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Methyl Cycle Genomic Analysis and Supplementation

    

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, 1/4 of their kids will be homozygous (-/-), ½ will be heterozygous (+/-), and 1/4 will be homozygous (+/+)				With   (+/+) and (+/-) parents, ½ of their kids will be homozygous +/+), and ½ of their kids will be   heterozygous (+/-)

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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 overdosing 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.

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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).

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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 overdosinging you with methyl groups.

Too many methyl groups can lead to mood swings. Panic attacks and bi-polar mood disorder are seen with greater frequency in COMT (+) individuals; this makes sense. COMT (-) individuals, on the other hand, need and tolerate methyl groups. A third, and less frequently encountered COMT abnormality, COMT 61, is a down regulation defect. Individuals (+) for COMT 61 breakdown dopamine quite rapidly and are at greatest need for methyl donors. To summarize in chart form:

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

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

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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.

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.

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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.

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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 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.

*Long list in the appendix

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

MAO A: Monoamine Oxidase A

Monoamine Oxidase A breaks down serotonin, a neurotransmitter that is generated from the dietary amino acid tryptophan, in a BH4 requiring reaction. Many anti-depressant drugs, including the SSRIs (Serotonin Selective Reuptake Inhibitors) work by blocking the breakdown of serotonin. Defects in serotonin metabolism have been associated with mood and neurological disorders.

How best to address the MAO A R297R abnormality is not clear to me. As serotonin metabolism is adversely affected, individuals with the R297R defect should avoid large doses of high tryptophan foods (see appendix).

High doses of St. John’s Wort, often taken to address depression, could lead to mood swings as serotonin levels fluctuate. Dr. Yasko recommends frequent dosing in small amounts of St. John’s Wort, 5HTP (a tryptophan metabolite), and the Mood S RNA formula if serotonin support is needed. If serotonin production is impaired on the basis of BH4 deficiency secondary to a Methyl Cycle abnormality, as the abnormality itself is addressed, BH4 levels should stabilize, hopefully normalizing serotonin production.

ACAT 102: Acetyl Co-Enzyme A Acetyltransferase

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

AHCY 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 1/8^th 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.

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Appendix I: Foods High in Tyrosine or Tryptophan

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).

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
•  Lentils
• White Beans
• Small amount of nuts (except those on the high sulfur list)
• Macadamia
• Pine
• Cashew
• Pistachio
• Walnuts
• Almonds
• Pumpkin
• Sunflower seeds
• 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:

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.

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Appendix III: Foods High in Excitotoxins

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:

1. Is an elevated urine sulfate diagnostic of a Methyl Cycle defect?
2. Are there false positives (high sulfate with normal genes) and false negatives (low sulfate and abnormal genes)?
3. Is there a quantitative relationship between the sulfate level and the severity of the genomic impairment?
4. 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.

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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

#4 Avocado 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

Office prices may be different – to include shipping and handling

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 2^nd 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

Overview

You are +/- for one of the CBS up regulations and +/- for the BHMT 2-8 down regulations (which acts like CBS up regulations). Homocysteine (and its methyl cycle precursors) is thus 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 excitotoxin activation), 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 as opposed to nitric oxide, predisposing you to hypertension and cardiovascular disease (compounding this problem you are +/+ for ACE, meaning that you are generating excessive angiotensin II and aldosterone, and +/- for NOS, meaning that the nitric oxide synthase enzyme itself is not functioning at full strength). After the problems in the trans-sulfuration pathway (CBS and BHMT) have come under control, BH4 can be added to your treatment program. MTR uses 5-methyl folate and methyl-B12 to convert homocysteine in to methionine.

You are +/+ for MTHFR C766T, meaning that you are having trouble converting folic acid in to 5-methyl folate, a block that is easy to overcome with 5-methyl folate supplementation. You are also +/- for two of the MTRR alleles, meaning that you are having trouble converting B12 in to methyl-B12, a problem that we will address with methyl-B12 supplementation and other measures designed to increase production of methyl-B12. You are homozygous +/+ 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 increased. The CBS up regulation/BHMT down regulation leads actually to increased production of sulfite, which must be converted to less toxic sulfate by SUOX. In this situation, SUOX is “overworked”, and its co-factors become depleted; thus we supplement with SUOX co-factors. Your SUOX is not functioning normally, as you are +/- for this enzyme; thus our measures to address CBS/BHMT and supplement SUOX assume greater importance.

Gene by Gene Approach – CBS +/-, BHMT +/-, and SUOX +/-

Our most important problem is that you are +/- for one of the CBS up regulations and +/- for three of the BHMT down regulations (which act like CBS up regulations). Homocysteine (as well as its methyl cycle precursors) is being drawn down the trans-sulfuration 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). Being +/- for SUOX, this enzyme system is both overworked and dysfunctional, compromising conversion of sulfite in to less toxic sulfate.

To address this constellation of alleles I will recommend:

1. No animal protein diet (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. Monitor urine sulfite and urine sulfate every 7 days. Low levels of sulfate (400 or 400-800) 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 in to 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.
5. Avoid excitotoxins (see list of foods) 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. The former three all contain methyl groups, which are a plus as you are COMT -/- and VDR Taq -/-, and thus in need of methyl groups.
8. After your sulfur and ammonia pools have been depleted down towards normal we will treat you with BH4, and we can be more liberal with other methyl cycle supplements. 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/ SUOX (more on BHMT later)

 

1. Begin the diet discussed above and the supplements checked on the supplement sheet.
2. Check the sulfur (sulfite) content of your supplements (this is why you have reacted poorly to glucosamine sulfate and DMPS, both high in sulfur), as well as the content of B6 (which stimulates CBS and is thus best minimized – Ultimate Cardio Fusion contains only 10 mg of B6 and is thus OK, and it provides you Co-Enzyme Q10 and Carnitine which you need). Do not use DMSA, DMPS, Lipoic acid, or N-Acetyl Cysteine as they are rich is sulfur. You can use the Life Wave Glutathione patch (lifewave.com/chc) to promote endogenous generation of Glutathione from sulfur containing precursor molecules already present in your body; this will enhance your antioxidant defense capacity, promote detoxification, and hopefully use up some of the excess sulfur containing molecules that you cannot metabolize properly.
3. Monitor urine sulfite and urine sulfate every 7 days (and please chart the levels) – this will be our primary measuring stick – our goal is a urine sulfate of 400 (one yellow and three pink) but we can live with a urine sulfate of 800 (two yellow and two 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. Ultimate Cardio Fusion does contain some B6, but as stated above is otherwise of value to you; thus we will not switch to another general nutritional unless your sulfate levels do not fall. Please add in Trace Minerals Complex at 2 drops/day for general mineral support. Please add Molybdenum 6 drops twice a day, Vitamin E succinate 400 IU daily, Boron 3 mg/day, and hydroxy-B12 2000 mcg twice daily to stimulate SUOX.
6. Add NADH one per day to your program (Ultimate Cardiofusion contains Co-Enzyme Q10 and Carnitine and you take Ribose before and after you run so energy production/mitochondrial fnciton is covered).
7. GABA 500 mg or Zen (GABA 275 mg with Theanine, a methyl donor) twice a day to blunt excitotoxicity makes sense, if you feel anxious or “wired up”; if you feel that GABA is helping a lot than you can increase the dose.
8. In eight weeks 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.
9. Wear the Glutathione patch 6 hours a day, the idea here being to use up some of the free sulfur molecules floating around to generate Glutathione, a key antioxidant and detoxifier.

OUR MOST IMPORTANT INITIAL GOAL WILL BE TO

REDUCE YOUR SULFITE/SULFATE STORES

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

Being COMT -/- and VRD Taq +/+ means that you are not making enough dopamine and that you are breaking it down readily, and in this process you are using up methyl groups. This means that you need and will tolerate methyl donors. This combination, along with MTRR +/- is discussed on pages 112-115, which also covers our approach to BHMT.

MTR combines 5-methyl folate with homocysteine, in a methyl-B12 dependent process, to generate methionine, the precursor substance for the universal methyl donor SAMe (S-Adenosyl Methionine). The MTRR abnormality means that you are not converting B12 in to methyl-B12, compromising your ability to detoxify homocysteine (and to pull it away from the “CBS drain”), and to generate SAMe.

As you are COMT -/- and VDR +/+ you should tolerate methyl group supplementation reasonable well, so begin supplementation with methyl-B12 5 mg daily, advancing to twice a 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.

As you are COMT -/- and VDR +/+, you are not making 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, melatonin, turmeric, and SAMe (only after sulfate levels have decreased), and dopamine precursors (foods high in tyrosine). You might benefit from quercetin and macuna puriens, both of which support dopamine production, and the Mood D RNA preparation, which does the same.

“Over methylation” producing mood swings due to excessive fluctuations in dopamine levels is not likely as you are COMT -/- VDR Taq +/+, but could occur; in this case simply decrease the quantity of methyl donors in your program.

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).

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

1. Methyl-B12 5 mg daily, increasing to twice daily after urine sulfate levels fall.
2. Quercetin + and Pedi-Active daily.
3. Lipophos EDTA ½ bottle twice a week.

Gene by Gene Approach – ACE +/+

Angiotensin II activity is up regulated, predisposing you to hypertension and increasing your risk for atherosclerotic vascular disease. If drug therapy is needed for hypertension, the best agents will be tissue specific ACE inhibitors (Quinapril, Ramipril) and/or Spironolactone, a relatively weak diuretic that blocks the action of Aldosterone, which when up regulated plays a role in the development and progression of heart disease and heart failure.

Of interest, individuals with this genotype respond to statin therapy with greater drops in LDL and more pronounced blunting of plaque progression than do ACE -/- individuals. ACE may cause anxiety, which could be addressed with the Anxiety Support RNA product. Your BP is normal and you do not have active cardiovascular disease so drug intervention in not needed or appropriate.