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Methyl Cycle Genomics

The Methyl Cycle is the backbone of our physiology.  It's functional status determines our resistance or susceptibility to environmental toxins and microbes.  This is a confusing array of biochemistry, but suffice it to say, a defect at any one point in these interlocking cycles will inevitably affect the  remaining pathways, and your overall health will then suffer.  Methyl Cycle abnormalities explain why you are sick from environmental toxins while the guy next door is just fine, why you are autistic while your fraternal twin brother is not.  While we cannot change your DNA, if we know your weak links we can create "nutritional workarounds" - we can supplement alternative pathways or withhold from your diet molecules that you cannot handle.  If we do not address the Methyl Cycle abnormalities that underlie unexplained or chronic illness - well then the illnesses will remain chronic and unexplained,   because it is the Methyl Cycle Abnormalities that predisposed you to ill health.

 Methyl Cycle Genomic Analysis and Supplementation

CBS:  Cystathione Beta Synthase

MTHFR C677T:  5,10-Methylenetetrahydrofolate Reductase (Þ 5-Methyl-Folate)

SHMT:  Serine Hydroxymethyltransferase

MTR:  Methionine Synthase

MTRR:  Methionine Synthase Reductase

BHMT:  Betaine-Homocysteine Methyltransferase

COMT:  Catechol–O–Methyl Transferase

VDR Taq:  Vitamin D Receptor Taq Abnormality

MTHFR A1298C:  5,10-Methylene TetraHydroFolate Reductase (Þ BH4)

NOS:  Nitric Oxide Synthase

ACE:  Angiotensin Converting Enzyme

Glutamate – GABA Imbalance Þ Excitotoxicity

MAO A, ACAT, AHCY, and VDR Fok

Appendix I:  Foods High in Tyrosine or Tryptophan 

Appendix II:  Foods High in Sulfur

Appendix III:  Foods High in Excitotoxins

Nurtigenomic Supplements and Supplies

Ordering Supplements from Websites 

Methyl Cycle Genomic Analysis and Supplementation

Understanding how to incorporate the basic science of Methyl Cycle Genomics in to your  treatment program, and how best to monitor your response, will be a challenge to both of us.  If we accept this challenge, and spend time, energy, and resources in dealing with your Methyl Cycle Abnormalities, then you can take strides forward in improving your health.  If we do not – well, most of you are undergoing Methyl Cycle testing because you have a health problem that makes little sense; you have seen multiple doctors and you are not getting better – if we do not address your Methyl Cycle abnormalities then we cannot expect that you will get better – because it is the
                        
                                                         Methyl Cycle Abnormality that predisposed you to ill health.

What is a Methyl Cycle Abnormality?  The chart above describes mutations, scientifically a correct descriptor, but not a good common language description of your condition.  You do not have a “mutation”, a one-time genetic accident that occurred during your embryonic development.  Methyl Cycle Abnormalities are not disease specific or smoking gun genetic defects.  Yes, there are specific genetic abnormalities that code for Sickle Cell Anemia, Huntington’s Chorea, or Phenylketonuria, and if you are born with these genotypes (referring to one’s genetic code), then we can be 100% certain that you will develop these disease states (the phenotype, or expression of the genetic code).  There is a great deal or dread and anxiety regarding testing for these genes.  After all, if you can’t do anything to prevent the phenotype, why even look for the genotype? 

Methyl Cycle Defects are different.  None code for a specific disease state, but all play a role in predisposing you to disease in general.  The more Methyl Cycle Defects present in your genotype, the greater is your susceptibility to toxicity and infection, and the greater will be your risk for these (usually) age-related degenerative disease states that plaque our society today.  These disease states are usually age-related (but are occurring in you earlier than in others) because it takes time for toxicity to build up within you, to overcome the still intact defense systems that are trying to defend your physiology.  On the other hand, a little bit of toxicity during a vulnerable time period can do a lot of damage to an individual with impaired Methyl Cycle defenses.  The frequency of Methyl Cycle Defects in autistic kids will likely be 100% - a little bit of Mercury in a genetically defenseless kid will damage a developing brain.  Their parents and grandparents harbored these genes (likely in lower concentration) but when they were born our uterine and early life environment was toxin free.  Their brains had the chance to develop normally.  Exposing them to toxicity now isn’t good for them, but their brains did have the chance to develop normally, so they do not develop “adult onset autism”.  But individuals harboring Methyl Cycle Defects are going to get sick, before their time, likely with conditions that make little sense such as Fibromyalgia, Chronic Fatigue, Multiple Chemical Sensitivity, or they will present early in life with what used to be diseases seen only in “old people”: - coronary disease, cardiomyopathy, Parkinson’s disease, and dementia. 

I’ve looked at disease as a combination of lifestyle, environment, and heredity.  Yes, if you smoke, you will eventually experience lung disease.  If you are exposed to lead then it will eventually build up in your body and cause hypertension and kidney disease.  But some people smoke and get lung disease at an early age, some only at old age, and some seem to be able to puff away into their 80s.  We are all exposed to multiple toxins, we all live in the same general environment, but only some of us get heart disease and cancer – why?  If toxicity is so bad, then why don’t all of us have toxicity associated cancer?  Well, we’re on our way, but some of us can live within this toxic environment unscathed.  How can one boy be autistic while his fraternal twin is normal - same uterine environment, same maternal diet, same vaccinations – but different genotypes.  It is our genotype, specifically the status of the genes making up our Methyl Cycle that render us more or less susceptible to environmental influences (toxins and microbes). 

The term “methyl group” refers to CH3, one carbon atom attached to three hydrogens.  The enzymes of the Methyl Cycle add or subtract a methyl group from another molecule to open or close biochemical pathways, to open our DNA when it should be read, or to close it when it would not be in our best interest to decode a specific gene.  We need methyl groups to silence viral RNA, to defend against other microbes, and to defend against environmental toxins.  Optimal methylation is thus more important today than it was in years past, when the environment was less toxic.  Individuals with Methyl Cycle Defects are the canaries of our society.  Toxins will hurt all of us eventually but those of us with Methyl Cycle Defects will be the first to go down.

                     I am now looking at disease as a combination of lifestyle, environment, and Methyl Cycle Genomic Defects.

Your packet contains your genotype.  It is up to you to adjust your diet, and it is up to me to change your treatment program, in order to optimize your phenotype.  We can’t change your genotype, but we can change its expression.  We can eliminate from your diet and treatment program substances that you cannot handle, and we can supplement you with substances that you cannot make on your own.  We can bridge gaps in your metabolic software and shore up your weak links – now that we know what your weak links are.  This will be a lot of work and involve a not insignificant out-of-pocket expense, and likely a major change in your diet.  This may irritate you.  You may initially be frustrated and mad.  If you want to be mad, you can be mad at me – but don’t go after me on a busy day – I am COMT -/- and VDR Taq +/+; thus if you stress me out too much I will be susceptible to a fall off in dopamine, serotonin, and norepinephrine, so I won’t think so well (a little Methyl Cycle humor).  Please do not take out your frustration on my staff.  If you are really angry you can complain to your parents, Charles Darwin, or God – a better idea will be to accept and understand this challenge and get to work addressing it.  Along with your genotype report, your packet will contain Dr. Yasko’s general recommendations (which focuses on kids with Autism), my analysis of your genotype with specific recommendations for diet change, nutritional supplementation, and follow-up testing.  Information regarding sulfur avoidance (critical for CBS and SUOX genotypes) and food excitotoxin avoidance (useful for all of us) will be enclosed, along with a supplement check list and information regarding how to obtain these supplements on line or at the office. 

90% of you will have an abnormality in the trans-sulfuration pathway (CBS and/or SUOX).  Sulfites and Chronic Disease, by Rick Williams (available at the office or you can go to www.readingtarget.com/nosulfites) contains a great deal of information regarding the sulfite/sulfate content of common foods and pharmaceuticals.  Read and research on your own, particularly with respect to diet, and report back to us on what worked and what didn’t work with respect to lowering your sulfate/sulfite levels – with feedback from you we can improve our general recommendations.   

Regarding our terminology:  homozygous, heterozygous, (+/+), (+/-), and alleles, let’s start with a review of genetics and gene distribution - we can use me as an example.  I am homozygous (+/+) for MTHFR C677T.  C (cytosine) has been replaced by T (thymidine) in the 699^th nucleotide position in my genes for the MTHFR enzyme.  C codes for the amino acid alanine and T for the amino acid valine.  Thus I have a valine where I should have an alanine within the amino acid structure of 100% of my MTHFR enzymes.  This enzyme will not work well.  It will not efficiently convert folic acid in to one of its active forms, 5-methyl folate.  I can take all the folic acid I want, but I cannot use it.  With respect to this biochemical step, folic acid will actually be toxic to me, as it will crowd out the sparse methyl-folate present in my diet.  If my diet is confined only to folic acid, I am going to have trouble metabolizing homocysteine, and I am going to have trouble carrying out many other critical biochemical steps.  I will be at risk for premature cardiovascular and neurological disease.  If on the other hand I supplement with 5-methyl folic acid, I will have bypassed this genetic block, my biochemistry will revert to normal, and my increased individual risk associated with the C677T abnormality will be 100% resolved.  I also realize that 100% of my kids will be at least heterozygous (+/-) for the C677T allele (if they are not then we will have to look closely at the mailman), and if my wife is heterozygous (+/-) or homozygous (+/+) for the C677T allele, then they too may be homozygous (+/+).  “Allele” refers to a variant, or a slightly different copy, of a gene.  You get one allele for each of your genes from your Mother, and one allele from your Father.  If you know the genotype of both parents, you can predict genotype likelihoods of their offspring (allowing nutritional planning before and during pregnancy – how’s that for intelligent early intervention).  I am heterozygous for MTRR A66G.  A (adenine) has been replaced by G (guanidine) at the 66^th position in 50% of my genes form MTRR.  Thus 50% of my MTRR enzymes will be defective.  I may have received the A66G allele from my Mother or from my Father.  I am going to have trouble converting B12 in to methyl-B12, and this will compromise my health, but as 50% of my MTRR enzymes will function normally, my relative need for methyl-B12 is less than my relative need for methyl-folate, as 100% of my MTHFR enzymes are functioning abnormally.  There are also Methyl Cycle Defects involving deletions or insertion of nucleotides (components of the genetic code) within a gene, and they are referred to by number.  I am (+/+) for ACE Del16.  This means that nucleotides that should be present at position16 of the ACE gene are not present.  This heightens my risk for CV disease.  Other Methyl Cycle Defects are named after the scientist who first described them, such as in VDR Taq or VDR Fok. 

Punnett Square analysis allows us to predict the genotype of our offspring as a function of the genotype of both parents; several examples are presented below.  I’ve used myself as an example, so you’ve seen that I share with you several genetic liabilities – and I am not sick.  Just because you have genetic predispositions it doesn’t follow that you have to be sick.  I haven’t missed a day of work in 15 years and once a year I run a 26 mile Marathon – but I do try to take care of myself, I do take a lot of nutritional supplements, and I have applied the principles of heavy metal and hydrocarbon detoxification to myself.  Now that I understand my Methyl Cycle predispositions, I will be in a better position to promote my own good health.  We want to help you to do the same thing.  Of interest, based upon my current understanding of the link between the Methyl Cycle and disease susceptibility, and what we are seeing in the Methyl Cycle findings of our own patients, I think that if I was born today I would likely suffer from Autism.  But in 1955 there was little if any toxicity in the environment.  The fish did not contain mercury, my Mom did not have Mercury amalgam fillings, and we were not then using Mercury containing vaccines, so my brain was allowed to develop normally.  I will still be susceptible to Mercury and other toxins, but it is a lot easier to defend a fully developed and otherwise healthy physiology from Mercury, microbes, and other toxins, than it is to defend an immature or developing physiology from the same noxious influences.

Cost issues - this will not be insignificant, nor can we expect much help from your health insurance.  American Medicine focuses on doing procedures or prescribing drugs to deal with advanced pathology.  This is what we get paid to do, so this is the medicine you get.  The concept of using nutritional supplements and dietary change, specific to your genotype, to prevent or stabilize disease states such that you will require less drug therapy and invasive treatment will not be well received or encouraged.  Your insurer will consider such concepts to be “experimental” or not “evidence based”.  There is no point in arguing with these people; they don’t get it.  Treatment cost (basically the cost of your supplements) will be your responsibility.  Early on this may run up to $200 per month, but as your sulfate and ammonia burdens fall, so will your requirement for supplementation.  If your genetic challenge lies within the trans-sulfuration pathway (90% or you) our most important approach will be dietary change, and these foodstuffs are less expensive than the foods that you have been eating that have been making you sick.  Also, please put all this in proper perspective.  What did you pay for your car?  Isn’t your health worth a fraction of what you paid for your car?  What is a year of your life worth, to you and to your family?  Do you wish to be vital and/or vocationally active in your 70s, or confined to a nursing home due to a health problem related to a Methyl Cycle predisposition?  Now, if you are on board with me intellectually but are limited with respect to funds, we can try to stream line your program, and again, the harder you work on diet the less you will need to spend on supplements, but please do your best to follow the supplement program. 

Lab testing will be important, and to some extent will be covered by your insurer.  Vitamin D, homocysteine, and blood ammonia levels will likely change in response to our treatments and we will wish to follow these parameters; the cost of these blood levels will likely be covered.  Urine sulfate and/or sulfite testing is critical; here you purchase the urine dipsticks and test yourself and record the results.  We will need to follow your mineral status, as specific nutrients will be drawn in to pathways that were previously closed.  The best approach is a 24 hour urine study for nutritional minerals (with a concomitant measurement of toxic metals, which should start coming out on their own as your detox pathways open up).  If a 24 hour urine is not possible we could use a first AM void “spot urine” or a red blood cell mineral assessment (go to doctorsdata.com for more information on these tests).  Dr. Cowden has reconfigured the Asyra software to help us screen for Methyl Cycle abnormalities.  If ammonia shows up, and you do not work with fertilizer or cleaning solutions, you likely have a problem in trans-sulfuration (CBS and or BHMT) or within the ammonia detoxification pathway (here the NOS enzyme).  If sulfate and/or sulfite show up, then the problem likely lies in CBS/BHMT, while if we see sulfite but no sulfate, then SUOX (converts sulfite to sulfate) is likely the culprit.  Asyra can never be as accurate as actual genomic testing, and at this point we do not have enough experience to say that your Asyra findings will correlate well with your genomic findings, but Asyra is low in cost and easy to carry out and lab testing is often high in cost and logistically difficult to carry out, so we will attempt to get the most information that we can out of the Asyra methodology.  Regarding the urine sulfate determination, to our knowledge a high level of urine sulfate, especially coupled with a low blood homocysteine level, is indicative of a trans-sulfuration (CBS and/or BHMT) defect, but there could be conditions associated with a “false positive” urine sulfate.  Also, if an “upstream” defect limits generation of homocysteine, or if for any other reason you have been limiting animal protein in your diet, you could harbor a CBS defect and have a low urine sulfate.  Thus none of these screening tests can be perfect.  We will need to interpret your test results in the context of what we know of your health and your genotype.  Incidentally, you do not need to repeat your Methyl Cycle Genomics test – these findings will never change. 

Individualized medicine, based upon analysis of one’s unique genetic code, is the future of medicine.  We will do our best to provide you with this approach in 2008.  Right now, our understanding of the Methyl Cycle allows us to translate your unique genomic pattern in to beneficial clinical recommendations.  Over time, more science will become available, as will our expertise in treating abnormalities in your genotype.  Your feedback can only make us better.

The brain behind Methyl Cycle is Amy Yasko PhD.  Dr. Yasko’s area of clinical expertise is in the treatment of Autism.  You can learn much more form her website holistichealth.com.  We use Dr. Yasko’s lab for Methyl Cycle testing, and many of the supplements discussed below can be obtained from her holisticheal.com website.  As Dr. Yasko points out, Methyl Cycle abnormalities are not just the predisposing cause of Autism; they are the predisposing cause of disease in general, the link between environmental toxicity and the degenerative disease states that now plaque our society.  Doctors like me are attempting to utilize Dr. Yasko’s teachings in the care of individuals of all ages (and to optimize their own health). 

Now let’s discuss the individual genes, and our approach to the abnormal patterns that we see in our patients.  90% of the patients who we have tested returned with abnormalities in the trans-sulfuration pathway, specifically in the CBS gene, so we will start with the CBS up regulation.

                                                                                       CBS:  Cystathionine Beta Synthase
 

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), excess ammonia (in the process wasting BH4 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 – 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) will speed up conversion of sulfite in to sulfate.  Vitamin E succinate 400 IU/day and hydroxy-B12 2000 mcg/day are also felt 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.  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.  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.  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.  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 1^st 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 heterozygous 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 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 or methyl cycle supplements, 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 HHC multi is low in B6).  You will need additional (sulfur free) mineral supplementation.  Begin Trace Minerals Complex at 4 drops/day.
4.  To stimulate SUOX begin Molybdenum 3 drops twice a day, Vitamin E succinate 400 IU/day, 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) supplement with NADH one/day, along with Co-enzyme Q10, carnitine, and Idebenone (dosed in accordance with your COMT status) and Ribose 5 grams in water, two to three times a day.
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 4-7 days.  Our goal is to reduce your reading to 400 mg/L (one yellow and three pink squares) and 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 BH4 supplementation 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.
10. Undergo a LED and Nutritional Asyra evaluation (looking for the signals of ammonia, sulfite, and sulfate) which we hope to be able to use to energetically follow the results of our dietary/supplementation efforts. 
11.  In 6-10 weeks we will likely wish to:
a. Repeat some of the lab work.
b. Carry out 24 hour (or first AM voided) urine studies for ammonia and amino acids, with a second study for toxic and nutritional minerals, along with a repeat Asyra evaluation.  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 require more intensive supplementation.  Favorable results will also allow us to back off on the dose of now less necessary supplements.

  MTHFR C677T:  5,10-Methylenetetrahydrofolate Reductase (Þ 5-Methyl-Folate)

The MTHFR C677T defect is easy to understand and even easier to treat, but the consequence of the MTHFR abnormality in kids appears to be profound, such that the parents of Autistic kids add a few more vowels to MTHFR in naming it.  Dietary folic acid, which usually is not in short supply, is readily converted in to one of the active forms of folic acid, known as tetrahydrofolate, or THF.  MTHFR converts THF in to 5-methyl THF, more commonly referred to as 5-methyl folate.  MTR (methionine synthase) then combines 5-methyl folate with homocysteine to form methionine.  Individuals who are (+/+) for MTHFR C677T (10% of the population, including me) have a great deal of trouble using dietary folic acid to detoxify homocysteine, as we cannot efficiently convert dietary folic acid into its 5-methyl folate form.  Elevated homocysteine leads to free radical stress, vascular plaque formation, abnormal clotting, and an increased risk for cardiovascular and neurologic disease – yikes!  If you are (+/+) or (+/-) for MTHFR (another 20% of the population), supplementation with folic acid is not the answer – it can’t help you.  However, low dose 5-methyl folate supplementation will bypass this defect with 100% efficacy.  If you have a MTHFR C677T defect, we need to provide you with 5-methyl folate.
 

Sources of 5-methyl folate include Folapro (800 mcg 5-methyl folate), Metanx (5-methyl folate 2.8 mg, P5P 25 mg, and methyl-B12 2 mg), and Cerafolin NAC (5-methyl folate 5.6 mg, NAC 500 mg, and methyl-B12 2 mg).  Folapro is available over-the-counter, at the office or on line.  Metanx and Cerafolin are available as prescription agents, but your health insurance typically will not cover their cost as they “are just vitamins”. 

Of interest, homocysteine is a known bad actor.  An elevated homocysteine level increases your risk for cardiovascular and neurological disease.  Many studies have been carried out, utilizing various cocktails of folic acid, B6, and B12, or a placebo agent in large groups of individuals, with or without known disease states.  Average homocysteine levels will fall, but not all subjects will respond with a reduction in homocysteine.  Clinical event rates typically fall in response to supplementation, but some studies show no effect, and one study of folic acid supplementation in the elderly showed an increased rate of dementia.  Why did this occur?  You’ve already figured it out.  If we give folic acid to individuals with an elevated homocysteine level and normal MTHFR function, they will respond with a reduction in homocysteine and a reduction in disease risk or event rate, but if we give folic acid to an individual who is MTHFR (+/+) or (+/-), then not much happens.  Actually, if we flood you with folic acid that you cannot use, we can block absorption of the sparse 5-methyl folate present in your diet, so your homocysteine level might even rise.  Also, excess folic acid can be converted in to alpha-ketoglutarate, aggravating a co-existent CBS abnormality.  Thus we can understand how supplementation inappropriate for one’s genotype can have an undesired negative consequence.  I used to think of homocysteine as an individual bad actor, a cause of cardiovascular and neurological disease.  Now I look at an elevated homocysteine not as a bad actor, but as a marker of a real bad actor, that being a Methyl Cycle abnormality.  To further confuse and befuddle research attempting to link homocysteine with disease states, we must also point out that the sickest patients, or the still healthy but at greatest risk individuals in our society, are those with the lowest homocysteine levels, because their homocysteine levels are low not due to a good diet, but because they harbor the CBS up regulation.  I could go on and try to link homocysteine levels with the story of the three bears, but instead we will cover the SHMT abnormality in THF (dietary folate) processing, and then move on to MTR/MTRR. 

                                             SHMT C1420T:  Serine Hydroxymethyltransferase
The “forward” MTHFR 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.  SHMT converts THF in to 5,10-methylene THF (upper left in the diagram above), more commonly known as folinic acid, a building block for DNA.  This defect is easy to overcome with folinic acid supplementation.

  MTR:  Methionine Synthase 

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-B.  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 be compromise.  We treat the MTR up regulation either with methyl-B12 or measures designed to increase formation of methyl-B12.  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).   

MTRR:  Methionine Synthase Reductase

MTRR generates the methyl-B12 needed by MTR and many other methyl-B12 requiring enzymes.  Blood B-12 levels may be normal, but if MTRR is (+/+) or (+/-), methyl-B12 formation will be compromised, homocysteine levels will be elevated, methylation in general will be compromised, and your physiology will be compromised.    

MTR Up Regulation (+) and MTRR Down Regulation (+)

This combination leads to a double whammy on methyl-B12.  You can’t make much because MTRR is not functioning well, and any B12 that you do make gets sucked up by the overactive MTR.  Here the need to supplement with methyl-B12 (or to help you make it on your own) is greatest.  You’d think that the treatment would be straight forward – give the patient methyl-B12.  But remember, this is the Methyl Cycle that we are talking about, the most convoluted, conflicting, and therapeutically confusing physiologic system in the body. 

We will talk about COMT a little later.  COMT degrades dopamine, in the process using up methyl groups.  Individuals who are COMT (+/+) degrade dopamine slowly, and as such have a lot of methyl groups floating around.  If we supplement a COMT (+/+) individuals with methyl-B12 (or any other methyl donor for that matter) we can “OD” them with free methyl groups, too much of a good thing, and this leads to mood swings related to fluctuations in neurotransmitter levels.  Individuals who are COMT (-/-) have normal COMT function; they break down dopamine rapidly, using up methyl groups in the process.  COMT (-/-) individuals need and tolerate methyl donors quite well.  So if you are (+) for the MTR up regulation and/or (+) for the MTRR down regulation, and you are also COMT (-/-), all we need to do is to give you methyl-B12.  We are giving you the methyl-B12 that you need, and any extra methyl groups left over can be put to good use.  Conversely, if you are COMT (+/+), we know that you have an excess of methyl groups floating around.  We will give you hydroxy-B12, expecting it to combine with the methyl groups available to form the methyl-B12 you need (without ODing you with too many free methyl groups).  This is all very confusing, and it gets worse when we consider the individual who is (+/-) for COMT, and when we factor in how one’s VDR gene status interacts with their COMT status.  I will give you specific recommendations, whether you need methyl-B12, hydroxy-B12, or both in combination, in my analysis of your Methyl Cycle genotype.  B12 is reasonably well absorbed orally or via the sublingual route, and we can also administer it by injection, depending upon your individual needs and preferences.  Now let’s move on to the previously alluded to “backdoor” reaction. 

This combination produces a double whammy on methyl-B12.  You can’t make it well because MTRR is not functioning well, and any B12 that you do make gets sucked up by the overactive MTR.  Here the need to supplement with B12 is greatest.

BHMT:  Betaine-Homocysteine Methyltransferase

 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.  Phosphatidylserine 100 mg daily, or as an alternative, Phosphatidylcholine, to stimulate the BHMT reaction.  The former is less expensive and easier to take, while the later, administered as Lipophos Forte orally or as Lipostabile/Plaquex IV, stimulates HDL-mediated reverse cholesterol transport, providing a powerful anti-atherosclerotic benefit.  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 metyl 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 

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.  To summarize in chart form: 

* I am COMT H62H and L136L (-/-), but my wife refuses to believe this! 

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.

VDR Taq:  Vitamin D Receptor Taq Abnormality

Vitamin D has many functions, an issue because 90% of my patients have low or low normal Vitamin D levels.  Pertinent to this discussion, Vitamin D stimulate the enzymes that generate dopamine, a good reason to keep your Vitamin D level up, as we need dopamine to defend against microbes and metals, and to keep our mood up.  While we utilize SAMe (and indirectly other methyl group donors) to degrade dopamine, we also utilize methyl donors to generate dopamine.  Individuals with a normal Vitamin D receptor, those who are VDR Taq (-/-), make plenty of dopamine.  They tend not to need or to tolerate methyl groups or dopamine precursor substances.  With respect to methyl group need and tolerance, they behave like COMT (+) individuals.  Individuals (+/+) or (+/-) for VDR Taq defect have lower Vitamin D levels, make less dopamine, and will need and tolerate dopamine precursor substances and methyl donors.  With respect to methyl donor tolerance, VDR Taq (+) individuals behave like COMT (-) individuals.  All sorts of permutations are possible here, impacting on your tolerance and need for dopamine precursors and methyl groups.  I acknowledge that this is all very difficult to understand.  Hopefully the chart below will help.

MTHFR A1298C:  5,10-MethyleneTetraHydroFolate Reductase (Þ BH4)

The MTHFR C677T defect effects the “forward reaction”, the conversion of THF in to 5-methyl folate.  MTHFR A1298C has no adverse affect on 5-methyl folate production, but it does compromise the “backward” reaction, whereby 5-methyl folate is converted back in to THF, in the process generating one molecule of BH4.  Individuals with abnormalities in CBS and BHMT will be low in BH4, as it is being used up detoxifying ammonia that these defects have generated, so their combination with MTHFR A1298C leads to a BH4 deficiency double whammy.  DHPR is the enzyme that regenerates BH4 from BH2.  It is poisoned by mercury, lead, and especially aluminum.  These toxins are wide spread in our environment, and individuals with Methyl Cycle abnormalities have particular trouble dealing with them.  The result is a progressive drain on BH4, a progressive impairment in neurotransmitter production, and conversion of arginine not in to nitric oxide but instead in to free radicals such as superoxide and peroxynitrite.  We treat MTHFR A1298C with 5-methyl folate supplementation (aiming to push the reaction backwards) and, after your other Methyl Cycle challenges have been addressed, nutritional doses of BH4.  Metal detoxification will help here and with every other biochemical function in your body, and will be part of our overall program for you.  We will also endeavor to decrease your need for BH4.  If you are COMT (-/-), we can provide nutritional support to help maintain dopamine levels, such that you will need to use less BH4 to generate more.  If you are MAO A (-/-), we can do the same thing with serotonin precursors such as high tryptophan foodstuffs.  The basic philosophy is to stimulate the action of still open pathways to take the stress off your impaired pathways.

NOS:  Nitric Oxide Synthase 

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.  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.  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.  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.   

ACE:  Angiotensin Converting Enzyme

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.  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, 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. 

Glutamate – GABA Imbalance Þ Excitotoxicity

Glutamate 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.  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 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 (preferably enhanced with a static magnetic field therapy; of interest, toxicity due to mercury is aggravated by glutamate excess – they synergize to damage nerve cells).  

*Long list in the appendix 

The Methyl Cycle abnormalities presented below are not as well understood (at least by myself):                                        

                                                   MAO A:  Monoamine Oxidase A
Monoamine Oxidase A breaks down serotonin, a neurotransmitter that is generated from the dietary amino acid tryptophan, in a BH4 requiring reaction.  Many anti-depressant drugs, including the SSRIs (Serotonin Selective Reuptake Inhibitors) work by blocking the breakdown of serotonin.  Defects in serotonin metabolism have been associated with mood and neurological disorders.  How best to address the MAO A R297R abnormality is not clear to me.  As serotonin metabolism is adversely affected, individuals with the R297R defect should avoid large doses of high tryptophan foods (see appendix).  High doses of St. John’s Wort, often taken to address depression, could lead to mood swings as serotonin levels fluctuate.  Dr. Yasko recommends frequent dosing in small amounts of St. John’s Wort, 5HTP (a tryptophan metabolite), and the Mood S RNA formula if serotonin support is needed.  If serotonin production is impaired on the basis of BH4 deficiency secondary to a Methyl Cycle abnormality, as the abnormality itself is addressed, BH4 levels should stabilize, hopefully normalizing serotonin production.   

                                       ACAT 102:  Acetyl Co-Enzyme A Acetyltransferase
ACAT is involved in cholesterol and energy metabolism, helping to mediate the conversion of foodstuffs into biological energy.  ACAT dysfunction may lead to B12 deficiency.  Right now, I do not understand ACAT well and am not sure how important this is. 

                                           AHCY