MTHFR mutations

[theos]

Here's link to a talk radio broadcast on MTHFR

_http://www.blogtalkradio.com/undergroundwellness/2014/11/19/dr-ben-lynch-mthfr-made-easy

 

[RedFox]

That being said, we fortunately don’t have to choose, and all of these things can be complementary. If you know that you have mutations which block your methylation pathway and prevents normal detoxing, then taking the appropriate supplements to counteract that blockage can be a significant factor in healing your body, in much the same way that one might use 5-HTP and GABA to correct brain chemistry imbalance. It makes sense to me that doing this would put us in a better position to Work on ourselves and help others, because we’re helping our body in a position to operate more optimally, which will in turn impact emotions and enable us to think more clearly.

Indeed, that's a good way to put it. Extra support may be needed in many cases, and it can't hurt. But I think it's a bit tricky. To believe that those supplements are needed in order for a person to be in a better position to Work on themselves can be both the truth, or an excuse to not start Working on themselves right now. It would depend on the person, I guess.

Is it really because of the gene mutation that some of us don't detox properly, or viceversa? And can we say that taking a supplement for an issue such as this mutation will be better or more beneficial than other changes in our lifestyle? AFAIK, once your system is healthier (with the ketogenic diet, for example), your cells (and your genes) can heal, and the mutated genes commit "suicide" (apoptosis) and leave room for the healthy genes to work better. In fact, many of the papers we've read about supplements say that if you are keto-adapted, your body is perfectly capable of producing the substances you need, without the need for supplementation. They even go as far as to say that taking supplements can sometimes be counterproductive. Because it's telling the body that it's incapable of healing by itself, thus feeding a vicious cycle. Again, some extra support may be beneficial (especially in the beginning!), in some cases and depending on the person.

I'd like to add some research to this. I suspected a MTHFR mutation after digging into it and my genetic tests revealed that I have one or both (can't remember the complete breakdown right now).
One of my personal characteristics (which as I've researched appears tied to, or at least to make things worse) is an obsession with 'This is the answer and will fix everything!'. Basically black and white thinking in responce to all the long standing symptoms. It'll drive me to spend far to much time/energy/money in 'researching' these things and trying out supplements etc.
Both a plus and a minus because it has eventually led me to a place where the results are that I don't obsess so much anymore and I have balanced out my low energy levels. from all I've studied it seems that there are two sides to this trap that feed each other - the bodies/brains capacity to adapt (to stress), and your personal psychology (how much stress do you add to the system through wrong thinking/overthinking/holding false beliefs etc).

I've watched a few videos on the subject but this one had a few particularly good nuggets:

https://youtu.be/QRHif2aVPvw

One was the connection to stress, methylation (which is reduced with this mutation) is needed to cope with stress (physical/emotional/toxicity etc). Given Gabor Mates and others work we know how much stress gets passed on from parent to child, and how the symptoms that manifest are usually described as 'inherited genetic disorders'. It is also needed to detox the body of toxins.

Another was his discussion of ethnic groups and that in parts of Italy this mutation is very common, yet the people live completely healthy normal lives. He put it down to the Mediterranean diet but I have a sneaking suspicion it's a cultural/social/environmental thing too. I know Italians have very strong family connections for one.

Methylation is also required for gene regulation (epigenetic switches), so if you are already in a compromised state (from chronic stress and depletion of resources) it's particularly difficult to flip those switches back on again.

So this leads (in a cycle) back to the last problem, methylation is required for learning/adaption. So it can end up as a vicious cycle purely in the form of wrong thinking. Your ability to learn, adapt and even flip epigenetic switches become compromised, and all you have left to rely on is the learned thinking/behaviours that got you into the mess in the first place (see Gabor Mate).

It has ties to many mental/emotional/health conditions, and what I realised was that the mental/emotional conditions (poor coping mechanisms, negative self image, emotional repression, narcissism etc) may be triggers for depletion of and thus trapping in a poor methylated state. Whatever mental pattern existed becomes somewhat more fixed and potentially black and white/obsessive because of the brains lack of resources to adapt through error processing/correction:

_http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0025253

A Hypomethylating Variant of MTHFR, 677C>T, Blunts the Neural Response to Errors in Patients with Schizophrenia and Healthy Individuals

Introduction

Learning from mistakes is fundamental to adaptive, flexible behavior. To correct course, we must recognize and respond to errors, processes mediated by the dorsal anterior cingulate cortex (dACC). Individuals who mount stronger dACC responses to errors ultimately make fewer mistakes [1]. But what underlies variation in dACC function during errors? As suggested by previous work [2], [3], genetic factors likely contribute. However, epigenetic variables such as DNA methylation and chromatin remodeling could also modulate the brain's responsiveness to errors, as they play an essential role in neural plasticity [4]. While epigenetic phenomena cannot be measured directly in the living brain, we have used functional MRI to investigate whether a genetic variant in methylenetetrahydrofolate reductase (MTHFR) that strongly influences the one-carbon milieu also regulates dACC activity during error processing.

MTHFR is a key supplier of one-carbon moieties for intracellular methylation reactions, including DNA methylation and homocysteine metabolism. Specifically, MTHFR irreversibly reduces 5,10-methylenetetrahydrofolate (5,10-MTHF), which is derived from dietary folate intake, to 5-methyltetrahyrdofolate (5-MTHF). In turn, 5-MTHF supplies one-carbon moieties for downstream methylation reactions, including those catalyzed by methionine synthetase, DNA methyltransferases, and other vital transmethylation reactions. A common, well-characterized variant in the MTHFR gene, rs1801133 (677C>T) causes an amino acid substitution (222Ala>Val), each copy of which confers a 35% reduction in MTHFR activity [5]. Accordingly, individuals who carry the 677T allele exhibit lower genomic DNA methylation, especially in the setting of low serum folate, which supplies the substrate for MTHFR [6]. Reduced global DNA methylation has also been observed in heterozygous and homozygous Mthfr knockout mice [7], with numerous consequences for neurodevelopment and behavior. Mthfr −/− mice exhibit pronounced deficits including developmental retardation, altered cerebellar cytoarchitecture, and reduced survival at 5 weeks of age [7], while heterozygotes appear more grossly normal but exhibit hyperlocomotion and impaired recognition memory [8].

MTHFR 677C>T genotype has also been studied in relation to a variety of neuropsychiatric illnesses [9], [10]. A meta-analysis of 20 case-control studies indicated that the 677T variant augments risk for schizophrenia [11], a disorder characterized by blunted responses to errors [1] and rigid, perseverative behavior. Further, the 677T allele increases perseverative errors in schizophrenia [12], and was associated with diminished error-related dACC activation in a preliminary study of 18 patients [13]. However, as patient studies are confounded by the effects of chronic illness, including co-morbidities and antipsychotic use, it is unclear whether MTHFR effects on error processing in schizophrenia represent an epiphenomenon or a core aspect of the illness. Another possibility, one with broader implications for cognitive neuroscience, is that MTHFR exerts a more fundamental effect on error processing that transcends diagnosis, a plausible notion given the importance of one-carbon metabolism to normal brain development and function [4]. Here, we addressed this possibility by examining effects of MTHFR genotype on error-related brain activation in a cohort of 25 healthy individuals and 31 demographically matched patients with schizophrenia.

Participants underwent functional MRI using a 3.0 T scanner equipped for echo planar imaging (Siemens Medical Systems, Erlangen, Germany). During scanning participants performed a variant of the antisaccade task, which requires a gaze away from a suddenly appearing visual stimulus. Errors occur when participants fail to inhibit the prepotent response of looking towards the stimulus. Schizophrenia patients consistently show a higher antisaccade error rate and lower error-related activation of the dACC than healthy individuals [1]. We initially focused on regions-of-interest in the bilateral dACC, comparing error-related activation, based on the contrast of erroneous versus correct antisaccades, in C homozygotes and T allele carriers (i.e., C/T and T/T genotypes combined).

The dACC is a structurally and functionally heterogeneous region. In addition to its contributions to error processing, it is also thought to exert ‘top-down’ control on other ocular motor regions during preparation for antisaccades [14]. To determine the specificity of the MTHFR effect on error processing, we also examined whether MTHFR influenced dACC activation related to the preparation and execution of antisaccades, a different aspect of dACC function.

[..]

Discussion

The identification of genetic risk variants that influence neuropsychiatric disease risk or alter the course of illness has provided new insights into the neural and molecular mechanisms that underlie normal human cognition [26]. The MTHFR 677C>T variant is one of only a small number of functional polymorphisms that have been consistently associated with schizophrenia risk [11], and specifically with cognitive impairment among schizophrenia patients [12], [27]. Here, we found that both healthy participants and schizophrenia patients who carried the low-methyl 677T variant exhibited blunted error-related dACC activation, and that the magnitude of dACC activation was predicted by allele load. Previous work demonstrated that when genotype is not taken into account, the degree of error-related dACC activation predicts performance (error rate), suggesting the importance of intact dACC function to learning from errors [22]. However, here we found this relationship to be disrupted among all participants who carried the 677T allele, regardless of diagnosis. To the extent that MTHFR 677C>T genotype indexes genomic methylation status in vivo, as seen in previous work [6], [7], this finding suggests a novel epigenetic mechanism for understanding the neural response to errors.

In addition to its association with reduced global DNA methylation [6], the 677T allele also induces hypomethylation within glioblastoma cells [28] and promoter hypomethylation within colon cancer genes [29]. Similarly, altered DNA or histone methylation in the setting of the low-functioning 677T allele could influence the expression of other genes salient to error processing, although the mechanism by which these genes might be selectively targeted remains unknown. Previous work suggests that the 677T allele potentiates the metabolism of dopamine [12], [30], which has been postulated to modulate error-related dACC activation via striatal projections [31], and strongly influences prefrontally-mediated executive function [32]. However, other mechanisms could contribute to MTHFR effects on error processing circuitry; for example the 677T allele also inhibits the metabolism of homocysteine [6], which is toxic to dopamine neurons in culture [33]. It is also important to note that other regions in which dopamine neurons are putatively involved in error processing, such as the striatum, did not show MTHFR effects on error-related fMRI activation in the present study. Additional work is needed to understand the apparent selectivity of MTHFR 677C>T effects on dACC activation during error processing despite the more global effect of this variant on intracellular methylation processes.

The only previous study to examine effects of MTHFR genotype on brain function in healthy individuals found no significant effects of the 677T allele on working memory load-dependent prefrontal or dACC activation [30]. Among schizophrenia patients who participated in the same study, the 677T allele was associated with reduced dorsolateral prefrontal, but not dACC activation. This is consistent with our present findings that MTHFR genotype did not mediate the dACC response during the preparation and execution of antisaccades in either the patient or healthy groups. The dACC is thought to play a role in top-down control of motor regions while performing cognitively demanding tasks. Taken together these findings suggest an MTHFR effect on dACC function during error processing, but not on cognitive control during other executive function tasks (working memory or antisaccade generation).

Although the 677T allele has been consistently associated with increased schizophrenia risk [11], the mechanisms underlying this association remain uncertain. In the present study MTHFR genotype effects within the dACC were similar in similar patients and healthy participants, suggesting that by itself, the 677T variant does not contribute to error processing deficits in schizophrenia any more so than it does in the general population. However, in the context of altered prefrontal physiology, functional consequences of 677T allele-related dACC blunting during errors may be exacerbated in schizophrenia. Genome-wide profiling of DNA methylation using postmortem prefrontal cortex tissue has indicated numerous sites with altered methylation in schizophrenia, including genes that regulate glutamate and GABA signaling [34]. The presence of the hypofunctional 677T allele could augment these differences across a number of metabolic pathways that contribute to schizophrenia, not only those salient to error processing.

It is also noteworthy that error-related MTHFR genotype effects outside of the dACC differed in patients and healthy participants. Significant genotype×diagnosis interactions were observed in the left fusiform gyrus, left hippocampus, and right superior parietal cortex. These findings were largely driven by C/C>T carrier effects that were unique to healthy participants, although interestingly patients exhibited non-significant T carrier>C/C effects within these regions. These interactions were not expected, as they occurred in regions that are not typically associated with error processing. Within the error processing network, only healthy participants demonstrated significant C/C>T carrier effects in bilateral insula, but did not differ significantly from patients in this regard (i.e., the genotype×diagnosis interaction was not significant). The interpretation of these findings is not straightforward, and they should be considered preliminary until replicated. Still, in light of equivalent task performance by genotype within each diagnostic group, these patterns could provide insights into differing adaptations to MTHFR effects in patients and healthy participants, both within and external to the error processing network.

Epigenetic mechanisms are dynamic and reversible, even in mature neurons [35]. Folate status, in particular, may influence the degree to which hypofunctional MTHFR variants influence downstream methylation events. Among healthy individuals homozygous for the 677T allele, genomic DNA methylation and homocysteine metabolism are substantially lower than for those with C/C genotype, differences that are even more pronounced in the setting of low serum folate levels [6]. Similarly, among T/T schizophrenia patients, those with low folate levels exhibit more severe negative symptoms (which are closely related to cognitive impairment), while those with high folate exhibit more favorable negative symptom scores (similar to C/C and C/T patients, for whom negative symptom scores do not depend on folate levels) [18]. Among schizophrenia patients who carry the 677T allele and who receive folate supplementation, improvement in negative symptoms scores correlates with increase in serum folate level [36]. It is possible that folate level might also modulate the neural response to errors in 677T allele carriers and that folate supplementation might augment it, suggesting a potential intervention for blunted learning from errors.

Limitations

There are several limitations to the present study. As direct observation of MTHFR genotype effects on downstream methylation measures is not possible in vivo, we cannot directly ascribe the MTHFR effect on error-related neural activation to specific patterns of DNA or histone methylation. In addition, dietary or serum folate levels were not available from study participants, precluding the study of interactive folate×MTHFR genotype effects on dACC function. The number of participants in each genotype×diagnosis group was relatively small. However, that the results were nearly identical in two groups (healthy participants and patients) and also echo those seen in a previous, smaller study of schizophrenia patients that used a different version of the antisaccade paradigm[13], suggests a low likelihood of Type I error. Finally, although study participants were predominantly Caucasian, the use of a racially admixed cohort raises the possibility of population stratification artifact; however, MTHFR genotype groups did not differ with regard to racial composition, and MTHFR effects persisted when only participants of European origin were included in the analysis, diminishing this concern.

Conclusion

In summary, the present results demonstrate that a genetic variant implicated in schizophrenia risk alters the neural response to errors. They also suggest the importance of epigenetic control over error processing circuitry, implicating a novel molecular mechanism for how we regulate and flexibly modify our behavior.

So this highlights the nugget from the video above about people with this mutation living healthy normal lives with this mutation.
It may be that those with it that have undergone prolonged stress or sudden large traumas may need suppliments to help them out of that trap.

Another part is giving the body the resources for the epigenetic changes of diet and cold adaption to take place. If a person with these mutations is attempting those changes they may struggle to adapt.

The biggest part from my perspective though is being able to correct your own thinking without crippling yourself physically i.e. do the Work!
The literal biological effort for me to question my own errors was to much to handle in a depleted state (stressed, tired, hungry etc). I couldn't even conceve that the way I thought about any and everything may be in error because it was to painful/debilitating. You become convinced you know 'what the answer is' because to step outside that and use the error correction part of the brain (to even admit you may be in error) requires resources you may not have, you end up 'certain' of 'facts' and everything becomes black and white.
With years of practice you can become an expert in avoiding your own error processing circuitry!

The irony is that black and white/obsessive thinking uses More resources than the initial spike needed to correct your own thinking, because the constant side stepping of objective truth (activation of the brains error processing) is a dance that takes so much energy it's ridiculous - especially for anyone with a mutation that limits your available energy!

It's like being constantly cold (and using tons of energy to keep warm) vs choosing to take once ice cold shower for 10 minutes and then feel warm for the rest of the day by adapting. The trick though is you may need a supplement protocol in order to be able to make the initial changes.

I am following an amalgamation of protocols I've read about and paring things down to there basics to gather as much data as possible.
My main source of research is based on what others have been experimenting with and can be found here:
_http://phoenixrising.me/treating-cfs-chronic-fatigue-syndrome-me/treating-chronic-fatigue-syndrome-mecfs-glutathione-and-the-methylation-cycle
_http://forums.phoenixrising.me/index.php?threads/b-12-the-hidden-story.142/
_http://forums.phoenixrising.me/index.php?threads/active-b12-protocol-basics.10138/

I will try and condense the research as soon as I can. There are a bunch of genetic traits to take into account, so it requires a lot of tweaking/adaption.

 

[shijing]

Here are a couple of recent articles by Chas Grant on methylation, which are fairly short and straightforward -- the first one mentions some of the affects on lifestyle and personality which Redfox discussed in his post above:

http://info.nihadc.com/integrative-health-blog/bid/70946/Methylation-101-What-it-Means-for-Your-Health

http://info.nihadc.com/integrative-health-blog/bid/71424/Methylation-102-A-Deeper-Look-at-the-MTHFR-Gene

 

[shijing]

I've recently started going through some of the videos at beyondmthfr.com, and wanted to share some of them here. I've linked to the parent articles above the videos in case anyone wants to read the accompanying text.

This one is about a couple of specific genes and how they interact with cortisol and adrenaline:

http://beyondmthfr.com/2014/11/04/a-genetic-cause-of-pain-and-anxiety-comt-mao-and-mthfr/

https://youtu.be/xehiaWFafBM

These are about interactions between MTHFR mutations and gut health:

http://beyondmthfr.com/2014/09/09/mthfr-and-sibo/

https://youtu.be/bQEbGOAWLeA

https://youtu.be/BqStfpXDIME

http://beyondmthfr.com/2014/12/28/the-gut-origin-of-methylation-problems/

https://youtu.be/cYNeviaw_1o

https://youtu.be/jylTZ-tVEE0

 

[shijing]

Ben Lynch sent this out to his email list today, regarding his recent segment on the Anxiety Summit that ends tomorrow:

Hello -

Did you miss the Anxiety Summit?

Or did you enjoy it and want to hear it again?

I just received news that my session on methylfolate and anxiety was the most requested session for an encore replay.

It's encouraging to know that this information was helpful to so many - it's why I do what I do.

And now you have a chance to hear a free replay of the most requested sessions including my session - "How Methylfolate Can Make You Feel Worse & Even Cause Anxiety".

These sessions will be replayed this Wednesday starting at 9am for 24 hours.

Here is the line-up:

Trudy Scott CN, "New 2015 Food/Nutrient Research on Anxiety and Speaker Highlights"
Dr. Benjamin Lynch ND, "How Methylfolate can make you Feel Worse and even Cause Anxiety, and What to do about it"
Dr. Daniel Amen MD, "The Brain Warriors Way to Attacking Anxiety, Depression and Aging"
Yasmina Ykelenstam, "Histamine-containing Foods: their Role in Anxiety, Depression and Schizophrenia"
Dr. Peter Osborne DC, "Grainflammation - How Grain Consumption Contributes to Anxiety and other Mood Disorders"
Trudy Scott CN, "Pyroluria, Amino Acids and Anxiety: Troubleshooting when you are not getting results"
Trudy Scott CN, "Closing call: 60+ Nutritional & Biochemical Causes of Anxiety and Recommended Supplements"

Here's the link to access this replay - http://www.easywebautomation.com/app/?af=1608545

Keep learning, keep empowering yourself to greater health!

In Health,

Dr. Ben Lynch

His segment is based on (and expands) this original article:

http://mthfr.net/methylfolate-side-effects/2012/03/01/

 

[RedFox]

I wanted to report on the MTHFR protocol I've tried over the last 6 months or so.
I started out doing plenty of research and will try and break things down into the most important parts.
Firstly if you have a chronic medical condition, please work with a medical practitioner.
Secondly, rule out heavy metal and environmental toxicity (mould/chemicals/diet/candida etc) first.
It's really important to rule out mercury toxicity, as the methly supplements make mercury more toxic - this is especially important for those with nerve/neurological problems.

Noticeable results:
Neurological healing (this has been quite pronounced) - better motor control (I can do things without needing to think about how I move), increased muscle stamina and tone (and a desire to exercise), increased vagal control (I can hold a note much better and have more desire to sing!), better balance, increased senses of smell and taste, less hypersensitive to touch/sound/light/emf, improved learning, increased mental and emotional clarity. I also noticed a balance in brain chemicals and a deepening of sleep.
Greater energy
Improved detox
Less sensitivity to inflammatory things
Improved healing
Weight and muscle gain

Firstly the protocol I used (stripped down)
http://forums.phoenixrising.me/index.php?threads/active-b12-protocol-basics.10138/

Absolutely critical minimums for basic healing.
Jarrow Formulas 5mg Methyl B12, under upper lip or tongue for at least 45 minutes for best effectiveness {from the research they've done on the forum the brand is important}
Enzymatic Therapy 1mg B12 infusion, under upper lip or tongue for at least 45-120 minutes for best effectiveness {I must have missed this one as I didn't include it}
Solgar Metafolin 800mcg

At this time I can no longer suggest any folic acid or folinic acid containing supplements for people in general. If a person has trialed folic/folinic acid containing supplements and compared it to trial of Metafolin for some months on each with several cycles and found no difference, then the folic acid would appear to not be causing paradoxical folate deficiency. As this is a very real risk for many who need b12 and folate I suggest using Metafolin only. In myself and others, food folate and food extract folate may affect one the same as folic/folinic acid and cause paradoxical folate deficiency. This deficiency reaction causes symptoms that is usually identified as "detox". {avoid folate supplements except metafolin, introduce metafolin slowly}

Source Naturals Dibencozide 10mg under upper lip or tongue for at least 45-120 minutes for best effectiveness, from 1 per day to 1 per week {this is particularly strong! it is the key component to neurological healing, and needs to be added in slowly. I started with 1/4 of a tablet}

B-complexes containing methylfolate or Metafolin instead of folic/folinic acid and methylcobalamin instead of cyanocobalamin {I used jarrows B-Right}


POTASSIUM -

Potassium is far more critical than I realized with version 1 of this page. Most people starting the active b12s and Metafolin will have low potassium symptoms which can include unusual spasms, muscle weakness, mood and personality changes, nausea, heart palpitations and a long list of other possible symptoms which makes it difficult to identify. Many people misidentify low potassium symptoms as "detox". This is a dangerous mistake to make.

Potassium, your choice of brand and form - this is insurance against hypokalemia triggered by sudden healing and potentially fatal - if you have blood tests, potassium is usually checked, mid-range, around 4.5 is good. Some people will have problems at bottom of "normal" range, 3.5-4.2.

Omega3 fishoils - essential for myelin sheathing for the nerves, many brands will do, 2-6+ capsules per day, I buy it at Costco, house brand. This kind of product is available in many supermarkets.

Essential, usually needs supplementing
Zinc - 50 mg
Calcium/magnesium supplement
D3 - 3000-5000 IU total
A&D from fish oil, 10,000-(400-800-1000 D) Vitamin A should be 10,000, D might be any of 3 numbers with additional D to be taken
Vitamin E, Gamma complex
Vitamin C 4000+mg/day

Possibly Critical Cofactors, add after initial stages, any number of these in any combination may be required for maximum effectiveness
{I tested each one by introducing them individually}

SAM-e - 200-400mg/day, makes methylb12 more effective, possibly much more effective, increases energy, improves mood {Helped for the first week or so, then sent my mood/mind screwy}

TMG - enhances SAM-e, methylb12, l-carnitine-fumarate
{Seems to be generally good - stopped after several months}

L-carnitine fumarate, works with adenosylb12, lack can completely prevent effectiveness of adenosylb12, increases energy, aerobic endurance, improves mood
{Seems to be generally good - stopped after several months}

Alpha Lipoic Acid - enhances l-carnitine-fumarate and adenosylb12
{Important, but shouldn't be overdone due to possible detox issues}

D-Ribose - enhances adenosylb12, l-carnitine, alpha lipoic acid, improves exercise recovery and energy

Additional possibly helpful cofactors

Selenium
Lecithin {I took choline, either lecithin or choline is really important for neurological healing! It gave me a great boost}
Chromium GTF
many other supplements

{I will add Lithium Orate. This should be researched but it enhances B12 absorption into cells making the entire protocol more potent - as such it should be introduced slowly and after some time getting use to the B12 supplements, and after introducing metafolin. You will most likely need extra potassium here as it's like hitting the accelerator pedal on the healing. Be aware that getting use to it takes some time, and it can cause dizziness and nausea to begin with.}

THINGS TO AVOID

Glutathione and glutathione precursors such as NAC and glutamine, undenatured whey. The glutathione induces immediate active b12 deficiencies, apparently by converting active methylb12 to inactive glutathionylb12 and rapidly excreting it. This then causes the methylfolate to be dumped from the cells in a process called the "methyl trap". This leads to a high serum folate but a low cellular folate causing a severe folate deficiency with increasingly severe symptoms over time. This is often mistakenly called "detox". NAC can produce these same folate and b12 deficiencies also misidentified as "detox".

{I had mixed results here. Glutathionine should definitely be avoided. NAC is more complex. NAC will need magnesium to be taken with it, and shouldn't produce problems after a certain level of healing has occurred.}

DEEP NEUROLOGICAL HEALING

The most frequent neurological problems are peripheral neuropathies, often in characteristic stocking-glove distribution. Sublingual methylb12 and adenosylb12 appear quite satisfactory in healing these in a sizable percentage of the time. There exists a class of more severe neurological damage. This is sometimes identified as subacute combined degeneration and takes place in the brain and spinal cord. This can occur in people severely deprived of active b12s by diet or lack of absorbtion by other reasons. Another hypothetical cause may occur in people who for unknown reasons have a depressed Cerebral Spinal Fluid cobalamin level compared to their blood serum levels. In addition there may be mood and personality changes, hallucinations, sensory changes, psychosis and an abundance of neuropsychiatric changes. Some of these changes can be corrected with sublingual active b12s but some require much higher levels of active b12s than are usually achieved with sublingual tablets. In these situations usually only injections will help. Low CSF levels of cobalamin along with elevated CSF-MMA and/or CSF-Hcy is associated with CFS, FMS, ME, Parkinson's, MS, ALzheimer's and a number of other neurological diseases.


B12 INJECTIONS
The usual kinds of b12 injections, cyanocobalamin and hydroxycobalamin, are virtually always ineffective on any schedule. The once a month schedule for cyanob12 and the once each three months schedule for hydroxyb12 is useless as well. Daily sublingual active b12s are far superior to these in every way. These occasional injections were developed as a means to prevent people with pernicious anemia from dying. They do not promote neurological healing in any significant way. In order to promote neurological healing methylb12 injections of larger than usual size and greater than usual frequency must be used. My own experience is given below and corresponds with the ZONES defined on another posting. All injections are subcutaneous as that produces a slower diffusion into the blood maintaining a steadier serum peak. Methylb12 solution must be prepared under a deep red (fast orthochromatic film) safelight. The vials must be wrapped in foil to exclude all light. The syringe must be wrapped in foil preventing all light exposure. A small amount of exposure to room light will cause photolytic breakdown to hydroxycbl-aquacbl often causing acne type lesions and lack of effectiveness.


1. Single or multiple injections per day to 5mg methylb12, each injection. ZONE 2, fully equivalent to sublingual tablets, did not stop continued neurological deterioration and progressive numbing of feet of 15 years duration.
2. Single 7.5mg methylb12 injection per day stopped the progressive numbing of feet of 15 years duration. ZONE 3A1
3. Two 7.5mg methylb12 injections per day caused some small reversal of numbing of feet and of neuropsychiatric symptoms. ZONE 3A1
4. Four 7.5mg methylb12 injections per day have caused substantial sustained reversal of numbing in feet and of neuropsychiatric symptoms. ZONE 3A2
5. Three 10.0mg methylb12 injections per day have caused substantial sustained reversal of numbing in feet and of neuropsychiatric symptoms. ZONE 3A2
6. Two 15.0mg methylb12 injections per day have caused substantial sustained reversal of numbing in feet and of neuropsychiatric symptoms. ZONE 3A2

[..]

Assumptions - Methylcobalamin and adenosylcobalamin are brands tested as 5 star for absorption and compared to injection by effect and colorimetry achieving 15% absorption or greater in 45 minutes or greater absorption in longer times.

ZONE 1 Cyanob12, oral or injected any size dose, hydroxyb12, oral or injected any size dose, methylb12 oral in doses of 500mcg or less. Limited results largely confined to those changes requiring lab tests to see; reduced hcy, reduced uMMA, sometimes reduced MCV, occasionally mild changes in paresthesias and peripheral neuropathies over time. From literature and experience
. ZONE 2A methylcobalamin (Jarrow or Enzymatic Therapies) sublingual 1mg to 50mg/day, single sublingual doses to 25mg and IM and SC injections up to 5mg. Dose proportionate healing of widespread symptomology. From literature, tests and experiences. Heals neurology, endothelial tissues, epithelial tissues, energy and mood. Some healing, hematological at least, is dependent upon adequate methylfolate being present. It appears that about 95% of healing takes place in Zone 2A & 2B.
ZONE 2B adenosylcobalamin sublingual, 3mg to 60mg/day and single doses to 24mg. Less obvious dose proportionate correction and healing of a smaller more specific array of symptoms. Heals muscles, allows them to grow, energy, mood, affects neurology differently from methylb12.
ZONE 3A1 Methylb12 injection, 7.5mgs SC to 25mgs SC per dose, 1-2 doses per day or 50-60mgs sublingual (Jarrow) saturating oral cavity for 90-120 minutes, 1-2 doses per day. Brain and cord healing, energy and mood, appears dependent upon sufficient methylfolate being present. Neurological deterioration stops, limited amount of healing
ZONE 3A2 Methylb12 injection, 7.5mgs SC to 25mgs SC per dose, 3-4 doses per day or 50-60mgs sublingual (Jarrow) saturating oral cavity for 90-120 minutes, 3-4 doses per day. Substantial brain and cord healing, energy and mood, appears dependent upon sufficient methylfolate being present.
ZONE 3B1 Adenosylb12 sublingual (Source Naturals), 40-60mgs per dose saturating oral cavity for 90-120 minutes, 1 dose per week to 1 dose per month. Brain and cord healing, energy and mood, but different from methylb12 was achieved with adenosylb12
ZONE 3B2 Adenosylb12 sublingual (Source Naturals), 10-20mgs per dose under upper lip for 90-120 minutes, 1 dose per day to 1 dose per week taken in conjunction with 7.5mg mb12 injection, allowing diffusion into CSF with mb12. Brain and cord healing, energy and mood, but different from methylb12 was achieved with adenosylb12
ZONE 4 Intrathecal injection. Enhanced neurological healing in intentionally damaged rats. Japanese research with diabetic neuropathy in humans, 2.5mg injected, indicated benefit as long as CSF cobalamin level remained high lasting from 3 months to 4 years depending upon person. From literature.

[..]

REASONS WHY B12 AND FOLATE THERAPIES DON'T WORK FOR MANY PEOPLE
Version 2.0 - 03/10/11
Version 2.1 - 05/08/11


1. They take an inactive b12, either cyanob12 or hydroxyb12. The research validating their use was primarily for reducing blood cell size in Pernicious Anemia, keeping the serum b12 level over 300pg/ml at the end of the period between injections. They make a statistically significant effect that can be seen in lab tests in a significant percentage of people compared to placebo. They do not heal most damage done by active b12 deficiencies and have little or no effect on the vast majority of symptoms. They may even block active b12 from receptor sites hindering the effects of real b12. They both cause a keyhole effect of having only a very limited amount (estimated at 10mcg/day) that can actually be bound and converted to active forms. They in no way increase the level of unbound active cobalamins which appear required for most healing. They do nothing beneficial in a substantial percentage of people (20-40%) while giving the illusion that the problem is being treated and if it doesnt work, oh well, thats the accepted therapy. There is no dose proportionate healing with these inactive b12s because it all has to go through this keyhole. Some people are totally incapable of converting these to active forms because they lack the enzyme
2. They take active b12 as an oral tablet reducing absorbtion to below 1%. A 1000mcg active b12 oral tablet might bind as much as 10mcg of b12. Again the b12 has to be squeezed through a keyhole that limits the amount and is subject to binding problems in the person whether genetic or acquired.
3. They take a sublingual tablet of active b12 and chew it or slurp it down quickly reducing absorbtion back to that same 1% and limited to binding capacity. With sublingual tablets absorbtion is proportionate to time in contact with tissues. I performed a series of absorbtion tests comparing sublingual absorbtion to injection via hypersensitive response and urine colorimetry.
4. Of the many brands of sublingual methylb12 only some are very effective. Some are completely ineffective and some have a little effect.
5. For injectable methylb12, if it is exposed to too much light (very little light actually is too much) it breaks down. Broken down methylb12 is hydroxyb12. It doesnt work at healing brain/cord problems of those who have a presumed low CSF cobalamin level. That requires a flood of unbound methylb12 and adenosylb12 (2 separate deficiencies) that can enter by diffusion. Adenosylb12 from sublinguals can ride along with injected methylb12.
6. They dont take BOTH active b12s.
7. They dont take enough active b12s for the purpose.
8. Lack of methylfolate
9. Folic acid is taken which can block at least 4 times as much methylfolate from being active inducing folate deficiency even if methylfolate is also taken. These induced deficiency symptoms are often called "detox" symptoms.
10. Folinic acid is taken which can block at least 5 times as much methylfolate from being active inducing folate deficiency even if methylfolate is also taken. These induced deficiency symptoms are often called "detox" symptoms.
11. Lack of other critical cofactors.
12. Lack of basic cofactors
13. Glutathione, glutathione direct precursors or NAC is taken causing what is often called "detox" while actually being induced folate and b12 deficiencies.

What I did was start with the Jarrow Formulas 5mg Methyl B12 over a period of a week along with the added cofactors, and worked up to 40mg a day by week 6.
I introduced the Source Naturals Dibencozide (2.5mg - 1/4 a tablet) by week 2 and worked upto 20mg by week 6. I then introduced 5mg of lithium orate (people with severe conditions will probably need to go in at a lower dose).
I introduced the methylfolate at week 3, starting at a low dose and working upto 200% rda by week 6. The literature suggests that methylfolate should be introduced after B12 and cofactors has been replenished.

One thing that is discussed by people following these protocols is that old health conditions may re-occur. That is as things heal, earlier health conditions come to the surface and are then healed - although they may need additional attention.
Week 2-4 I saw signs of peripheral neuropathy (tingling, burning and numbness in my extremities) that was quite unpleasant. This passed and what I was left with was all of the neurological effects I described above, starting with reduced hypersensitivity to stimulus, followed by increased taste/smell, vagal tone and then muscle tone and weight gain.
The introduction of the lithium orate re-triggered the neuropathy symptoms a week or two later (although not as bad), and again after the symptoms passed I was left with neurological improvements. This time it seemed more so with memory and mood.

I also learned that in order to help the healing process I had to unlearn/push past (carefully) all the programming this problems caused. The biggest thing being balancing pushing to hard (burn out) vs avoiding Any stress. I had to learn to get in touch with my body and emotions more in order to gauge what I could and couldn't do.

One health condition that then appeared (and I got stuck with for some time until I worked it out) was apparent blood sugar problems (insulin resistance) and stress problems (see the cortisol resistance thread).
The main thing I introduced at this point was Phosphaidylserine and neurologically calming supplements (taurine and l-theanine - incidentaly black tea has lots of l-theanine in).

I'm quite a skinny guy and have never been able to put much fat or muscle on (despite eating a lot). Generally eating a lot left me feeling drained and gave me head fog. This cleared up around week 4. I could eat as much as I wanted then without problems, but still wasn't gaining much weight. Muscle stamina was increased but still seemed to have a maximum I couldn't get past. Before that I exercise would leave me debilitated for a week or two, and I'd loose muscle mass.

The phosphaidylserine (which has a lot of research around healing neurological conditions such as alziemers and dementia. It can only be created in the body if it has enough B12 and folate, and is a buffer to stress/elevated cortisol) really changed things.
It did need me to take it for a week or so (with additional fish oil) before it started effecting my body.
Several distinct things happened, following heavy exercise for a period of a week I gain about 2kg of muscle and 2kg of fat! Eating extra protein now seems to cause me to gain muscle weight despite not always exercising, and eating additional carbs causes me to gain fat. I have never in my life been able to gain and keep weight like this!
In the last 3 weeks I've gone from 64kg to 70kg (which is the most I've weighed since starting to track my weight over 4 years).

Previous to this no amount of food and/or exercise would have this effect. The most I could gain in a week would be 1/2kg of muscle and fat combined, both of which would evaporate after 1-2days. A stressful event, eating too many carbs/protein, lack or sleep, heavy exercise or illness would cause me to loose about 3-6kg in a week (mostly in muscle weight).
The cortisol connection is also useful for those that can't loose body fat (same mechanism, different genetics).

I encourage anyone who is thinking of trying this to research it, and I'd suggest adding the phosphaidylserine at the beginning of the protocol.
For those in need of additional neurological healing, add extra fish oil and choline.
Additionally a good regime of minerals should be taken (including boron).

 

[RedFox]

Cross posting for reference to the autoimmune thread:

I re-watched some MTHFR videos yesterday, and one of the key points I came away with is that those with the mutation methylation pathway breaks down under stress/disease.
Not only does the breakdown of the system lead to chronic disease, but so does chronic disease lead to the breakdown of the system. Catch 22.

The emphasis was in order to get the system working again all burdens to methylation should be corrected (lifestyle, diet, gut health, stress, toxicity etc).

A parasitic or bacterial infestation of the body is going to be the number one problem (when all the above are accounted for) and demand the most from the methylation pathways

Having said that, it needs to be noted that antibiotics and the toxins from pathogens being killed will also have the potential to shut down methylation pathways in those with the mutation.
So again extreme caution should be used with this protocol.

If cortisone is employed and the protocol followed, but health deteriorates a MTHFR mutation should be considered (along with a B12/folate deficiency - so age and how much stress a person has endured in there life should also be considered).
Without that, immune defences will be compromised, toxcicity won't be able to be processed and you will be open to future infection.

Those with the mutation probably should be considered highly likely to have an infection.

I'm going to attempt this antibiotic protocol in the next few weeks, so will update on the results to see if it matches the above hypothesis.

Now I've considered the possibility there seems to be plenty of data to back this up.

Methylation Inhibited by Candida’s Toxin

Repairing the digestive system and optimizing the flora should be one of the first steps in correcting methylation deficiency. [..]

Methionine synthase has a few potent inhibiting compounds and one is produced from Candida

Candida albicans produces a toxic byproduct called acetylaldehyde.[1]

Research cites:

“Acetaldehyde-induced inhibition of liver methionine synthase activity is thus proposed as the most likely explanation of the reported in vivo effect of ethanol upon methionine synthase.” [2]
Acetylaldehyde is also a byproduct of ethanol.

Let’s make this very clear.

What are the major symptoms of a hangover?

headache
foggy thinking
irritability and/or depression
fatigue
soreness
sensitivity

What are the major symptoms of yeast overgrowth?

headache
foggy thinking
irritability and/or depression
fatigue
soreness
sensitivity

What are some major symptoms of reduced methylation?

headache
foggy thinking
irritability and/or depression
fatigue
soreness
sensitivity
[..]

I can attest to those being my most common symptoms! Waking up feeling 'hungover' - it's insanely frustrating.

Things That Plague Us: Viruses, Bacteria and NeuroImmune Disease (see original article for lots of further links)

Gather together some MTHFR patients and start talking about what ails them. There’s a laundry list of associated illnesses for people with methylation defects and those illnesses do present among MTHFR patients. Autism, cancer, heart disease, fibromyalgia, infertility and recurrent miscarriages, Parkinson’s disease, polycystic ovarian syndrome and stroke are just a few of the chronic conditions where MTHFR gene mutations have been identified as a contributing factor. So any doctor who tells you that MTHFR isn’t a big deal either doesn’t know what he is talking about or is lying through his teeth. Because that inability to detoxify that I’ve been talking about doesn’t just apply to household chemicals, medications and foods that you’re allergic to. It also applies to toxins like viruses, bacteria, fungus and parasites, which we are literally plagued with. And this is where the health problems start to come into the picture. If you haven’t been tested for MTHFR it’s probably because you haven’t gotten sick (yet).

It is important to remember that a methylation defect does not usually cause health problems all by itself. As Dr. Kendal Stewart of NeuroSensory Centers of America explains in his methylation overview:

Most health conditions in society today are multifactorial in nature. In essence, there is an underlying genetically determined risk that requires a significant infectious or environmental “trigger” to initiate the process….if an individual has enough mutations or weaknesses in their methylation pathway, it may be sufficient to cause the multifactorial disease by itself, as methylation cycle mutations can lead to chronic infectious diseases, increased environmental toxin burdens and have secondary effects on genetic expression.

His linked paper is very interesting and I strongly encourage anyone dealing with methylation issues to read it for an explanation of how these issues all tie together. As he notes in his excellent series of podcasts about autism and contributing factors, we’ve all been exposed to toxins. Most human beings have some latent germy junk lying dormant in our systems just waiting for that moment of trauma or period of suppressed immunity to rear their ugly heads. Proper treatment of chronic health conditions cannot occur without exploring all possible causative factors. And I’m not sure how well-known this information is among your average doctors and patients.

I will be exploring the subject of methylation-related health conditions in this new series here on MTHFR Living. We will explore not just neuro-immune diseases but also other related illnesses and health conditions. If you feel overwhelmed by all of this and perhaps a little down on yourself for having these mutations, please don’t. Consider the fact that our environment has become increasingly more toxic since the Industrial Revolution. Children are exposed to dozens more vaccines at an earlier age today than they were in 1983. Our food sources are less clean and have fewer nutrients than they once did. Viruses and bacteria are pervasive, even if they exist simply as latent infections that act together to complicate things. I’ve recently updated the resources page on this site to include informational websites on some of these ‘root causes.’ If you’re having chronic health problems it is essential to get to the bottom of what is causing them. We cannot blame everything on MTHFR and other gene mutations.

Some recent pieces of media that I’ve come across in my research will be wonderful for allowing health practitioners to explain these factors to you. These people are either experts in this area and/or see this multifactorial causation with their patients or in their research on a regular basis. The first item is a great lecture by Dr. Randall Tent of Diverse Health Services in Novi, Michigan. The first hour of this lecture focuses on the story of how SV40 was introduced to millions of people with the polio vaccine. I have read quite a bit about SV40 and the most important thing I learned, especially after reading The Virus and The Vaccine: The True Story of a Cancer-Causing Monkey Virus, a Contaminated Vaccine, and the Millions of Americans Exposed (St. Martin’s Press 2004), is that we are not safe. This history proves that government health agencies cannot be completely trusted to protect the people and balance the interests of the human population with those of the pharmaceutical companies. The corruption and incompetence demonstrated in this book will astound readers.

https://youtu.be/r8FCJ_VPyns

Contrary to claims that exposure to the virus was limited and that it no longer has any bearing on the health of our population, SV40 is still being discovered in people today. It is found in people who are too young to have received the contaminated vaccines. The virus is, in fact, present in human cancers and it “disrupts critical cell cycle control pathways” (Vilchez, Butel 2004). A polyoma virus, SV40 is tiny and was not killed during virus inactivation in the making of the polio vaccine. Nine new human polyoma viruses have been discovered sine 2007 with one of these being linked to a lethal form of skin cancer. It has been proven that viruses cause cancer and the study of these viruses led to discoveries about the workings of cellular oncogenes. These viruses may not be what Dr. Janet Butel calls “complete carcinogens” but they play a strong supporting role in tumor formation, particularly during periods of weakened immunity.

So if viruses can cause cancer, what else can they cause? And what viruses are we talking about here? The cancer viruses discussed in the aforementioned studies include Epstein–Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), human T-lymphotropic virus Type 1 (HTLV-1) and Kaposi’s sarcoma-associated herpesvirus (KSHV). If you’re short on time, jump to the second half of Dr. Tent’s lecture and listen to the case studies of patients and their symptoms and the root causes he discovers. He runs a viral panel on his patients that includes tests for EBV, cytomegalovirus (CMV), herpes 1 (HSV-1), herpes 2 (HSV-2), herpes 6 (HHV6), herpes antibodies (HSV), parvovirus B19 and thyroid antibodies. His patients have complained of conditions like lupus, multiple sclerosis (MS), fibromyalgia, arthritis, muscle aches, muscle spasms, night sweats, headaches, numbness, Bell’s Palsy, blurry vision, tinnitus, sinusitis, food allergies, digestive issues, hives, encephalomyelitis, chronic pain and swelling. Tent discovered viruses in most of his patients.

Dr. Stewart also talks about viruses as co-factors in his patients, who are being treated for conditions like autism spectrum disorders (ASD), headaches, ADD/ADHD, vertigo, Alzheimer’s, dementia, MS, fibromyalgia and chronic pain. So far I have listened to his first three podcasts, which mention sources of inflammation like viruses, fungus, parasites, spirochetes, vaccines, antibiotics, yeast and bacteria, which contribute to what he calls “Neuro-Sensory disorders.” Among these he mentions HHV6, streptococcus, parvovirus, varicella zoster virus (VZV) and other herpes simplex viruses (of which there are at least 24). I encourage a listen to the podcasts even if you aren’t dealing with autism; just as Dr. Amy Yasko’s methylation work can benefit everyone, so can Dr Stewart’s work on the causative factors of neuroimmune disease. Any work related to ASD is significant for people suffering from chronic neuroimmune diseases because of the work of Richard A. Van Konynenburg, Ph.D., who drew parallels between chronic fatigue syndrome and autism.

The causative effects of biological toxins like viruses and bacteria are also supported by other research in the scientific community. A 2010 study found that chronic bacterial and viral infections are involved in the progressive chronic diseases discussed in this post, along with others that I have not mentioned. EBV has been linked to systemic autoimmune diseases (SADs) like rheumatoid arthritis (RA), systemic scleroderma (SSc) and systemic lupus erythematosus (SLE). Another study found the EBV, CMV, HHV6 and HHV7 viruses to be strong pathogenic triggers for MS. Hashimoto’s Thyroiditis may be caused by the human herpes virus. Parvovirus B19 has been linked to miscarriages, rheumatoid arthritis and SLE. These are just a few samples pulled from the available literature.

So what does all this have to do with MTHFR? Dr. Stewart talks about a genetic predisposition to chronic health problems like ASD. Certainly a discussion about the relationship of MTHFR to each illness is outside of the scope of this blog post. But put very simply, pathogens like viruses and bacteria cannot be effectively killed and eliminated when methylation is impaired. Gut problems, which are common when people are not detoxifying properly (usually due to a decrease in glutathione levels), lead to a weakened immune system, which triggers the re-activation of latent viruses and bacteria. So in the same way a disease is caused by many factors, methylation defects contribute multiple causative factors to chronic health conditions.

I hope you will join me in this new series as we explore our various ailments. I will delve further into some of the autoimmune and neuroimmune disorders mentioned in this post in more detail as the series progresses. In the meantime, if you are suffering from chronic illness or unexplained symptoms, it may be a good idea to speak to a knowledgeable doctor about potential viral, bacterial and other biological causes and the appropriate testing.

Although we can't blame everything on MTHFR (and other) mutations, it should be considered when following the autoimmune protocol.

 

[shijing]

I'm posting below the entirety of chapter 20 from Amy Yasko's book Feel Good Nutrigenomics. I was originally only going to post a couple of excerpts on the autoimmune/infection thread, but after re-reading the chapter, I thought it was important enough to post in its entirety and decided to do it here instead. It includes several topics, including both physical and psychological conditions, that have been under discussion recently on the forum. Bolding is from the original:

Methylation Sits at the Center or Multifactorial Conditions: Why You Should be Concerned if Your Cycle is Not Working Properly

“Methylation happens over a billion times a second. It is like one big dance, with biochemicals passing methyl groups from one partner to another” (Braly, The H Factor Solution).

This is the most scientific chapter of this book and also one of the most important chapters. Please take your time and slowly read through to understand how methylation impacts virtually every aspect of your health. I want you to truly understand why methylation is so critical and why you should be concerned if you are not supporting this pathway in your body.

Methylation is central to such critical reactions in the body as:

• Repairing and building RNA and DNA
• Immune function (how your body responds to and fights infection)
• Digestive issues
• DNA silencing
• Neurotransmitter balance
• Metal detoxification
• Inflammation
• Membrane fluidity
• Energy production
• Protein activity
• Myelination
• Cancer prevention

Methylation is involved in almost every reaction in your body. Aside from its critical editing function, without proper methylation, there is increased vulnerability to viruses, impaired attention span, and less efficient nerve transmission and a greater predisposition to cancer.

For an organism to live, it must create new cells as fast as cells die. This requires that the body make millions of cells every minute, relying on DNA and RNA synthesis. DNA carries the blueprint, or genetic coding, needed to build the components of living organisms. Every time your body needs to repair the gut lining, or create an immune cell to respond to an immune threat, or to heal when you have cut yourself, you need to synthesize new DNA. But without a functioning methylation cycle, your DNA is not going to replicate properly. Mutations in the methylation pathway can cripple the ability of the body to make the building blocks needed for new DNA and RNA synthesis. Very similar to DNA is RNA, which is crucial to building proteins, transferring the information carried by your DNA and regulating your genes. In fact, RNA is even more abundant in your body than DNA. This reduced capacity for new DNA and RNA synthesis means that any new cell synthesis is impaired. A reduced synthesis capacity due to methylation cycle mutations is a particular issue for cells that already have difficulties meeting their needs for DNA and RNA synthesis under normal conditions. Problems in the methylation pathway limit nucleotide building blocks that the brain and other organs need for repair and growth. Bone marrow cells, lymphocytes, erythrocytes and some brain cells cannot make some of the DNA and RNA bases that they need for synthesis. Intestinal mucosa cells cannot make enough building blocks to fulfill the body’s requirement for healthy gut. Stress increases the need for these building blocks to overcome negative effects of hormones released during stressful conditions. Cell repair after injury increases the need for nucleotide building blocks. The brain has the highest concentration of RNA in the body, and therefore has the highest requirement for RNA building blocks.

Universal lack of methylation and the inability to produce these building blocks for RNA synthesis also results in a situation where the body is lacking the required elements for specific genetic regulation. This regulation or silencing is a multistep process that involves RNA as well as methylation to be certain that only the desired genetic material is expressed. As described earlier, epigenetics is the mechanism used by the body to turn on and off genes. It is the editing system that gives the body a second chance to get around direct mutations in our DNA. Epigenetic modification of DNA occurs mainly on a very specific DNA building block called cytosine. Cytosine is one of the four DNA bases found in organisms, including humans. It is one of the DNA building blocks that are produced by optimal functioning of the Methylation Cycle. So, take a moment and think about this… Methylation Cycle function is needed to produce the building blocks for DNA that are in turn the recipients of methylation groups in order to turn on and off that same DNA. You can start to see how intimately related your DNA synthesis and function is with respect to the Methylation Cycle. Methylation of these cytosine bases is generally correlated with silencing of genes.

Methylation is important for turning on and off mammalian DNA. This is true for silencing viral DNA in the body as well as cellular DNA. There are sections of the DNA that are regulatory regions, requiring methylation such that they turn on and off the information portions as they should. During development DNA methylation patterns are established and are essential for normal development. During new cell synthesis these patterns are then replicated. When these regions do not have the correct amount of methyl groups bound to them it can prevent the information from being turned off, resulting in autoimmunity, aging and cancer.

It has been estimated that 70 to 80% of the cytosines found in particular patterns in the DNA are methylated in humans. The other 20% of these cytosine patterns that are not methylated are found in clusters known as “islands”. These nonmethylated islands are most often found in the region that turns on the gene. Thus methylation of cytosines creates two distinct regions in the DNA, “unmethylated islands” and “methylated cytosine pattern sites” that are distributed throughout the genome. These methylated regions tend to be located at mutational hot spots; one third of all single base mutations associated with cancer are at these sites.

Methylation of cytosine also helps to maintain the large amount of the non-utilized portion of the human DNA in an inert state as well as helping to silence harmful DNAs. If you are short on methyl groups due to methylation cycle mutations then you will have less methyl groups for preventing autoimmunity and silencing genomes. This is true for silencing viral genomes as well as for regulating your own DNA. The methylation process prevents the reading of inserted viral sequences. One of the consequences of loss of methylation function is that it could cause the potentially harmful expression of these inserted viral genes. Under-methylation in normally silent regions of the DNA can cause the expression of inserted viral genes.

Certain disease states occur as a result of increases in the length of specific repeat sections in the genome. These special “repeat regions” are prior to the information or coding region of the DNA. These trinucleotide repeats are involved in certain disorders such as Friedreich’s ataxia, Fragile X and Huntington’s disease. When there is insufficient methylation capacity (mutations in the pathway) there is often not enough methyl groups to bind to these repeat regions, so they are able to multiply. This results in very long repeat sections, much longer than they should be. Studies have shown that inhibition of DNA methylation resulted in a 1000-fold increase in these three-base repeat sections. Therefore, decreased DNA methylation results in increases in trinucleotide repeats and increases the risks for these disorders. This creates a catch-22 as these long repeated sections then attract the limited methyl groups that are available. The consequent overmethylation of these repeat sections results in shutting off genes inappropriately.

Females contain two copies of the X chromosome. Silencing one of these two copies is essential for normal development. Methylation of the DNA is the mechanism by which the second X chromosome is silenced. The normally nonmethylated “islands” become methylated as part of this silencing process. A similar strategy is utilized to silence one of two copies of genes other than those on the X chromosome. In these cases the inactivated gene can be of either maternal or paternal origin. Loss of normal silencing as a result of decreased methylation contributes to a number of inherited diseases including Beckwith-Wiedemann, Prader-Willi and Angelman syndromes, among others.

The expression of many cellular genes is modulated by something called “histone acetylation” in addition to DNA methylation. Interestingly, methylation also plays a role in the histone acetylation process. Methylation also plays a pivotal role in establishing and maintaining an inactive state of a gene by rendering the chromatin structure inaccessible. Methylation therefore plays an important role in development, imprinting, X-chromosome inactivation and tissue-specific gene expression. Changes in DNA methylation profiles are common features of development and in a number of human diseases.

You can start to see how proper Methylation Cycle function would play a role in fetal development. It also plays a role in successful preconception supplementation to prevent miscarriages. Mutations in the MTHFR genes of the methylation pathway as well as mutations that lead to decreased B12 are risk factors for neural tube defects. Mutations in the methylation pathway, specifically certain MTR and MTRR SNPs, as well as elevated homocysteine are risk factors for having a child with Down’s Syndrome.

It is important to consider methylation pathway mutations when looking at supplementing with folate during pregnancy. One way to understand this more easily is to think about the studies on folate and neural tube defects. Using folate during pregnancy helps to decrease the risk of neural tube defects. This is not changing the DNA but having a regulatory effect on the ability of the DNA to be expressed, known as epigenetics. Now, if folate can make a difference in DNA expression, but you have a mutation so that you cannot use folate, then taking folate may not do any good; it is almost as if you never supplemented at all. Running a nutrigenomic test to determine the form of folate that will bypass mutations in your folate pathway will enable you to supplement with the appropriate form of folate and should help to reduce the risk of neural tube defects in a similar way to the use of plain folate in the absence of mutations in this pathway. The genetics of the parent are reflected in the child. So that if a pregnant mother has mutations that make her unable to utilize plain folate, you should consider testing the infant for similar weaknesses in this pathway. The sooner that you know if and where a newborn’s genetic weaknesses reside in the methylation pathway the sooner you can start to supplement to bypass these mutations. Remember, by supplementing properly you should have the potential to bypass and compensate for the mutations. If this is commenced from day one you do not allow time for virus to build in the system (remember that methylation is necessary to silence virus). In addition, some of the mutations in the methylation cycle make it difficult to make new T cells which are a critical part of your immune system. This may make it easier for the immune system of infants to react to vaccines in the correct fashion. If the methylation cycle is working properly from day one it should help with myelination, immune regulation and the ability to make new DNA and RNA that is needed for growing cells.

In the methylation pathway, one crucial component for neurotransmitter balance is the component S-adenosyl methionine, or SAMe. SAMe is the most active methyl donor in your body, bringing methyl groups to numerous chemical compounds in your body. It is a required participant in at least forty different critical reactions in the body. It also acts upon the neurotransmitters by changing them into other needed compounds. If we don’t have sufficient SAMe – or if SAMe can’t be recycled due to weaknesses in the methylation cycle, this can result in imbalances in our neurotransmitters, which in turn can impact mood, focus, sleep patterns, as well as a range of behaviors. The methylation cycle not only has to produce SAMe, it also has to recycle it. Once SAMe has given up its methyl groups to help create neurotransmitters, it is then “recycled” – that is, remethylated. After SAMe has received its new methyl groups, it can perform its job all over again. Because of its essential role in reactions involving neurotransmitters, it’s not surprising that a lack of SAMe plays a role in neurodegenerative conditions. Due to methylation cycle weaknesses, some people can neither produce nor recycle SAMe. Furthermore, issues with the level of SAMe in the body became a larger problem as we age. Fortunately, we can supplement SAMe to bypass mutations and attain its many benefits.

Some specific reactions that involve SAMe include:

• Converting serotonin to melatonin which supports healthy sleep
• Glutathione synthesis which is critical for detoxification
• In the formation of myelin which surrounds and protects nerves
• To convert the neurotransmitter norepinephrine into epinephrine (also known as adrenaline). Together, norepinephrine and epinephrine regulate the fight-or-flight response and, along with dopamine, are critical for attention and focus.
• In the creation of CoQ10, creatine, and carnitine, compounds essential to the work of the mitochondria, the energy factories of cells

Adequate levels of CoQ10 have also been identified as necessary nutrients to help prevent congestive heart failure. Clinically the supplement CoQ10 has been used in the treatment of angina, heart failure, prevention of reperfusion injury after coronary artery bypass and cardiomyopathy. The synthesis of CoQ10 in the body requires components of the methylation cycle; in particular it requires adequate levels of the compound SAMe (s-adrenal methionine) that is generated by the methylation cycle. Cholesterol-lowering drugs (statin drugs) decrease the supply of CoQ10 in the body. It may be particularly important for individuals taking statin drugs to be aware of the methylation status in their body and replenish CoQ10. In addition, the relationship between elevated homocysteine levels, an increased risk of heart disease and the genetic risk associated with certain MTHFR mutations in the methylation cycle has been recognized for quite some time. Appropriate supplementation of the methylation cycle should be able to help compensate for this mutation.

The mitochondria are the energy producing organelles within each cell. Decreased mitochondrial energy has been implicated in chronic fatigue, fibromyalgia and mitochondrial disease. CoQ10 is also important for its role in energy production in the mitochondrial respiratory chain. Again, as mentioned above, methylation cycle function is necessary for the synthesis of CoQ10 in the body. Carnitine is another nutrient produced by the body that is involved in mitochondrial energy production. Mitochondria fatty acid oxidation is the main energy source for heart and skeletal muscle. Carnitine is also involved in the transport of these fatty acids into the mitochondrial matrix. As with CoQ10, the synthesis of carnitine by the body requires methylation cycle function. Synthesis of carnitine begins with methylation via the action of SAMe. Low muscle tone and extreme muscle weakness may in part be due to decreased mitochondrial energy as well as myelination problems due to reduced methylation cycle capacity. Methylation is also needed to produce creatine in the body. The methyl group for this reaction is again donated by SAMe. Creatine is a supplement taken by many weight-lifters due to its role in muscle energy; creatine has also been reported to play a role in speech, language, attention span and ability to follow commands.

There is literature to suggest that ADD/ADHD can be helped by the addition of SAMe. SAMe is a critical intermediate in the methylation cycle. SAMe is also a methyl donor for reactions that involve dopamine, epinephrine and norepinephrine. Imbalances in this dopamine, epinephrine and norepinephrine have been implicated in ADD/ADHD. One can envision that methylation cycle function is needed to produce SAMe as a methyl donor for the dopamine/epinephrine/norepinephrine pathways to help prevent ADD/ADHD. Impaired methylation results in a lack of components needed to generate fell-good neurotransmitters like serotonin which regulates mood, emotion and appetite, as well as problems converting serotonin to melatonin so we can sleep at night. Many children with autism have difficulty sleeping as well as adults with chronic fatigue and fibromyalgia will frequently note sleep issues. Imbalances in methylation also affect dopamine levels as well as the dopamine receptor itself. Proper dopamine signaling requires that the dopamine receptor can move freely in the cell membrane. Methylation supports receptor activity by keeping the components of the cell membrane (phospholipids) more fluid. Imbalances in dopamine receptor signaling have been implicated in ADD/ADHD.

Myelin coating on nerves is important for proper neurotransmission. Myelin is a sheath that wraps around the neuronal wiring to insulate and facilitate faster transmission of electrical potentials. You can think of myelin as the coating around the electrical wires in your home. If those wires are not covered then even a single drop of water can cause the wire to short out. So too, your nerves are more vulnerable to assaults if they are not coated in myelin. Without adequate methylation, the nerves cannot myelinate in the first place, nor remyelinate after insults such as viral infection or heavy metal toxicity. In addition, methylation helps to stabilize myelin against degradation. Proper levels of methylation are also directly related to the body’s ability to both myelinate nerves and to prune nerves. A secondary effect of a lack of methylation and hence decreased myelination is inadequate pruning of nerves. Pruning helps to prevent excessive wiring of unused neural connections and reduces the synaptic density. Without adequate pruning the brain cell connections are misdirected and proliferate into dense, bunched thickets. All of these changes, when they occur in utero or in very young children, can alter brain development and can also set up metabolic changes that cause ongoing compromise of brain function. These metabolically-caused changes in brain function may, however, be mitigated if the underlying nutrigenomic weaknesses that are causing these changes are identified and supplemented nutritionally.

Methylation of cytosine is generally correlated with silencing of genes. One difference between bacterial and human genomes is that bacterial genes are not methylated at specific cytosine regions. Research has shown that when mammalian genes are not methylated at these regions it can trick the immune system into reacting against itself and causing autoimmunity. New cell synthesis is needed in order for certain types of immune cells to expand and respond properly to an immune assault. These same immune cells are also involved in controlling the overall immune response, keeping it in balance. If there are methylation cycle problems or mutations, you may have trouble making the bases that are needed for new DNA synthesis. Of you cannot make new DNA, then you cannot make these specialized immune cells and as a result you may lack immune system regulatory cells.

The immune system has the B cell “arm” that makes antibodies, known as humoral immunity and the T cell “arm” known as cellular immunity. If yo re having trouble making new T cells, then the immune response may become more heavily weighted in the direction of B cells. The B cells have the ability to respond by making antibody, or auto-antibody rather than making the range of T cells that regulate as well as fight infections. B cell clones expand and then are available for the future. So there is a somewhat greater need for new DNA synthesis for the T cell response than for the B cell response. Individuals with methylation cycle mutations are more at risk as they will have problems making regulatory T cells that help the body to control the B cells and prevent autoimmune antibodies. Auto-antibodies can occur as a result of imbalances in immune regulation. If you are not making adequate T cells (methylation pathway mutations) then you may lack regulatory T cells and can end up with auto-antibodies.

Methylation also plays a role in the ability of the immune system to recognize foreign bodies or antigens that it needs to respond to. Research has shown that methylation is decreased in humans with autoimmune conditions. Impaired methylation of T cells may be involved in the production of auto-antibodies. Studies form patients with systemic lupus erythrematosis (SLE) have shown that their T cells are undermethylated. As proper methylation function is resptored, it should help in regaining immune function regulation. In several cases I have seen the level of auto-antibodies decline after proper methylation cycle treatment.

Methylation of DNA is also used to regulate immune cells. Immune receptor DNA is initially in the “OFF” state and is maintained that way until the immune cells need to differentiate. At that time the methyl groups are removed from the DNA in a highly regulated fashion.

Studies show that decreased methylation of cytosine regions in these immune genes may influence the balance of immune inflammatory cells known as TH1 and TH2. The effect of methyl groups on the TH1/TH2 balance may be another mechanism by which decreased methylation may increase allergies. There are two sets of T helper cells in the immune system, TH1 and TH2 cells. While TH1 cells are involved in cell-mediated immune responses and toning down or regulating TH2 activity, the TH2 cells have been associated with humoral or B cell-mediated responses and allergic responses. TH2 cells trigger the activation and recruitment of IgE antibody-producing B cells, mast cells and eosinophils that are involved in allergic inflammation. In addition, when methylation is impaired it can lead to abnormally high levels of histamine. Optimal methylation function is needed to break down histamine so that it does not build up in the body, in addition to the effect of methylation on histamine levels.

The levels of various metabolites of the methylation pathway are important for protection from side-effects of anesthesia. As early as 1942 it was recognized that the addition of methionine is preventative for side-effects from the use of chloroform. Methionine affords protection from liver injury as a result of chloroform anesthesia. Methionine also protects against effects of nitrous oxide anesthesia. Nitrous oxide disrupts the activity of MTR, a central enzyme in the methylation cycle. Again, preloading with methionine appears to accelerate recovery and reduce side-effects associated with this form of anesthesia. The neurological deterioration and death of an infant boy has been reported who had been anesthetized twice within a short time with the anesthetic nitrous oxide. Postmortem studies determined that this child had a deficiency of the MTHFR which is a principle enzyme in the methylation cycle.

The relationship between environmental toxins and DNA methylation is extremely complex. Environmental toxins can impact the extent to which DNA is methylated. “A hypothesis that is gaining ground is that environmental factors achieve their effect by altering the epigenetic profile of the cell” conversely epigenetics may “thus explain why certain individuals are more susceptible to certain environmental toxins” (Traynor, Neuron). Furthermore, methylation is also required to clear environmental toxins from the body. This process involves conjugating methyl groups to the toxins prior to removal. Most of the methyl groups that are used for detoxification are donated by SAMe. Elimination of inorganic arsenic from the body requires methylation. After methylation arsenic can be eliminated from the body in the urine. Differences in methylation may also account for susceptibility of different tissues to cadmium toxicity. In animal studies, methylation was necessary to induce metallotionein activity that was required for cadmium excretion. The methylation process is also the major means of detoxifying excess selenium in the body. Nutritional support for the methylation pathway was able to prevent strychnine-induced seizures and death in animal models, as well as to be protective against carbon tetrachloride-induced toxicity. Supplementation was also able to prevent ethanol-induced decreases in methylation cycle function. Compounding the situation, environmental toxins are also able to have a negative impact on methylation. In experimental models, exposure of animals to environmental toxins during development appears to alter the pattern of DNA methylation. This change in DNA methylation is then maintained and carried forward to future generations of offspring. The heavy metals arsenic, nickel and chromium are able to cause overmethylation of DNA. This can result in turning “OFF” of important regulatory genes such as tumor suppressor genes. In addition, other environmental contaminants such as polycyclic aromatic hydrocarbons (PAH) and benzo(a)pyrene diol epoxide (PBDE) are able to bind to methylated cytosine regions of the DNA. Cadmium also inhibits the methylation of phospholipids, interfering with cellular membrane functions.

Undermethylation of the entire genome is referred to as global hypomethylation. Global hypomethylation when paired with overmethylation of highly select repeated regions of the gene is associated with both aging and cancer.

Intermediates of the methylation pathway are known to decrease with age along with a decline in methylation cycle function. DNA methylation is also known to decrease with aging. Age-related decreases in methylation can lead to decreased methylation of T cells which may in part explain changes in immune function with age. Age-related decreases in methylation can result in increased levels of homocysteine, increasing the risk of arthritis, cancer, depression and heart disease. This would suggest that increasing the body’s level of methylation through supplementation may extend a healthy life span. Both undermethylation of tumor-causing genes (no turn OFF) and overmethylation of tumor-suppressing genes (turned OFF) have been well characterized as contributing factors to cancer.

Methylation is used to inactivate excess levels of endogenous products that may be harmful to the body. For instance, excess estrogen is inactivated by methylation, with SAMe donating a methyl group for this process. The inability to inactivate excess estrogen has been linked to an increased susceptibility to hormone-sensitive cancers. Epidemiologic and mechanistic evidence suggests mutations in the methylation cycle are involved in colorectal neoplasia. Specifically, the role of certain MTHFR mutations, MTR and MTRR mutations have been implicated in colorectal cancer.

The overwhelming impact of methylation cycle mutations is exemplified by the article in Science News which reported that although identical twins have identical DNA, they often have differences in a number of traits including disease susceptibility. This study suggests that as twins go through life the environmental influences to which they are exposed affects which genes are actually turned on or off. Methyl groups can attach to the DNA in a similar way that charms attach to a charm bracelet. This modification of the DNA is what I have already described as epigenetic regulation. The combination of environmentally-determined addition of these “charms” to the bracelet of DNA, combined with inherited DNA changes or mutations lead to an individual’s susceptibility to disease. According to the scientist who headed this study, Dr. Manuel Estseller, “My belief is that people are 50 percent genetics and 50 percent environment”.

This statement should give us some understanding as to why mutations in the methylation cycle can be so devastating. Mutations in the methylation cycle affect the 50% that represents genetic susceptibility; this would be analogous to defects in the links of the chain of our charm bracelet. In addition, because methylation is also necessary for the epigenetic modification of the DNA, methylation also affect the environmental 50%.

If we take the analogy a step further to really understand the global impact of defects in this pathway we an view genetically inherited mutations in the methylation pathway as causing problems in the links of the bracelet and environmental effects creating a problem with the ability to put charms on the bracelet of DNA. Problems in the methylation cycle therefore can affect 100% of our susceptibility to disease. This is why it is critical for health reasons to understand where our weaknesses in this pathway reside and then supplement appropriately to bypass these mutations.

A second study that has also addressed the nature versus nurture question used animal models to look at this issue. Researchers were able to show that the adult response to stressful situations was heavily influenced by the interactions these same animals had as pups with their mothers at birth. Those pups with higher levels of care showed differences in the methylation patterns of stress-related genes when compared with pups in the lower care test group. Dr. Szyf from the team at McGill University that conducted the study has stated that their study results “…have bridged the gap, nurture is nature”.

This work does suggest that the bridge between “nature and nurture” is the ability of nurturing to influence DNA methylation. However, nurture alone cannot be the answer. According to this study nurturing can influence epigenetic modification of DNA, so nurturing can affect the number of “charms on the bracelet”. However, if there are genetic mutations in the DNA sequence itself, the actual “links of the bracelet”, this will also affect the overall methylation capacity in the body. Without the mechanisms to produce the methyl groups, all of the nurturing in the world will not be able to overcome the lack in the production capacity for methylation. In other words, if the body cannot produce the charms for the bracelet it becomes a moot point how easily you are able to attach them to the bracelet. Nutrigenomic support to bypass these mutations is one mechanism to address the weaknesses in the DNA that would result in reduced capacity in this pathway.

One point relevant to the autoimmune/infection thread is that if you attempt and anti-bacterial (or anti-fungal or anti-viral) protocol, even if you are initially successful, your chances for relapse are probably heightened considerably if you don't take care of your methylation needs due to the interplay between the methylation cycle and the immune system.

More generally, a really important point to understand is the part about the methylation cycle and the silencing of DNA. If you have mutations in any other part of your genome, it won't necessarily be a problem as long as you are able to methylate and your body is able to use methyl groups to tag mutations and "fix" them epigenetically (as discussed by Dr. Rostenberg on yesterday's Health & Wellness show). But if you have mutations that directly affect the methylation system itself, not only can it not repair itself, it also loses the ability to repair all other mutations throughout the rest of the genome. The methylation cycle is your body's mutation editor, and without it all mutations gain the ability to express themselves. One example of this would be retroviral sequences triggering cancer.

For more on why it is important to be able to silence these sequences, see some of the articles linked to Gaby's article The Ketogenic Diet: An Overview (particularly On viral 'junk' DNA, a DNA-enhancing Ketogenic diet, and cometary kicks and Heart attacks, CFS, herpes virus infection and the vagus nerve; see also New Light on the Black Death: The Viral and Cosmic Connection)

 

[H-KQGE]

Many thanks for posting this in its entirety Shijing. I thought that it was well written & clear. This thread started numbing my brain & I was beginning to get a little cross-eyed, (that'll be cuz of the effects of a crapped-out methylation cycle) this is the type of information I can print & give to a good doctor.

“My belief is that people are 50 percent genetics and 50 percent environment”.

An accurate number or not, it's still a pretty profound statement in relation to the information that's been amassed on the forum (including the C's vital clues)

A second study that has also addressed the nature versus nurture question used animal models to look at this issue. Researchers were able to show that the adult response to stressful situations was heavily influenced by the interactions these same animals had as pups with their mothers at birth. Those pups with higher levels of care showed differences in the methylation patterns of stress-related genes when compared with pups in the lower care test group. Dr. Szyf from the team at McGill University that conducted the study has stated that their study results “…have bridged the gap, nurture is nature”.

This work does suggest that the bridge between “nature and nurture” is the ability of nurturing to influence DNA methylation. However, nurture alone cannot be the answer. According to this study nurturing can influence epigenetic modification of DNA, so nurturing can affect the number of “charms on the bracelet”. However, if there are genetic mutations in the DNA sequence itself, the actual “links of the bracelet”, this will also affect the overall methylation capacity in the body. Without the mechanisms to produce the methyl groups, all of the nurturing in the world will not be able to overcome the lack in the production capacity for methylation. In other words, if the body cannot produce the charms for the bracelet it becomes a moot point how easily you are able to attach them to the bracelet. Nutrigenomic support to bypass these mutations is one mechanism to address the weaknesses in the DNA that would result in reduced capacity in this pathway.

Now I'm wondering what our distant progenitors were like..... practically superhuman I'd bet. Thanks to all the participants on this thread & the autoimmune thread. Good luck to everyone in their endeavours with these protocols.


Edit: added quotes.

 

[Yas]

Thank you all for putting all this information together.

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.

I was looking into Jarrow Formulas B-complex (B-Right) and thought of buying that one, but...

What I did was start with the Jarrow Formulas 5mg Methyl B12 over a period of a week along with the added cofactors, and worked up to 40mg a day by week 6.
I introduced the Source Naturals Dibencozide (2.5mg - 1/4 a tablet) by week 2 and worked upto 20mg by week 6. I then introduced 5mg of lithium orate (people with severe conditions will probably need to go in at a lower dose).
I introduced the methylfolate at week 3, starting at a low dose and working upto 200% rda by week 6. The literature suggests that methylfolate should be introduced after B12 and cofactors has been replenished.

So, would you say that it's better to start with plain B-12 with some cofactors and then introduce Dibencozide and methylfolate? I mean, instead of one complex that already brings all the other B vitamins and methylfolate in it.

It's interesting that you mentioned Lithium orate... My younger brother, who has been diagnosed with Asperger (part of the Autism spectrum) took it by presciption of our functional physician and, even though there are other factors that can be part of his healing, his behaviour changed completely after taking it. He had important aggressive behavior and rage outbursts, this is what has stopped almost completely after Lithium orate supplementation. He's also interacting a lot more with people around and even seeking interaction.

I think that my family might fit the profile of an MTHFR mutation, but I still need to read more about the subject. I mentioned my brother already, and I had also been told that I had ADHD several times, but no definite diagnosis... it improved a lot with the diet changes, but I'm still dealing with allergies and autoimmune disease. My mother has several autoimmune conditions and her diagnosis now is Borderline Personality disorder, yet, I think this is the consequence of mainstream psychiatry and the medications she's been taking (anti-depressant, lithium -the bad kind-, etc...) diet (vegetarian for a long time) and life issues. The story says she was particularly sensitive from a very young age so I think that maybe she could have had a mutation and the symptoms just got worse (and maybe irreversible) overtime without the proper treatment and with other treatments that worsened her brain/body balance.

 

[shijing]

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?

So, would you say that it's better to start with plain B-12 with some cofactors and then introduce Dibencozide and methylfolate? I mean, instead of one complex that already brings all the other B vitamins and methylfolate in it.

I think that's probably OK (you want to make sure the B-12 is methylcobalamin), although RedFox has been more meticulous than I've been in both researching the individual supplements as well as trying them individually, so he may have more specific advice. When I first became aware of the MTHFR issue (through being tested myself), my doctor started me on a single complex supplement, and I didn't do any additional experimentation until relatively recently -- I'm only now looking into things like Dibencozide (adenosylcobalamin) and lithium orate/orotate, which I probably would have tried in the beginning if I would have known a lot more than I did at that time.

 

[Carl]

Interesting study here. They used big doses of Methylfolate (much higher than we can generally achieve with supplements *Edit - There are actually 5mg Methylfolate supplements out there -) over 6 weeks and noticed a large improvement in ADD/ADHD symptoms among kids.

https://aap.confex.com/aap/2013/webprogram/Paper20581.html

Patients were selected randomly for open label treatment with a high-dose L-methylfolate chewable tablet (0.2 mg/kg/day in a single dose). “High-dose” is considered to be a dose greater than 800 mcg of folate - conventionally available without a prescription. 59 patients were enrolled in the study, aging 5 to 18 years. The study population included 47 males, 12 females with 27 patients on stimulant therapy and 31 patients not on stimulant therapy. The Vanderbilt Assessment Scale Total Symptom Score (TSS) was used in scoring of behavioral symptoms at the start of enrollment and again at six weeks. The starting average TSS score was 30. All patients were treated with L-methylfolate.

Results:
At the end of the six week study period, the average TSS score was 22 (a 27% reduction). 31 patients (53%) exhibited a TSS score reduction of greater than 25%. 16 patients (27%) had a greater than 50% reduction in TSS score. The patients already on stimulant therapy had an average TSS score of 23 at the end of the study, with 10 patients having an improvement of 49% in TSS score without having to adjust their stimulant dose. The patients on L-methylfolate alone had an average TSS score of 21 at end of study (34% improvement). 21 of the 32 patients on L-methylfolate alone demonstrated a 53% improvement in their VAS score.

 

[RedFox]

So, would you say that it's better to start with plain B-12 with some cofactors and then introduce Dibencozide and methylfolate? I mean, instead of one complex that already brings all the other B vitamins and methylfolate in it.

I think that's probably OK (you want to make sure the B-12 is methylcobalamin), although RedFox has been more meticulous than I've been in both researching the individual supplements as well as trying them individually, so he may have more specific advice. When I first became aware of the MTHFR issue (through being tested myself), my doctor started me on a single complex supplement, and I didn't do any additional experimentation until relatively recently -- I'm only now looking into things like Dibencozide (adenosylcobalamin) and lithium orate/orotate, which I probably would have tried in the beginning if I would have known a lot more than I did at that time.

Plain B-12 would need to be qualified. If you do have the mutation or a depletion of B-12, any standard B-12 supplement won't help. And from what I've read (and tried) will make things worse.
fwiw it seems that standard B-12 supplements (cyanocobalamin) are designed to stop anemia and deficiency symptoms. i.e. they keep you alive, but don't actually do there job. They'll give you a nice B-12 blood test reading and that's about it.
The body can just about use them if it's already in good health. If it's not, then all the chemical pathways gets blocked.

http://www.naturalnews.com/032766_cyanocobalamin_vitamin_B-12.html

Vitamin B-12 warning: Avoid cyanocobalamin, take only methylcobalamin

(NaturalNews) One of the pitfalls of pursuing a healthy diet is that we are sometimes blind to nutrients we may be missing. And in the world of healthy eating, one of the most common nutrient deficiencies involves vitamin B-12, a crucial nutrient for nerve health and the construction of red blood cells that carry oxygen throughout your body.

Vitamin B-12 deficiency is especially common among vegetarians and vegans, but it's also surprisingly common in meat eaters, too. Why? Because vitamin B-12 can only be absorbed in the small intestine, and due to common intestinal ailments, even many meat eaters who consume high levels of B-12 are unable to absorb it in their gut.

This leads to a series of seemingly "mystery" health symptoms that actually have a simple common cause: Vitamin B-12 deficiency!

Symptoms of B-12 deficiency

B-12 deficiency is shockingly widespread. Studies now show that up to 40% of the population may be deficient in vitamin B-12.

Here are some of the most common symptoms of deficiency (do you experience any of these?):

* Chest pain or shortness of breath
* Fatigue or unexplained weakness
* Dizziness, trouble with balance, and fainting
* Confusion, memory loss or dementia
* Coldness, numbness or tingling in the hands and feet
* Slow reflexes or diminished nervous system function
* Pale skin or yellowing of the skin
* Sore mouth and tongue

... in addition, vitamin B-12 deficiency can actually cause brain shrinkage, according to a University of Oxford study. Although more work needs to be done, research is already suggesting a link between vitamin B-12 deficiency and Alzheimer's.

If you (or someone you know) shows any of the symptoms listed above, I urge you to immediately investigate vitamin B-12 and determine if a deficiency in this nutrient may be causing your symptoms!

Again, vitamin B-12 deficiency is especially common in vegans and vegetarians because typical vitamin B-12 sources (meats, yogurt, etc.) are simply not present in their diets. But even meat eaters can be deficient in B-12 due to poor digestion. This is especially true for older people who suffer a diminished ability to absorb nutrients in their small intestine.

In addition, diabetes medications and even pain pills can interfere with B-12 absorption, and intestinal parasites can also strongly block its absorption in the gut.

Solutions for vitamin B-12

Traditionally, people who are deficient in vitamin B-12 have received injections of B-12. This is extremely effective because it bypasses the digestive tract and goes right into the bloodstream. But it has one obvious downside: It requires being injected! So most people aren't interested in this method.

Instead, most people supplement their vitamin B-12 using nutritional supplements. But here's where this can go wrong: The most commonly available form of vitamin B-12 on the market is the cheap synthetic form that's actually bound to a cyanide molecule (yes, cyanide, the poison). It's called cyanocobalamin, and you'll find it in all the cheap vitamins made by pharmaceutical companies and sold at grocery stores and big box stores.

Action item: If you have any vitamin B-12 supplements, check the ingredients label right now to see what form of vitamin B-12 they contain. If they contain cyanocobalamin, throw them out!

Cyanocobalamin is a cheap, synthetic chemical made in a laboratory. It's virtually impossible for you to find this form in nature. Low-end vitamin manufacturers use it because it can be bought in bulk and added to products with claims that they "contain vitamin B-12!" What they don't tell you is that the vitamin is bound to a toxic, poisonous cyanide molecule that must then be removed from your body by your liver. Cyanocobalamin is also up to 100 times cheaper than the higher quality methylcobalamin which we'll talk about below.

As Wikipedia explains: "A common synthetic form of the vitamin, cyanocobalamin, does not occur in nature, but is used in many pharmaceuticals and supplements, and as a food additive, because of its lower cost. In the body it is converted to the physiological forms, methylcobalamin and adenosylcobalamin, leaving behind the cyanide..." (http://en.wikipedia.org/wiki/Vitamin_B12)

Removing the cyanide molecule from the vitamin and then flushing it out of your body requires using up so-called "methyl groups" of molecules in your body that are needed to fight things like homocysteine (high levels cause heart disease). By taking low-quality cyanobalamin, you're actually stealing methyl groups from your body and making it do more work at the biochemical level. This uses up substances such as glutathione that are often in short supply anyway, potentially worsening your overall health situation rather than helping it. This is one of the reasons why low-grade vitamins may actually be worse for your body than taking nothing at all!

Cyanocobalamin, in summary, is a low-grade, low-quality and slightly toxic (cyanide) form of vitamin B-12 that's used by all the cheap vitamin manufacturers. I recommend avoiding it completely. It won't kill you to take it, of course, but there's a better solution for B-12.

The better choice: Methylcobalamin

The proper form of vitamin B-12 to supplement is called methylcobalamin. This is the form that exists in nature, and it is pre-methylated, meaning it's ready for your biochemistry to put to immediate use. Methylcobalamin has several key advantages over cyanocobalamin:

* Increased absorption
* Better retention in tissues
* Contains no toxic cyanide
* Supports production of SAMe

As explained by Ed Sharpe:

"The coenzyme form of vitamin B12 is known as methylcobalamin or methyl B12. It's the only form of vitamin B12 which can directly participate in homocysteine metabolism. In addition, converting homocysteine to methionine via methyl B12 generates an increased supply of SAMe (S-adenosyl methionine), the body's most important methyl donor."

Every informed nutritionist knows that methylcobalamin is far superior to cyanocobalamin. That's why companies like Ola Loa use only the high-end "methyl" form of B-12.

Why 99% of vitamin B-12 supplements are wasted

Taking vitamin B-12 as an oral dose is largely a waste of money. As much as 99% of what you swallow is not even absorbed... it's just passed through your body.

There are really only three methods for absorbing vitamin B-12 that reliably work:

#1) B-12 injections.
#2) Sublingual absorption.
#3) Skin absorption.

B-12 injections obviously require injections from a trained medical professional, so few people pursue this route. Sublingual absorption is a viable route, but nearly all the sublingual B-12 products use the cyanocobalamin form of the vitamin (with the cyanide molecule).

A vitamin B-12 skin patch is now available that delivers methylcobalamin through the skin, using a small medical-grade patch placed behind the ear. Each patch delivers 1000 mcg of methylcobalamin (1,666% DV) in a steady release over a 1-2 day period, after which the patch may be removed and discarded.

In addition to methylcobalamin, each path also delivers 400mcg of Folic Acid (another form of a B vitamin), which is widely known to work synergistically with methylcobalamin to help support healthy heart function and nervous system function*.

B-12 energy patch works through skin absorption

The B-12 Energy Patch is available now in packs of 8 patches (a 1-2 month supply) from the NaturalNews Store. This 8-pack carries a list price of $39.95, but through our volume purchasing, we are able to offer it to NaturalNews readers at 53% off the list price.

When purchased in a 3-pack (total of 24 patches), the price is lowered even more to 57% off the list price.

Click here to see the products in our store.

* These products are not intended to treat, diagnose, prevent or cure any disease.

What customers say about this B-12 patch

(From Amazon.com) For me a much better alternative to effective sublingual pills

"B12 is running low in my family tree. A couple of relatives have been regular at getting B12 shots. I never felt like I needed the shots, because I thought I could get by with red meat, liver and sublingual pills. I decided to try the patches just to see... I did not expect them to be more effective than sublingual pills.

I must say I was wrong. From the first patch I noticed the boost, which is at first more subtle than the more noticeable boost of the sublingual pills giving you more B12 in a shorter time span. But it picks up over time and feels way more efficient. By way of example, I used the big plate in my road bike and did not pant at the top of three bad climbs hours after getting the patch. To get this kind of effect with sublingual pills after getting low of B12 would take over ten days for me and quite a bit of dedication remembering to keep supplementing. It can get rather tedious waiting for the pills to dissolve under the tongue.

The second day I used two patches right behind the ear, but they both fell off, presumably from the sweat biking. Yet the day before the one patch I tried less close to the ear stayed put biking and after two showers, and I had no dropped patches since. If you exercise, watch out for areas where sweat would accumulate.

I think there is no comparison between this brand and the other one advertised. For four bucks more, you get half the patches and the wrong type of B12 -- cyanocobalamin instead of methylcobalamin. Read about it because cyanocobalamin has to be turned into methylcobalamin by the liver. You can spare that. My doctor put me on cyanocobalamin initially and I turned to methylcobalamin with much greater results. Also, this brand I review has the daily allowance of folic acid as an added bonus (read up on the benefits of taking folic acid with B12), rather than selenium.

I've had no side effects and no skin reactions with this product. I am so satisfied I have ordered a B-complex as a patch from a different company. It is advised to have a B-complex if you supplement in big doses with any vitamin of the B family."

Click here to get these vitamin B-12 patches.

They're on sale now at an incredible price through the NaturalNews Store.

Whatever form of vitamin B-12 you use, remember this: avoid cyanocobalamin! (Unless you enjoy eating cyanide, that is...)

I've read a lot on what others have done and tried from the phoenix rising forum and other places, and the sub-lingual B-12 seems best. The specific brands highlighted seem even better (so at least try the Jarrows sub-lingual Methyl B-12, or another brand).
I break them up and place them on my gums rather than under my tongue so they last longer (greater chance of absorption).

Also be careful that anything you take doesn't have folic acid in. You should only have methyl-folate, and you should start slow/low dose. NAC can be problematic to start with.
Niacin can be thought of as a brake pedal for methylation - so if you take too much methylfolate and speed up the system too much (and potentially trigger a large detox) you can use that to slow things down. As you are trying to get things moving, niacin should only be taken occasionally.

Interesting study here. They used big doses of Methylfolate (much higher than we can generally achieve with supplements *Edit - There are actually 5mg Methylfolate supplements out there -) over 6 weeks and noticed a large improvement in ADD/ADHD symptoms among kids.

Interesting.
http://www.mthfrsupport.com.au/condition/addadhd/

Research

Gokcen et al (2011) examined the relationship between (MTHFR) polymorphisms and Attention Deficit Hyperactivity Disorder (ADHD) in a sample of Turkish children. Of the two main mutations studied, the A1298C allele was found to be linked with with diagnosed with ADD/ADHD. This small study therefore suggests a link between MTHFR and ADHD.

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 (unless your willing to use raw liver trans-dermaly/sub-lingually - which I don't think it a good idea).

A a quick update, I'd reduced my supplements down to virtually nothing again just to see where things stood. Turns out I needed zinc, b-6 and carnatine (I'm getting really quite good at being able to read what my body needs).
Apparently zinc is needed for B-12 absorption too.
I had something rather interesting happen that I hadn't had on the protocol before - methyl-overdrive.
It was like having rocket fuel. The only down side is my brain got 'overheated' including an overproduction of some neurotransmitters (ending up with mild paranoia and rapid thoughts). NAC and niacin calmed that down within a few minutes.

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.
I was supporting digestion too (needing zinc means I wasn't digesting things properly), and can't add digestive support anymore (I get gas and bloating) as my body seems to have taken over.

I don't need the zinc/b-6 any more (only needed a low dose over a week or so), but probably should be eating more liver (b-12, b-6)/heart (carnitine).
It's interesting to watch things balance out to the point where I need very little/no supplements to hold a good level of energy. I can also fast now without fat levels dropping rapidly.

 

[RedFox]

Just to add a few more observations, re:food.
Steak seems to be rather important - specifically rare/medium cooked steak.

Rare/medium cooked steak gives me a huge energy boost, compared to fully cooked steak.
Fully cooked steak doesn't provide much in the way of a boost, and actually feels more like a challenge energy wise. Poor quality meat is not good either.
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.

I use to have problems eating green things and rare steak, so this is quite an interesting difference.
So I could be wrong about not being able to balance these things naturally, it may just need good digestion and lots of rare steak/green leaf salads.
I got the idea to try those after reading about the prevalence of the MTHFR mutation in the mediterranean population.

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.

 

[Yas]

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 ;)

So, would you say that it's better to start with plain B-12 with some cofactors and then introduce Dibencozide and methylfolate? I mean, instead of one complex that already brings all the other B vitamins and methylfolate in it.

I think that's probably OK (you want to make sure the B-12 is methylcobalamin), although RedFox has been more meticulous than I've been in both researching the individual supplements as well as trying them individually, so he may have more specific advice. When I first became aware of the MTHFR issue (through being tested myself), my doctor started me on a single complex supplement, and I didn't do any additional experimentation until relatively recently -- I'm only now looking into things like Dibencozide (adenosylcobalamin) and lithium orate/orotate, which I probably would have tried in the beginning if I would have known a lot more than I did at that time.

Plain B-12 would need to be qualified. If you do have the mutation or a depletion of B-12, any standard B-12 supplement won't help. And from what I've read (and tried) will make things worse.
fwiw it seems that standard B-12 supplements (cyanocobalamin) are designed to stop anemia and deficiency symptoms. i.e. they keep you alive, but don't actually do there job. They'll give you a nice B-12 blood test reading and that's about it.
The body can just about use them if it's already in good health. If it's not, then all the chemical pathways gets blocked.

Thanks for the info and the update RedFox. I was aware that if I take B-12, it has to be methylcobalamin and if it has folate, it has to be methyl-folate. I actually took a standard B-complex recently and I felt REALLY bad afterwards. The only one I've found so far is Jarrow formulas, so I guess I'll try that one. But I'm going to do some testing before... I just want to gather all the info I can so I can discuss it with my doctor.

I'm also considering Water Kefir as a probiotic to heal my gut too.

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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.