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Overview

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 function of the remaining pathways. While we cannot change your genetics, if we know your weaknesses, we can create "nutritional workarounds" - we can supplement alternative pathways or withhold from your diet molecules that you cannot handle. For example, MTRR (Methionine Synthase Reductase) regenerates Methyl-B12, needed in the detoxification of Homocysteine to Methionine. If your MTRR pathway is defective, then we can "nutritionally bypass" it by supplementing you with Methyl-B12. Conversely, the common defects in CBS (Cystathione b-Synthase) is an up regulation - excessive production of sulfur containing compounds and excessive ammonia production, leading to brain fog and secondarily to depletion of BH4 (needed to detoxify ammonia), with multiple tertiary metabolic consequences. Here we would recommend a vegetarian-type, low sulfur diet, with periodic measurement of urine sulfur and ammonia levels, and nutritional steps designed to neutralize ammonia, such that your BH4 stores are spared. In ten years, individualized medicine based upon analysis of your individual genetic strengths and weaknesses will be routine, but right now, in 2008, we can use our understanding of Methyl Cycle Nutrigenomics to help our patients. The brains behind this approach is Amy Yasko PhD. Her book - Genetic ByPass, is our guide book. If you desire additional information, you can spend several weekends (I did) reviewing her websites (start with holistichealth.com). Our nutrigenomic testing is carried out through Genetic Profiling Systems, LLC, with which Dr. Yasko is affiliated. Additional testing, designed to understand the consequences of methyl cycle abnormalities, and to help monitor treatment, is carried out through Doctor's Data in Chicago (doctorsdata.com). Below I will discuss the individual genetic defects, but the real key here is to understand the interaction between the defects, and to make nutritional/diet recommendations based upon an understanding of the entire genetic and clinical picture - what we try to do at Comprehensive Heart Care and the Advanced Magnetic Research Institute of NW Ohio.

The idea here is to identify and nutritionally stimulate the enzymes that are genetically down regulated - and then to supplement with downstream intermediates and methyl donors which are in short supply due to the specific defect(s) present. For example, the MTHFR C677T (forward) defect prevents you from converting THF (derived from folic acid) in to 5-methyl THF. Supplementing you with folic acid would be inappropriate; instead we would supplement you with 5-methyl THF. If “front door” conversion of homocysteine into methionine is compromised by defects in MTHFR (forward), MTR, and MTRR, then we can stimulate the “backdoor reaction” with supplementation designed to stimulate the activity of BHMT (center of third circle).

Some of the defects lead to up regulation - overactive function of a specific enzyme. The MTR defect leads to overactive conversion of homocysteine in to methionine, depleting you of methyl-B12. The CBS up regulation “pulls down the drain” all methyl cycle intermediates, generating ammonia and sulfur breakdown products. We must control this defect before we aggressively supplement you with methyl cycle intermediates; otherwise the intermediates will “fall down the drain”, aggravating your condition.

COMT and VDR determine your overall sensitivity to methyl donors. Their status will determine whether we give you methylated or un-methylated forms of the various intermediates involved in the overall methyl cycle.

Methyl cycle defects leave you sensitive to environmental toxins, compromise your defense against microbial infection, and complicate proper reading of your remaining genes. Methyl cycle dysfunction explains why one individual is damaged by environmental toxins, while others living in the same environment enjoy good health.

As the methyl cycle starts up in response to appropriate supplementation, the individual will begin to excrete metal toxins previously retained. A detox reaction (malaise, irritability, fatigue) may occur. A spot urine for toxic metals will show an increase in toxic excretion, indicating that the problem is not toxicity from the supplements, but that detoxification is going on.

Lab studies will help us monitor your progress. A urine (or plasma) amino acid assessment will allow us to quantify the levels of ammonia and sulfur containing amino acids. The urine dipstick test for sulfur will tell us whether or not our efforts have been successful in lowering a sulfur burden brought on by the CBS up regulation defect. An increase in urinary excretion of toxic metals will tell us that your methyl cycle is back on line. Urine (or red cell) mineral studies will allow us to assess your nutritional status, and allow appropriate supplementation of minerals used up by the detoxification process.

Your insurance company will not cover the cost of genomic testing, the report that we construct, nor the cost of the supplements you will need to address the abnormalities present. I will not write letters requesting pre-authorization; this would be a waste of time and might “red flag” you with your insurer. The cost of methyl cycle testing and our report is $1,125 (we got involved in methyl cycle testing to improve outcome in patients undergoing MME, so if you undergo 100 or more hours of MME, you will receive a 2% discount if you first undergo methyl cycle testing).

Methyl cycle testing makes the most sense in individuals with disease states closely linked with sensitivity to environmental toxicity, such as childhood neurological conditions (autism, learning disability), early onset neurodegenerative disease (Parkinson’s or Alzheimer’s disease), people who are not getting better despite what appears to be appropriate therapy, and patients with difficult to treat chronic infections or disease states that really don’t make any sense such as chronic fatigue and fibromyalgia. Individuals with elevated homocysteine not responsive to folic acid supplementation and individuals with elevated urine sulfate levels likely harbor methyl cycle genomic defects.

Dealing with methyl cycle defects should greatly improve your response to any form of detoxification therapy. Actually, dealing with a methyl cycle defect that made you sensitive to environmental toxins can in theory turn you into an efficient “self detoxifier”, decreasing your need for ongoing medical attention and treatment. Methyl cycle genomic testing (and genomic testing in general) is the future of medicine. We are pleased to be able to offer methyl cycle genomic testing in 2008.

MTHFR: 5,10-Methylenetetrahydrofolate Reductase (Þ 5-Methyl Folate)
C677T	+/- (C/T) +/+(C/C)	C substituted for T as site 677
Function	Converts 5,10-tetrahydrofolate into 5-mehtyl tetrahydrofolate (5-methyl folate)
Findings	Elevated Homocysteine not responsive to folic acid (as you can’t activate it to 5-methyl folate)
Problem	You cannot detoxify homocysteine (increasing risk of cardiovascular, clotting, and neurologic sequelae), and you cannot generate SAMe. High levels of homocysteine lead to high levels of SAH (s-adenosyl homocysteine) which inhibits several enzymes within the methyl pathway, including COMT (creating mood swings in individuals already COMT +/+ or +/-), and it inhibits enzymes that transfer methyl groups to DNA.
Treatment	1. 5-methyl folate supplementation (and avoid folic acid which will only compete for absorption). An adult could take prescription Cerafolin or Metanx, and a child could take ½ to 1 Folapro. 2. Low level supplementation of down stream methyl donors makes sense, as does supplementing the backdoor reaction to help clear Homocysteine. 3. The Methyl Support RNA product could also be used.

MTR: Methionine Synthase
A2756G	+/- (A/G) +/+(A/A)	A substituted for G as site 2756.
Function	Adds a Methyl group obtained from 5-Methyl Folate to Homocysteine (in a process that requires the presence of Methyl-B12, generated by MTRR), to form Methionine, which goes on to be converted into SAMe.
Findings	Variable Homocysteine levels, B12 function will be deficient, and downstream methyl cycle intermediates such as SAMe will be deficient
Problem	This is an up regulation defect, which produces a global deficiency of Methyl-B12, as it is drawing all the Methyl-B12 generated by MTRR into the pathway. Folic acid and 5 methyl-folic acid will also be drawn down by the overactive MTR and will require supplementation to a greater degree than will the other methyl cycle intermediates.
Treatment	1. Supplement with B12 - Hydroxy-B12 if Methyl groups are in excess (COMT +, VDR -, status) or Methyl-B12 if they are not, or a combination of the above. Start with 5 mg of sublingual or chewable B12 daily, advancing as tolerated to three doses a day. Mood swings (suggesting excessive dopamine) will prompt a treatment shift away from methyl-B12 and towards more hydroxy-B12. 2. Supplement the backdoor Homocysteine to Methionine pathway (via BHMT) with TMG (trimethylglycine) or phosphatidylserine. Avoid dimethylglycine (DMG) which would actually slow down the homocysteine to Methionine conversion.
Modifier	MTRR: if abnormal will need even more B12, as without MTRR you cannot make Methyl-B12.
Modifier	COMT: if +/+ or +/- there will be delayed reduced breakdown of Dopamine via Methylation so there will be extra Methyl groups available so we would tend to use Hydroxy rather than Methyl-B12 VDR Bsm/Taq: -/- is normal and allows for higher levels of dopamine and free methyl groups, so here you would tend to use Hydroxy-B12, while +/+ leads to lower dopamine and Methyl group status so here you would tend to use Methyl-B12. So if you are (+) for COMT and (-) for VDR you will have high dopamine levels and lots of Methyl groups, while is you are COMT (-) and VDR (+) you will have low dopamine levels and lower levels of available Methyl groups so you would tend to use Methyl-B12 to help overcome the defect in MTRR.
Modifier	CBS – if abnormal will drain additional methyl cycle intermediates, beyond methyl B12 alone as occurs with the MTR up regulation
Note	The VDR Fok abnormality deals with sugar balance and not methyl issues

MTRR: Methionine Synthase Reductase
A66G	+/- (A/G) +/+(A/A)	A substituted for G at site 66.
H595Y	+/- (H/Y) +/+(H/H)	H substituted for Y at site 595.
Function	Generates the Methyl-B12 used by MTR to convert 5-Methyl-THF into Methionine.
Findings	Homocysteine levels will likely be elevated.
Problem	Methyl-B12 cannot be generated to allow MTR to convert Homocysteine and 5-Methyl-THF into Methionine. Homocysteine toxicity will occur as well as impaired formation of S-Adenosyl Methionine (SAMe) such that methylation in general will be impaired
Treatment	1. Supplement with B12, Hydroxy-B12 if Methyl groups are in excess or Methyl-B12 if they are not, or a combination of the above. 2. Supplement the backdoor Homocysteine to Methionine pathway (via BHMT) with TMG (trimethylglycine), phosphatidylserine, or phosphatidylcholine. Avoid dimethylglycine (DMG) which would actually slow down the Homocysteine to Methionine conversion.
Monitoring	None except Homocysteine levels if elevated pre-treatment
Modifier	MTR – if abnormal will need even more B12, as this is an up regulation, increasing the demand for Methyl-B12 (see graphic below).
Modifier	COMT: if +/+ or +/- there will be delayed breakdown of Dopamine via Methylation so there will be extra Methyl groups available so we would tend to use Hydroxy rather than Methyl-B12 VDR Bsm/Taq: -/- is normal and allows for higher levels of dopamine and higher methyl group status, so here you would tend to use Hydorxy-B12, while +/+ VDR status leads to lower dopamine and Methyl status such that Methyl-B12 would be more appropriate than the hydroxyl-B12 form. So if you are (+) for COMT and (-) for VDR you will have high dopamine levels and lots of Methyl groups, while is you are COMT (-) and VDR (+) you will have low dopamine levels and lower levels of available Methyl groups so you would tend to use Methyl-B12 to help overcome the defect in MTRR.

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.

COMT: Catechol – O – Methyl Transferase
V158M	+/- (V/M) +/+(V/V)	V substituted for M at site 158.
H62H	+/- (H/H) +/+(H/H)	H substituted for H at site 62.
Function	Inactivates dopamine, norepinephrine, and other catecholamines by transferring to them a methyl group from SAMe. This activity “uses up” methyl groups generated elsewhere within the methyl cycle.
Problem	The (+) form is less active; therefore dopamine levels will be elevated and there will be an excess of SAMe and other methyl groups (not all bad as this will protect you from toxins and viruses and lessen your need for BH4 and metal detoxification) and you will be sensitive to methyl donors and foods/supplements that raise dopamine.
Treatment if (+/+) or (+/-)	1. Be cautious with supplements that provide methyl groups, including methyl-B12, MSM, TMG, DMG, curcumin, melatonin, caffeinated tea, quercetin, and the RNA products Mood D, Mood focus or SAMe (could use Methionine instead). 2. Avoid high dopamine (tyrosine) foods (see list below). Tyrosine (dopamine precursor) and tryptophan (serotonin precursor) compete with each other for uptake, so if you have too much dopamine (COMT +) and/or not enough serotonin (low BH4, high ammonia) emphasize foods high in tryptophan (see list).
Treatment if (-/-)	1. Here you are draining SAMe and methyl groups in general, so supplement liberally with methyl donors, such as those listed above. 2. SAH (S-adenosyl homocysteine) puts a break on COMT, and will be generated from the SAMe that you are taking to provide methyl groups, 3. Support dopamine with agents such as Mood D (1/4 dropper 1-2 times a day), Mood Focus (1/8-1/4 dropper daily), quercetin, ginko, and macuna puriens. No need to avoid high dopamine foods. Dopamine protects nerve cells from metal toxicity, especially if glutathione is lacking.
Modifier	VDR Bsm/Taq: -/- is normal and allows for higher levels of dopamine and higher methyl status. With respect to sensitivity to methyl cycle supplementation, this will aggravate the COMT (+/+) situation. VDR Bsm/Taq: +/+ prevents Vitamin D from increasing dopamine production, so you tend to be low in dopamine (just as in the COMT (-) situation). Methyl status will be low so you will be less sensitive to supplementation with methyl groups. So if you are (+) for COMT and (-) for VDR you will have high dopamine levels and lots of Methyl groups, while is you are COMT (-) and VDR (+) you will have low dopamine levels and lower levels of available Methyl groups so you would tend to use Methyl-B12 to help overcome defects in MTR and/or MTRR.

VDR: Vitamin D Receptor
VDR Taq and Taq/Bsm affect methyl cycle		VDR Fok affects sugar metabolism; not relevant
Function	Mediates an increase in dopamine production in response to Vitamin D. As there is less need of methyl groups to support dopamine production, there is an increased supply of available methyl groups for other methyl cycle activities (not all bad as this will protect you from toxins and viruses and lessen your need for BH4 and metal detoxification).
Problem	The (+) form is less active; therefore dopamine levels will be lower, methyl groups will be used up making dopamine, so free methyl groups will be in short supply (and methyl group supplementation will be better tolerated).
Modifier: COMT Status	COMT and VDR are essentially inversely related with respect to dopamine and methyl groups levels; as such: COMT (+/+) and VDR (-/-) will have the highest dopamine levels and free methyl groups and will be susceptible to mood swings with supplementation. COMT (-/-) and VDR (+/+) will have the lowest dopamine levels and will be in greater need of and more tolerant to methyl groups supplementation. COMT (+/-) and VDR (-/-) behaves like COMT (+/+) COMT (+/-) and VDR (+/+) behaves like COMT (-/-)

CBS: Cystathione Beta Synthase
C699T	+/- (C/T) +/+(C/C)	C substituted for T as site 699 in exon 8
A360A	+/- (A/A) +/+(A/A)	A substituted for A as site 360 (weaker defect)
Function	Converts Homocysteine into Cystathione – The Trans-Sulfuration Pathway
Findings	Low fasting and post-Methionine loading Homocysteine levels. Sensitivity to sulfur products and sulfa containing antibiotics and drugs. Elevated ammonia if the remaining enzymes of the Methyl cycle are intact.
Problem	Up to 10-fold up regulation, generating sulfur breakdown products, depleting glutathione, and generating Ammonia, leading to “brain fog” and stressing the Urea cycle such that BH4 levels fall, leading to a decrease in serotonin and dopamine production. Sulfur activates the stress/cortisol/adrenaline response, creating chronic “fight or flight”. G6PDH may be affected, leading to abnormalities in sugar control. Excess Alpha-Keto-Glutarate can lead to excitotoxin activity, especially if Aluminum and Mercury are present. Methylation intermediates will “fall through this drain”, so the entire system suffers; our defense against viral invasion and toxicity suffers. Co-Q10 and Carnitine generation will fall off due to impaired Methylation, and ATP levels fall, and in this case, more Alpha-Keto-Glutarate will be generated and converted into hydrogen sulfide, also contributing to “brain fog”. The Ammonia detoxifying Urea cycle is strained, more BH4 is used up to neutralize ammonia. Without adequate BH4 NOS (Nitric Oxide Synthase) generates Superoxide instead of Nitric Oxide, compromising cardiovascular function.
Treatment	1. Avoidance (strict in homozygotes) of dietary sulfur, sulfite and sulfate. Avoid vegetables rich in sulfur such as garlic, onions, eggs, broccoli, and other cruciferous vegetables. Drugs and supplements containing Sulfur should be avoided (Glutathione, N-Acetyl Cysteine, Taurine, DMSA, DMPS) until the body’s sulfur pool has been reduced to normal (when the test strips turn pink). Avoid animal protein (anything with eyes). In heterozygotes (+/-) treat other Methyl cycle abnormalities with caution until the sulfur pool has been depleted back in to a physiologic range (otherwise the methyl cycle intermediates supplemented will be drained down the CBS pathway to create additional sulfur breakdown products); be even more deliberate with homozygotes (-/-). COMT +/+ and or VDR -/- individuals will have higher dopamine and BH4 levels, may be less ill, but will be more sensitive to methyl cycle intermediates, which could increase dopamine too much, causing irritability/manic behavior. 2. To reduce/neutralize Ammonia, Dr. Yasko recommends Ammonia Support RNA ½ dropper with meals and with methyl cycle supplements, along with a charcoal supplement (or bentonite) at bedtime (away form 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/day may help with ammonia detoxification. SAMe, carnitine, and methionine help neutralize ammonia (but their levels will be difficult to maintain as they will be drained down the up regulated CBS pathway). 3. Supplement with Molybdenum to stimulate SUOX (can measure Molybdenum in a RBC or urine mineral test); high doses may be necessary. Homogenized dairy products contain Xanthine Oxidase, which further depletes Molybdenum, and should be avoided if Molybdenum levels are low. 4. GABA may help neutralize excitotoxin activity on the basis of excessive Alpha-Keto-Glutarate. 5. BH4 can be given after the sulfur pool is reduced. 6. Dr. Yasko also recommends Health foundation, Stress foundation, and Nerve Calm RNA preparations to all patients with Autism and methyl cycle defects. 7. We need B6 for many activities but B6 drives the CBS enzyme; therefore supplement with the P5P form of B6 as opposed to B6 if possible.
Monitoring	Urine sulfate test strips – Yellow reflects high sulfate, light red low sulfate
Monitoring	Urine amino acid profile - Allows quantification of ammonia and sulfur containing amino acids. A 24 hour urine collection is best, but if not possible a first morning specimen will work. If urine collection is not possible, then a plasma amino acid determination can be utilized.
Modifier	SUOX – Sulfite Oxidase – If abnormal (-/-) will have trouble converting the Sulfate generated into Sulfite.
Modifier	BHMT-2, 4, & 8, when abnormal act as if CBS is up regulated
Modifier	The A1298C mutation of MTHFR will further deplete BH4

MTHFR: 5,10-MethyleneTetraHydroFolate Reductase (BH4 Formation)
A1298C	+/- (A/C) +/+(A/A)	A substituted for C as site 1298
Function	SAMe cannot bind to MTHFR such that its reverse reaction, which generates BH4, is compromised. This is the “backward” defect of MTHFR. The “forward” reaction is intact: 5-methyl folate can still be formed.
Problem	BH4 is critical. You need BH4 to neutralize ammonia, to generate dopamine and serotonin, and to generate nitric oxide form Arginine (without BH4 you get the free radical superoxide instead). BH4 protects nerve cells from metal toxicity (best worked out with arsenic) and glutathione depletion. Low BH4 is associated with CV disease, diabetes, and parasitic infections.
Treatment	1. Do all you can to limit ammonia production (thus sparing available BH4). 2. Remove mercury, lead, and especially aluminum; these toxins poison DHPR, the enzyme which recycles BH2 back in to BH4. 3. Supplement the methyl cycle in general, considering COMT and VDR status. 4. Consider supplementing to increase dopamine (if COMT - and/or VDR +), or serotonin (if COMT + and/or VDR -), as levels may be low and BH4 is required for their production. 4. BH4 supplementation.
Modifier	A CBS up regulation creates ammonia, which depletes BH4, compounding the problem.

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

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

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

1. Addressing any CBS up regulation issues to decrease alpha-ketoglutarate production.
2. Decreasing intake of food precursors of glutamate (see list below).
3. Supplementing with GABA
4. Copper inhibits conversion of glutamate to GABA by glutamate decarboxylase so avoid copper excess, or better stated, an imbalance between copper and zinc.
5. Calcium is involved in glutamate toxicity, so supplement with magnesium to keep calcium in check.
6. Remove heavy metals with a chelating agent, preferably enhanced with a static magnetic field therapy (of interest, toxicity due to mercury is aggravated by glutamate excess – they synergize to damage nerve cells).

Sources of Excitotoxins
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

BHMT: Betaine-Homocysteine Methyltransferase
	+/- or +/+ for one of the forms of BHMT
Function	“Back Door” conversion of Homocysteine into Methionine by combining TMG and Homocysteine to form Methionine and DMG (dimethylglycine).
Significance	BHMT stimulation helps adjust for abnormalities in MTHFR, MTR, and MTRR.
Defects	BHMT-02, 04, and 08 heterozygotes may behave like CBS +
Treatment	If COMT +/+ and VDR -/- (here you need and can handle methyl groups): 1. Phosphatidylserine alone and/or combined with the methyl donor DMAE (Pedi-Active). 2. Low dose TMG (trimethylglycine) may help (in kids the HHC multi 1-2/day provides this. 3. Phosphatidylcholine (Lipophos Forte or Lipophos EDTA). If COMT -/- and VDR +/+ (relatively sensitive to methyl groups): 1. Phosphatidylserine alone, without DMAE. 2. HHC multi but lighten up if mood swings occur (methyl groups in TMG). 3. Phosphatidylcholine (Lipophos Forte or Lipophos EDTA).

ACE: Angiotensin Converting Enzyme
ACE/ID	Insertion/deletion in intron 16	+/- +/+
Function	Converts Angiotensin I, a weak vasoconstrictor, into Angiotensin II, a powerful vasoconstrictor, which causes endothelial dysfunction, free radical stress, and which stimulates the release of aldosterone from the adrenal gland, which in turn wastes magnesium and potassium, retains sodium, and stiffens the heart. Drug therapy for heart failure and hypertension in adults targets this system.
Problem	This defect up regulates ACE, so you have too much Angiotensin II and aldosterone.
Treatment	In adults we will use drug therapy to block ACE and aldosterone. In kids we will pay attention to electrolyte levels. Dr. Yasko recommends the use of kidney support RNA, OraKidney, OraAdrenal, Stress and Anxiety Support RNA, and BioNativus multi-mineral support.

NOS: Nitric Oxide Synthase
E298D	Missense glu-298-to-asp in exon 7	+/- +/+
Function	In a BH4 dependent process, NOS converts arginine into nitric oxide. Pertaining to metyl cycle physiology, NOS assists in ammonia detoxification.
Problem	Nitric oxide (NO) protects against CV disease, vasospasm, and clotting. This defect is associated with an increased risk of CV disease and poor outcome following angioplasty or heart attack (as you have trouble making NO).
Treatment Theory	In adults with CV disease, numerous measures are available to support NOS. Pertaining to methyl cycle dysfunction, the key here is to minimize ammonia excess, as BH4 will be drained in the ammonia detoxification process. In the absence of BH4, NOS will convert Arginine not in to nitric oxide, but rather into peroxynitrite or superoxide, both “bad guy” free radicals. Treatment of NOS dysfunction is similar to that of CBS and MTHFR A1298C with respect to addressing ammonia excess and BH4 deficiency.
Treatment	1. Be conservative with dietary protein intake (generates ammonia), and if ammonia is elevated it can be addressed with Stress RNA, charcoal, and Yucca. 2. BH4 supplementation should improve NOS functional integrity.

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 +