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Methyl Cycle NutriGenomics


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

CBS: Alternate Explanation and Generic Plan of Action

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

Approaches to Detoxification

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

Appendix IV:  Elevated Urine Sulfate - What Do You Do Next?

Appendix V:  General Recommendations Based Upon the Sulfate Value 

Appendix VI:  Methyl Cycle Recipes 

Nurtigenomic Supplements and Supplies

Ordering Supplements from Websites 

What You Can and Cannot Expect From Us

Sample Report

Life Wave Patch Instructions


Methyl Cycle Genomic Analysis and Supplementation

Understanding how to incorporate the science of Methyl Cycle Genomics in to your treatment program, and how best to monitor your individual 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 (your health status – the expression of your genotype).  We can’t change your genotype, but we can optimize 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 677th 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 66th 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.

  

Both Parents (+/+)
100% of kids (+/+)

Mother (+/+)

Both Parents (-/-)
100% of kids (-/-)

Mother (-/-)

+

+

-

-

Father (+/+)

+

+/+

+/+

Father (-/-)

-

-/-

-/-

+

+/+

+/+

-

-/-

-/-

When both parents are homozygous (+/+) all of their kids will be homozygous (+/+)

When both parents are homozygous (-/-) all of their kids will be homozygous (-/-)

 

 

 

 

 

 

 

 

Both Parents (+/-)
Kids will be

Mother (+/-)

Parents
(+/+) and (+/-)

Mother (+/-)

+

-

+

-

Father (+/-)

+

+/+

+/-

Father  (+/+)

+

+/+

+/-

-

+/-

-/-

+

+/+

+/-

When both parents are heterozygous,
 1
/of their kids will be homozygous (-/-),
 ½ will be heterozygous (+/-), and
1
/will be homozygous (+/+)

With (+/+) and (+/-) parents,
½  of their kids will be homozygous +/+), and          ½ of their kids will be heterozygous (+/-)

 

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.  The 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 (we often see deficiencies in Molybdenum, Boron, and Copper).  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 have seen false positive and false negative Asyra Methyl cycle 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 (AHCY +/+ or +/- does this), 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 (we do see this).  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, which stimulate the stress/cortisol “fight or flight” response), 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), 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.  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 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 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 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, 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 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. 


CBS: Alternate Explanation and Generic Plan of Action

Gene by Gene Approach – CBS +/- or +/+ with/without BHMT +/- or +/+


CBS (Cystathionine Beta-Synthase) is discussed on pages 48-53 of Dr. Yasko’s book, Genetic Bypass.  Additional information is available on our heartfixer.com website.  You are +/+ (all CBS enzymes abnormal) or +/- (half of your CBS enzymes abnormal) for one of the two CBS up regulations and you may also be +/+ or +/- for one of the BHMT down regulations (which act like CBS up regulations).  Homocysteine (and its Methyl Cycle precursors) is being drawn down the trans-sulfuration pathway, in this process generating excessive sulfur break down products (sulfite and sulfate, which stimulate the stress/cortisol “fight or flight” response), too much alpha-ketoglutarate (which leads to glutaminergic excitotoxicity), hydrogen sulfide (to produce brain fog), and too much ammonia (which depletes BH4, leading to insufficient dopamine and serotonin production).  This deficiency in BH4 allows NOS (nitric oxide synthase) to convert arginine in to free radicals (superoxide and peroxynitrite) as opposed to nitric oxide, predisposing you to hypertension and  cardiovascular and inflammatory disease states. 

During normal physiology, metabolic flow down the CBS pathway is designed to generate the important anti-oxidant and detoxifying molecules glutathione, taurine and cysteine (all involved in detoxification and endothelial health), and alpha-ketoglutarate (which can be converted into GABA, a calming neurotransmitter).  The CBS C677T and A360A genes code for enzyme function that is pathologically up regulated.  Of the two, the C677T allele is the most important, producing enzyme activity that is 10 fold greater than normal.  You thus suffer from “too much of a good thing and way too much of several bad things”. 

While sulfate and sulfhydryl (-SH) bearing molecules are important in detoxification, sulfate/sulfite/-SH excess blocks cellular up take of the key detoxifiers glutathione and cysteine.  Endogenous detoxification is thus blunted (nearly all kids with Autism Spectrum Disorders bear CBS up regulations – why they are compromised by environmental toxins and the kid next door is just fine).  Conversely, after we decrease your sulfate/sulfite pool, your detox pathways open up (and why, if we move too fast, you will experience detox phenomena).

The excess ammonia generated must be detoxified, and to do so BH4 (tetrahydrobiopterin) must be “spent”.  This is a problem in that we need BH4 to generate neurotransmitters (serotonin to maintain calm/prevent depression and dopamine to maintain motivation and drive).  Without BH4, we cannot convert arginine in to nitric oxide; instead vascular wall toxic free radicals such as superoxide and peroxynitrite are created, leading to hypertension and cardiovascular disease.

Alpha-ketoglutarate, in moderation, is not a problem.  We should be able to interconvert alpha-ketoglutarate into glutamate, glutamine, and GABA.  However, when alpha-ketoglutarate is in excess, or if toxic metals compromise the interconversion enzymes, then we suffer a buildup of the excitatory neurotransmitter glutamate.  Glutamate is involved in alertness and learning, but excess glutamate leads to irritability and over-excitement; toxic levels may play a role in seizure activity and cardiac arrhythmia (could this be why we are seeing so much atrial fibrillation now then we were ten years ago)? 

CBS up regulations lead to an initial buildup of potentially neurotoxic sulfite, which is then metabolized by SUOX (Sulfite Oxidase) to the less neurotoxic (but still problematic at high levels) sulfate.  SUOX activity requires molybdenum, which is thus depleted in CBS + individuals.  Homogenized dairy products contain xanthine oxidase, which uses up molybdenum, and are best avoided or minimized.  Vitamin E succinate, boron, and B12 are felt to stimulate SUOX activity.

 As Methyl Cycle function is needed in the biosynthesis of Co-Enzyme Q10 and Carnitine, individuals + for CBS will likely be energy depleted, and here supplementation (in relation to your COMT/VDR status) with Co-Enzyme Q10, Carnitine, and NADH may be helpful.

 
BHMT (Betaine Homocysteine Methyl Transferase) directly methylates homocysteine back in to methionine, serving as a “back door” pathway to “pull” homocysteine away from the CBS “sulfate drain”.  Thus if you bear CBS or BHMT abnormalities, it makes sense to support BHMT function.  DMG (dimethylglycine) and TMG (trimethylglycine) stimulate BHMT, and can be utilized if you are not overly sensitive to methyl group supplementation (based upon you COMT/VDR status).  Phosphatidylserine stimulates BHMT (and we also use it to moderate elevated cortisol levels), as does phosphatidylcholine (which we use to treat atherosclerosis).  Phosphatidylcholine can be admixed with EDTA (detoxifies metals), creating a quite useful supplement. 

 Many of you with CBS and BHMT abnormalities will also bear MTHFR (compromising methyl-folate generation) and MTRR (compromising methyl-B12) abnormalities, and thus you will need and benefit from corresponding supplementation (with these molecules that they are having trouble making).  However, if we treat you with methyl-folate, methyl-B12, or BH4, before we have the CBS problem under control (sulfite/sulfate levels decreased enough to allow for appropriate glutathione and cysteine assimilation) then we will be subjecting you to “incomplete detoxification”.  You will feel great for 1-2 days, as beneficial neurotransmitters are generated.  Methyl-folate and methyl-B12 detox pathways will then open up, creating toxic intermediates that cannot be metabolized further due to the block in glutathione utilization – and you will feel horrible.  Thus we need to resist the temptation to treat your MTHFR/MTRR abnormalities until CBS/BHMT are under control.  You’ve lived your entire life with a gene set that is maladaptive to the toxic environment of modern man.  It will take us some time to change your internal environment to “bypass” these genomic challenges.    

 

Plan of action for CBS +/- or +/+ (BHMT discussed further in other sections)
(made out of context of your MTHFR, MTR, MTRR, COMT, VDR, and personal health status)

To address this constellation of alleles I will recommend:
1. Moderate* animal protein intake (anything with eyes) and avoid sulfur rich vegetables, sulfur containing supplements,  and sulfur containing drugs (see attached sulfur avoidance instruction sheets and read Sulfites and Chronic Disease by Rick Williams, available at the office or at www.readingtarget.com/nosulfites/. 
2. Check the sulfate/sulfite content of your supplements and prescription agents (many listed in the Williams book) and whenever possible switch to agents with lower sulfate/sulfite content.
3. Monitor urine sulfate levels every 3-7 days (or when you feel particularly good or poorly, or after adding a new treatment or changing your diet).  Please chart the levels – this will be our primary measuring stick – our goal is a urine sulfate of 400 (one yellow and three pink) to 800 (two yellow and two pink).  Low levels will allow an increase in methyl cycle supplementation and later the addition of BH4 and/or a liberalization of your diet.  Conversely, persistent high sulfate spills indicates that your diet/treatment program needs further modification.
3. To neutralize ammonia (generated from animal protein), you can use Ammonia Support RNA ½ dropper with meals and with methyl cycle supplements (relatively expensive), along with a charcoal supplement at bedtime every other evening, away from other supplements (magnesium citrate may be used as needed to keep the GI tract moving as charcoal may lead to constipation).  Yucca, beginning at ½ capsule, twice a day, (or sprinkled on food containing protein), may help with ammonia detoxification.  These supplements can be tapered down as ammonia levels fall.
4. Sparga Detox, 10 drops in water (wait at least one minute before consuming), twice a day makes sense.  Sparga was developed by fellow Cardiologist Dr. Lee Cowden, specifically to address the CBS abnormality (see www.nutramedix.ec).
5. For nutritional support, a low-sulfate multi such as Dr. Yasko’s All in One, two twice a day, makes sense.  To stimulate SUOX activity, please use sublingual hydroxy-B12 2000 mcg/day, along with Molybdenum and Boron.  They may be taken individually as Molybdenum 3 drops in water twice a day and Boron 3 mg once a day, while our Complete Mineral Complex, 3 daily will cover the mineral base.  Avoid B6 (unless you need it for other functions), which stimulates CBS.  The active form of B6, P-5-P, is less of a problem here and serves as a B6 substitute.
6. Glutathione supplementation runs the risk off adding to your sulfite/sulfate burden.  Right now this “good thing” could actually set you back.  However, if we could convince your biochemistry to up regulate biosynthesis of glutathione, then your anti-oxidant and detox capacity will increase, with concomitant utilization of free sulfate/sulfhydryl groups – a double win for you.  This can be achieved with the use of the Life Wave (needleless acupuncture) Glutathione patch.  The Life Wave people have demonstrated an increase in Glutathione levels in relation to patch use (please see separate information sheet on Life Wave patch use).  Toxicity testing** may also be carried out.
7. If you feel anxious or “wired up” (glutamate overload), take GABA 500 mg or Zen (GABA 550 mg with Theanine 200 mg, a methyl donor) twice a day.  Individuals who need methyl groups (normal COMT and/or abnormal VDR Taq alleles) will do better with Zen, while individuals who are methyl group sensitive (COMT+) will likely do better with GABA.  If they are helpful you can double the dose.  GABA does not work rapidly, but if you take it twice a day you will build up a GABA reserve to balance the glutamate overload you are experiencing due to your CBS up regulation.  Magnesium supplementation may help with GABA physiology and often helps with sleep.  
8. If energy is low, or if deficiencies are identified on your NutrEval study, we can supplement you with Co-Enzyme Q and Carnitine, keeping in mind that these substances provide methyl groups, to which you may be sensitive.  NADH does not provide methyl groups and should be well tolerate by all.
9. Your homocysteine level will give us important information as to the functional expression of your CBS/BHMT genomic abnormalities, and should be drawn before any diet change/nutritional intervention is carried out.  Formal nutritional testing will be carried out in 8-12 weeks.  This could involve separate 24 hour urine studies for nutritional minerals and for ammonia/amino acids, or we might use the Genova Labs NutrEval.  We need to make sure your mineral/nutritional stores are replete, and we are looking for low levels of ammonia, taurine, glutamate, and cysteine, to demonstrate that flow down the CBS pathway has been decreased to a physiologic level.
10. After sulfate levels have fallen (to a level that you and I feel is optimal for you, based upon your clinical and genomic status), then we will begin supplementation with methyl-folate, methyl-B12, and BH4.  This will take some time.
11. Be self-observant and keep records.  Which foods, supplements, or other maneuvers increase or decrease your sulfate spill?  Which make you feel better or worse?  Always keep in mind that detoxification is not a fun experience.  You may need to accept some transient fatigue, malaise, and achiness to allow toxic molecules to be cleared.  Conversely, if detox symptoms are debilitating or compromise your ability to work or care for your family, then we need to back off on your treatments.  Balance needs to be achieved.  Rectifying your genomic predispositions and detoxifying your system is not a sprint – it is a marathon.  And, as your genes are not going to change, and as the environment is not going to become less toxic, you will need to be mindful of these principles for the rest of your (long and healthy) life.

* How tightly should you restrict dietary protein?  The degree of protein restriction best suited for you will be in relation to your personal health characteristics and your clinical and biochemical (urine sulfate and ammonia levels) response to treatment.  We need to keep in mind that Methyl Cycle Genomics is not the sole determinant of your health.  A low protein diet could become a high carbohydrate, weight gain diet in an overweight individual with adult onset diabetes, nor do we wish to create an essential amino acid deficiency.  Individuals with chronic, unexplained illness or significant toxicity would do well to follow the “nothing with eyes” diet until urine sulfate and ammonia levels have fallen; later on we will liberalize your diet, while keeping an eye on these biochemical markers.  This maneuver isn’t fun and will require personal strength, but it also may turn your health around.  Individuals in whom the CBS up regulation is less important (A360A as opposed to C677T, lower urine sulfate and ammonia levels, and better overall health), could simply cut back on animal protein.  In addition, the greater representation of ammonia reducing (Yucca, Charcoal, Sparga, Ammonia Support RNA) treatments in your program, the more protein you will be able to take in without compromising your biochemistry.  This is all about balancing diet against treatment response.  

 

** The point of Methyl Cycle analysis/treatment is to help you become a more efficient detoxifier.  Toxicity testing (discussed in more detail in other presentations and on heartfixer.com) thus makes sense.  This could take the form of:
A. The NutrEval provides us some information regarding organic pollutants and gives us red cell (reflecting what your physiology has been exposed to over the preceding three months) toxic metals ($170 with commercial insurance; fully covered under non-HMO Medicare).
B. The US BioTek study gives us information on seven major organic pollutants ($126).
C. A formal provocative challenge gives us our best assessment of tissue metal burden.
D. The Hunt Digital picture approach assesses for toxicity (and other health challenges) by analyzing the frequencies emitted by your body (and tells us which Digital Homeopathic Patches would be most appropriate).  I can’t prove this approach with an allopathic lab test but it has been quite helpful in solving complex medical problems in my personal patients.  Dr. Hunts CD is available for your review and you can go to www.auraexplorationpatches.com for additional information.
                                                                                        

OUR FIRST GOAL WILL BE TO REDUCE YOUR SULFATE STORES
                                                                                    AND DECREASE AMMONIA AND GLUTAMATE GENERATION                                                                                                                                                                                                             


  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
 

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.  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).


  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-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 be 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).
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.   


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.  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 

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: 

COMT H62H  (+/+)
COMT L136L (+/+)
COMT 61         (-/-)

Highest dopamine levels
Lowest need for and tolerance to methyl group donors
Greatest susceptibility to mood swings

COMT H62H  (-/-)
COMT L136L (-/-)
COMT 61       (+/+)

Lowest dopamine levels
Greatest need for and tolerance to methyl group donors
Lower susceptibility to mood swings*

* 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.

 

 

 

 

 

COMT    (+/+)

VDR Taq (-/-)

Highest dopamine levels
Better tolerance to toxins and microbes
Low need tolerance for dopamine precursors and methyl donors
Greatest susceptibility to mood swings

In such as individual, we would utilize the “un methylated” forms of Methyl Cycle intermediates.  If an MTR/MTRR defect increases your need for methyl-B12, in this individual we would start with hydroxy-B12, to avoid ODing you with methyl groups, expecting that with enough hydroxy-B12 and free methyl groups floating around you will form up some methyl-B12, even if MTRR activity is compromised by a defect.  We would not give your dopamine precursors such as quercetin or the herb macuna puriens.  We would not advise a diet high in tyrosine, the amino acid precursor of dopamine.  COMT (+/+) VDR Taq (-/-) individuals will be susceptible to iodine and lithium depletion as they detoxify, and we will have to watch for this and supplement accordingly.

COMT    (-/-)

VDR Taq (+/+)

Lowest dopamine levels
Poor tolerance to toxins and microbes
Needs and tolerates dopamine precursors and methyl donors
Lowest susceptibility to mood swings

In such an individual, we would utilize the methylated forms of Methyl Cycle intermediates, including methyl-B12 if n TR/MTRR defect is present.  Dopamine precursors such as quercetin, ginkgo biloba, and the herb macuna puriens might be helpful, as would a diet high in tyrosine, the amino acid precursor to dopamine.  Other methyl donors, including melatonin, TMG, turmeric, theanine, along with MSM and SAMe (the latter two only for CBS (-/-) individuals) would make sense. To support BHMT, instead of Phosphatidylserine, we would use Pedi-Activ, which contains Phosphatidylserine and DMAE, a methyl donor.  Rather than using GABA to deal with excitotoxicity, we would use Zen, which combines GABA with the methyl donor threanine.

COMT (+/-) and VDR (-/-) behaves like COMT (+/+)
COMT (+/-) and VDR (+/+) behaves like COMT (-/-)

Multiple (+/-) combinations of COMT and VDR Taq are possible.  We will address these “intermediate” genotypes with intermediate levels of methyl group supplementation.  I will be more specific on your individual report.

 


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, with nutritional doses of BH4.  Metal detoxification will help here and with every other biochemical function in your body, and will be part of your overall program.  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 (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.    

 


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 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.

 

Sources of Excitotoxins – Short List*

Glutamate

Glutamic acid, glutamine, MSG, peas, tomatoes, parmesan cheese

Aspartate

Aspartame, Nutrasweet

Whey protein

Soy protein

Hydrolyzed anything

Cysteine

Malted barley

Malt extract

Natural flavoring(s)

Guar gum

Gelatin

Carrgeenan

Soy sauce

Bouillon

Vegetable gum

Broth/Stock

Yeast extract

Autolyzed anything

*Long list in the appendix 

Treatment Options

Pycnogenol and grape seen extract help balance Glutamate/GABA

Taurine helps in this balance (but contains sulfur so avoid if CBS (+)

Montief GABA

ZEN

Contains threanine, which has methyl groups; avoid if COMT (+)

   


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  S-Adenosylhomocysteine Hydrolase
S-Adenosyl Methionine (SAMe), the key methyl donor generated from methionine, is metabolized in to S-Adenosyl Methionine, and then on to homocysteine by AHCY.  Individuals (+) for both AHCY and CBS often have low baseline urine sulfate levels, which then rise and fall  in response to treatment.  Early on the levels rise, as the “bottle neck” abnormal AHCY enzyme has been “limiting the supply” of homocysteine.  Once the cycle starts to spin, homocysteine is made available to CBS, and urine sulfate will rise.  Later, in response to a low animal protein/low sulfur diet, urine sulfate levels will fall.  Defects in AHCY are addressed by measures designed to improve overall Methyl Cycle function, such as Methyl support RNA 1/8th dropper per day.

                                                                         VDR Fok
The VDR (Vitamin D Receptor) Fok defect affects blood sugar control and pancreatic function.  It does not affect dopamine metabolism.  Dr. Yasko recommends Vitamin K and generalized support of pancreatic function and sugar regulation (low carbohydrate diet, supplementation with chromium, etc.) when the VDR Fok abnormality is an issue.


Approaches to Detoxification

Overview – Environmental toxicity (organic pollutants and heavy metals) is a grave threat to health – your health and that of your descendents.  Lifestyle factors (which you can alter) interact with genomic “weak links” (which we can analyze and help you bypass) to determine at what age you will become ill (when the toxins will get to you).  The most important thing that we can do (after getting you through an acute health care crisis) is to optimize your intracellular nutritional status, and then move Heaven and Earth to identify, and then remove, every toxic molecule from your body – to return your biochemistry to the pristine state that Evolution and/or Our Creator intended.  A goal of Methyl Cycle analysis/treatment is to help you become a more efficient detoxifier.  Toxicity testing and detoxification thus makes sense.  These concepts are outlined below and are discussed in greater detail on heartfixer.com and in our presentations (DVDs and information sheets are available to you).

Diagnosis – Which toxins do you bear and why did you retain them? 

1. Genomic Analysis:  While we can and will detoxify you without knowledge of your genomic status, an understanding of your inherited weak links will alter (and improve) our approach.
Methyl Cycle Nutrigenomics:  The Methyl Cycle is the backbone of your biochemistry.  Methyl Cycle defects prevent you from coping with environmental toxins, viral and bacterial invaders, and compromise proper reading of your genetic code.  Chronic, difficult to explain disease states, neurodegenerative conditions involving the young and premature “age related” conditions likely reflect an interaction between environmental toxins and Methyl Cycle predispositions.  While we can’t change your DNA, if we know your weaknesses, we can create nutritional “work arounds”, improving your ability to detoxify and defend.  Methyl Cycle testing is available (
» $550 via holisticheal.com and » $100 through 23andme.com).  This information will alter the way I treat you.  Upon request, I can create a detailed analysis/treatment plan, based upon your DNA findings, personal health and nutritional status, and toxin burden.
Detoxification Genomics:  We vary in our ability to activate (Phase I) a toxin, and then to combine it with a chaperone molecule (Phase II) that escorts it out through the kidneys or GI tract.  If I know your detox weak links then I can support them with specific supplements/dietary interventions. Detox Genomic testing is available through Genova Diagnostics (
» $500) or through 23andme.com (included in the $100 for your Methyl Cycle data).

2. Organic Pollutants:  These are non-metallic, fat-soluble molecules that bioaccumulate and compromise our physiology (and that of our offspring), particularly with respect to weight gain, diabetes, and neurologic disease.  Agent Orange, phyllates, bisphenol A, pesticides, and petroleum products are a few of the 100s of organic pollutants to which we (and our Mothers) have been exposed to (yes, this stuff readily crosses the placenta).  Fat, liver, and nerve biopsies would give us the most complete measure of organic pollutant burden but obviously are not practical.  We can estimate your tissue pollutant burden with:
A. The US BioTek organic pollutant screen looks at seven common organic pollutants and compares your personal levels against that of the rest of the US population.  This $125 test is easily done at home (a dipstick is dipped in a morning urine sample and then sent to the lab). 
Its downside is that it weighted more towards recent exposure then to chronic body burden.
B. The Genova Labs NutrEval gives us markers of Styrene and Petroleum product exposure, along with a great deal of ancillary information regarding nutritional and detox function.  The NutrEval is covered by Medicare (not with Aetna/Humana secondary); with commercial insurance the out-of-pocket co-pay is $170.  This is the best single test in Metabolic Medicine.
C. Metametrics provides more extensive organic pollutant testing, at a cost between $ 250 and
$ 600.  This is the best test available but perhaps not the best use of your resources.

3. Heavy Metals:  Metals enter our tissues, bind to proteins, and leave only slowly - if at all (the half-life of mercury in the nervous system is 10-20 years).  Metal exposure may vary, in relation to where you live and work, but as innate detox is so slow, metals bioaccumulate.  Tissue levels rise with age, with a concomitant increase in your risk for metal-induced or metal-aggravated disease states (conditions associated with inflammation or oxidative stress – neurologic and cardiovascular).  We need to estimate your body burden and then remove these elements that can do nothing but harm. So how best to estimate the level of metal accumulation within your internal organs?
A. Blood levels reflect recent exposure, and are of value in monitoring lead exposure in kids, industrial exposure in adults, and in epidemiology studies.  However, blood metal levels bear little relation to body burden, and are not of value in adult detoxification medicine.
B. Red cell metal levels tell us what your physiology has been exposed to over the preceding three months.  Red cell metals (and minerals) is included in the NutrEval, or could be obtained for $ 136 from Drs. Data.
C. Provocative Challenge is the accepted best estimate of body burden.  Here we administer oral and IV metal binding agents, with metal quantitative in a subsequent six hour urine collection.  Your cost ($250) includes our fee, the lab fee, and the IV and oral chelating agents utilized.
D. QuickSilver provides a blood, hair, and urine mercury assessment, and estimates the percentage of your mercury burden that is organic vs. inorganic in nature.  Cost is $ 350.

Treatment – How do we get this stuff out of you?
Methyl Cycle and Detoxification Genomic Abnormalities:  Nutritional supplementation and dietary avoidance measures are recommended, specific to your individual inherited weak links.
Chelation Therapy:  A generic term referring to the administration of agents that bind to and then remove toxic metals (but not organic pollutants) from your body.
1.  Mg-EDTA:  A series (20-30) of 3-hour IV infusions containing Mg-EDTA, B-Complex and Vitamin C.  Mg-EDTA was used in the NIH sponsored Trial to Assess Chelation Therapy (TACT, which demonstrated an 18-38% reduction in 5-year adverse event rate when chelation therapy was added to standard pharmaceutical/interventional management in individuals with prior heart attack). I have been treating my patients with Mg-EDTA for 20 years; we were first amongst cardiology practices and third overall with respect to patient participation in TACT).    When Lead and Cadmium are the problem, EDTA is the most effective chelator, and IV therapy is the most efficient approach.  The magnesium content is also helpful in BP management.
2. Ca-EDTA:  Calcium-EDTA alone is infused over 10 minutes.  With respect to metal removal, both IV approaches are likely equally effective, but here you do not receive IV nutritional support.  We favor Mg-EDTA in individuals with cardiovascular disease/hypertension and Ca-EDTA in younger patients (or if time constraints preclude you receiving a three hour treatment).
3. Essential Daily Defense (EDD):  EDD is a mixed oral chelator that is taken concomitant to any IV chelation (blocks recycling of bound metals from the GI tract back to the circulation).
4. DMPS:  25 years ago, our only toxin was Lead, and EDTA was all we needed.  Today we are being bombarded with “new and improved” toxins, particularly Mercury.  EDTA does not remove Mercury from your cells!  We remove mercury with “di-thiol” chelators:  DMSA and DMPS.  We can address Mercury toxicity with IV DMPS, but the application of liposomal DMPS complexed with Glutathione to your skin is easier for you and is more cost-effective.  Compared to EDTA, DMPS binds less avidly to Lead and is not an efficient Cadmium chelator.
5. DMSA:  Available over-the-counter or by standard or compounded prescription, DMSA will bind to and remove Mercury, Lead, and Cadmium, but DMSA is not as powerful as EDTA or DMPS.  DMSA is typically taken as 500 mg, 3 times a day, over 3 consecutive days, once a month, or within a program of DMSA 500 mg near bedtime, 10 nights on, 5 nights off.
6. Liposomal Phosphatidylcholine-EDTA (DetoxMax Plus):  Liposomes of Phosphatidylcholine serve as drug delivery vehicles for EDTA, dramatically enhancing its absorption following oral administration.  Lipophos EDTA serves as a slow and steady approach to metal detoxification, of particular value to patients with vascular insufficiency (please see our DVD presentation).
7. Med Five:  Med Five is a patented enteric coated EDTA/phosphatidylcholine tablet that we feel is better absorbed than standard oral EDTA preparations (see www.medfive.com).  I helped design Med Five and am a co-holder of its patent.  My personal patients can obtain Med Five at a discount (you receive a password).  The discount is a plus for you and resolves conflict of interest concerns (otherwise I would not be able to talk to my own patients about a health promoting approach that I helped create).
8. Battle Plan for Mercury:  This protocol, which addresses heavy metal overload with specific focus on Mercury, was developed by my mentor and good friend Dr. Robert Battle.  Dr. Battle Plan is typically run over 2-3 months and consist of:
A. Algas, 10 drops in 2 oz. of water (let it sit 1 minute before drinking) twice a day – odd days,
B. NDF, 8 drops sublingual twice a day - even days (start at 1 drop and increase as tolerated), &
C. Chlorella 5 twice a day, all days.
This protocol is typically well tolerated by individuals with CBS up regulations, but if detox symptoms (fatigue, malaise, muscle aching) develop, then the doses of Algas and NDF may be decreased.  Dr. Battle often uses this protocol to help clear Mercury before beginning Lead and Cadmium detoxification with EDTA.
9. Metalloclear:  This Metagenics product promotes metal and organic pollutant detoxification.  Nrf2, when translocated to the nucleus, codes for the production of antioxidant and detoxification enzymes.  Metalloclear promotes nuclear translocation of Nrf2 and MTE (Metal Transcription Factor), which codes for the generation of our endogenous metal binder Metallothionine.  Metallothione’s job in health is to store Zinc and Copper, but it will also bind, and then transport to the liver for elimination, toxic metals such as Lead, Cadmium, and Mercury.  Monotherapy with MetalloClear involves three tablets twice a day (with food) over 10 days, but we often use it as an adjunctive or maintenance therapy at one tab twice a day.
10. Glutaclear:  This Metagenics product provides N-Acetyl Cysteine, Selenium, and Vitamin C, to increase Glutathione production, along with Broccoli extract, to promote Nrf2 translocation.  We typically recommend one tab twice a day.
11. Aura (Digital Homeopathy) Organ Detox Patches:  Digital homeopathy is an in-depth discussion (so we have DVDs, CDs, and handouts), but basically the patches emit frequencies that permeate your meridian system and neutralize toxins that you bear.  The toxins will not be removed, but rather electrostatically neutralized (allowing us to remove them in a deliberate fashion).  We can’t prove that this method works, but I think it does, and it is relatively inexpensive ($35 for a one month supply – typically worn over 2-3 months).  This methodology can also be used to estimate your body burden of toxins and screen for other health challenges.
12. Static Magnetic Field Chelation:  Exposure to a static magnetic field increases intracellular energy potential and increases the efficiency of any metal chelation program that we might employ.  This is the basis for MME and magnetic sleep pad assisted chelation – a huge step forward!  MME combined with chelation is providing outcomes that aren’t supposed to occur – please review the website to see what we are accomplishing.  My personal patients receive a discount when they purchase a negative field only sleep pad at magneticosleep.com.
13. Asyra Homeopathic Detoxification:  Utilizing a physics similar to that of the Aura Patches, our Asyra device imprints treatment frequencies, specific to you, into a homeopathic carrier liquid – you take sublingual drops twice a day.  Asyra is repeated and new drops are generated every 2-3 months over 1-2 years.  Again, we cannot prove this approach with an allopathic lab study, but our observation is that our patients receive benefit from this approach.
14. Platinum Footbath:  Your feet or hands are immersed in salt water, in to which specific frequencies are applied.  The water is ionized; the field enters your body, and appears to break ionic bonds between toxins and your normal molecules.  The toxins are drawn out in to the water in a sort of “reverse electroplating” or “forced sweating” effect.  That toxins are being removed has been verified by third party chemical evaluations (see Asyra.com).  I’m not sure whether metals can be removed by the footbath, but hydrocarbon toxins are, and it seems to be particularly well suited to patients with gout.  Footbath therapy lends itself well to in-home use.
15. Glutathione Patch – Your body’s own production of Glutathione increases (and blood levels rise) while you wear this drug free, non-transdermal skin patch (see lifewave.com/chc).
16. Far Infrared Sauna (FIS):  Sweat carries out with it toxic substances.  We sweat less as we age (aluminum containing anti-perspirants harm us here).  Regular sauna will sweat out toxins, but the extreme heat will not be tolerated by many of you.  FIS utilizes lower heat levels coupled with low level radiant energy derived from ceramic plates to generate active sweating.  FIS is therapeutic in several cardiovascular conditions (FIS is covered under Medicare, but we don’t offer this treatment - we can’t have people prancing around the office in their bathing suits). 
17. Frequency Specific Microcurrent (FSM):  FSM applies frequencies (via skin electrodes or a moistened towel) at 1/5000th the amplitude of the TENS unit.  While TENS therapy seeks to obliterate pain signals, with FSM we seek to communicate with or entrain our physiology to carry out a desired activity.  FSM can be applied to many health challenges (see our information sheet or www.frequencyspecific.com).

Costs – Your insurer will not cover the costs of any form of detoxification therapy.  They will describe it as “medically unnecessary” or “experimental”.  I will not write letters to request “pre-authorization” – this is simply a waste of time and risks labeling you as a “troublemaker”.  Detoxification is a comprehensive and often long-term process, and it is not inexpensive, but I think that you are worth it.  Please consider what you spend on a new car, or on a vacation, and then ask yourself what your health is worth.  If you do not wish, or cannot afford, to undergo detoxification, then we can still help you - and we will help you - but our focus then (by necessity) will be confined to nutritional intervention that you can afford and the administration of insurance covered drugs and invasive treatments to deal with the consequences of long-term toxicity.  Why not prevent this?  I personally spend a lot of time and money on my personal health (supplements, detox, home FSM, and lots of running shoes).  I like the idea of vibrant health and a vibrant mind, and I also realize that being sick ultimately will cost me more than staying healthy.  I also realize that “next day” and “fully covered” surgical approaches to preventable health conditions may not be available to me in later years (what is the wait time for bypass surgery or a knee replacement in England or Canada)?

Politics – Leave this at the door.  I am not interested in verbally sparing with other physicians who don’t know anything more about nutritional biochemistry and detoxification than I do about delivering babies or removing gall bladders.  Do not expect me to compromise on science to meet the expectations of other doctors, insurance companies, or government agencies that just don’t understand (or wish to understand) the devastating consequences of organic pollutant and metal accumulation on our health and the health of our children and grandchildren.  

 


 Appendix I:  Foods High in Tyrosine or Tryptophan 

Foods High In Dopamine (or Amino Acid Precursor Tyrosine)

Bananas, Red plums, Figs, Raisins

  Eggplant, Green Bean pods, Italian broad beans

Salami, Sausage, Liver

  Commercial gravies and Soy sauce

Salted dried fish (Herring, Cod)

  Canned meats, Aged game

  Canned meats, Aged game

Homemade yeast breads

  Some alcoholic beverages (not all)

Yeast concentrates, Marmite, soup cubes

 Aged Cheese (Blue, Boursalt, Brick, Brie, Camembert, Cheddar, Colby, Emmental, Gouda,
 Mozarella, Parmisan, Provolone, Romano, Roquefort, and Stilton)

   

Foods High In Serotonin (or Amino Acid Precursor Tryptophan)

Turkey, Chicken, Chicken Liver, Tofu

  Almonds, Peanuts, Soy Nuts

Milk, Yoghurt, Cottage cheese

 Spirulina (seaweed), Brewer’s yeast

Watermelon Seeds

 

 


Appendix II:  Foods High in Sulfur
(but please review Sulfites and Chronic Disease, by Rick Williams (available at the office or you can go to www.readingtarget.com/nosulfites)  

Dietary Sulfur Issues

Sulfur is necessary for many metabolic functions, but sulfur deficiency is rarely an issue, as most foods contain sulfur or sulfur containing compounds.  Excess sulfur can be a problem for those with CBS, BHMT, and SUOX mutations – here one needs to avoid foods and supplements high in sulfur (sulfites and sulfates).

Supplements High In Sulfur

Taurine

  Cysteine

  Methionine

  Glutathione

Glucosamine Sulfate

  Chondroitin Sulfate and MSM

Epsom Salts

  Magnesium Sulfate Cream

  Canned meats, Aged game

Homemade yeast breads

  DMSA and DMPS (Metal Chelators)

Milk thistle, Beyond C, and Heparin

 

Foods High In Sulfur

Vegetables:

 

 

 

Garlic, Onion Family

Kale

Collards

Pickles

Cabbage

Brussel Sprouts

Kohlrabi

Broccoli

Cauliflower

Bok Choy

Mizuna

Broccoli Rabe

Chinese Cabbage

Napa Cabbage

Turnip / Rutabaga

Canola / Rape Seeds; Greens

Mustard Seeds

Tatsoi

Radish

Daikon

Horseradish

Japanese Horseradish

Arugula

Watercress

Peas

Spinach

 

 

Fruits:

 

 

 

Raspberry

Cranberry

Currents

All Dried Fruit

Others:

 

 

 

Vinegar (especially if prepared from wine)

 

Alcohol Beverages (especially wine; not vodka - beer is less of an issue, especially German beer)

Soft Drinks

Animal Products

Dairy

Eggs

Brazil Nuts

Peanuts

Soy

 

 All packaged and commercially prepared foods contain food additives, many of which contain sulfur; often this is not on the label. Organic foods are preferable here.  Do not begin taking horsetail grass, spirulina, dandelion leaf, or parsley, as they contain low levels of sulfur.  If they are already part of your protocol, you may continue taking them. Eliminate them only if having trouble turning your strips pink. Recognize that methionine and SAMe do contain sulfur, as do the sulfur containing amino acids taurine and cysteine.  After strict sulfur elimination for 3 to 4 months you will have eliminated the deep stores of sulfur in your body. Thereafter, you can begin adding very small amounts of sulfur and ammonia producing products back into your diet, while watching your strips to be sure they stay pink.

 “What Can I Eat?”

 

Low Sulfur Foods: 

¨      Quinoa hot & cold in salads or with fruit

¨      Brown rice, non-gluten grains

¨      Fruit (except those on the high sulfur list)

¨      Vegetables (except those on the high sulfur list)

¨      Small amount of beans

o   Lentils

o   White Beans

¨      Small amount of nuts (except those on the high sulfur list)

o   Macadamia

o   Pine

o   Cashew

o   Pistachio

o   Walnuts

o   Almonds

o   Pumpkin

o   Sunflower seeds

o   Chestnuts

¨      Make milk from nuts: soak almonds overnight.

¨      Bamboo Shoots

¨      Corn

¨      Mung Bean Sprouts

¨      Boiling removes much of the sulfur from foodstuffs (make sure you discard the water)

 

Meals:

¨      Alkaline vegetable soup:

Add cut carrots, green beans, zucchini squash, and celery to alkaline water.

Simmer one hour; flavor with salt as needed.

¨      Vegetables with olive oil and salt or other flavorings – add quinoa to make a meal

¨      Plain millet and Kamut cereal puffs with nut or rice milk and fruit

¨      Plain Mochi puffs, stuffed with apple, berry, or spicy sauce

¨      Sauté squash and other vegetables in olive oil and top with non gluten grain

¨      Healthy Fries:

o   Cut up sweet and/or white potatoes in strips and coat with oil and seasoning. Lay flat on baking sheet and bake until crispy.

¨      Salads without high sulfur veggies and dressing.

¨      Apple or berry sauce mixed with flax seed

¨      Nut-Milk Shake:

Take frozen fruit chunks, stevia, fiber such as flax and blend with rice or nut milk until smooth

¨      Cut vegetables, mix with olive oil and seasonings and bake

¨      Brown rice tortillas chips:

Coat pan with olive oil. Cut up brown rice tortillas (found at Trader Joe’s) place on baking sheet. Season as desired, and bake until crispy.

¨      Vegan burger:

Combine cooked sweet potato or yams, quinoa, chopped vegetables, salt or other seasonings. Add enough non gluten flour (chickpea, rice), and form into patties. Brown in olive oil.

¨      Mashed Squash:

Take acorn, butternut, or other hard squash and steam. Mash with xylitol and cinnamon, nutmeg, or ginger.

¨      Squash Fries:

Take acorn, butternut, or other hard squash and cut in half. Cut into thin slices and bake flat until crispy.

¨      White bean or lentil soups with rice crackers.

¨      Cold quinoa with cut vegetables and Italian dressing.

¨      Boil vegetables like potatoes and dress with olive oil and seasoning.


Appendix III:  Foods High in Excitotoxins 

Sources of Excitotoxins

Glutamate

Glutamic acid, glutamine, and MSG.  High levels are found in foods such as peas, tomatoes, parmesan cheese, milk, mushrooms, fish, and many vegetables

Aspartate

Aspartame, NutraSweet

Other “Names” for Excitotoxins

Monosodium Glutamate

Glutamate

Natural Flavor(s)

Maltodextrin

Carrageenan

Gelatin

Spice(s)

Seasoning(s)

Seasoned Salt

Dough Conditioner(s) Isolate

Autolyzed Yeast

Autolyzed Yeast Extract

Autolyzed Anything

Broth

Stock

Soup Base

Chicken/Pork/Beef “Flavoring”

Hydrolyzed Vegetable Protein (HPV)

Hydrolyzed Plant Protein

Hydrolyzed Oat Flour

Hydrolyzed Anything

Yeast Extract

Sodium Caseinate

Calcium Caseinate

Caseinate

Disodium Guanyiate

Disodium Inosinate

Disodium Caseinate

Hydrolyzed Protein

Chicken/Pork/Beef “Base”

Bouillon

Vegetable Gum

Plant Protein Extract

Smoke Flavoring(s)

Malted Barley Flour

Malt Extract

Malt Flavoring(s)

Malted Barley

Malted Anything

Textured Protein

Guar Gum

Soy Extract

Soy Protein

Soy Protein Concentrate

Soy Sauce

Whey Protein

Whey Protein Isolate

Whey Protein Concentrate

L-Cysteine

Ajinomoto

Kombu Extract

Natural Flavoring(s)

Barley Malt

Foods with MSG (Monosodium Glutamate)

Hydrolyzed Protein

Hydrolyzed Oat Flour

Sodium Caseinate / Calcium Caseinate

Gelatin

Glutamic Acid

Monosodium Glutamate

Autolyzed Yeast or Yeast Extract

 

 

Possible Sources of MSG

Textured Protein

Carrageenan Or Vegetable Gum

Seasonings Or Spices

Flavorings Or Natural Flavorings

Chicken, Beef, Pork, Smoke Flavorings

Bouillon, Broth, Or Stock

Barley Malt, Malt Extract, Malt Flavoring

Whey Protein, Whey Protein Isolate, Or Concentrate

 

  

 

Other Sources of MSG

Food From Fast-Food Chains

OTC Medications

Chicken Pox Vaccine

NutraSweet

Binders and Fillers in  Supplements

Prescription Medications

Foods with Glutamates

Doritos

Pringles

KFC Fried Chicken

Boar’s Head Cold Cuts/Hot Dogs

Progresso Soups

Lipton Soups/Sauces

Gravy Master

Planter’s Salted Peanuts

Sausages / Processed Meats / Cold Cuts

Processed Cheese Spread

Molasses

Supermarket Turkey And Chicken (Injected)

Restaurant Gravy

Ramen Noodles

Bouillon

Instant Soup Mixes / Stocks

Salad Dressings / Croutons

Salty, Powdered Dry Food Mixes

Flavored Potato Chips

Restaurants Soups Made From Soup Base

Gelatin

Soy Sauce

Worcestershire Sauce

Kombu Extract

Dry Milk Or Whey Powder

Dough Conditioners

Body Builder Protein Mixes

Parmesan Cheese

Fresh Produce Sprayed With Auxigro In The Field

Some Spices

Skim, 1%, 2%, Non-Fat, Or Dry Milk

Whipped Cream Topping Substitutes

Non-Dairy Creamers

Chocolates / Candy Bars

Low-Fat / Diet Foods

Cereals

Baked Goods From Bakeries

Frostings And Fillings

Catsup

Mayonnaise

Chili Sauce

Mustards

Pickles

Bottled Spaghetti Sauce

Citric Acid Made From Processed Corn

Canned And Smoked Tuna, Oysters, Clams

Barbeque Sauce

Canned, Frozen, Or Dry Entrees And Potpies

Fresh And Frozen Pizza

Flavored Teas, Sodas

Seasoned Anything

Some Bagged Salads And Vegetables

Tomato Sauce / Stewed Tomatoes

Egg Substitute

Flour

Canned Refried Beans

Tofu And Other Fermented Soy Products

Table Salts

Anything With Corn Syrup Added

Anything With Milk Solids

Anything Fermented

Anything Vitamin Enriched

Anything Protein Fortified

Anything Enzyme Modified

Anything Ultra-Pasteurized

Carmel Flavoring/Coloring

Pectin

Cornstarch

Flowing Agents

Xanthan Gum / Other “Gums”

L-Cysteine

 

 


Appendix IV:  Elevated Urine Sulfate - What Do You Do Next?

Elevated Urine Sulfate – Above 1600 mg/liter

You are receiving this communication because a spot urine sample returned with an elevated sulfate level.  As you are by now aware, we are actively involved in Methyl Cycle Genomic testing, looking for the underlying “common denominator” causes of the otherwise difficult to explain and address disease states with which many of our patients present.  The vast majority of chronically ill or unexplained ill individuals who we have tested have demonstrated abnormalities in the Trans-Sulfuration pathway of Homocysteine metabolism.  Dietary change, medication adjustment, and specific nutritional support, all tailored to the individual’s genotype, can lead to a major change in the health of these individuals.

Methyl Cycle testing is expensive:  $1,150 for the testing, analysis, and recommendations.  Obviously it doesn’t make sense to test every patient who we see, but on the other hand it doesn’t make sense to keep doing the same ineffective thing over and over because we really do not know why a chronically sick person is chronically sick.

There are clinical “tip offs” to a Trans-Sulfuration pathway defect, the most important of which is an elevated urine sulfate level (the CBS up regulation and/or BHMT down regulations force Homocysteine down the Trans-Sulfuration pathway, generating excessive sulfite/sulfate).  Methyl Cycle Genomic testing costs $1,150, while the urine sulfate test costs $10 - so we carried out the urine sulfate test in you and it returned above 1,600 mg/liter.

So what exactly does this mean?  What should you do know?  Is the study 100% diagnostic?  Right now, we do not have absolute answers to these questions; nor does anyone else.  However, we are on to something very important here and it likely affects you.

The questions that we have regarding the link between urine sulfate and the presence/absence of a specific genomic defect are:
A.  Is an elevated urine sulfate diagnostic of a Methyl Cycle defect?
B.  Are there false positives (high sulfate with normal genes) and false negatives (low sulfate and abnormal genes)?
C.  Is there a quantitative relationship between the sulfate level and the severity of the genomic impairment?
D.  Will the sulfate level vary day to day and with time of day or meals?

We are comparing the urine sulfate levels against the genomic findings in all patients who are undergoing genomic testing.  My initial impression is that individuals with markedly elevated urine sulfate levels all have CBS and/or BHMT abnormalities.  We have seen a few false negatives (CBS/BHMT abnormality present but urine sulfate only in the 400 mg/liter range); these individuals have “upstream” abnormalities that limited Homocysteine production, giving CBS/BHMT less homocysteine to force down the Trans-Sulfuration pathway, or a “downstream” defect in SUOX (Sulfite Oxidase), such that sulfate could not be generated from sulfite (the entity actually generated by CBS), and/or they were already on a Vegan type diet.  So far we have not identified any false positive patients, and when patients with known CBS/BHMT abnormalities switch to a low sulfur, low animal protein diet, their urine sulfate levels do fall.  Still, there could be causes for a false positive study.  Many drugs and nutritional supplements are loaded with sulfite/sulfate (typically not a problem for individuals who do not harbor Trans-Sulfuration defects).  It is not inconceivable that if you take these drugs or supplements that your urine sulfate will be elevated regardless of your genomic status. 

So what should you do with this information?  If money is not a concern, then undergo Methyl Cycle testing.  Knowledge as to what is wrong with you (or what could go wrong with you in the future) can only help us optimize your health.  If money is an issue but you wish to take some positive steps, you could change your diet “as if” you have a CBS/BHMT abnormality, and this is a better diet than the one most of us are currently following.  We could also, in a step-by-step fashion, adjust your drugs and nutritionals while watching your urine sulfate level.  The supplements we use in CBS/BHMT individuals are all benign.  Please review the attached instruction sheet.  You can learn more at our monthly Methyl Cycle support group meetings (third Monday of every month at the Secor Clarion - $5 admission) and by studying the information discussed above in this section of the website.  You can also review Dr. Yasko’s website holistichealth.com, keeping in mind that her focus is on Autism, while ours is on adults with chronic or unexplained illnesses.  You could also wait.  As we gain more experience in this area, our diagnostic and treatment methods will evolve and improve – it‘s always been this way.  

Again, we will have more definitive information in the future, but this is too important a concept to just “sit on”; thus the urine sulfate screening, this letter, and our invitation to you to learn more.


Appendix V:  General Recommendations Based Upon the Sulfate Value 

Approach to Patients with Presumed Trans-Sulfuration Pathway Abnormalities

Methyl Cycle Genomic analysis is demonstrating Trans-Sulfuration (CBS up regulation or BHMT down regulation) abnormalities in 90% of our patients with unexplained disease states who undergo testing.  Dietary change and nutritional supplementation, designed to fit the genotype of the patient, is turning around the lives of some previously quite ill people.  The “tip offs” to a Trans-Sulfuration Methyl Cycle defect are sulfite sensitivity (and to a lesser extent asthma and easy bruising), a low or low normal homocysteine level, and an elevated urine sulfate level – but so far sick people who are not getting better all seem to have this problem!  Methyl Cycle testing is expensive - $1,150.  Some individuals may choose to omit Methyl Cycle testing and proceed directly to treatment, as if they have this genomic defect.  Others may wish to take action while waiting the two months for the lab results to return.  As there is nothing inherently dangerous about our approach to CBS/BHMT dysregulation, this approach is medically reasonable.  The following general recommendations make sense for individuals who may harbor a Trans-Sulfuration pathway abnormality and who do not wish to undergo Methyl Cycle testing or who do not wish to wait until their lab results return. 

Overview

We assume that you are +/- or +/+ for one of the CBS up regulations and +/+ or +/- for BHMT 1-8, which act like CBS up regulations.  Homocysteine (as well as its methyl cycle precursors) is being drawn down the transulfuration pathway, in this process generating too much sulfite and sulfate (which stimulate the stress/cortisol “fight or flight” response), too much alpha-ketoglutarate (which leads to excitotoxin activation), and too much ammonia, which depletes BH4 (leading to insufficient dopamine and serotonin production, and a lack of nitric oxide).  

To address CBS up regulation/BHMT down regulation we typically recommend:
1. No animal protein diet (anything with eyes) and avoid sulfur rich vegetables, sulfur containing supplements,  and sulfur containing drugs (see CBS and Appendix II:  Foods High in Sulfur and/or read Sulfites and Chronic Disease by Rick Williams, available at the office or at www.readingtarget.com/nosulfites/. 
2. Monitor urine sulfate every 4-7 days.  Low levels (400 or 400-800 mg/liter) will allow an increase in methyl cycle supplementation and later the addition of BH4 and/or a liberalization of your diet.
3. To neutralize ammonia, use Ammonia Support RNA, 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), and Yucca.  These supplements can be tapered down as ammonia levels fall.
4. Molybdenum to help SUOX break down sulfite into less toxic sulfate.  Homogenized dairy products contain xanthine oxidase, which uses up molybdenum, and are best avoided or minimized.  Vitamin E succinate, Boron, and B12 are felt to stimulate SUOX activity (SUOX is “overworked” by the sulfite load presented to it by CBS/BHMT - SUOX co-factors become depleted, thus the need for supplementation).  
5. Avoid excitotoxins (see list on heartfixer.com) and supplement with GABA twice a day.
6. Minimize B6, which stimulates CBS; P-5-P will be less of an issue.
7. Co-Q, Carnitine, Idebenone, and NADH will help increase energy production; supplementation will be helpful but probably not critical. 
8. After your sulfur and ammonia pools have been depleted down towards normal we can be more liberal with other methyl cycle supplements, and/or add in BH4.  We do not wish to aggressively correct other methyl cycle defects until we have the CBS issue under control – otherwise the intermediates that we do supplement or generate will fall down the “CBS drain” into ammonia, sulfate, and alpha-ketoglutarate.  Thus the first priority is to decrease blood and urine ammonia levels (easy to achieve with diet and supplementation) and urine sulfate levels (this will take time – likely several months).  

                                                                                                                Plan of action for CBS/BHMT

1. Begin the diet discussed above and the supplements described below.. 
2. Check the sulfur (sulfite) content of your medications and supplements, and we will try to phase out anything high is sulfur.    
3. Monitor urine sulfate every 4-7 days (and please chart the levels) – this will be our primary measuring stick – our goal is 400 mg/liter (one yellow and three pink). 
4. To neutralize ammonia, use Ammonia Support RNA ½ dropper with meals and with methyl cycle supplements, along with 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).  Yucca, beginning at ½ capsule, twice a day, (or sprinkled on food containing protein), may help with ammonia detoxification. 
5. Regarding nutritional support, your current multi likely contains B6.  A better program involves the Yasko NHF multi, two twice a day along with Trace Minerals Complex at 4 drops/day.  Begin Molybdenum 3 drops twice a day, Boron 3 mg/day, and hydroxy-B12 2000 mcg daily to stimulate SUOX (the enzyme that converts sulfite in to less toxic sulfate).  These are the key nutritional interventions.
6. Co-Enzyme Q10 100 mg/day, Carnitine 500 mg twice a day, and NADH one per day are ideal but not critical.
7. Add GABA 500 mg once a day to blunt excitotoxicity; if you feel that GABA is helping a lot then you can increase the dose; if it is not doing anything for you then it can be discontinued.
8. If not already done, baseline Vitamin D, homocysteine, and ammonia levels will be helpful (and will be considered at your next office visit).
9. In eight weeks (ideal but obviously not mandatory) we can carry out a 24 hour urine for ammonia and amino acids and a separate 24 hour urine for nutritional and toxic metals, and use the results to refine your supplementation program. If a 24 hour urine collection is not possible than we could use a first AM void urine for the ammonia/amino acid levels and a red cell mineral study. 
10. Lipophos Forte 900 mg/day will stimulate BHMT, thus drawing homocysteine away from the CBS “drain”.  Lipophos EDTA, ½ bottle twice a week, will also remove heavy metals, the clearance of which appears to be reduced in individuals with Methyl Cycle abnormalities.


Appendix VI:  Methyl Cycle Recipes 

Veggie Organic Soup

2 T. Olive Oil
3 Stalks Organic Celery (sliced ¼”)
6-8 oz small Organic Carrots
3 T. Fresh Basil
2 T. Fresh Oregano
2 small Zucchini (green and yellow) sliced ¼”
1 T. Celtic Sea Salt
1 T .Fresh Ground Pepper 

Sauté about 15 min 

Add 2 L. Alkaline Water (about 2 quarts) then add
2 Fresh Tomatoes (peeled and chopped) to peel/score add to boiling water 15-30 sec.
 watch for peel to come off then add to ice bath or 1 can 14.5 oz Organic diced Tomatoes

 2 15oz cans white beans rinsed and drained 

12 oz fresh long cut Green Beans 

Bring to Boil 20 min/ add more sea salt and pepper to taste 

The last 6-7 min add 1 cup Quinoa Pasta Veggie Curls 

In a separate pot boil 6-8 Gold Potatoes until tender
Add half of potatoes to soup/ the other half mash until creamy (this will give the soup a creamy texture)

 Do Your Best to buy All Organic—Enjoy!

 Created by Cheryl Church

 Orange Spaghetti Sauce

 2 T. Olive Oil
3 Stalks Celery/diced
1 Orange Bell Pepper/diced
1 Med Carrot/diced
Sauté until tender, and then add
1 T. Oregano
1 T. Celtic Sea Salt
1 T. Black Pepper
3- 14.5 oz can Dice Tomatoes
Sprinkle small amount of Sugar to cut acid if desired
Bring to boil and simmer about 20-30 minutes

Cook 8 oz box of Quinoa Pasta Spaghetti Noodles

Sprinkle with chopped fresh Basil

Serve with long cut Green Beans or Zucchini chopped and sauté in Olive Oil

Makes about 5 cups sauce

Created by Cheryl Church

Quinoa and Yam Salad

1 cup Quinoa
2 cups water
3 cups yams/ chopped
2 T. olive oil
1 medium red bell pepper/chopped
1 tsp cumin
¼ cup fresh cilantro/chopped
2 T. Fresh lemon juice
1 T. Brown Rice Vinegar
1 T. Real Maple Syrup

 In a medium saucepan, stir together the quinoa and water. Bring to a boil, cover and reduce heat to medium low. Simmer for 15 minutes or until cooked. Fluff with a fork and set aside to cool. In a large frying pan on medium heat, sauté the yams until they are tender but firm to the bite. Add the peppers and cumin and sauté for an additional 2 minutes. Set aside until cool. In a large bowl, combine the quinoa, yams, cilantro, lemon juice, vinegar and maple syrup. Mix well and cool in refrigerator.
Serve chilled.
Makes 6 servings 

Recipe altered from The Garden of Vegan by Tanya Barnard & Sarah Kramer

Breakfast Ideas

#1 Quinoa Flakes/ Hot Cereal
Any kind of Fruit (  blueberries, peaches etc)
1-2 tea, cinnamon
1-2 tea real maple syrup 

# 2 Brown Rice Crisps
Fruit (blueberries)
Rice Milk

 #3 Roasted Potatoes with beets ,zucchini, peppers whatever veggie you like.  Drizzle  with Olive Oil. Bake at 350 degree oven for 20-25 minutes Season to taste.

 Snacks

 #1 Almond Butter with Rice Cakes and Bananas

#2   Almond Butter with Celery

#3 Bean Dip

1 can 15 oz   Great Northern Organic White Beans
1 Fresh Lemon/ juiced
1   tsp.  Celtic Sea Salt

Blend in food processor until smooth
Sprinkle with chopped fresh parsley

Serve with Rice Chips or Sweet potato and Beet Chips

 #4Avocado Dip

1 medium size avocado/mashed with potato masher
1 chopped medium tomato
1 fresh squeezed lemon
1 T. coarse ground black pepper

Mix well and serve with Rice Chips

#5  Smoothies

1 large Banana
4-5 large Frozen Strawberries
1 cup Rice Milk

Blend until smooth /Freezes well

Spiced Squash Soup

Bake @ 350 degree oven
1 large Butternut Squash, brush with olive oil and bake until golden  brown about 1 hour

3 stalks of celery (chopped)
2 small sweet potatoes (peeled and chopped)
1 large apple (peeled and chopped)
1 T. olive oil

Sauté 4 above items until a little brown then add 3 cups alkaline water or filtered water, 1 tsp Celtic sea salt, 1 tsp. fresh cracked pepper, 1 bay leaf, ¼ tsp cinnamon, ¼ tsp cumin, ¼ tsp thyme, 1/8 tsp red pepper (cayenne) and a dash of nutmeg. Simmer for 15 minutes. Add all to blender and mix until smooth. Sprinkle with fresh basil and small amount of Parmesan Reggiano.

Makes about 6-7 cups

 To add protein serve over quinoa pasta.

 Created by Cheryl Church

 Corn and Potato Chowder

2-3 T. olive oil
2 ½ cups chopped organic celery
4 cups organic corn (from can or cut from cob)

Sauté until celery is a little tender.
Add 4 cups chopped red skin potatoes, 1 T. Celtic Sea Salt, 1 T. Fresh cracked pepper, if you like pepper this soup tastes great with lots of black pepper, 1 T. Celery Blend a product made by Celtic Sea Salt Selina Naturally.
Cover with alkaline water or filtered water. Bring to boil and simmer until potatoes are tender about 15-20 minutes.

In separate pot boil 4 cups chopped red skins potatoes to mash and add to soup for creamy texture.

To add protein serve over cooked quinoa.

Created by Cheryl Church


Nurtigenomic Supplements and Supplies

Nurtigenomic Supplements and Supplies (* are available at office)

Holistic Health (Dr. Yasko)

www.holisticheal.com

Emerson Ecologics

www.emersonecologics.com

Life Extension Foundation

ww.lef.org

Order Code

Supplement

Source

Comments

SKU:30204

Sulfate Test*

HH

$55 for a package of 100 sulfate test strips

SKU:30205

Sulfite Test*

HH

$55 for a package of 100 sulfite test strips

SKU:540

See RNA

HH

Ammonia support (neutralizes ammonia)*

SKU:560

Products

HH

Methylation support (general methyl cycle support)*

SKU:

All $85

 

Other RNAs:

SKU:02041

Yucca*

HH

600 mg – 60 for $17.46

SKU:01129

Charcoal*

HH

100 260 mg capsules for $9.99

TRAC9

Trace Minerals*

EE

2.5 month supply for $10.10

SKU:30054

NHF Multi*

HH

Dr. Yasko’s 6-a-day multi for neuro health – $29.99 for 180

SKU:01092

Hydroxy-B12*

HH

Perque 2000 mcg hydroxy-B12, $28.95

SKU:01082

Molybdenum*

HH

75 mcg/3 drops – 2 oz. for $12.20

BOR04 Boron HH 3 mg - 100 for $6.50

SKU:30020

Vit E Succinate*

HH

400 IU - $24

GABA 7

Montiff GABA*

EE

500 mg Montiff GABA, 100 for $21

SKU:01049

NADH*

HH

5 mg tabs, 30 for $33.99

SKU:01023

Zen*

HH

275 mg GABA and 100 mg Threanine – 60 for $21 

CAR48

Carnitine*

EE

Carnitine 500 mg – 60 for $39.90

01226

Co-Q10*

LEF

Ubiquinol 100 mg – 60 for $55

Office

Idebenone*

 

100 mg – 60 for $40.00

00537

Methyl-B12*

LEF

5 mg chewable tablet - 60 for $32

Office

LipophosEDTA*

 

Phosphatidyl Choline with EDTA – 1 bottle for $30

Office Lipophos Forte*   Phosphatidyl Choline

SKU:01043

PS*

HH

100 mg phosphatidyl serine – 60 for $39.90

SKU:01044

Pedi-Activ*

HH

50 mg phosphatidyl serine with 50 mg DMAE – 120 for $28.99

LITH2

Lithium*

EE

100 caps for $11.19

Office

Iodoral*

 

12.5 mg – 90 for $27

IOD14

E-lyte 9

EE

2 oz. bottle providing 265 doses for $12.20

TMG

TMG

EE

750 mg TMG – 100 caps for $15.60

SKU:01088

Quercetin Plus*

HH

Quercetin 500 mg with Bioflavonoids – 50 for $14.05

00453

SAMe*

LEF

200 mg SAMe – 50 for $33.75

SKU:02017

Folapro*

HH

5-methyl folate 800 mcg, 60 for $17.49

FOL17

Folinic Acid*

EE

800 mcg/tablet - 60 for $11

 

Methyl Folate

Drug

Metanx:  2.8 mg methyl folate, 25 mg P5P, & 2 mg methyl-B12

 

Cerafolin NAC

Drug

5 mg methyl folate, 2 mg methyl B12, and 500 mg NAC

00961

GliSODin*

LEF

Stabilized Super Oxide dismutase – 90 for $28

Office

Glutathione*

 

15 for $90 (each should last for 7 days) - lifewave.com/chc

Office prices may be different – to include shipping and handling


How to Order Supplements from Websites 

Ordering from Holistic Health website:

·                     Go to www.holisticheal.com

·                     Click on Advance search

·                     Scroll down to box that states “Search for product”

·                     Click on Advance search option

·                     You will see: search category:      

   sku:

   price:

·                     Enter sku # from list for the product you are looking for

·                     Click on search

·                     Under Quantity enter how many you want to order

·                     Click on add all items to cart

·                     Screen will show items in cart

·                     Click on Advance search and follow same protocol until all items are in cart

·                     Then click “check out”

·                     Review order and select delivery option

·                     If everything is ok then where you see update click “GO”

·                     Enter your delivery information and submit

·                     Follow directions for payment 

 

Ordering from Emerson Ecologics

·                     Log onto www.emersonecologics.com

·                     On left side of screen click on “Product search”

·                     Enter code from list in box “By Product Code”

·                     Do not use any spaces with letters or numbers

·                     Check selection box

·                     Click add to shopping cart

·                     Then click add more product

·                     Follow same protocol for other items

·                     When all items are selected proceed to check out

·                     Follow directions to “Register Now”

·                     Click “I am a patient”

·                     Click continue

·                     Enter all info requested

·                     Click continue and follow directions for payment

 

Ordering from Life Extension Foundation

·                     Log onto www.lef.org

·                     On right side of screen enter product code in Search Catalog Number

·                     Then click add to cart


Methyl Cycle Genomic Testing and Treatment - What you Can and Cannot Expect from Us

 

We got involved in Methyl Cycle testing not because we had to, and not because we don’t have anything else to do.  No - we got involved in Methyl Cycle testing for the usual reason, to  

Help Patients Who We (and Nobody Else in the Area) Could Previously Help 

This is why we were the 2nd practice in Ohio to get involved in EECP 12 years ago.  This is why we brought MME to town 4 years ago, and why we continue to bring innovative and low risk diagnostic and therapeutic modalities to NW Ohio.  We do this because our current best methods are not good enough; there are always patients who we cannot help so we are always looking for better methods (and these days the developers of better methods are bringing them to us). 

New treatments, especially new treatments not available elsewhere in the area, always generate a lot of questions.  We’d like to answer all of your questions, on an individual basis, and do so in a timely fashion, but in reality we can’t.  We realize this and we need you to realize this as well.  Staff members cannot answer questions regarding the biochemical genetics of specific Methyl Cycle pathways, just as they can’t explain the biophysics that allow the Glutathione patch to work or the bioengineering that allows the MME machine to regenerate damaged cells.   

Dr. Roberts can answer these questions (well, most of them), but he cannot answer them for you, on an individual basis, outside of your office visits – it’s just not logistically possible.  If you cannot accept this then please undergo Methyl Cycle Genomic testing elsewhere.  Your $1,125 fee covers the cost of the laboratory Methyl Cycle testing, Dr. Yasko’s report, and Dr. Roberts’ analysis and recommendations, which integrates the Methyl Cycle findings into your past and current medical status.  It takes Dr. Roberts considerable time to write what will be a 4-5 page report – but you are paying for this – and you are getting value for your money. 

We have added to our program various means by which you can learn more, ranging from our monthly Methyl Cycle support group meetings to individual sessions with Krista McCarthy Mignin MS.  Take advantage of these resources. 

Please do not call the office with open ended questions or requests such as “I want someone to explain this to me” or “I want Dr. Roberts to call me”.  We can’t do this.  All of you know how hard I work.  I am so busy with our current programs that I had to give up all past hospital activities except for doing heart catheterizations every other Thursday.  I am not going to call you up (and you may not answer your phone at night or on weekends) to answer non-emergency questions, the answer to which 75% of the time will be in my written report.

Please do not call with questions like “what can I eat”, or “is a certain food OK”?  We do not have ready answers to these questions.  We do put a lot of information regarding diet in to our Methyl Cycle reports.  We do give you resources where you can learn more, but please remember, we are not dietitians nor are we nutritional counselors (but Krista McCarthy Mignin is).  Also, please avoid expressing anger at staff members.  We realize that you are sick, that you feel lousy, and that dietary change is difficult, but it’s not our fault that you’re sick, and it’s not our fault that your genes are what they are.  If you are upset about your genetic makeup, have a heated discussion with Charles Darwin or God (but they are not going to give in).  Remember, just because we found an important problem that may be difficult to address, it doesn’t follow that we caused the problem. 

It also doesn’t follow that we should work for free or lose money, just because we are the first practice in the area to provide Methyl Cycle testing and you have a lot of questions.  Please remember, when a staff member takes your message, pulls your chart, brings the issue to my attention, and then  transmit my answer back to you, a lot of staff time is taken up – and I am paying for it.  We provide a lot of innovative services that generate a lot of questions, and the staff overhead generated can easily get out of hand.   

If we are to continue to provide new and innovative services like Methyl Cycle testing, well, we are going to need your cooperation.  Call us when you need to (and there will be times when you need to) but if a question can wait, please put it off until your office visit or until the next Methyl Cycle support group meeting. 

                                                                                                                                                                          James C. Roberts MD FACC 8/24/08


 Sample Report

Methyl Cycle Nutrigenomic Report

Methylation Panel Abnormalities for Genes with Characterized SNPs

Gene Name

Variation

Finding

COMT

V158M

OK

COMT

H62H

OK

COMT

61

OK

VDR

Bsm

OK

VDR

Taq

Homozygous (+/+)

MAO A

R297R

Homozygous (+/+)

ACAT

102

OK

MTHFR

C677T

Heterozygous (+/-)

MTHFR

3

OK

MTHFR

A1298C

OK

MTR

A2756G

OK

MTRR

A66G

Heterozygous (+/-)

MTRR

H595Y

OK

MTRR

K350A

OK

MTRR

R415T

OK

MTRR

A664A

OK

BHMT

2

OK

BHMT

4

OK

BHMT

8

OK

AHCY

1

OK

AHCY

2

OK

AHCY

19

OK

CBS

C699T

Heterozygous (+/-)

CBS

A360A

Heterozygous (+/-)

CBS

N212N

OK

SHMT

C1420T

Heterozygous (+/-)

  

Overview

You are +/- for both of the CBS up regulations. Homocysteine (and its Methyl Cycle precursors) is thus being drawn down the trans-sulfuration pathway, in this process generating excessive sulfur breakdown products (sulfite and sulfate – and your urine sulfate is 1600 - which stimulate the stress/cortisol “fight or flight” response), too much alpha-ketoglutarate (which may lead to glutaminergic excitotoxin activation), and too much ammonia, which depletes BH4, leading to insufficient dopamine and serotonin production.  This deficiency in BH4 predisposes NOS (nitric oxide synthase) to convert Arginine in to free radicals as opposed to nitric oxide, predisposing you to hypertension and cardiovascular disease.  You are already on BH4 and methyl-folate, and after the up regulated trans-sulfuration pathway (CBS) has come under control, the BH4 and methyl-folate doses could be increased. 

CBS actually generates sulfite, which must be processed to sulfate, by SUOX (sulfite oxidase).  Even thought your urine sulfite level is normal, support for this enzyme with hydroxy-B12, molybdenum, boron, and Vitamin E succinate can be considered.

MTR uses 5-methyl folate and methyl-B12 to convert homocysteine in to methionine, which is then converted in to SAMe, the universal methyl donor.  You are +/- for MTHFR C677T, meaning that you have some difficulty converting folic acid in to 5-methyl folate, a block that is (biochemically) easy to overcome with 5-methyl folate supplementation (already in place). 

You are also +/- for one of the MTRR alleles, meaning that you are having some trouble converting B12 in to methyl-B12, a problem that you have already addressed with methyl-B12 supplementation.  You are +/+ for VDR Taq, such that Vitamin D will be less efficient in generating dopamine, and -/- for COMT, meaning that you can breakdown  dopamine rapidly, using up methyl groups in doing so, and thus you will have an increased susceptibility to toxic metals and viral infection.  Conversely, your need and tolerance for methyl groups and methyl donors will be relatively increased (your problem is not sensitivity to methyl donors but rather sensitivity to sulfites/ammonia/glutamate that are generated when these agents spin forward the Methyl Cycle and homocysteine is drawn down the up regulated CBS “drain”). 

SHMT combines the amino acid serine with folic acid to form 5,10-methylene THF, which is used to generate the building blocks for DNA and RNA generation.  We can bypass this block with 5,10-methylene THF, also known as Folinic acid.

Being +/+ for MAO A, you are having trouble breaking down serotonin, an issue that we can address by favoring foods rich in tyrosine, the precursor to dopamine, which you need, over foods rich in tryptophan, the precursor for serotonin.  Early on, however, an overall restriction of dietary animal protein will be suggested, to decrease the ammonia burden imposed on you by your CBS up regulation status.

My knowledge of Detoxification Genomics is far less extensive than that of the Methyl Cycle, but my understanding is that the CYP1B1 alleles present are an up regulation, favoring 4-hydroxyglation of estradiol/estrone, thus increasing one’s risk of breast/prostate malignancy.  Hydrocarbon pollutants are activated by 1B1, and if they cannot be neutralized by phase II enzyme systems, oxidative tissue damage may follow.  CYP2C19 metabolizes a number of commonly utilized pharmaceuticals, and is also responsible for activating Plavix.  Thus you may not be experiencing the same anti-platelet effect vs. an individual with intact 2C19 status (likely not an issue now, one year out from stent placement, but if another stent is required one of the newer agents that does not require 2C19 activation would be preferred).  Methylation based (COMT) phase II detoxification is intact, but you harbor alleles compromising acetylation and SOD (superoxide dismutase) generation (thus neutralization of superoxide will be compromised, but on board you have SOD up regulators in the form of Losartan, Crestor, and Berberine). 

The Gene by Gene Approach sections provide general information about the alleles you possess, while the Plan of Action sections contain specific recommendations.  Approaches that make the most sense to me receive a (Ö).  Those that are less critical (or more costly) are designated (+/-).  Based upon review of your medical history, I have a number of additional diagnostic and therapeutic ideas (please see below). 

Gene by Gene Approach – CBS +/-


CBS (Cystathionine Beta-Synthase) is discussed on pages 48-53 of Dr. Yasko’s book, Genetic Bypass.  Additional information is available on our heartfixer.com website.  You are +/- (half of your CBS enzymes abnormal) for both of the two CBS up regulations.  Fortunately you are -/- (normal function or “wild type”) for the BHMT down regulations (which act like CBS up regulations).  Given your CBS up regulations, Homocysteine (and its Methyl Cycle precursors) is being drawn down the trans-sulfuration pathway, in this process generating excessive sulfur break down products (sulfite and sulfate, which stimulate the stress/cortisol “fight or flight” response), too much alpha-ketoglutarate (which leads to glutaminergic excitotoxicity), hydrogen sulfide (to produce brain fog), and too much ammonia (which depletes BH4, leading to insufficient dopamine and serotonin production).  This deficiency in BH4 allows NOS (nitric oxide synthase) to convert arginine in to free radicals (superoxide and peroxynitrite) as opposed to nitric oxide, predisposing you to hypertension, cardiovascular and inflammatory disease states. 

 

During normal physiology, metabolic flow down the CBS pathway is designed to generate the important anti-oxidant and detoxifying molecules glutathione, taurine and cysteine (all involved in detoxification and endothelial health), and alpha-ketoglutarate (which can be converted into GABA, a calming neurotransmitter).  The CBS C677T and A360A genes code for enzyme function that is pathologically up regulated.  Of the two, the C677T allele is the most important, producing enzyme activity that is 10 fold greater than normal.  You thus suffer from “too much of a good thing and way too much of several bad things”. 

While sulfate and sulfhydryl (-SH) bearing molecules are important in detoxification, sulfate/sulfite/-SH excess blocks cellular up take of the key detoxifiers glutathione and cysteine.  Endogenous detoxification is thus blunted (nearly all kids with Autism Spectrum Disorders bear CBS up regulations – why they are compromised by environmental toxins and the kid next door is just fine).  Conversely, after we decrease your sulfate/sulfite pool, your detox pathways open up (and why, if we move too fast, you will experience detox phenomena).

The excess ammonia generated must be detoxified, and to do so BH4 (tetrahydrobiopterin) must be “spent”.  This is a problem in that we need BH4 to generate neurotransmitters (serotonin to maintain calm/prevent depression and dopamine to maintain motivation and drive).  Without BH4, we cannot convert arginine in to nitric oxide; instead vascular wall toxic free radicals such as superoxide and peroxynitrite are created, leading to hypertension and cardiovascular disease.

 

 

 

Alpha-ketoglutarate, in moderation, is not a problem.  We should be able to interconvert alpha-ketoglutarate into glutamate, glutamine, and GABA.  However, when alpha-ketoglutarate is in excess, or if toxic metals compromise the interconversion enzymes, then we suffer a buildup of the excitatory neurotransmitter glutamate.  Glutamate is involved in alertness and learning, but excess glutamate leads to irritability and over-excitement; toxic levels may play a role in seizure activity and cardiac arrhythmia (could this be why we are seeing so much atrial fibrillation)? 

CBS up regulations lead to an initial buildup of potentially neurotoxic sulfite, which is then metabolized by SUOX (Sulfite Oxidase) to the less neurotoxic (but still problematic at high levels) sulfate.  SUOX activity requires molybdenum, which is thus depleted in CBS + individuals.  Homogenized dairy products contain xanthine oxidase, which uses up molybdenum, and are best avoided or minimized.  Vitamin E succinate, boron, and B12 are felt to stimulate SUOX activity.

 As methyl cycle function is needed in the biosynthesis of Co-Enzyme Q10 and Carnitine, individuals + for CBS will likely be energy depleted, and here supplementation (in relation to your COMT/VDR status) with Co-Enzyme Q10, Carnitine, and NADH may be helpful.   

Statin therapy predictably depletes Co-Enzyme Q; adding 100-200 mg/day of Co-Enzyme Q makes sense or we could measure your Co-Q level with a Genova Labs NutrEval study.

 BHMT (Betaine Homocysteine Methyl Transferase) directly methylates homocysteine back in to methionine, serving as a “back door” pathway to “pull” homocysteine away from the CBS “sulfate drain”.  Thus if you bear CBS or BHMT abnormalities, it makes sense to support BHMT function.  DMG (dimethylglycine) and TMG (trimethylglycine) stimulate BHMT, and can be utilized if you are not overly sensitive to methyl group supplementation (based upon you COMT/VDR status).  Phosphatidylserine stimulates BHMT (and we also use it to moderate elevated cortisol levels), as does phosphatidylcholine (which we use to treat atherosclerosis).  Phosphatidylcholine can be admixed with EDTA (detoxifies metals), creating a quite useful supplement. 

 Many of you with CBS and BHMT abnormalities will also bear MTHFR (compromising methyl-folate generation) and MTRR (compromising methyl-B12) abnormalities, and thus you will need and benefit from corresponding supplementation (with these molecules that they are having trouble making).  However, if we treat you with methyl-folate, methy-B12, or BH4, before we have the CBS problem under control (sulfite/sulfate levels decreased enough to allow for appropriate glutathione and cysteine assimilation) then we will be subjecting you to “incomplete detoxification”.  You will feel great for 1-2 days, as beneficial neurotransmitters are generated.  Methyl-folate and methyl-B12 detox pathways will then open up, creating toxic intermediates that cannot be metabolized further due to the block in glutathione utilization – and you will feel horrible.  Thus we need to resist the temptation to treat your MTHFR/MTRR abnormalities until CBS/BHMT are under control. 

However, you are already on methyl-folate, methyl-B12, and BH4 and I do not think that you need to stop them simply on the basis of this “new Methyl Cycle patient” principle.    

  

Plan of action for CBS +/-

To address this constellation of alleles I will recommend:
1. Moderate* animal protein intake (anything with eyes) and avoid sulfur rich vegetables, sulfur containing supplements,  and sulfur containing drugs (see attached sulfur avoidance instruction sheets and read Sulfites and Chronic Disease by Rick Williams, available at the office or at www.readingtarget.com/nosulfites/. 
2. Check the sulfate/sulfite content of your supplements and prescription agents (many listed in the Williams book) and whenever possible switch to agents with lower sulfate/sulfite content.
3. Monitor urine sulfate levels every 3-7 days (or when you feel particularly good or poorly, or after adding a new treatment or changing your diet).  Please chart the levels – this will be our primary measuring stick – our goal is a urine sulfate of 400 (one yellow and three pink) to 800 (two yellow and two pink).  Low levels will allow an increase in methyl cycle supplementation and later the addition of BH4 and/or a liberalization of your diet.  Conversely, persistent high sulfate spills indicates that your diet/treatment program needs further modification.
3. To neutralize ammonia (generated from animal protein), you can use Ammonia Support RNA ½ dropper with meals and with methyl cycle supplements (relatively expensive), along with a charcoal supplement at bedtime every other evening, away from other supplements (magnesium citrate may be used as needed to keep the GI tract moving as charcoal may lead to constipation).  Yucca, beginning at ½ capsule, twice a day, (or sprinkled on food containing protein), may help with ammonia detoxification.  These supplements can be tapered down as ammonia levels fall.
4. Sparga Detox, 10 drops in water (wait at least one minute before consuming), twice a day makes sense.  Sparga was developed by fellow Cardiologist Dr. Lee Cowden, specifically to address the CBS abnormality (see www.nutramedix.ec).
5. For nutritional support, a low-sulfate multi such as Dr. Yasko’s Neurological Health Formula, 3-6/day, makes sense (or we may have you on another preparation in relation to your other health concerns).  To stimulate SUOX activity, please use sublingual hydroxy-B12 2000 mcg/day, along with Molybdenum and Boron.  They may be taken individually as Molybdenum 3 drops in water twice a day and Boron 3 mg once a day, while our Complete Mineral Complex, 3 daily will cover the mineral base.  Avoid B6 (unless you need it for other functions), which stimulates CBS.  The active form of B6, P-5-P, is less of a problem here and serves as a B6 substitute.

6. Glutathione supplementation runs the risk off adding to your sulfite/sulfate burden.  Right now this “good thing” could actually set you back.  However, if we could convince your biochemistry to up regulate biosynthesis of glutathione, then your anti-oxidant and detox capacity will increase, with concomitant utilization of free sulfate/sulfhydryl groups – a double win for you.  This can be achieved with the use of the Life Wave (needleless acupuncture) Glutathione patch.  The Life Wave people have demonstrated an increase in Glutathione levels in relation to patch use (please see separate information sheet on Life Wave patch use).

7. If you feel anxious or “wired up” (glutamate overload), take GABA 500 mg or Zen (GABA 550 mg with Theanine 200 mg, a methyl donor) twice a day.  Individuals who need methyl groups (normal COMT and/or abnormal VDR Taq alleles – your situation) will do better with Zen, while individuals who are methyl group sensitive (COMT+) will likely do better with GABA.  If they are helpful you can double the dose.  GABA/Zen do not work rapidly, but if you take these supplements twice a day you will build up a GABA reserve to balance the glutamate overload you may be experiencing due to your CBS up regulation.  Magnesium supplementation may help with GABA physiology and often helps with sleep. 
8. If energy is low, or if deficiencies are identified on your NutrEval study, we can supplement you with Co-Enzyme Q and Carnitine.  NADH does not provide methyl groups and should be well tolerate by all.
9. What is your homocysteine level?  A low level suggests that your CBS up regulation is of great functional significance, with a homocysteine “drain” overcoming the MTHFR and MTRR abnormalities (which otherwise would be associated with an elevated homocysteine level).  If not previously measured we should check it now.  Further nutritional testing can be carried out in 8-12 weeks.  This could involve separate 24 hour urine studies for nutritional minerals and for ammonia/amino acids, or we could use the Genova Labs NutrEval.  We need to make sure your mineral/nutritional stores are replete, and we are looking for low levels of ammonia, taurine, glutamate, and cysteine, to demonstrate that flow down the CBS pathway has been decreased to a physiologic level.
10. After sulfate levels have fallen (to a level that you and I feel is optimal for you, based upon your clinical and genomic status), we could advance supplementation with methyl-folate, methyl-B12, and BH4 (nutritional testing will help with decision making here).

11. A key goal of Methyl Cycle analysis is to improve your ability to detoxify, and thus toxicity testing** (which you have already undergone) and treatment make sense.  I can’t back this up with a clinical study, but the use of Aura Organ Detox patches for two months may help you.  This approach does not remove toxins but is felt to homeopathically neutralize them).  Later, after your sulfate levels have fallen, we can take further aim at the toxins themselves.  Dr. Hunt’s CD is available for your review and you can go to www.auraexplorationpatches.com for additional information.  This approach has been helpful when I have been stumped despite a full allopathic laboratory work up, and I am now liberal with its use.
12. Sauna therapy increases BH4 production and promotes detoxification, and could be utilized (low exposure at first, watching for detox reactions).  Footbath therapy is another means of removing toxins without adding foreign molecules to your body.
11. Be self-observant and keep records.  Which foods, supplements, or other maneuvers increase or decrease your sulfate spill?  Which make you feel better or worse?  Always keep in mind that detoxification is not a fun experience.  You may need to accept some transient fatigue, malaise, and achiness to allow toxic molecules to be cleared.  Conversely, if detox symptoms are debilitating or compromise your ability to work or care for your family, then we need to back off on your treatments.  Balance needs to be achieved.  Rectifying your genomic predispositions and detoxifying your system is not a sprint – it is a marathon.  And, as your genes are not going to change, and as the environment is not going to become less toxic, you will need to be mindful of these principles for the rest of your (long and healthy) life.

 * How tightly should you restrict dietary protein?  The degree of protein restriction best suited for you will be in relation to your personal health characteristics and your clinical and biochemical (urine sulfate and ammonia levels) response to treatment.  We need to keep in mind that Methyl Cycle Genomics is not the sole determinant of your health.  A low protein diet can become a high carbohydrate, weight gaining diet in an overweight individual with type two diabetes.  Individuals with chronic, unexplained illness or significant toxicity would do well to follow the “nothing with eyes” diet until urine sulfate and ammonia levels have fallen; later on we will liberalize your diet, while keeping an eye on these biochemical markers.  This dietary maneuver isn’t fun but may also turn one’s your health around.  Individuals in whom the CBS up regulation is less important (A360A as opposed to C677T, lower urine sulfate and ammonia levels, and better overall health), could simply cut back on animal protein.  In addition, the greater representation of ammonia reducing (Yucca, Charcoal, Sparga, Ammonia Support RNA) treatments in your program, the more protein you will be able to take in without compromising your biochemistry.  This is all about balancing diet against treatment response.  

** The point of Methyl Cycle analysis/treatment is to help you become a more efficient detoxifier.  Toxicity testing (discussed in more detail in other presentations and on heartfixer.com) thus makes sense.  You have already undergone toxicity testing (and I would like to review with you the results).  Testing options for new patients include:
A. The NutrEval provides us some information regarding organic pollutants and gives us red cell (reflecting what your physiology has been exposed to over the preceding three months) toxic metals ($170 with commercial insurance; fully covered under non-HMO Medicare).
B. The US BioTek study gives us information on seven major organic pollutants ($126); this is less extensive than the Metametrix study that you have already carried out and will not add any new information.
C. A formal provocative challenge ($250) gives us our best assessment of tissue metal burden.
D. The Hunt Digital picture approach ($350) assesses for toxicity (and other health challenges) by analyzing the frequencies emitted by your body (and tells us which Digital Homeopathic Patches would be most appropriate).  I can’t prove this approach with an allopathic lab test but it has been quite helpful in solving complex medical problems in my personal patients.  Dr. Hunts CD is available for your review and you can go to www.auraexplorationpatches.com for additional information.
 

OUR MOST IMPORTANT INITIAL GOAL WILL BE TO

REDUCE YOUR SULFATE STORES

 

Gene by Gene Approach – COMT -/- with VDR Taq +/+ and MTRR +/- or +/+

This constellation of alleles is discussed on pages 112-115 of Dr. Yasko’s book, Genetic Bypass.  Additional information is available on our heartfixer.com website.  VDR Taq influences dopamine production.  Being +/+ for VDR Taq means that dopamine production is compromised.  Being COMT -/- means that you are breaking down dopamine rapidly and in doing so using up available methyl groups, compromising your ability to deal with toxins and microbes (thus you are more likely than COMT +/- or COMT +/+ individuals to bear a metal burden).  You need and should tolerate dopamine precursors and methyl donors. 

MTR uses 5-methyl folate and methyl-B12 to convert homocysteine in to methionine.  Being MTRR +/- or +/+, you are having trouble converting B12 into methyl-B12, a problem that is biochemically easy to overcome with methyl-B12 supplementation. 

As you are COMT -/- and VDR +/+ you should tolerate methyl group supplementation reasonable well, so  begin supplementation with methyl-B12 (already on board) with a plan to increase the dose to 5 mg per day after urine sulfate levels have fallen.  Why wait for sulfate to fall?  Methyl-B12 supplementation, by moving the cycle of homocysteine metabolism forward, could lead to increased ammonia and sulfite/sulfate generation, so normally we do not push with methyl-B12 until urine sulfate levels have decreased.  If you possessed normal CBS alleles, then sulfate generation is not an issue, but you harbor a genomic challenged in this pathway and thus we need to move slowly with respect to methyl-B12 (and methyl-folate) supplementation.

 As you are COMT -/- and VDR +/+, you are making less dopamine in response to
Vitamin D and you are breaking dopamine down rapidly.  Thus you need and should tolerate methyl donors such as Methyl-B12, TMG, melatonin, curcumin, SAMe, or MSM (hold off on  MSM if urine sulfate levels are high).  You might benefit from quercetin and macuna puriens, both of which support dopamine production, or Procite-D, which does the same

 By stimulating BHMT, we can bypass any block that MTRR places on homocysteine detoxification, and this maneuver will also draw methyl cycle intermediates away from sulfate/sulfite production.  Pedi-Activ contains phosphatidyl serine, which stimulates BHMT, and DMAE, a methyl donor, and its use makes sense.  Lipophos Forte provides phosphatidyl choline which stimulates BHMT.  Lipophos EDTA provides phosphatidyl choline to stimulate BHMT and EDTA to remove lead (which compromises function of multiple enzymes, whether they are genetically normal or abnormal, including GAD, which converts glutamate in to GABA) and cadmium (which contributes to hypertension and cancer risk). 

 If you are troubled by agitation or anxiety (perhaps on the basis of excessive glutamate production due to a CBS up regulation), we can address this with GABA or Zen (GABA + Theanine).  As you are COMT -/- and VDR Taq +/+, you should tolerate and benefit from the methyl groups provided by theanine.  However, if agitation occurs, suggesting methyl group excess, we can utilize GABA, which does not contain methyl groups (both GABA and theanine stimulate the GABA receptor, and thus provide a “Valium” like effect without concern for drowsiness or dependency).  Neither GABA or Zen work quickly (we have other supplements for “as needed” use) and are best taken twice a day as a nutritional approach to combat the biochemical consequences of stress (emotional or glutamate-induced stress).  Other approaches to dealing with an imbalance between glutamate and GABA include avoiding glutamate rich food products (see website) and supplementation with grape seed extract 100 mg/day and/or (if a CBS up regulation is not present) taurine 500 -1000 mg/day.  Lipophos EDTA provides phosphatidyl choline to stimulate BHMT and EDTA to remove lead (which compromises function of multiple enzymes, whether they are genetically normal or abnormal, including GAD, which converts glutamate in to GABA).  EDTA efficiently removes lead and cadmium, and has activity against aluminum, nickel, and arsenic.  EDTA is not an efficient mercury chelator.  EDTA is typically well tolerated in individuals with a CBS up regulation.      

Plan of action for COMT -/- with VDR Taq +/+, and MTRR +/-
 

1. Methyl-B12 is already present at 1,000 mcg daily; please advance to 5,000 mcg daily after urine sulfate levels have fallen to 800 (or if subsequent testing indicates an increased need for B12 nutriture).
2. Quercetin + daily to provide methyl group, antioxidant, and dopamine support makes sense; ginkgo biloba, macuna puriens, and Procite-D serve as alternative approaches to augment dopamine status.
3. Unless agitation (suggesting too many free methyl groups) occurs, you may supplement freely with methyl donors such as melatonin, curcumin, TMG, or SAMe).
3. Lipophos Forte 900 mg (one teaspoon) daily mixed in juice or Phosphatidyl serine can be utilized to stimulate the BHMT pathway (unsaturated phosphatidylcholine has anti-atherosclerotic activity and of the two is thus preferred).   Alternatively, if metal detoxification is appropriate, Lipophos EDTA ½ - ½ bottles twice a week can be matched with Lipophos Forte five days a week.
4. Zen (GABA and the methyl donor theanine) twice a day if anxiety or agitation is an issue for you.  
5. Supplement to keep Vitamin D » 50.  
6. At some point in the future, after urine sulfate levels have declined, try adding SAMe 200 mg/day to your program.  While we would prefer that you generate SAMe endogenously, exogenous SAMe will provide methylation support and with your COMT -/- and VDT+R Taq +/+ status you should tolerate it well.                                                       

 

MTR (Methionine Synthase) transfers a methyl group from Methyl-folate to Homocysteine to form Methionine.  MTRR (Methionine Synthase Reductase) adds the Methyl group to otherwise inactive B-12.  MTRR abnormalities compromise the generation of methyl-12.  Without methyl-B12, MTR cannot use methyl-folate to recycle homocysteine into methionine.

 

        

VDR Taq +/+ or +/- (impaired) status compromises the production of dopamine.  COMT -/- (normal function) allows rapid breakdown of the dopamine you can generate.  VDR Taq+/+ with COMT -/- individuals will experience low dopamine levels (with consequent increased sensitivity to metal overload) and will benefit from dopamine precursor therapy and from methyl group donors.

COMT V158M  (+/+)
COMT H62H (+/+)
COMT 61         (-/-)

Highest dopamine levels
Lowest need for and tolerance to methyl group donors
Greatest susceptibility to mood swings

COMT V158M (-/-)
COMT H62H  (-/-)
COMT 61       (+/+)

Lowest dopamine levels
Greatest need for and tolerance to methyl group donors
Lower susceptibility to mood swings

  

Gene by Gene Approach – MTHFR C677T +/-

Here the MTHFR enzyme present is having trouble converting folic acid into 5-methyl folate.  Without 5-mehtyl folate MTR cannot detoxify homocysteine in to methionine.  5-methyl folate has another role here - it can neutralize peroxynitrite.  When NOS (nitric oxide synthase) is not functioning normally (i.e. when BH4 is deficient), arginine is converted not into the vasoprotective molecule nitric oxide, but rather into the damaging free radicals superoxide and peroxynitrite.  Superoxide (neutralized by Vitamin C) can further degrade nitric oxide, while peroxynitrite degrades BH4 (stimulating a vicious cycle).  5-methyl folate can neutralize peroxynitrite, thus sparing BH4, keeping it available such that NOS can generate nitric oxide, the vasoprotective molecule that we need - thus the need to maintain healthy production/levels of 5-methyl folate.  We can easily bypass the MTHFR C677T block with 5-methyl folate supplementation.  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).   

Plan of Action – MTHFR C677T +/-

Please continue with methyl-folate at 1,000 mcg per day; after urine sulfate levels fall we will advance the dose (and possibly advance BH4).

Gene by Gene Approach – SHMT +/-

SHMT combines the amino acid serine with folic acid to form 5,10-methylene THF, which is used to generate the building blocks for DNA and RNA generation.  We can bypass this block with 5,10-methylene THF, also known as Folinic acid.

  Plan of Action – SHMT +/-

Begin Folinic Acid 800 mcg/day; this should not produce any tolerance issues. 

Gene by Gene Approach – MAO A +/+

MAO breaks down serotonin and to a lesser extent dopamine and norepinephrine.  This disorder is associated with an increased tendency to mood swings and panic disorders, related to fluctuations in serotonin levels.  Serotonin formation may pick up as BH4 levels are restored with other maneuvers to address methyl cycle abnormalities.  Tryptophan in food is converted into serotonin and tyrosine in food in to dopamine.  If one is abnormal for MAO and normal for COMT, then emphasizing foods higher in tyrosine (see Appendix I) than in tryptophan makes sense (however, our initial goal is to lower sulfate, so the recommendation to avoid animal protein overrides the recommendation to take in foods high in tyrosine).

                                                                                                                               Additional Thoughts

1. You have likely undergone an extensive nutritional/risk factor/toxicity work up, but if you have not I have the following thoughts -

A. With respect to atherosclerosis, please check:
a. Lp(a), and if at all elevated begin Lp(a) neutralizing therapy with lysine, proline, and additional Vitamin C.
b. Free testosterone and estradiol, and if no prostate contraindications supplement to obtain high normal free testosterone and low normal estradiol levels.
c. Fibrinogen – if high you can use turmeric or nattokinase to lower the level and thus blood viscosity.
d. Ferritin (predominately under genomic control), and if elevated undergo periodic phlebotomy/give blood to the Red Cross, aiming for a ferritin » 100.
e. EndoPAT endothelial function testing, and if subpar you could advance Arginine further (most clinical trials used 2-,4000 mg two to three times a day) or add in Citrulline (likely boosts intracellular arginine).

B. With respect to atherosclerosis management, immune modulation could be added to your program (particular is CRP or other inflammatory markers are elevated).  Proven approaches include Pentoxifylline (please see DVD) and Colchicine (best article attached).  Testosterone works within this framework as well.

C. With respect to organic pollutant detoxification, the following detox modalities are available:
a. Far Infrared Sauna – detox at home while watching the playoffs.
b. Footbath therapy – the Ion Cleanse people demonstrated that organic materials are removed with their device.  As the principle involved is common to all of the devices available, most likely they all are effective.  We have switched to the Platinum Footbath device which seems to be more effective and user friendly.  This approach can be used at home as well.
C. The best approach is supplementation with agents that up regulate phase I and to a greater extent phase II.  All contain sulfhydryl donors (sometimes a problem is CBS + individuals), but if tolerance is not an issue, an effective approach would be to carry out a 10 day organic pollutant detox, three times a year, utilizing the Metagenics Clear Change program (other nutraceutical companies have similar programs), with an agent such as Metagenics Metalloclear or Glutaclear (up regulate detox/antioxidant pathways – incidentally Berberine also does this) when not on the Clear Change program.  You could repeat the Metametrix pollutant panel in the future; the Genova NutrEval gives similar but less extensive information regarding organic pollutant burden (and if covered under Medicare).

D. Regarding metals, in TACT we demonstrated that old-fashioned, one size fits all EDTA chelation therapy improves outcome when added to standard post-infarction management.  Stated otherwise, metals seem to be playing an important role in the oxidative stress and immune dysregulation that characterize atherosclerosis.  In your case, IV EDTA is the most powerful approach to lead and cadmium removal, while Lipophos EDTA will up regulate your BHMT pathway and unsaturated phosphatidylcholine (please see DVD) has an anti-atherosclerotic effect.  However, EDTA is a poor mercury chelator.  Here we typically use oral DMSA or IV or topical DMPS, but both are sulfhydryl group rich, and might not be well tolerated, given your CBS + status.  This creates a treatment dilemma – these agents you need are the ones you tolerate the least.  Here you could try DMSA, three times a day, three days in a row, once a month, beginning at 100 mg and working up to 500 mg, and you might tolerate it well.  Static magnetic field therapy seems to synergize with biochemical chelation and is a thought (I have been sleeping on a negative filed sleep pad over the past 10 years).  In DMSA/DMPS intolerant individuals, another approach involves the use of QuickSilver resin or Pectasol (modified citrus pectin – please see econeugenics.com).

E. Regarding CYP1B1 and the risk of malignancy, Genova has a urine estrone/estradiol hydroxylation/methylation study.  If 1B1 is functionally significant, your ration of 4-OH to 2-OH will be high.  This can be rectified with 1B1 down regulators and 1A1 (promotes 2-hydroxylation) up regulators such as DIM or I3C (please see Estrogen Metabolism section on the website).

2. Attached are DVDs, information sheets, and papers pertaining to the topics discussed above.

3. We could carry out a phone consultation regarding the above if you wish, and/or carry out the diagnostic studies listed above.  I am happy to help in any capacity.                                                                                                                                                     
                                                                                                                                                                                                James C. Roberts MD FACC FAARFM    1/4/14        
                                                                                                                 


Life Wave Patch Instructions

The Life Wave patches utilize a needless acupuncture concept to favorably influence physiology.  The science and clinical studies underlying this concept can be reviewed at lifewave.com/chc, which we encourage you to study.  No physical molecules leave the patch (in contrast to a Nitropatch or an Estrogen patch); they are technically described as “non-transdermal”.  The Life Wave patches are not homeopathic (as are the Aura patches that we also use).  The Life Wave patches do not spontaneously emit energies; rather they absorb frequencies emanating from your body and then selectively return some of them.  When you place a patch on or near your body, frequencies leaving your body cause the molecules within the patch to self-assemble in to a crystal structure.  The crystal structure serves as an antenna, capturing frequencies leaving your body (kind of like a FM receiver), and then, depending on the function of the patch, it selectively emanates frequencies into the Meridian communication system, as a function of where on the system the patch is placed.  Energy flow within the Meridian system is increased, directing your body to carry out actions that it currently is not carrying out, or not carrying out efficiently.  The Life Wave patch is like a program that we insert into your computer to make certain programs run more efficiently. 

Each type of patch comes with step by step instructions.  We can increase the cost-effectiveness of this system.  The instructions tell you to discard a patch after it has been removed; however, each patch appears to be able to work for 48 hours of contact time.  The patch is activated when it is placed on or near your body (so do not carry them around in your pocket).  It inactivates when it is removed.  So if a patch works over 48 hours, you could wear it 48 hours straight, or you could wear it for 6 hours/day over 8 days (adhesive tape may be needed). 

The most important patch is the Y-Age Glutathione patch.  This patch directs your body to manufacture more glutathione, using raw materials already present and your body’s own enzyme systems.  Glutathione is the key antioxidant/detoxification molecule in your body.  Conversely, glutathione depletion occurs in response to chronic oxidative stress and toxicity (as in the average American).  IV administration of glutathione increases excretion of toxic substances.  Oral glutathione is not absorbed; instead we give your its precursor substance N-Acetyl Cysteine (used in Medicine to prevent kidney failure during angiographic procedures, tolerance to long-acting nitrates, or liver failure in Tylenol overdose situations).  Those of you with the Methyl Cycle Cystathionine Beta Synthase (CBS) up regulation will not tolerate N-Acetyl Cysteine (due to its Sulfur content), but you should have no trouble with the patch.  The patch does not provide you with Sulfur-containing molecules; rather it directs you to assemble these molecules into glutathione, a molecule that you can put to good use and a molecule that you likely need. 

A note of caution - If you wear the patch glutathione production will increase, and if you are loaded with toxins – then you will begin to detoxify.  Drink plenty of water to facilitate this process, and if you feel poorly simply remove the patch – then put it back on the next day (it should give your 48 hours of service).  If you are vigorous and healthy, you will likely be able to wear the patch for 6-8 hours on your first day, but if you are ill, you might want to try only 2-4 hours on your first day, and then gradually increase your “patch on” time on a day-by-day basis.  Another issue, Vitamin C and N-Acetyl Cysteine both resolve Nitrate tolerance (loss of clinical effect due to Nitrate-induced glutathione depletion), and when we use these agents we sometimes have to back off on your Nitrate dose.  The same may occur with the patch - a “good problem”.

The pain patch system is a little different.  Place the tan patch over the point of greatest pain, and then the white patch 4-6 inches away.  A reduction of pain is typically noted within 10 seconds.  Positioning of the white patch can be altered to obtain the best result.  In my mind I think of the white patch as “draining pain away” from the tan patch (this isn’t actually what is happening, but the concept helps when considering patch placement).  There are also patch placement positions to deal with total body pain.  You can wear two sets, one for total body pain and another to address a focal source of pain.  You can then place a glutathione patch in the palm of your right hand.  If this maneuver lowers pain even more, than it makes sense to wear the glutathione patch, over one of the specific glutathione control points, to augment pain relief.  Feel free to experiment with patch positioning.  Remember, you do not have to remove the backing of a patch to activate it.  It is energy (frequencies) emanating from your body that activate the patch.  Wear the pain patches for 48 hours or as you see fit (if the effect attenuates at 24-36 hours, then replace the patches on this schedule).  If they fall off, then tape them back on.  If an injury is minor, then the patches might actually speed up healing (by drawing energy into the region of pain, just as standard needle Acupuncture does).  A deep injury is obviously not going to heal with energy flow alone, but if the patch system allows you to use less pain medication, and/or less anti-inflammatory drug therapy, then a goal has been achieved.  

The Carnosine patch directs your body to produce carnosine, a powerful antioxidant.  I alternate between the two, glutathione one day and carnosine the next.  We do not yet have any experience with the weight loss or sleep patches.  Regarding the weight patch, Life Wave recommends that you wear the glutathione patch for 2 months before beginning the weight loss program, the idea being that your body (in its wisdom) packs fat-soluble toxins like pesticides and herbicides in to body fat, to protect more important regions (like your nervous system).  When you attempt to lose weight, you may feel poorly, as these toxins are released.  It also may be that your body actively blocks your attempts at weight loss (by down regulating metabolism) because it wants to protect you from the release of toxicity (this theory may or may not be true but it makes sense biologically).  In any event, more glutathione cannot be anything but good you.        
                                                                                                                                                                                                            James C. Roberts MD FACC 5/27/08