an essential factor or cofactor for the enzymes in the biological pathways necessary for synthesizing catecholamines (dopamine, noradrenaline/norepinephrine) and indolamines (serotonin and melatonin), as well as for all three isotypes of nitric oxide synthases (NOS in the Urea cycle). BH4 is a cofactor for tyrosine and trytophan hydroxylase, the enzymes involved in catecholamine and indolamine synthesis respectively. The rate of BH4 formation determines the rate of production of these important neurotransmitters, because BH4 happens to be the rate limiting factor here. How much of it is present affects the ability to synthesize neurotransmitters like dopamine, norepinephrine, serotonin etc. and also affects the outcome of the Urea Cycle.

Tyrosine (amino acid) is converted to dopamine through a series of reactions involving the enzyme dihydroxyphenylalaninereductase (DHPR). Dopamine can be further metabolized to norepinephrine by the enzyme dopamine-b-hydroxylase. Dopamine and norepinephrine can also be metabolized by the enzyme monoamine oxidase (MAO) to 3,4,-dihydroxyphenylacetic acid or the enzyme Catechol-O-MethylTransferase (COMT) to 3-methoxytyramine. Action by both enzymes results in the formation of homovanillic acid (HVA or 3-methoxy-4hydroxy-phenylacetic acid ) and VMA.

Serotonin (5-HT) is synthesized from the amino acid tryptophan in two steps catalyzed by the enzymes tryptophan hydroxylase and L-amino acid decarboxylase. Serotonin is metabolized by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid (HIAA).

Serotonin can also be methylated (first acetylated i.e. addition of acetyl group and then methylated) to form Melatonin. The enzyme involved in the acetylation of serotonin to form N-acetylserotonin is serotonin-N-acetyltransferase. N-acetylserotonin is methylated (addition of methyl group) to form melatonin by the enzyme HydroxyIndole-O-MethylTransferase.

The A1298C mutation in the MTHFr enzyme affects the conversion of dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4). Less amounts of BH4 will therefore put a strain on the conversion of trytophan to serotonin and tyrosine to dopamine. This will lead to low levels of neurotransmitters such as dopamine, norepinephrine, serotonin and melatonin.
In addition the activity level of the COMT enzyme will further affect the levels of dopamine and norepinephrine.

COMT: Catechol-O-MethylTransferase is the enzyme involved in the metabolism of dopamine and norepinephrine into subsequent compounds such as HVA and VMA. The rate of activity of COMT will determine how fast these neurotransmitters will be broken down. Mutations in the COMT enzyme (COMT ++ or COMT +-) actually slow down the activity of the enzyme. Normal COMT activity (no mutations) is depicted as COMT --
Mutations in the COMT enzyme will slow down the breakdown of dopamine, therefore individuals who are COMT ++ or +- have higher (as in good) levels of dopamine compared to COMT -- individuals who are rapidly draining their dopamine stores. This condition is further exacerbated if the individual has the A1298C mutation (++ or +-) because their dopamine levels are low to begin with (remember these individuals have less BH4, so less dopamine gets made).

Undermethylators: Dr.Amy categorizes individuals who are COMT -- as undermethylators.
One of the ways the COMT enzyme breaks down dopamine is by using a methyl group donated by SAMe (remember it is the universal methyl donor). Therefore a COMT -- individual will be in constant need of methyl groups as they are rapidly metabolizing dopamine. This puts a strain on the Methylation cycle as the demand on SAMe for methyl groups is increased. Think of this as COMT constantly demanding methyl groups from SAMe. If there are issues in the Methylation cycle or Folate cycle that affect the levels of SAMe (which in turn is dependent on the levels of methionine), there will be less methyl groups to begin with and even less to go around. It is like a domino affect. A break or strain in one cycle has a ripple effect on the rest as they are all co-dependent. Less methyl groups -> less methylation -> less RNA/DNA/protein synthesis/heavier viral load due to lack of methylation etc.

Overmethylators: These are the individuals who are COMT ++. Mutations make the COMT enzyme slower, so it will not break down dopamine as rapidly. Since it is slower in metabolizing dopamine, its demand for methyl groups is also reduced. Subsequently there is less of a strain on SAMe for methyl groups. So there will be relatively more methyl groups available for other biochemical reactions and to go around the various cycles.

Remember these are just relative terms. An undermethylator is low in methyl groups and an overmethylator has a higher store of them, in comparison. Remember one of the reasons we are in this predicament with autism is because we have problems with methylation, regardless of the under or over status.

In addition the strain on the BH4 cycle, the amount of BH4 will also affect the functioning of the Urea cycle. BH4 is the rate limiting factor for the Urea cycle. Two molecules of BH4 are necessary to drive the Urea cycle. One molecule will in turn generate peroxynitrite and if the individual has no BH4 left, super oxide is formed. Peroxynitrite and super oxide in combination cause damage to neurons when they accumulate in excess. . Peroxynitrite is a potent oxidant, which is capable of DNA strand scission (breaks open the bonds that keep the two DNA strands bound in a double-helix) , and nitrating tyrosine, all of which wreak havoc on the nervous system, especially a developing nervous system as in children. The ability to detoxify superoxide is facilitated by the enzyme superoxidedismutase (SOD).

Urea Cycle: Urea is the chief nitrogenous waste of mammals. Most of our nitrogenous waste comes from the breakdown of amino acids. Breakdown of amino acids results in the production of ammonia (NH3). Ammonia is a toxic compound that is converted into its safer counterpart urea, by enzymes in the liver. Urea is then eliminated by our kidneys. Essentially the urea cycle involves the conversion of ammonia into urea with the help of the intermediates listed below.
Arginine from our diet or from protein metabolism is converted to ornithine and urea by the enzyme Arginase. Ornithine is then converted to citrulline by ornithine transcabamoylase. This is the reaction on the far left side of the pathway diagram. Citrulline is converted back to arginine. This cycling of Arginine through the various intermediates is what converts ammonia to urea.
Arginine is also required for the production of Nitric Oxide (NO) by the enzyme nitric oxide synthase (NOS or eNOS). This reaction is dependent on the levels of BH4 available from the BH4 cycle. Remember two molecules of BH4 are needed to generate Citrulline and NO. One molecule of BH4 will in turn generate peroxynitrite and if there is no BH4, super oxide is formed. If we do not have enough BH4 to go around because of the A1298C mutation, we are going to have trouble with ammonia. Because ammonia is dangerous to the body, any BH4 we have is going to be used to try to get rid of the ammonia rather than to be making neurotransmitters like serotonin and dopamine. Furthermore mutations in the NOS (eNOS) exacerbate the situation as they will affect the synthesis of NO. NO is needed for several functions including secretion of certain hormones, addressing inflammation, killing pathogens etc.

In essence if the limited supply of BH4 puts a strain on the functioning of this pathway, excess ammonia will accumulate as there is not enough BH4 to help convert it to urea. In addition the lack of BH4 also creates damaging free radicals like peroxynitrite and super oxide (SOD is needed to detoxify superoxide)."

 

[RedFox]

Thanks Huxley

Thought it may be worth mentioning (on the COMT side of things - neurotransmitter breakdown)

http://resqua.com/100001600189727/what-does-the-comt-gene-mutation-mean

Red or purple berries and herbs:
The COMT enzyme processes the colors red and purple so that consuming red or purple herbs or foods and drinks actually slows this enzyme down further. This is a side issue from those with the CBS having difficulty processing phenols. For those with a complete COMT mutation, the simple act of eating too many delicious summer fruits and herbs often leads to more neurotransmitter peaks and valleys. For some, this leads to roller coaster mood or “dopamine swings,” while for others it translates toward more nor- epinephrine surges and restlessness or anxiety. Even so, the synthetic phenols used as coloring agents are even more problematic. *Many become irritable or agitated and struggle with insomnia, and/or develop flushed, red cheeks and ears. In many cases, those with a complete mutation are more sensitive to berries and may develop allergies to them.

Additionally, headaches, insomnia, and heat intolerance are also commonly seen in those with phenol sensitivities. This may be considerably aggravated in the presence of a CBS defect, as it impacts the PST enzyme (please see phenol discussion).

So if you have a MTHFR mutation and normal COMT (slower filling of the methyl bucket, and normal emptying speed) you'll tend to have lower neurotransmitter levels.
One thing that I seem to have done for years is self medicate with berries. Berry tea works just as well.
Berries use up COMT and slow the breakdown of neurotransmitters. Do watch that they don't make you anxious though, that can be a sign of too many neurotransmitters.

Another thing is the role of methyl groups in epigenetics (turning genes off through methylation of DNA - donation of methyl groups from the methyl bucket).

https://en.wikipedia.org/wiki/Nutriepigenomics

Two major epigenetic mechanisms implicated in nutriepigenomics are DNA methylation and histone modification. DNA methylation in gene promoter regions usually results in gene silencing and influences gene expression. While this form of gene silencing is extremely important in development and cellular differentiation, aberrant DNA methylation can be detrimental and has been linked to various disease processes, such as cancer.[2] The methyl groups used in DNA methylation are often derived from dietary sources, such as folate and choline, and explains why diet can have a significant impact on methylation patterns and gene expression.[3] Gene silencing can also be reinforced through the recruitment of histone deacetylases to decrease transcriptional activation. Conversely, histone acetylation induces transcriptional activation to increase gene expression. Dietary components can influence these epigenetic events, thereby altering gene expression and disturbing functions such as appetite control, metabolic balance and fuel utilization.[1]

And as dietary availability of methyl groups can alter epigenetics, so can internal reserves of methyl groups based on the mutation.
From a personal perspective I probably wasn't in full fat burning mode until I got my methyl bucket refilled.

Methyl donor availability effects learning and memory too (probably related to low neurotransmitter levels).
We've also seen how low neurotransmitter levels in childhood can lead to addiction (Gabor Mate).
Stress (social, physical, emotional, infection etc) also depletes metyl levels!

So if the bucket is low/empty your ability to handle and (epigenetically/mentally/emotionally) adapt to stress of any kind will be limited, and your default responses automatic and rigid.
That may be any kind of stress, from every day events or attempting to learn new skills. You may have always been a 'slow learner' and found that things then just 'click'.
This will also relate to the stress of going keto and attempting to face yourself in the Work.
Your body/mind may be 'slow to adapt'.

Freeing yourself from the wrong kind of stress (wasting energy) reduces the speed of emptying of the methyl bucket. You can then use the reserves to face useful stress (the Work) and adapt.

The number one drain on these resources is chronic disease and lack of good quality sleep. The second largest drain is social/emotional stress (either external or internal in the form of anxieties/thought loops and negative self image). Lastly there is things like cold showers, going keto, exams, and heavy prolonged exercise.

One of the default programs this can generate is stress avoidance (laziness, procrastination, even social anxiety).
Being clever rather than frugal with this limited resource is the way through it.
Some short term stress is needed in order to adapt, so a critical eye is needed to watch where this resource is spent.

Incidentally refilling my methyl bucket with the protocol I mentioned earlier in the thread led to an uncovering and amplification of past issues and programs.
Lots of memories came back, lots of emotions surfaced that needed processing and my avoidance and disassociation behavior became more pronounced in response.
In short, I realized I was still burning through my methyl resources at a higher rate despite replenishing them. And I had to face these things (the stress of facing them) and adapt in order to change that.

 

[patty2292]

I have a simple but annoying query:
With regards to the lozenge supplements, Im sort of struggling keeping it in my mouth un-dissolved for a very long time. Especially Dibencozide, which the above quoted protocol advises a big 45-120 minutes in length .
I can barely keep the Methly B12 5mg under my tongue for 45 minutes, never mind a pill a third of its size. Im trying to keep them as still as possible, but my mouth floods with saliva a few minutes in. I do naturally have alot of saliva production, especially when using lozenges.

I seem to have had better success using multiple 1mg Methly B12 through the day, compared to the single 5mg dose. So that may be the route i can go down for now if i cant manage to hold it. But is there any tips for getting full effectiveness and allowing them to not dissolve as fast? Would it be advised to not swallow the saliva, and keep it all in my mouth for as long as possible?

 

[RedFox]

Yeah, that one stumped me until I found out what others had been doing.
Split the pills up (I bite them in half) and place them under your upper lip, between the lip and the gum. They'll then last 45-120 minutes. :)

 

[patty2292]

Yeah, that one stumped me until I found out what others had been doing.
Split the pills up (I bite them in half) and place them under your upper lip, between the lip and the gum. They'll then last 45-120 minutes. :)

Thanks RedFox, thats a great idea! Hopefully people in work wont notice the difference :D

I imagined it to last longer on the upper lip, but couldnt suss how to sit it there comfortably.

 

[patty2292]

Thought i would give an update to my progress with the b-vitamin/methylation protocol RedFox posted earlier in the thread.

It has involved all of the critical minimums, and all of the essential supplementation with the addition of Sam-E.

Just before i start i have found a list of potential adverse reactions, and also benefits to this protocal for people with CFS (Chronic Fatigue Syndrome)

http://www.drmyhill.co.uk/wiki/CFS_-_The_Methylation_Cycle

"The following symptoms of CFS have been reported to have been corrected by various PWCs on this treatment. Note that these are gathered from reports from many PWCs, so that not all have been reported by a single person.
Improvement in sleep (though a few have reported increased difficulty in sleeping initially).
Ending of the need for and intolerance of continued thyroid hormone supplementation.
Termination of excessive urination and night-time urination.
Restoration of normal body temperature from lower values.
Restoration of normal blood pressure from lower values.
Initiation of attack by immune system on longstanding infections.
Increased energy and ability to carry on higher levels of activity without post-exertional fatigue or malaise. Termination of "crashing."
Lifting of brain fog, increase in cognitive ability, return of memory.
Relief from hypoglycaemia symptoms.
Improvement in alcohol tolerance
Decrease in pain (though some have experienced increases in pain temporarily, as well as increased headaches, presumably as a result of detoxing).
Notice of and remarking by friends and therapists on improvements in the PWC's condition.
Necessity to adjust relationship with spouse, because not as much caregiving is needed. Need to work out more balanced responsibilities in relationship in view of improved health and improved desire and ability to be assertive.
Return of ability to read and retain what has been read.
Return of ability to take a shower standing up.
Return of ability to sit up for long times.
Return of ability to drive for long distances.
Improved tolerance for heat.
Feeling unusually calm.
Feeling "more normal and part of the world."
Ability to stop steroid hormone support without experiencing problems from doing it.
Lowered sensation of being under stress.
Loss of excess weight.
The following reported symptoms, also gathered from various PWCs trying this simplified treatment approach, are those that I suspect result from die-off and detox:
Headaches, "heavy head," "heavy-feeling headaches"
Alternated periods of mental "fuzziness" and greater mental clarity.
Feeling "muggy-headed" or "blah" or sick in the morning.
Transient malaise, flu-like symptoms.
Transiently increased fatigue, waxing and waning fatigue, feeling more tired and sluggish, weakness.
Dizziness.
Irritability.
Sensation of "brain firing: bing, bong, bing, bong," "brain moving very fast".
Depression, feeling overwhelmed, strong emotions.
Greater need for "healing naps."
Swollen or painful lymph nodes.
Mild fevers
Runny nose, low grade "sniffles," sneezing, coughing.
Sore throat.
Rashes.
Itching.
Increased perspiration, unusual smelling perspiration.
"Metallic" taste in mouth.
Transient nausea, "sick to stomach"
Abdominal cramping/pain.
Increased bowel movements.
Diarrhoea, loose stools, urgency.
Unusual colour of stools, e.g. green.
Temporarily increased urination
Transiently increased thirst.
Clear urine.
Unusual smelling urine
Transient increased muscle pain.

When i initially started the protocol, i have to admit it was the best results i have seen with ANY supplementation. Ive never truly felt any significant effect from most of the supplements people take here on the forum. So to be honest, i didnt expect much of this. But reading into it prior to beginning, just seeing how complex the process was, i had high hopes for some reason.
This is the first time in a very long time i have really felt my mind and body feel 'clean', really showing me how much brain fog and anxiety i have from day to day.

First noticeable effects where an increase in focus, calmness and ease when speaking to people at work. I could actually create steady back and forth conversation instead of the simple reply for replies sake. It truly did felt amazing. Everything seemed to glow alot more, and my attention to detail was increased. I was getting tired when it was getting dark, and when i was able to jump straight out of bed in the mornings without any fight. So overall i think my energy levels where alot more balanced and it had sorted my cortisal levels out as i didnt feel a pinch of stress.

At the start of this week i decided to introduce Sam-E into the regime, and coincidentally i have come down with a really bad fever or flu of sorts. Now i havnt gotten ill all year, and its too obvious that when i introduced it, i get ill. So i cant put it to anything else; no diet change, no exposure to extreme colds, no direct impact of stress ect.

Potassium was stressed from the get go on this protocol, and the first two days in i felt that lack of potassium. Cramping muscles, and heart/rib paint and mild palpitations. This passed as i knew what it was, instead of labeling it as a detox reaction.
But what i am feeling now, wont be soothed with anything really... Im taking an increased amount of potassium and Vit-C and it doesnt seem to feel like its from lack of either.
Im experiencing tightness in the chest (close to a chest infection i had years ago), terrible back, shoulder and neck pain, chronic head pressure - when i move my eyes the slightest it pulses into my skull. Also a very heavy brain fog - its even inhabiting me from writing this post somewhat.

I havnt yet stopped taking any of the supplementation and im still increasing my potassium amount. Having 4x 99mg Potassium Citrate capsules through the day and 3-4x 99mg Liquid Ionic Potassium.

So im thinking to back off on all the supplements abit, and cut out the Sam-E completely as from what ive seen it is most likely this that has caused it. Maybe a 'too soon, too fast'?

 

[RedFox]

It's good to hear it's helped you so much Huxley

So im thinking to back off on all the supplements abit, and cut out the Sam-E completely as from what ive seen it is most likely this that has caused it. Maybe a 'too soon, too fast'?

That would be my thinking. Sam-E is a methyl donor, so may be over driving things. If you still feel sick try putting the brakes on methylation with some niacin.
If that doesn't help there are two options left.

_http://www.pvmhmr.org/5-depression/article/13034-major-depression-serotonin-precursors-same

Safety and Dosing

Dosing for SAMe is typically between 800mg/day and 1600mg/day. SAMe is very safe at recommended dosages. Because it is essentially a protein, it has no real side effects other than gastrointestinal upset and the possibility of triggering mania in people with bipolar disorder.

SAMe increases the risk of developing a rare condition called serotonin syndrome (or serotonin toxicity) that produces mental confusion, agitation, headache, shivering, sweating, hypertension, tachycardia (fast heart rate), and other symptoms. Check with your health care provider before incorporating SAMe into your therapy.

This is a potentially deadly condition, so be careful!

Lastly is you may now be experiencing a detox reaction. Methylation needs to be working well to produce any glutathione.
So try some NAC, and possibly some EDTA/ALA (see heavy metal protocols).

*edit to add* Thinking further, it could be that your immune system is waking up and taking care of business. Especially if it's reduced your stress levels.
It's probably best to avoid SAM-e though. You could try reintroducing it again once symptoms have disappeared.
If it's genuinely a cold, get some zinc, selenium, b6, vit D along with vit C.

I introduced a low dose of zinc, b6, selenium, carnitine and vit D in the evening before bed a month or so ago. The first week or so my immune system seemed to kick into overdrive, and did seem to be fighting something off.
My energy levels started dropping after a few weeks, trying a few days of ALA seemed to provide the answer.

So my best guess is that methylation got to the point where my immune system could deal with things that had been put on hold - but needed a boost. The result of dealing with that probably released a bunch of heavy metals that the ALA mopped up (biofilms store toxins).