MTHFR mutations

[H-KQGE]

Re: Re: Endothelial dysfunction

The last one is pretty complex (to me at least) & he kind of whizzes through the presentation. It's a bit daunting to wrap my head around the small parts that I think I understand, the larger parts... well, like LQB said "Looks like there is a bazillion methylation support protocols out there."

Yes, for example, Yasko's methylation protocol for autistic children is as complex as anything I've ever seen [her Step 3 is remyelination of the nerves - parts of which we could all probably use - http://www.dramyyasko.com/resources/autism-pathways-to-recovery/chapter-8/]

Here is a source for L-methylfolate mixed with B12/B6: http://hsfighters.bioactivhealth.com/ingredients.htm.

I'll say! It's going to take a while to grok that information, a fair amount of crossovers on that myelination/remyelination list. I agree that we could all use several parts of that process, with A LOT of people likely to do well (if they haven't "fallen off of a cliff", so to speak) even though the focus is on autistic children. What bugs me when it comes to personal healthcare responsibility is the lack of it by people who are capable, & should know better, especially if they have the internet at their disposal. Worse, are those with obvious serious psychological/emotional/physical signs & refuse to act. Reminds me of the age-old male stereotype where men will just wait for problems to pass ("nah, it'll fix itself, no worries") which is fear in some cases, but basic wishful thinking.

She seems good ( based on what I gleaned from on yesterday's quick look) & I'm always more encouraged when these doctors are parents & of course, those certain credentials that complement each other ( alternative medical holistic care ) helps the more recognized one's.

PATHWAYS TO RECOVERY:

Today we stand at the dawn of the age of personalized medicine. Although it's been predicted that it may take several decades before these new understanding can be applied, why wait? There is urgent need today. We have the technology and knowledge-now. We are able to look at crucial nutritional pathways and examine their underlying genetics-now. We can customize programs to meet individual unique needs and make a difference-now. That's what the Yasko Protocol is all about.
From Pathways to Recovery by
Dr. Amy Yasko

I like this

Dr. Amy:
Information You Need Now

When my focus shifted from academic research and biotechnology to integrative healthcare, I changed the way I shared information—from scientific articles in peer reviewed journals—to books, internet, conferences, videos, and articles.

These quickly deliver the latest discoveries from clinical practice to those who need them most. As autism reaches epidemic proportions, this is critical because knowledge is power.

I share the core science to empower you, so that you can understand for yourself why this approach is valid. This information also helps you follow the program.

And

Additional Therapies
In this phase of the program, it also makes sense to integrate other therapies that enhance nerve growth and maturation, for example, magnetic therapy. While I haven’t found that it enhances metal excretion, I have seen a significant effect on subtle cognitive function. Recent work by Dr. Dean Bonlie confirms that electromagnetic therapy is safe and effective for a wide range of neurological problems, including regenerating and repairing damaged nerves and enhancing the body’s natural stem cells. Magnetic energy may also increase the oxygencarrying capacity of the blood, improving the assimilation of nutrients and oxygenation of tissues. The use of Nariwa magnetized water and Penta oxygenated water may also be useful adjuncts to any program to enhance nerve growth and demyelination.

The March 2004 issue of the Journal of Neuroscience describes environmental influences on the levels of BDNF (brain derived neurotrophic factor), which promotes neuronal growth and survival and regulates communication between neurons. An enriched environment (in which there is helpful communication, visual, auditory, and other stimuli) fostered significantly higher levels of this factor. Dr. Cheri Florence, a medical speech/language pathologist, has described tremendous personal success with her own son. She has made use of strategies that may help to create an enriched environment, such as enhancing visual thinking to help promote language.

Dr. David Steenblock, Dr. Barbara Brewitt, and Dr. Luis Aguilar have pioneered the direct use of certain brain growth factors for stroke as well as autism. Insulin like growth factor (IGF) has been found to stimulate enzymes in the methylation pathway in addition to its effects on neural development. Fibroblast growth factor (FgF) has also been found to have activities beyond its effects on nerve growth. FgF has been reported to increase dopamine levels, as well as to decrease seizure activity.

Dr. Edward Traub has developed CI (constraint induced) Movement therapy, which has proven to expedite recovery times after stroke. The basis of the therapy is helping the brain to overcome “learned non-use”. Some of these therapies may be applicable to autism in the future to help to accelerate recovery after the biochemical imbalances have been addressed.

Music therapy has been reported to be successful in helping to enhance speech in children. A number of scientific journals have found that music affects regions of the brain involved in cognitive, affective, and mnemonic processing. The entire July 2003 issue of Nature Neuroscience was devoted to music and neuroscience, as was the March 2004 issue of the New York Academy of Sciences magazine. Recent research from the University of London suggests that many children with autism have outstanding abilities in tone memory and discrimination. Music therapy may be an avenue worth exploring to help enhance language skills during this point of the program.

In Conclusion
Obviously, understanding and implementing this program will not happen overnight. It’s a slow process. As you immerse yourself in all of the science and begin the initial steps, know that you will be supported, helped, and guided by other veteran members of the support community on my website chat room. This will make the learning process smoother and easier.

This program is more than a laundry list of supplements for you to take. It’s a process that you must take the time to read, then reread, understand, and embrace in order to really obtain the benefit. Knowledge empowers. The information contained in this book better positions you to use all of what I have offered as tools for health. […] One principle of the site and of this work is to “pay it forward.” That way, each of us can ask for help when we need it and offer help when we are able to provide it. On that note, I would like to invite you to finish this book by reading a few of the many touching and powerful stories that parents and others have submitted. Please take the time to receive these shared words and thoughts on the pathway to recovery, and may they support you and your family on the journey to health.

With love and hope for recovery,
Dr. Amy

Thanks for the link on L-methylfolate with B12/B6. This folic acid versus folate businesses is bad, & I hope it doesn't get worse what with the information in the article posted by Gaby. I think I saw that on SOTT a little while ago too.

 

[shijing]

Anyway, perhaps not new to you or any others currently looking into this but I thought it worthwhile to still post a video or two on MTHFR & the four-pronged (interrupted) methylation cycle. Both are from Benjamin Lynch (MTHFR.net link you provided) & go with the other videos provided by the others on this thread. First: https://m.youtube.com/watch?v=Mwn7RjSx3zM - Folate Metabolism and MTHFR: An Introduction - secondly:
https://m.youtube.com/watch?v=-lCQp0KkSB4 -Folate and Methylation Defects and Metabolism in 2013: Clinical Breakthroughs and Updates

H-kqge, I just wanted to say thanks for the links to these two videos -- I finally had a chance to take notes on them yesterday (yes, they are very complicated!) and I think that they've got a lot of useful information; I've also started following Benjamin Lynch on Facebook. I'm embedding the videos below so they're more accessible:

http://<iframe width="560" height="...zM" frameborder="0" allowfullscreen></iframe>

http://<iframe width="560" height="...B4" frameborder="0" allowfullscreen></iframe>

 

[H-KQGE]

No problem, Shijing. You got the ball rolling & I just followed your lead. Thanks for embedding the videos, I'm unable to do that or else I would - I find video embeds more accessible myself. Here's some recent methylation news, how useful it is, I'm not sure.

http://m.hopkinsmedicine.org/news/media/releases/new_tool_pinpoints_genetic_sources_of_disease

New Tool Pinpoints Genetic Sources Of Disease

“Overlay” of genetic and epigenetic maps described

Release Date: March 20, 2014

Many diseases have their origins in either the genome or in reversible chemical changes to DNA known as the epigenome. Now, results of a new study from Johns Hopkins scientists show a connection between these two “maps.” The findings, reported March 20 on the website of the American Journal of Human Genetics, could help disease trackers find patterns in those overlays that could offer clues to the causes of and possible treatments for complex genetic conditions, including many cancers and metabolic disorders.

“By showing the connections between genetic variants and epigenetic information, we're providing epidemiologists with a road map,” says Andrew Feinberg, M.D., M.P.H., a Gilman Scholar, the King Fahd Professor of Medicine and the director of the Center for Epigenetics in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine. “Epigenetic tags show how disease-causing genetic variants might affect distant genes that in turn contribute to the disease.”

Feinberg says it has long been known that individual genetic variants in sections of DNA that don’t contain blueprints for proteins (once thought of as “junk DNA”) seem to alter the quantity of proteins produced far afield. That phenomenon has made it very hard for researchers to pinpoint the source of some genetic diseases or targets for their treatment. This study, Feinberg says, shows that these genetic variants may be acting on distant protein-forming genes by influencing epigenetic tags, or chemical add-ons, atop the DNA.

Feinberg; co-leader Dani Fallin, Ph.D., professor and chair of the Department of Mental Health at the Bloomberg School of Public Health and director of the Wendy Klag Center for Autism and Developmental Disabilities; and their team analyzed genetic data from hundreds of healthy participants in three studies to first figure out what a normal epigenetic pattern looks like. Although it’s now common to compare the genomes of healthy and sick populations to identify predispositions for diseases, it has not been possible to compare epigenomes this way. The researchers zoomed in on one type of epigenetic change, the attachment of a chemical tag called a methyl group to a particular site on DNA. Known as methylation, these tags affect whether genes produce any protein, and if so, how much.

The team then looked for the relationship between the resulting epigenetic data and genetic data. Human genetic code is marked by telltale blocks of DNA that children tend to inherit from their parents in unbroken chunks called haplotypes. One of these blocks is often fingered as a suspect when a genetic disease arises. However, since the blocks are comprised of hundreds of thousands of “letters” of DNA code, researchers are not often able to identify the culprit mutation, or the protein-forming genes it affects, which may lie somewhere else in the block.

Epigenetic signatures like methylation patterns also occur in blocks, which the team dubbed “GeMes,” for methylation blocks controlled by genes. The researchers found that the GeMes overlapped with the long genetic blocks but were much shorter.

That led them to suspect that the protein-coding genes turned on or off by those tags must be at the root of the disease associated with a particular genetic variant found elsewhere in the block.

“Previously, people could not pinpoint the variants within a long stretch of DNA that were responsible for the disease,” says Yun Liu, Ph.D., a postdoctoral fellow in Feinberg’s laboratory. “But now, by detecting just one variation in DNA methylation, or one GeMe, a researcher will know that one or more of the few hundred methylated nucleotides are possibly causing the disease.”

“These corresponding genetic and epigenetic maps provide new insights about the architecture of the genome and its regulatory epigenetic marks. This can inform the integration of multiple types of data in future large-scale epidemiologic studies,” says Fallin.

Feinberg says he hopes that researchers will see these findings as a reason to add epigenetic analyses to ongoing genetic analyses of disease. His group’s next step, he says, will be to look for GeMes associated with specific diseases, such as Crohn’s and cirrhosis, in which researchers have struggled to isolate the problematic part of the genetic code. “Researchers — ourselves included — can use this information to see if the implicated gene is turned on or off in patients compared to healthy people,” Feinberg says.

Sounds more like a potential than anything. There's links in the article to their other studies relating to this, such as metabolic disorders - BMI (Body Mass Index) & obesity. They "used a customized, genome-wide profiling method dubbed CHARM (comprehensive high-throughput arrays for relative methylation) to look for regions that were the most variable, all chemically marked by DNA methylation." I actually got more from that linked article than this one, which might just be my currently limited understanding.

Something else that may be worth a look is "Genes And Their Regulatory 'Tags' Conspire To Promote Rheumatoid Arthritis" which is another related article, this is at the bottom page of the quoted article above. There, the same guy (Andrew Feinberg) reports:

"several DNA mutations are known to confer risk for RA, but there seem to be additional factors that suppress or enhance that risk. One probable factor involves chemical “tags” that attach to DNA sequences, part of a so-called epigenetic system that helps regulate when and how DNA sequences are “read,” how they’re used to create proteins and how they affect the onset or progress of disease.

To complicate matters, Feinberg notes, the attachment of the tags to particular DNA sequences can itself be regulated by genes. “The details of what causes a particular sequence to be tagged are unclear, but it seems that some tagging events depend on certain DNA sequences. In other words, those tagging events are under genetic control,” he says. Other tagging events, however, seem to depend on cellular processes and environmental changes, some of which could be the result, rather than the cause, of disease."

I'll be going through these again soon. They may or may not help (me) in penetrating the complex layers of the Benjamin Lynch MTHFR videos. FWIW.

 

[shijing]

Thanks H-kqge for the link above -- as it turns out, I just received Amy Yasko's Feel Good Nutrigenomics yesterday:

http://www.holisticheal.com/feel-good-nutrigenomics-your-roadmap-to-health-book.html

She talks about this very thing -- the methylation roadmap and its relationship to epigenetics. This particular book is written specifically for the layperson and is pretty easy to digest -- I'm about halfway through it and will watch the Benjamin Lynch videos again after I've finished, because I think they'll be easier to understand with this foundation in place. I highly recommend the book -- it's not too expensive, and it came within two days of my ordering it.

One useful excerpt, where she lays out the four parts of the methylation pathway she discusses and their associated risks (p. 37):

Increased Homocysteine

• Renal Failure
• Stroke
• Heart Attack
• Diabetes
• Alzheimer's Disease
• Neural defects

Decreased Methylation

• Cancer
• Aging
• Cardiovascular disease
• Neurological issues
• Retroviral transmission
• Neural defects
• Down's syndrome

Decreased BH4

• Diabetes
• Atypical phenylketonuria (PKU)
• Decreased dopamine levels
• Decreased serotonin levels
• Hypertension
• Atherosclerosis
• Decreased NOS
• Endothelial dysfunction

Elevated Ammonia

• Flapping tremors of extended arms
• Disorientation, brain fog
• Hyperactive reflexes
• Activation of NMDA receptors leading to glutamate excitotoxicity
• Tremor of the hands
• Paranoia, panic attacks
• Memory loss
• Hyperventilation (often associated with decreased CO2)
• CNS toxicity
• Alzheimer's disease

 

[SMM]

Thanks H-kqge, LBQ and Shijing for the above videos from Benjamin Lynch, Amy Yasko's protocol, list of books dealing with this topic and all you have posted

Thanks H-kqge for the link above -- as it turns out, I just received Amy Yasko's Feel Good Nutrigenomics yesterday:

http://www.holisticheal.com/feel-good-nutrigenomics-your-roadmap-to-health-book.html

She talks about this very thing -- the methylation roadmap and its relationship to epigenetics. This particular book is written specifically for the layperson and is pretty easy to digest -- I'm about halfway through it and will watch the Benjamin Lynch videos again after I've finished, because I think they'll be easier to understand with this foundation in place. I highly recommend the book -- it's not too expensive, and it came within two days of my ordering it.

One useful excerpt, where she lays out the four parts of the methylation pathway she discusses and their associated risks (p. 37):

Increased Homocysteine

• Renal Failure
• Stroke
• Heart Attack
• Diabetes
• Alzheimer's Disease
• Neural defects

Decreased Methylation

• Cancer
• Aging
• Cardiovascular disease
• Neurological issues
• Retroviral transmission
• Neural defects
• Down's syndrome

Decreased BH4

• Diabetes
• Atypical phenylketonuria (PKU)
• Decreased dopamine levels
• Decreased serotonin levels
• Hypertension
• Atherosclerosis
• Decreased NOS
• Endothelial dysfunction

Elevated Ammonia

• Flapping tremors of extended arms
• Disorientation, brain fog
• Hyperactive reflexes
• Activation of NMDA receptors leading to glutamate excitotoxicity
• Tremor of the hands
• Paranoia, panic attacks
• Memory loss
• Hyperventilation (often associated with decreased CO2)
• CNS toxicity
• Alzheimer's disease

There are scores of pages to pour through on methylation pathways and epigenetics . The research currently being done is just the tip of the iceberg. OSIT.

I wanted to start a thread about this months ago but wasn't sure how to approach it so you can imagine my relief and joy ;) I am aware this thread deals with MTHFR mutations but there are other defects and mutations in the methylation pathway that easily interconnect. This I point out in relation to the previous thread we had split from, Endothelial Dysfunction, and how too it is affected by methylation.

Two things that have always stuck with me regarding methylation is that it aids a) cell division and b) turning genes on and off.

The diagrams above show fluid methylation maps, the latter tailored specifically for consequences of mutations of which Yasko defines the associated risks. It is interesting how the cycles interact. It isn't very explicit in demarcating what cycles occur where, which is why the next diagram is useful:

For increased ammonia and homocysteine levels here is some good information on: CBS, NOS, ACE, BHMT, COMT, SMHT, GAMT and the excitotoxicity pathway (abnormalities e.g. (+/+) for homozygous, (+/-) heterozygous), a few other processes that can be faulty and impact serum levels. The following website explains in detail different manifestations and mechanisms involving methylation pathway defects, of which plenty has already been covered on this thread, and you can go there to read more about what is understood to occur step-by-step:

Methyl Cycle Nutrigenomics: http://www.heartfixer.com/AMRI-Nutrigenomics.htm

The entire page is worth reading, albeit I'll just post concerning the aforementioned. My comments are in blue, key points in red. All the information is available on the above link, HeartFixer.com, unless stated otherwise.

[size=12pt]CBS: Cystathionine Beta Synthase [size=12pt]{5. Transulfuration Pathway}

CBS initiates the trans-sulfuration pathway, converting homocysteine in to cystathionine and its downstream metabolites. This is the most important Methyl Cycle defect and is present in 90% of the patients who we have tested. The CBS defect is an up regulation. CBS is operating at up to ten times its normal rate. Homocysteine and all of the upstream methyl cycle precursors will be “pulled down the CBS drain” to produce toxic levels of cystathionine metabolites. The C699T and (to a somewhat lesser extent) A360A defects are associated with CBS up regulation. Homozygotes (+/+) will be more severely affected than will be individuals heterozygous (+/-) for a CBS abnormality. We treat CBS ( +) individuals with dietary animal protein and sulfate restriction and supplements designed to neutralize ammonia and speed up clearance of sulfite/sulfate. Laboratory findings consist of an elevated urine sulfate level, a low or low normal blood homocysteine level, an elevated or high normal blood ammonia level, and positive findings of ammonia, sulfite, or sulfite upon Asyra testing. My initial observation is that individuals with high heavy metal burdens upon provocative challenge testing are likely to be CBS positive. CBS (+) individuals will be intolerant to sulfur containing drugs, nutritionals, and foodstuffs (I am +/- for CBS A360A and cannot tolerate DMPS or glucosamine sulfate. A cold beer tastes great but I do not like wine, which is high in sulfite).

Biochemistry – The 10-fold up regulation in CBS generates sulfur breakdown products (sulfite and sulfate, which stimulate the stress/cortisol “fight or flight” response), excess ammonia (in the process wasting BH4 {biopterin/neopterin} which is used up detoxifying ammonia), hydrogen sulfide (producing “brain fog”), and alpha-keto glutarate (leading to “excitotoxicity”). The G6PDH enzyme system may be affected, leading to abnormalities in sugar control. Methylation intermediates will “fall through this drain”, so the entire system suffers; our defenses against viral invasion and toxicity suffer. Co-Q10 and Carnitine generation will fall off due to impaired methylation, and ATP levels fall, robbing you of energy.

Ammonia is produced during the metabolism of dietary protein. The CBS up regulation drains methyl cycle intermediates in to ammonia, more ammonia than your system can handle. Ammonia detoxification is metabolically expense, using up two molecules of BH4 per molecule of ammonia. BH4 is necessary to generate neurotransmitters (dopamine, serotonin, and norepinephrine) and nitric oxide, our key vasoprotective molecule. Thus it is easy to see how a CBS up regulation, by generating ammonia and depleting BH4, can set you up for neurological, psychological, and cardiovascular disease states. We cannot change your DNA. We cannot stop CBS from generating excess ammonia, but if we restrict animal protein in your diet, we can decrease your ammonia burden, preserving BH4, such that you can start making neurotransmitters and nitric oxide again {goes a long way in partly explaining why the Ketogenic Diet is so effective, I recommend reading the thread}– in other words, we can compensate for your genetic challenge. The herb Yucca, Dr. Yasko’s Ammonia support RNA product, and supplementation with charcoal and carnitine will bind up or neutralize ammonia, and add to your dietary efforts.

Sulfite is neurotoxic. Sulfite will be over produced by the CBS up regulation, and then requires conversion in to the less toxic sulfate molecule by the enzyme Sulfite Oxidase (SUOX). SUOX can easily be overwhelmed. Molybdenum is required for SUOX function, and is typically depleted in CBS (+/+) or (+/-) individuals. Molybdenum supplementation (3 drops or 75 mcg of e-lyte Molybdenum twice a day), Boron 3 mg/day, Vitamin E succinate 400 IU/day, and hydroxy-B12 2000 mcg/day are also utilized to speed up SUOX activity.

While sulfate is less toxic than is sulfite, it will stimulate the adrenergic (fight or flight) limb of the autonomic nervous system and stimulate a cortisol stress response, revving you up into an unrelenting biochemical overdrive {how does The Polyvagal Theory parallel with this? In other words, is the vagus nerve impacted by sulfates/sulfites and how?}. If you have a CBS defect, we need to restrict your sulfur intake, at least until your urine sulfate (and your body sulfate burden) has decreased. The amino acids methionine, taurine, and cysteine all contain sulfur; they are concentrated in animal protein (thus the restriction on animal protein intake). Many nutritional supplements (MSM, N-acetyl cysteine, glutathione) that are good for most people are a problem for you {this is an ambiguous statement IMO. Clearing up a problem in another methyl cycle intermediate could ameliorate this or vice versa}. While certain aspects of your health will benefit from these agents, they will add to your sulfate/sulfite overload problem, adversely affecting the Methyl Cycle Defect that is the common denominator to all of your health problems {it behoves to test sulfate levels}. Many drugs are loaded with sulfur (sulfates, sulfites, metabolically active sulfur), so if you are CBS positive and I treat your hypertension with the diuretic hydrochlorothiazide, your diabetes with the sulfonylurea drug glipizide, and your urinary tract infection with a sulfa containing antibiotic, I will be lowering your blood pressure, lowering your blood sugar, and clearing bacteria from your bladder, but I will also be adding to your sulfate burden, compromising your biochemistry, and contributing to an ongoing decline in your health. I will be treating the manifestations of an underlying problem and at the same time adding to the underlying problem. If I treat your Mercury overload with DMSA or DMPS, I will remove a toxin from your body, but if you are CBS (+), I will be adding to your sulfate/sulfite pool, and sulfate/sulfite overload due to the CBS up regulation is likely playing a key role in your sensitivity to heavy metals and/or your inability to clear them. We can avoid this. We can hold sulfur containing agents until your sulfate burden has come under control. Learn all you can about the sulfur content of foodstuffs, supplements, and prescription drugs. Sulfites and Chronic Disease by Rick Williams (available at the office or at www.readingtarget.com/nosulfites) is an invaluable resource. Do not expect us to know the sulfur content of foodstuffs. Some tips on low sulfur eating are included at the end of this document, but do not expect us to tell you what to eat. We can’t do this. We do not have this knowledge. Please attend our monthly Methyl Cycle support groups meetings, and you may sign up for individual (or group) dietary change counseling. It is your responsibility to become expert in this area. I will work with you to phase out high-sulfur drugs and nutritionals from your program, but don’t expect me to get in right every time – please study your food, drug, and supplement labels.

Excitotoxicity – The CBS up regulation leads to excess production of alpha-ketoglutarate, which is converted in to glutamate, a stimulatory neurotransmitter. Under normal circumstances, glutamate will be converted in to GABA, a calming neurotransmitter, but the enzyme systems that convert glutamate in to GABA are compromised by lead and mercury, the clearance of which seems to be compromised in individuals with methyl cycle defects (here is a situation where dysfunction of a genetically abnormal enzyme leads to acquired dysfunction of a genetically normal enzyme system). The result is “excitotoxicity”, stimulatory behavior in autistic kids (“stims”) and anxiety and sleeplessness in adults. We approach this problem by limiting alpha-ketoglutarate and glutamate rich foods from your diet (more on Excitotoxicity to follow; diet tips in appendix) and by supplementing you with GABA, aiming to restore GABA:Glutamate balance. GABA is initiated at 500 mg once or twice a day, advancing the dose as you see fit by your response.

Abnormalities in BHMT (Betaine-Homocysteine Methyltransferase) aggravate and frequently co-exist with CBS defects. BHMT mediates the “backdoor” pathway of homocysteine metabolism, drawing homocysteine away from the trans-sulfuration pathway that is up regulated in CBS (+) individuals. A defect in BHMT, will thus mimic or add to a CBS defect. BHMT can be stimulated with Phosphatidylserine, Phosphatidylcholine (which is combined with the metal chelator EDTA in Lipophos EDTA), and the methyl donor TMG (Trimethylglycine), and one or more of these agents will be included in our treatment program for CBS (+) and/or BHMT (+) individuals.

In a sense, the key ultimate consequence of CBS/BHMT abnormalities will be BH4 deficiency. By neutralizing the consequence of your CBS up regulation and/or BHMT down regulations, your BH4 status should begin to return towards normal. We also can supplement you with BH4. It is strongly recommended that BH4 supplementation be held until all other Methyl Cycle pathways have been optimized {otherwise BH4 from supplementation is spent detoxifying, regulating and/or metabolising defective pathways - 1. Urea Cycle and 3. Folate Cycle intermediates (Arginine and NOS, DHPR enzyme toxicity respectively) offers clues on outcome of BH4 deficiency and depletion. The end result being oxidative-inflammatory disease, autoimmune diseases, etc.}. Pharmacological doses (200 mg/day) of BH4 has been shown to be safe and effective when used to treat endothelial dysfunction in hyperlipidemic individuals, and in dealing with Methyl Cycle defects, far lower nutritional doses (2.5 mg four times a day) are typically employed, but here a little bit of BH4 can go a long way, and we need to be prepared. If long-closed detox pathways are suddenly opened up, you could experience a detox reaction, so we need to get the rest of your systems up and running before we open these closed gates. If neurotransmitter generation suddenly comes back on line, and you are taking an anti-depressant drug or nutritional that preserves neurotransmitter levels, you could experience a neurotransmitter surge if we have not cut back on the drug dose. If we give you BH4 before you are ready, you will feel great for a day or two, and then “crash”, with fatigue and malaise, as we attempt to spin other metabolic wheels forward that are still stuck in the “off position”. Thus we need to be patient, take things step by step, with the long goal in mind.

Energy Production will falter. To generate ATP energy, you need Co-enzyme Q10 and Carnitine, but to manufacture these co-factors you need methyl groups, which tend to be in short supply in individuals with Methyl Cycle defects. To make matters worse, when energy is in short supply, homocysteine is shunted in to ammonia, hydrogen sulfide, and alpha-ketoglutarate, and not in to its one beneficial metabolic product, glutathione. NADH, Carnitine, Co-enzyme Q10, and its non-oxidizeable 1st cousin Idebenone will all help with ATP energy production, and their use makes sense in patients with CBS up regulations, especially if they have cardiovascular disease. (I am getting ahead of myself, so skip this entry if you wish, but the latter three agents also can serve as methyl donors. We will be more liberal with their use in individuals who are COMT (-/-), who need methyl donors, and more conservative in their dose in individuals who are COMT (+/+), who will be more sensitive to methyl group supplementation). Ribose increases ATP regeneration in individuals with cardiovascular disease or other conditions associated with energy deficiency, and can be taken as well.

SUOX (Sulfite Oxidase) converts sulfite in to sulfate. I am (+/-) for SUOX and (+/-) for CBS, meaning that I am overproducing sulfite and having trouble converting sulfite in to less toxic sulfate. I will thus need to be particularly vigilant with respect to supporting SUOX function. Molybdenum, in short supply in CBS + individuals, is also used up by the enzyme xanthine oxidase, a free radical generating enzyme system that plays a role in gout (it produces uric acid which precipitates in your joints to cause the pain and inflammation of gout). Xanthine oxidase is present in pasteurized milk, which is best avoided or minimized in CBS (+) individuals. A note regarding nomenclature; a defect in a Methyl Cycle enzyme is typically described with a (+). I am homozygous (+/+) for MTHFR C677T so 100% of my MTHFR enzymes are defective. For reasons that make no sense to me, someone decided that the normal designation for the SUOX gene should be (+/+); thus if you are (-/-) for SUOX you are homozygous abnormal. This is the only gene where (-/-) is abnormal and (+/+) is normal. In my shorthand, I will refer to any defect in any Methyl Cycle gene as a (+). If I refer to an individual as CBS (+), I am referring to an individual with a CBS abnormality, either (+/+) or (+/-). To keep things as clear as possible (and believe me I am trying) I will also can refer to individuals who are abnormal for SUOX as SUOX (+).

My general treatment program for CBS (+) individuals and for BMHT (+) individuals who are overproducing ammonia and sulfite/sulfite will consist of:
1. Restrict animal protein (anything with eyes) from your diet and limit your exposure to sulfur {added to many foods as a preservative, I can definitely tell when I eat something containing sulfites} group containing drugs and nutritionals.
2. To squelch ammonia, supplement with Yucca, ½ capsule twice a day (sprinkled on food containing protein), Ammonia Support RNA ½ dropper with meals, and a charcoal supplement at bedtime (away from other supplements; magnesium citrate may be used as needed to keep the GI tract moving as charcoal may lead to constipation).
3. Switch to a multi that does not contain B6 (B6 stimulate CBS; the P-5-P form of B6 is less of a problem – Dr. Yasko’s NHF multi is low in B6 - take two tablets three times a day). Additional mineral support will be needed and here we start with Trace Minerals Complex {i.e. Full Spectrum Minerals} at 4 drops/day.
4. To stimulate SUOX begin Molybdenum 3 drops twice a day, Boron 3 mg/day, Vitamin E succinate 400 IU/day (contained in the NHF multi), and hydroxy-B12 2000 mcg/day.
5. Supplement with GABA 500 mg once or twice a day to blunt excitotoxicity; if you feel that GABA is helping you can increase the dose.
6. To increase energy production (this step is less critical and can be omitted for cost containment, especially in individuals not troubled with CV disease) supplement with NADH 5 mg, Co-Enzyme Q10 100 mg or Idebenone 100 mg, Carnitine 500-1000 mg daily, and Ribose 5 grams in water {PQQ can potentially be added to this list}, two to three times a day. Co-Enzyme Q10, Carnitine, and Idebenone all provide Methyl groups, and are thus of additional value to COMT (-) and/or VDR Taq (+) individuals.
7. Additional measures designed to speed up the “back door” BHMT reaction will be discussed later.
8. Check and record your urine sulfate level every 7 days. Our goal is to reduce your reading to 400 mg/L (one yellow and three pink squares) or at least to 800 mg/L (two yellow and one pink), and then to keep it there for two months (at which time you will feel better). Measures that decrease your sulfate burden are beneficial. Conversely, any measure that increases your sulfate burden is either inappropriate or is being added to your program prematurely. A persistent reduction in your urine sulfate level will open the door to SAMe and/or BH4 supplementation[/colour] and an eventual liberalization in your diet. Your urine sulfate score will thus be our primary measuring stick.
9. If not done already, we need to check your baseline blood homocysteine, ammonia, and Vitamin D levels, along with kidney and liver chemistries (if not done recently).
10. Consider wearing the Life Wave Glutathione patch 4-6 hours each day, removing the patch if you feel poorly (this would reflect a detoxification reaction - see our info sheet and lifewave.com/chc), the idea here being to use up free sulfur groups to generate Glutathione.
11. In 8-10 weeks we will likely wish to:
a. Repeat some of the lab work.
b. Carry out 24 hour urine studies for ammonia and amino acids, with a second study for toxic and nutritional minerals, and possible a SpectraCell intracellular nutritional assessment. We will use the results to modify our nutritional measures, specifically looking for nutrients that have been drawn in to your now open pathways, nutritionals that will now require more intensive supplementation. Favorable results will also allow us to back off on the dose of now less necessary supplements.

[size=12pt]NOS: Nitric Oxide Synthase {1. Urea Cycle}

In a BH4 dependent reaction, Nitric Oxide Synthase (NOS) converts Arginine in to Nitric Oxide, the molecule that resists plaque formation, vasospasm, and abnormal clotting. If you can make and maintain Nitric Oxide then you will not develop cardiovascular disease. If you have cardiovascular disease and if we can successfully reboot your Nitric Oxide system, than we can stabilize your disease {this is what happened in my case. Energy production soared once I began supplementation with L-Arginine}. Every maneuver in drug and non-drug cardiovascular medicine that improves patient symptomatic status and outcome works on this system. Every risk factor (or causative factor for cardiovascular disease) compromises Nitric Oxide generation or maintenance. NOS is also involved in ammonia detoxification, a job that distracts it from its Nitric Oxide generating duties and which uses up BH4. Without adequate levels of BH4 Nitric Oxide Synthase will not convert Arginine in to beneficial Nitric Oxide, but rather in to undesirable free radical species such as superoxide or peroxynitrite.

The NOS D298E abnormality codes for a dysfunctional NOS enzyme. It has trouble breaking down ammonia and it has trouble generating Nitric Oxide. NOS (+) individuals are at greater risk for developing all forms of cardiovascular disease, for experiencing adverse events, and for restenosis following balloon angioplasty. A component of “a positive family history of cardiovascular disease” is related to genes coding for high cholesterol, elevated lipoprotein (a), and iron over absorption {iron over absorption has been extensively discussed here - see Hemochromatosis and Autoimmune Conditions thread}. The rest likely relates to inherited abnormalities in NOS, ACE, and the other Methyl Cycle genes. If you are NOS (+) we will pay particular attention to maneuvers designed to lower your ammonia burden, and to address risk factors that compromise Nitric Oxide. As the products of a compromised or genetically abnormal NOS system are the free radicals superoxide and peroxynitrite, aggressive antioxidant supplementation makes sense here (while a broad spectrum program of antioxidant supplementation is always wise, we specifically use Vitamin C to neutralize superoxide and 5-methyl folate to neutralize peroxynitrite). I give two separate two hour presentations on Endothelial Dysfunction, which we have on cassette tape (we will likely have a DVD presentation available late next fall). BH4 supplementation has been demonstrated to improve Nitric Oxide generation and endothelial function in individuals with risk factors such as hyperlipidemia, and we presume that it will do the same in individuals with Methyl Cycle abnormalities.

[size=12pt]ACE: Angiotensin Converting Enzyme {5. Transulfuration Cycle}

Angiotensin Converting Enzyme (ACE) converts Angiotensin I, a weak vasoconstrictor, into Angiotensin II, for our purposes a nasty angiochemical that mediates hypertension, plaque deposition, salt and water retention, magnesium and potassium wasting, and abnormal clotting. ACEI (angiotensin converting enzyme inhibitors) target this enzyme, seeking to block generation of Angiotensin II {Angiotensin II is a precursor of cortisol}. The potassium and magnesium sparing diuretic Spironolactone blocks the deleterious effects of Aldosterone, another mediator that is up regulated by Angiotensin II (of interest to those of you with CBS/BHMT problems, Spironolactone is low in Sulfur). The ACE Del16 involves the insertion and deletion of genetic material at a specific location (intron16) of the ACE gene, coding for an up regulated, or over active Angiotensin Converting Enzyme. ACE (+) individuals - I am ACE (+/+); yikes! - are at increased risk for hypertension and cardiovascular disease. If you are ACE (+) and have problems with BP or fluid control {the kidneys are implicated here}, we will have a low threshold for intervening pharmacologically with ACEI and Spironolactone. Of interest, a large study (HOPE) where a tissue specific ACEI (Ramipril, which like Quinapril enters the vascular wall and preserves endothelial function) was administered to individuals with diabetes and one other risk factor, demonstrated a reduction in cardiovascular event and death rate over the ensuing five years. ACE (+) individuals respond to statin drugs with larger reductions in cholesterol and plaque burden than do ACE (-) individuals (who presumably have less need for this form of intervention). Dr. Yasko recommends the use of Kidney Support RNA, OraKidney, and OraAdrenal in kids with ACE problems. ACE may be associated with increased anxiety; here she recommends use of the Stress and Anxiety Support RNA product.

And from other sources:

Abstract

Background

The angiotensin converting enzyme (ACE) has been repeatedly discussed as susceptibility factor for major depression (MD) and the bi-directional relation between MD and cardiovascular disorders (CVD). In this context, functional polymorphisms of the ACE gene have been linked to depression, to antidepressant treatment response, to ACE serum concentrations, as well as to hypertension, myocardial infarction and CVD risk markers. The mostly investigated ACE Ins/Del polymorphism accounts for ~40%–50% of the ACE serum concentration variance, the remaining half is probably determined by other genetic, environmental or epigenetic factors, but these are poorly understood.

Materials and Methods

The main aim of the present study was the analysis of the DNA methylation pattern in the regulatory region of the ACE gene in peripheral leukocytes of 81 MD patients and 81 healthy controls.

Results

We detected intensive DNA methylation within a recently described, functional important region of the ACE gene promoter including hypermethylation in depressed patients (p = 0.008) {using BH4} and a significant inverse correlation between the ACE serum concentration and ACE promoter methylation frequency in the total sample (p = 0.02). Furthermore, a significant inverse correlation between the concentrations of the inflammatory CVD risk markers ICAM-1, E-selectin and P-selectin and the degree of ACE promoter methylation in MD patients could be demonstrated (p = 0.01 - 0.04).

Conclusion

The results of the present study suggest that aberrations in ACE promoter DNA methylation may be an underlying cause of MD and probably a common pathogenic factor for the bi-directional relationship between MD and cardiovascular disorders.[/url]

Abstract
Somatic angiotensin-converting enzyme (sACE) is crucial in cardiovascular homeostasis and displays a tissue-specific profile. Epigenetic patterns modulate genes expression and their alterations were implied in pathologies including hypertension. However, the influence of DNA methylation and chromatin condensation state on the expression of sACE is unknown. We examined whether such epigenetic mechanisms could participate in the control of sACE expression in vitro and in vivo. We identified two CpG islands in the human ace-1 gene 3 kb proximal promoter region. Their methylation abolished the luciferase activity of ace-1 promoter/reporter constructs transfected into human liver (HepG2), colon (HT29), microvascular endothelial (HMEC-1) and lung (SUT) cell lines (p < 0.001). Bisulphite sequencing revealed a cell-type specific basal methylation pattern of the ace-1 gene -1,466/+25 region. As assessed by RT-qPCR, inhibition of DNA methylation by 5-aza-2'-deoxycytidine and/or of histone deacetylation by trichostatin A highly stimulated sACE mRNA expression cell-type specifically (p < 0.001 vs. vehicle treated cells). In the rat, in vivo 5-aza-cytidine injections demethylated the ace-1 promoter and increased sACE mRNA expression in the lungs and liver (p = 0.05), but not in the kidney. In conclusion, the expression level of somatic ACE is modulated by CpG-methylation and histone deacetylases inhibition {a related mutation possibly leading to aberrations}. The basal methylation pattern of the promoter of the ace-1 gene is cell-type specific and correlates to sACE transcription. DNMT inhibition is associated with altered methylation of the ace-1 promoter and a cell-type and tissue-specific increase of sACE mRNA levels. This study indicates a strong influence of epigenetic mechanisms on sACE expression.

BHMT: Betaine-Homocysteine Methyltransferase {4. Methione (Transmethylation) Cycle}

BHMT converts homocysteine directly in to methionine. Specifically it removes a methyl group from TMG (trimethylglycine) and tacks it on to homocysteine to form methionine and DMG (dimethylglycine). Stimulating a genetically normal BHMT system will partially ameliorate the adverse affects of Methyl Cycle defects elsewhere. For example, if we cannot convert homocysteine in to methionine because a MTHFR defect renders us deficient in methyl-folate, or if an MTR up regulation or MTRR down regulation leaves us short in the methyl-B12 department, we can bypass these blockages by stimulating BHMT to convert homocysteine directly in to methionine (I know this is difficult, but bypassing blocked enzymes sure beats surgery to bypass blocked arteries, so please read on). Our approach to BHMT, if it is defective, or when we want to stimulate BHMT to help bypass MTR/MTRR defects, or when we want to pull homocysteine away from a CBS up regulation, will be affected by your COMT (basic need for and tolerance to methyl group donors) status. The basic approach is as follows:

1. Phosphatidylcholine, or as a less expensive alternative, Phosphatidylserine 100 mg daily, to stimulate the BHMT reaction. The former, administered IV as Lipostabile/Plaquex, or in oral liposomal format as Lipophos Forte, provides a powerful anti-atherosclerotic benefit (discussed on the website and in a DVD). Oral Lipophos EDTA contains Phosphatidylcholine admixed with EDTA, providing us with BHMT stimulation, reverse cholesterol transport, and heavy metal detoxification, a triple benefit. In individuals who are COMT (-/-), who thus need methyl groups, Phosphatidylserine can be used in combination with the methyl donor DMAE as Pedi-Activ, one daily.

2. TMG can be used to stimulate BHMT (but not in COMT (+/+) individuals, who will be sensitive to free methyl groups).

COMT: Catechol–O–Methyl Transferase {2. Neurotransmitter (BH4) Cycle}

COMT degrades dopamine, norepinephrine, and to a somewhat lesser extent other neurotransmitter substances, by tacking on to them a free methyl group that COMT obtains from SAMe. The V158M and H62H alleles of COMT are down mutations. Individuals (+/+) or (+/-) for these genes will degrade dopamine only slowly. Now, while COMT (+) status is not the norm, from our perspective it is not necessarily a bad thing. We need dopamine to defend against microbes and heavy metals; here being (+) for COMT is actually in our favor. BH4 deficiency is the consequence of CBS, BHMT, and the “backward” MTHFR A1298C defects. We need BH4 to carry out multiple physiologic steps, including the generation of dopamine. If our COMT (+) status keeps us from breaking down dopamine, we do not need to “spend” BH4 to make dopamine, leaving more BH4 available for other critical functions. The downside of being COMT (+) is that you will have a lot of free methyl groups floating around, as you are not using them up breaking down dopamine. Thus if we need to give you other Methyl Cycle intermediates (such as methyl-B12 if you have MTR/MTRR issues), we risk ODing you with methyl groups. Too many methyl groups can lead to mood swings. Panic attacks and bi-polar mood disorder are seen with greater frequency in COMT (+) individuals; this makes sense. COMT (-) individuals, on the other hand, need and tolerate methyl groups. A third, and less frequently encountered COMT abnormality, COMT 61, is a down regulation defect. Individuals (+) for COMT 61 breakdown dopamine quite rapidly and are at greatest need for methyl donors. {There is a neat chart showing a summary on the website}

[...]

Dopamine levels as they relate to our COMT status will also be affected by the VDR Taq gene,
which influences dopamine production in relation to Vitamin D.

MTR: Methionine Synthase {3. Folate Cycle, 4. Methionine (Transmethylation) Cycle}

MTR combines 5-methyl folate and homocysteine to form methionine and tetrahydrofolate (THF). More specifically, MTR removes a methyl group from 5-methyl folate, then tacks it on to homocysteine to form methionine. In the process 5-methyl folate is converted back to THF.

The MTR A2756G defect is an up regulation. The enzyme is always on, grabbing every homocysteine and 5-methyl folate molecule that it can get its hands on, processing them to methionine and THF. Methyl-B12 is required for normal function of MTR, and with each spin of the MTR enzyme, one molecule of methyl-B12 is degraded.

MTRR (Methionine Synthase Reductase) serves the needs of MTR, regenerating methyl-B12 from available methyl donors and B12. Without methyl-B12, MTR cannot convert homocysteine in to methionine. Needed downstream methyl donors such as SAMe will not be generated. Methylation fails, so does your biochemistry, and there goes your health.

When the MTR A2756G defect is present, MTR is always on, using up methyl-B12 faster than MTRR can regenerate it. The consequence is deficient methyl-B12. B12 blood levels may be normal, but as levels of methyl-B12 will be low, normal B12 physiology cannot be carried out. Homocysteine levels will typically be elevated. SAMe generation and methylation in general will compromised. We can treat the MTR up regulation by:
a. Supplementing you with methyl-B12.
b. Measures designed to increase formation of methyl-B12.
c. We can also bypass the dysfunctional MTR step by stimulating the “backdoor” BHMT reaction, which converts homocysteine directly in to methionine (more on this approach later) {quoted above}.
d. When we do not need to limit sulfur intake (CBS normal or under control with low urine sulfate readings) we can simply supplement you with SAMe, our most important methyl donor, which is otherwise formed from the methionine generated by the MTR/MTRR reaction.

SHMT C1420T: Serine Hydroxymethyltransferase {3. Folate cycle, multiple pathways}


Our diagrams indicate that the MTHFR "forward reaction" converts THF (obtained from dietary folic acid) in to 5-methyl folate, which is then used by MTR to convert homocysteine in to methionine, in the process regenerating THF. In reality, an intermediate step is involved, catalyzed by SHMT. SHMT converts THF in to 5,10-methylene THF (upper left in the diagram). It is actually 5,10-methylene THF, not THF itself, that is converted in to 5-methyl folate by MTHFR. Some of the 5,10-methylene THF generated from THF by SHMT will take another metabolic pathway, being acted upon by SHMT a second time, whereby 5,10-methylene THF is converted in to 5-formyl folate (also known as folinic acid), which is used as a building block for DNA {an important enzyme it seems}. We can address a SHMT down regulation by supplementing you with its products, folinic acid, and 5-methyl folate (as without 5,10-methylene THF the MTHFR enzyme has nothing to work with).

[size=12pt]GAMT: Guanidinoacetate Methyltransferase {4. Methionine (Transmethylation) Cycle}

From http://www.nature.com/ki/journal/v64/n4/fig_tab/4494025f1.html:

Overview of homocysteine and creatine metabolism. Methionine is converted to S-adenosylmethionine, which is demethylated to S-adenosylhomocysteine by methyltransferases. Creatine is formed by methylation of guanidinoacetate, which is synthesized from glycine and arginine. Creatine supplementation decreases guanidinoacetate synthesis by repressing AGAT biosynthesis and consequent reduction of guanidinoacetate formation. Homocysteine is either remethylated to methionine or degraded in the transsulfuration pathway. Abbreviations are: AGAT, arginine:glycine amidinotransferase (EC 2.1.4.1); THF, tetrahydrofolate; 5CH3-THF, 5-methyltetrahydrofolate; 5,10-CH2-THF: 5,10 methylene tetrahydrofolate; Ser, serine; Gly, glycine.

"Creatine supplementation decreases homocysteine in an animal model of uremia.

Background - Hyperhomocysteinemia is prevalent in more than 85% of patients with end-stage renal disease (ESRD) and is thought to contribute to the excess cardiovascular mortality and morbidity. Creatine is synthesized by methylation {using SAMe in the 4th cycle} of guanidinoacetate with formation of S-adenosylhomocysteine {SAH} and subsequently, homocysteine (Hcy). Creatine supplementation down-regulates its endogenous synthesis and, thus, may reduce Hcy production. The present study investigates the effect of creatine supplementation on Hcy concentrations in an animal model of uremia."

From http://www.metbio.net/docs/MetBio-CaseReport-AGGE999941-14-06-2009.pdf:
"GAMT deficiency is a disorder of creatine synthesis1. Creatine is excreted by non-enzymatic conversion to creatinine and the excretion of creatinine is directly proportional to the total body creatine. The metabolic pathway of creatine synthesis, which occurs mainly in the liver, is shown below. There are three known defects in the pathway – two synthesis defects, AGAT deficiency and GAMT deficiency and an X-linked transporter defect affecting the cellular uptake of creatine in the brain."

From http://ajpendo.physiology.org/content/296/2/E256:

"ABSTRACT - Since creatinine excretion reflects a continuous loss of creatine and creatine phosphate, there is a need for creatine replacement, from the diet and/or by de novo synthesis. Creatine synthesis requires three amino acids, methionine, glycine, and arginine {found in methylation cycles}, and two enzymes, L-arginine:glycine amidinotransferase (AGAT)[/b], which produces guanidinoacetate acid (GAA), and guanidinoacetate methyltransferase (GAMT), which methylates GAA to produce creatine. In the rat, high activities of AGAT are found in the kidney, whereas high activities of GAMT occur in the liver. Rat hepatocytes readily convert GAA to creatine; this synthesis is stimulated by the addition of methionine, which increases cellular S-adenosylmethionine concentrations. These same hepatocytes are unable to produce creatine from methionine, arginine, and glycine. 15N from 15NH4Cl is readily incorporated into urea but not into creatine. Hepatic uptake of GAA is evident in vivo by livers of rats fed a creatine-free diet but not when rats were fed a creatine-supplemented diet. Rats fed the creatine-supplemented diet had greatly decreased renal AGAT activity and greatly decreased plasma [GAA] but no decrease in hepatic GAMT or in the capacity of hepatocytes to produce creatine from GAA. These studies indicate that hepatocytes are incapable of the entire synthesis of creatine but are capable of producing it from GAA. They also illustrate the interplay between the dietary provision of creatine and its de novo synthesis and point to the crucial role of renal AGAT expression in regulating creatine synthesis in the rat."

From http://www.rice.edu/~jenky/sports/creatine.html:

"The creatine that is normally present in human muscle may come from two potential sources, dietary (animal flesh), and/or internally manufactured. What isn't present in the diet is easily made by the liver and kidneys from a few amino acids (glycine, arginine, and methionine). A 70kg adult has about 120g of creatine in the muscles, and the daily turnover is roughly 2g. About half of this is replaced by the diet and half synthesized endogenously. The exogenous intake of creatine appears to exert negative feedback on the endogenous production of creatine (i.e., more creatine present in the diet means less production by the body). Creatine is eliminated from the body by the kidneys either as creatine, or as creatinine, which is formed from the metabolism of creatine."

Glutamate – GABA Imbalance Þ Excitotoxicity {Multiple pathways}

Glutamate {from glutamine, glutamic acid is another derivative} is the main excitatory neurotransmitter in the body. It is essential for learning and short and long-term memory. Glutamate is also the precursor to our primary inhibitory or calming neurotransmitter, GABA. GABA damps the propagation of sounds so that a distinction can be made between the onset of sound and a background noise. Many other physiologic processes require a balance between glutamate and GABA, which is usually easy to achieve as glutamate, glutamine, alpha-ketoglutarate, and GABA can be interconverted via the enzymes depicted above.

Genomic defects, viral illness, and heavy metals will compromise this balance, leading to excess glutamate, insufficient GABA, excitotoxicity, and eventual neuron loss {this is applicable to me}. Viral infection (individuals with Methyl Cycle defects cannot defend well against viral infection) can lead to antibodies against the vitamin B6 dependent enzyme glutamate decarboxylase (GAD), blocking GABA production (this is felt to occur in the pancreas in kids with juvenile onset diabetes). Aluminum poisons this enzyme as well. Excessive alpha-ketoglutarate generated due to the CBS up regulation can be converted into glutamate, but in the presence of lead and aluminum, the glutamate so created cannot be converted into GABA, glutamine, or back to alpha-ketoglutarate. The result is glutamate-GABA imbalance, agitated behavior, and eventually nerve loss.

Low GABA leads to impaired speech, anxiety, aggressive behavior, poor socialization, poor eye contact, nystagmus, and constipation. Glutamate excess does the same and also wastes glutathione and increases levels of TNF-alpha, an inflammatory mediator that can produce heart cell dysfunction and gut inflammation.

We can restore glutamate-GABA balance by:

1. Addressing CBS up regulation/BHMT down regulations to decrease alpha-ketoglutarate production.
2. Decreasing intake of food precursors of glutamate (see list below).
3. Supplementing with GABA
4. Copper inhibits conversion of glutamate to GABA by glutamate decarboxylase so avoid copper excess, or better stated, an imbalance between copper and zinc.
5. Calcium is involved in glutamate toxicity, so supplement with magnesium to keep calcium in check.
6. Remove heavy metals with a chelating agent. Of interest, toxicity due to mercury is aggravated by glutamate excess; mercury and glutamate synergize to damage nerve cells {No wonder the madhatter was mad with all that mercury used to make hats!}.

Towards the end there is dietary information for the 4 cycles. Some of the advice on diet is incomplete or misguided IMO. It is worth noting however that there are no dairy or gluten products mentioned, sugar only in the form of fructose (unless desired) and it is relatively low in carbohydrates in the methyl cycle recipes mentioned in Appendix VI. I wonder if part of the reason it is set out that way can be traced back to the standard modern food pyramid.

A few other links which may prove useful:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC425037/pdf/jcinvest00130-0182.pdf
https://www.orpha.net/data/patho/Pro/en/GuanidinoacetateMethyltransferaseDeficiency-FRenPro1726.pdf
http://ghr.nlm.nih.gov/condition/guanidinoacetate-methyltransferase-deficiency

Limitting the ratio of B3 and B6 to other B vitamics in their active or taking coenzymated B complex in moderation. Ascorbic acid, appropriate antioxidants, preoxidants and other supplements are also essential IMO.

It definitely ties in what Benjamin Lynch presents in his videos. I have this feeling that what Yasko's Feel Good Nutrigenomics book and the link above say overlap too. It wouldn't be surprising. Let us know how you find it Shijing. :)

 

[stellar]

Although I found this thread interesting, important and informative, I soon realised that it was a little out of my scope of understanding so I looked around and found these set of 4 short videos that helped me get the gist of it in simpler terms before I study it further. It may be helpful to others also: www.youtube.com/watch?v=uqEDK68vM It's titled Methylation Made Easy.

 

[truth seeker]

Thanks stellar. :) I'm not sure why, but youtube says the video doesn't exist. It might be because the http part needs to be added, dunno. I'll try and post it again below and I guess we'll see.

https://www.youtube.com/watch?v=o4uqEDK6BvM

 

[stellar]

Thanks stellar. :) I'm not sure why, but youtube says the video doesn't exist. It might be because the http part needs to be added, dunno. I'll try and post it again below and I guess we'll see.

https://www.youtube.com/watch?v=o4uqEDK6BvM

Those darn https's. Thanks truth seeker

 

[H-KQGE]

There are scores of pages to pour through on methylation pathways and epigenetics . The research currently being done is just the tip of the iceberg. OSIT.[…] I wanted to start a thread about this months ago but wasn't sure how to approach it so you can imagine my relief and joy

I'm usually looking to start a thread or participate in something & I usually doubt my ability to present it in an appropriate manner. Then there's that issue of "time" that starts to run away from me so I don't act, & I have articles to share which turns into several, then there's a backlog! I'm just glad there's so many knowledgeable & colinear people that can provide assistance for us all. Most times I'm relieved to see posts doing a better job than I would've done & break things down.

There really is an incredible amount to go through, this leads in every direction of health care. With doctors being drilled to treat symptoms by drugging everything & not dealing with root causes, we have the high probability that a large chunk of the population are misdiagnosed & then drugged to death. And medical science is so tribal that I think that doctors should be required to have, at least, a basic working knowledge of several disciplines. I did think this before but after going through your post yesterday, (most of the day) I kept going off into other tangents - sites, articles, journals, testimonials.

Lots of contradicting claims, out of date information & in some quarters, blatant guesses dressed-up as facts. Thankfully, there is a great deal of research being done & I agree, it's the tip of the iceberg because this topic points out the obviousness of the truth: everything is connected. Be it direct or indirect, human biochemistry is complex & needs special care & attention at the microscopic level. Thanks for the info SMM, I'll have to go through it a few more times for it to sink in, funnily enough it's already doing so but I want to be more confident about it. I have some bits & pieces on my end, but I'll need a while to sift through them again to see if you haven't already covered these areas. I think some articles I saw went as far as can be, colloquially (woo-hoo!) & even bigger clearer diagrams were used - though at this point (started around noon, ended around 6) in the day, everything started to blur. Code sequences, technical terms, protocols...

 

[H-KQGE]

Thanks H-kqge for the link above -- as it turns out, I just received Amy Yasko's Feel Good Nutrigenomics yesterday:

http://www.holisticheal.com/feel-good-nutrigenomics-your-roadmap-to-health-book.html

She talks about this very thing -- the methylation roadmap and its relationship to epigenetics. This particular book is written specifically for the layperson and is pretty easy to digest -- I'm about halfway through it and will watch the Benjamin Lynch videos again after I've finished, because I think they'll be easier to understand with this foundation in place. I highly recommend the book -- it's not too expensive, and it came within two days of my ordering it.

Written for the layperson? Excellent! I won't be getting it anytime soon as I've just spent a lot on vitamins, minerals & some detox stuff, & there's a few more to get too. The price is good though, that'll be a future purchase on my list.

 

[H-KQGE]

Thanks Stellar, thanks truthseeker! I'll have a look later on. :)

 

[shijing]

Thanks stellar. :) I'm not sure why, but youtube says the video doesn't exist. It might be because the http part needs to be added, dunno. I'll try and post it again below and I guess we'll see.

https://www.youtube.com/watch?v=o4uqEDK6BvM

Those darn https's. Thanks truth seeker

This was an excellent find, stellar, and thanks for posting it -- I just finished watching it early this morning and found it quite helpful. I'm going to embed this one below as well for ease of reference:

http://<iframe width="420" height="...vM" frameborder="0" allowfullscreen></iframe>

It definitely ties in what Benjamin Lynch presents in his videos. I have this feeling that what Yasko's Feel Good Nutrigenomics book and the link above say overlap too. It wouldn't be surprising. Let us know how you find it Shijing. :)

Written for the layperson? Excellent! I won't be getting it anytime soon as I've just spent a lot on vitamins, minerals & some detox stuff, & there's a few more to get too. The price is good though, that'll be a future purchase on my list.

I just finished this last night, and I think it's a very good introduction -- there are a couple of issues addressed that I haven't seen mentioned in other sources yet, such as the importance of getting your lithium balanced with B12. She has some excerpts of it available on her Scribd.com page:

http://www.Scribd.com/DrAmyYasko

Here are a couple of additional resources that she offers (a parent discussion group and nutrigenomic analysis):

http://www.ch3nutrigenomics.com/phpBB3/welcome.html

http://www.KnowYourGenetics.com/

Back to her book, here is a section from chapter 20 on viruses and bacteria that I thought was interesting:

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 of 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 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 cytosine's 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 know 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" abd "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.

[...] 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 of mutations, you may have trouble making the bases that are needed for new DNA synthesis. If you cannot make new DNA, then you cannot make these specialized immune cells and as a result you may lack immune system regulatory cells.

I also filled out my 23andme kit yesterday and mailed it in today. During the process, and also talking to my cardiologist about it, I realized that the reason why the raw data from 23andme is so unwieldy at present is because the FDA brought a suit against them last year which resulted in 23andme not being allowed to provide organized information about polymorphisms and accompanying health recommendations. They were able to do this up until November 23, 2013, but any kits processed after that date will not be organized in the same way. The reason seems to be that the FDA realized that with this information in hand, people with MTHFR polymorphisms would be able to learn how to heal themselves and would stop needing drugs for Parkinson's and other autoimmune diseases, SSRIs for depression, and so on. That situation could not, of course, be tolerated, hence the clampdown. However, there is a separate site now providing this service, which you can send your 23andme data to and they will organize it for you:

http://geneticgenie.org/

Note that it's a free service, but they accept donations.

 

[RedFox]

Just wanted to add that I exported my raw data from 23andme and ran it through promethease
_http://www.snpedia.com/index.php/Promethease

Promethease is a literature retrieval system that builds a personal DNA report based on the scientific literature cited in SNPedia and a file of genotype (DNA) data.

The results may not be as neat and tidy, but SNPedia has the most up to date data on recognised sections of DNA. This way you can then compare the results to the polymorphisms in the literature that's been discussed so far. :)

 

[SMM]

Great videos, thanks stellar :)

I have added Feel Good Nutrigenomics to my reading list.

I also filled out my 23andme kit yesterday and mailed it in today. During the process, and also talking to my cardiologist about it, I realized that the reason why the raw data from 23andme is so unwieldy at present is because the FDA brought a suit against them last year which resulted in 23andme not being allowed to provide organized information about polymorphisms and accompanying health recommendations. They were able to do this up until November 23, 2013, but any kits processed after that date will not be organized in the same way. The reason seems to be that the FDA realized that with this information in hand, people with MTHFR polymorphisms would be able to learn how to heal themselves and would stop needing drugs for Parkinson's and other autoimmune diseases, SSRIs for depression, and so on. That situation could not, of course, be tolerated, hence the clampdown. However, there is a separate site now providing this service, which you can send your 23andme data to and they will organize it for you:

http://geneticgenie.org/

Note that it's a free service, but they accept donations.

That is repulsive, while I am not in the least shocked.

 

[shijing]

Here's another really good video by Amy Yasko, the first in a series of videos on this page (I haven't figured out how to embed Vimeo -- if anyone knows, please feel free to explain):

Methylation: Why You Should Be Concerned

It covers a lot of ground -- part of it goes over the critical role of lithium; anyone following the Highly Sensitive Person thread might be interested in what she discusses in the last five minutes or so of the video.

I've also attached a free e-book on MTHFR polymorphisms that I was able to download from here.

I'm also happy to say that after a week of treatment with the right kind of B-12 and methylfolate, the symptoms I mentioned on the Endothelial Dysfunction thread seem to have cleared up. I'll keep observing, but so far I'm encouraged by the progress.

I really want to emphasize that if anyone suffers from autoimmune conditions (arthritis, diabetes, lupus, multiple sclerosis, etc), neurodegenerative disease (Alzheimer's, Parkinson's, etc), mitochondrial dysfunction (chronic fatigue syndrome), psychological disorders (depression, anxiety, bipolarism, schizophrenia, etc), cancer, cardiac disease -- or any number of other conditions -- you should be taking a look at the information on this thread.

Finally, I know there are certain members that have taken an active interest in this thread, but besides myself and Redfox, I don't know if anyone else has actually tested positively for any of these polymorphisms. Is there anyone else out there who knows that they have these (either MTHFR, or related polymorphisms like CBS, NOS, etc)?