Kathy Froese's Yasko panel and case analysis

[Guest guest]

(Kathy has given me permission to post comments on her case, as has

her daughter, Cheri.)

Hi, Kathy.

Thank you for sending me the results of your Complete Basic SNP

Panel I (Yasko panel). I would like to make some comments about

them, relate them to your daughter Cheri's Economy Basic SNP Panel

results, to your earlier urine amino acids test results, and to your

history and symptoms.

So, let's look at your Yasko panel:

The first thing to look for is CBS upregulations. As I predicted,

based on Cheri's panel results, you are heterozygous (have one copy)

for the CBS C699T SNP. As I had noted earlier, you had to have been

at least heterozygous for this one, since Cheri was homozygous.

Because your cystathionine level was not nearly as high as hers, and

your case of CFS, though serious, is not as serious as hers, I

suspected that you would be heterozygous, and sure enough, you are.

So what does this do? It causes homocysteine to be converted to

cystathionine more rapidly than normal, which causes a diversion of

the normal flow of sulfur metabolites back to methionine.

In reviewing your urine amino acids test, it can be seen that your

methionine level was low-normal (10 compared to 8-50 micromoles

excreted in 24 hours), your cystathionine was high (65 compared to 8-

60), and your homocystine (the oxidized product of homocysteine) was

below the detection limit. I think all of these are consistent with

your having this SNP. I think it is unusual that cystathionine

would be elevated as a result of this SNP alone, and I suspect that

you (and Cheri as well) probably also have a SNP in the enzyme

cystathionase, also known as cystathionine gamma lyase, which

converts cystathionine to cysteine. This enzyme is not

characterized in the Yasko panel. I suspect that this causes quite

a bit of the excess cystathionine to be excreted in the urine, which

represents a loss of sulfur metabolites from the body, but

apparently there is still an excess flowing into cysteine and the

rest of the transsulfuration pathway and sulfoxidation, in view of

your sensitivity to food, supplements and drugs containing sulfur.

This excess can also be expected to form more taurine, ammonia,

sulfite, and hydrogen sulfide, and lower production of glutathione.

Your urine amino acids test showed very high taurine (3750 compared

to 220-1420) as well as somewhat elevated ammonia (39500 compared to

12000-56000). I think you have reported sulfurous intestinal gas,

and I that would be consistent with hydrogen sulfide. Your red

blood cell total glutathione level was below the normal range. All

of this seems consistent with the CBS upregulation. The more

protein containing methionine and/or cyst(e)ine that is ingested,

the more exacerbated this excess flow is likely to be, and the more

production of ammonia and toxic sulfur species will occur.

Ingestion of excess protein in general, whether or not it contains

methionine or cyst(e)ine, will cause more ammonia production from

the breakdown of the amino acids.

The next one to look at is SUOX S370S. You show a (+/+) on this

one, which is actually the normal situation for this SNP, and that

means that your sulfite oxidase enzyme is probably operating

normally. This enzyme uses molybdenum as its cofactor, so it is

possible that if molybdenum is low, its activity will be below

normal. In any case, it will be receiving more flow than normal

because of the CBS upregulation, and it is apparently not able to

cope with the additional load when you consume sulfur-containing

substances. This produces a rise in sulfite, and this is toxic,

which accounts for your symptoms at those times.

Next is MTHFR A1298C, of which you have one copy. This SNP,

according to Amy Yasko, makes it difficult to maintain a normal

level of tetrahydrobiopterin (BH4), especially if you also have

aluminum toxicity, which blocks the other enzyme for making BH4, and

which she says is more common in females. Having a lower level of

BH4 hinders the synthesis of the neurotransmitters dopamine and

serotonin, and also hinders the operation of the enzyme nitric oxide

synthase and of the urea cycle for converting ammonia from protein

breakdown into urea for disposal. Thus, the presence of this SNP

compounds the problem with excess ammonia that is caused by the CBS

SNP. Your NOS enzyme does not have the D298E SNP, which is good,

but it appears that you will still have an excess ammonia problem

from these other two SNPs.

The next ones to look at are MTR and MTRR. You have MTR A2756G (+/-

), and you also have MTRR A66G (+/-) and MTRR S175L (+/+). MTR is

the enzyme methionine synthase, which converts homocysteine to

methionine, and you have one copy of a SNP that upregulates it,

causing it to use methylcobalamin faster than normal. MTRR is

methionine synthase reductase, the enzyme that recycles

methylcobalamin for reuse by MTR, and you have one copy of a SNP

that downregulates it and two copies of one that upregulates it.

I'm not sure of the relative magnitudes of these up- and

downregulations, but I suspect that you will have a depletion of

methylcobalamin because of them, and will need to supplement vitamin

B12. The form of B12 to use will depend on other SNPs (see below).

The significance of having these SNPs in MTR and MTRR in your case

is that they further exacerbate the abnormal shift in flow of

homocysteine away from the methionine-forming reaction and toward

the cystathionine-forming reaction.

Fortunately, you don't have the MTHFR C677T SNP. This one would

have further interfered with your folate metabolism and methylation

cycle, but you don't have it!

Now let's look at your COMT SNPs. You have a quadruple whammy

here! You are homozygous for both the COMT V158M and the COMT

H62H. Both these SNPs downregulate the enzyme catechol-O-

methyltransferase, and you have two copies of each. It is

responsible for taking methyl groups from SAMe and attaching them to

dopamine and epinephrine as part of the process for breaking them

down. You do also have VDR Bsm/Taq (+/+), which will counter this

somewhat, and the MTHFR SNP discussed above will also help to

compensate, because the rate of production of these

neurotransmitters will also be slower than normal because of the low

BH4. It's hard to say what the ultimate effects will be on the

neurotransmitter levels. If they rise, other feedback systems can

then cause their levels to oscillate, which can cause mood swings.

If you experience mood swings, this could be the reason. If you

don't, perhaps these SNPs are canceling out each other's effects.

The lowered activity of COMT will also cause a lower demand for

methyl groups from SAMe, and I suspect that might be why you had a

normal creatinine level on your amino acids test (1270 compared to

600 to 1900 mg). (Creatinine arises as a breakdown product of

creatine, and creatine synthesis normally requires 70% of the

methylation capacity of SAMe.)

The remaining ones are the VDR Fok (+/-), which Amy Yasko says can

interfere with control of blood sugar level, the VDR Taq (+/+), of

which I don't know the effects, and the combination of ACE Del 16

(+/+) and MAO A R297R (+/-). ACE stands for angiotensin converting

enzyme. This SNP causes it to be at a higher concentration, leading

to more conversion of angiotensin I to angiotensin II and elevation

of aldosterone secretion by the adrenals. Higher aldosterone causes

the kidneys to retain more sodium in the blood and excrete more

potassium in the urine. If the adrenals become exhausted from

producing excess aldosterone, this can drop off, and then the blood

can become higher in potassium and lower in sodium. This SNP is

associated with higher risk of heart disease, MAO A is responsible

for breakdown of serotonin, and the SNP downregulates it, allowing

serotonin to rise. This can trigger a feedback loop that will cause

the serotonin level to oscillate, producing mood swings. The

combination of the ACE and MAO A SNPs can cause a greater tendency

toward anxiety and a low threshold for frustration.

Before going further, I think it would be interesting to comment on

Cheri's panel results in the light of yours. According to the way

genetics works, Cheri must have at least one copy of any SNP of

which you have two copies. Since Cheri got the Economy panel, we

can only look at the ones she was tested for. This includes ACE,

COMT V158M, and VDR Bsm/Taq, and these check out as expected. Also,

Cheri can't have more than one copy of the ones you don't have at

all. This includes MTHFR C677T and NOS, and they also check out as

expected. So that's one way to check on the accuracy of these

tests. We can also infer some aspects of your husband's SNPs, but

since I didn't ask for his permission, I won't comment on his SNPs

here.

Now, what else can we say with regard to your urine amino acids test

in the light of the Yasko panel results and your red blood cell

total glutathione test result?

First, I note from this urine test and an earlier one you reported

that you have a higher than normal 24-hour urine volume. You also

reported a while back that when you were getting intravenous

glutathione, you had less thirst, and were able to leave home

without carrying a lot of water with you. I think the explanation

is that you definitely are depleted in glutathione, and that the

depletion of glutathione in your hypothalamus inhibits the secretion

of arginine vasopressin and gives you what would be classified as a

mild case of diabetes insipidus. When your glutathione was

temporarily raised, the diabetes insipidus lessened. I think this

agrees with the experience Hall has reported on this list.

Your urine amino acids test also showed a high phenylalanine level

(130 compared to 25-120) in the presence of a low-normal tyrosine

level (82 compared to 38-190). I think this corresponds to the low

BH4 level predicted by your Yasko panel. On the other hand, your

glycine does not appear to be driven strongly to serine, which

suggests that 5,10 methylene tetrahydrofolate is not building up,

which is consistent with your not having the MTHFR C677T SNP.

The comments I made in April on the other amino acids in your urine

amino acids test that I haven't discussed here are still valid, I

believe.

Since I've gone through and reviewed my file on you again in

connection with analyzing the Yasko panel results, I have some other

thoughts to offer as well:

As you know, you tested low in glutathione, and when you started

your intravenous glutathione infusions, they were beneficial at

first, in terms of giving you more energy, helping your lungs (less

coughing), less sensitivity to chemicals, less problem with

allergies, less sensitivity to light and noise, and less thirst.

However, after four I.V.'s, they began to produce more fatigue. You

also reported that nebulized glutathione helped you, at least

initially. I don't recall if you said that it was not beneficial

after a while or not. What's the explanation for this glutathione

behavior?

I think that you are clearly depleted in glutathione, and we now

know why: You inherited some serious SNPs in enzymes impacting your

methylation cycle, and, combined with some major demands on your

glutathione at a certain time in your life, this resulted in a

vicious circle that has been holding down your glutathione for

years. So why does putting glutathione in actually turn against

you? The reason is that you have a CBS upregulation combined with a

block in your methionine synthase reaction. Too much of your

ingested sulfur passes down your transsulfuration pathway and

overloads your sulfite oxidase enzyme. When you add glutathione

intravenously, most of it goes to your kidneys. The kidneys have an

active gamma glutamyl cycle, which breaks down and reforms

glutathione, but some is broken down permanently, and this adds to

the flow in the transsulfuration pathway and exacerbates your

sulfite excess, producing symptoms. So you experienced benefit from

the added glutathione, but it also ended up producing more sulfite

and making you more fatigued.

I'm sorry that you went through all these problems when you tried to

build glutathione. I realize that I am partly responsible, since I

encouraged you to do it. At the time, I didn't know about the CBS

SNP and how it could affect a person's ability to tolerate

glutathione supplementation, nor dit I know that you had this

particular SNP. So, I'm sorry about that, and I'm hopeful that we

now have a much better understanding of what's going on at the root

cause level, and can deal with that, so that glutathione will be

able to come up naturally, and you will have the benefits of it

without those downsides. I appreciate your hanging in there with

me, Kathy, with all the false starts, as we struggle up the learning

curve.

You've discussed your hypothyroid situation and your use of thyroid

supplementation. I think that it's likely that glutathione

depletion in your thyroid gland is what initially caused the

hypothyroid condition, because of the buildup of hydrogen peroxide

in the thyroid cells, as I discussed in my 2004 poster paper. If

this is the case, it may be that your thyroid function will return

if the glutathione level can be restored, as Hall reported to

be true in his case. I suspect that your body's inability to

convert T4 to T3 readily is a result of selenium depletion, caused

by mercury toxicity, in turn caused by inhalation of mercury from

your amalgams in the face of insufficient glutathione to carry it

out of your body. Mercury binds with selenium to form a very stable

complex, taking both out of bioavailability.

You mentioned that you can't tolerate heat. In view of what we have

learned from Dr. Cheney over the past year or so, I suspect that

this means that you have low blood flow to your skin, which is a

compensation for low cardiac output, possibly caused by diastolic

dysfunction, secondary to glutathione depletion in the mitochondria

of the heart muscle cells.

Some time ago you mentioned having blood spots on your forearms, and

also easy bruising of your legs if you scratch them. Furthermore

you reported that you have osteopenia and major gut problems.

Putting all this together, I have come to suspect that you might be

deficient in vitamin K. Vitamin K comes in from the diet and is

also synthesized by bacteria in the normal gut. It is important for

supporting the blood coagulation system as well as directing calcium

to the bones, and out of the arteries. With your gut problems, you

may not be getting enough vitamin K, and that might explain the

blood spots and the osteopenia. I don't know if you have any

atherosclerosis building up in your arteries, but low vitamin K

might cause that, too.

Now, why the gut problems? I think they could be partly due to low

glutathione in the gut, and perhaps also due to serotonin problems

as a result of the things discussed above. Most of the serotonin in

the body is in the gut, and it is very important for controlling gut

motility.

Why all the lung problems? I suspect they result from glutathione

depletion. Normally glutathione is at high concentration in the

fluid lining the lungs, and it serves as a protection against

oxidizing free radicals from either air pollution or the response of

macrophages in the lung to infections that start from inhaled

pathogens. Without enough glutathione there, the lungs would be

constantly irritated.

You reported trying lysine for the cold sores, and it seemed to

suppress the cold sores while you were able to use it, but it caused

you pain and fatigue. Why was that? I suspect that it did affect

the histones in the nuclei of the nerve cells in such a way as to

slow the replication of the herpes simplex virus, but it also

increased the level of ammonia when it was broken down, adding to

your ammonia problem that resulted from your CBS and MTHFR SNPs.

There were indications that you were low in vitamin B6. Vitamin B6

is necessary for transamination reactions that convert amino acids.

Since you apparently have a relatively high protein diet (based on

your elevated 1-methylhistidine), you are probably using a lot of

transamination in order to convert your amino acids to use for

energy production. That may put extra demands on your B6.

Cold sores: why have you had such a severe problem with them since

you were a child? Probably because your SNPs make it difficult to

maintain enough glutathione in your nerve cells to suppress the

herpes simplex virus and keep it in its latent state.

Epsom salt baths: I don't know why these would tire you out, unless

you are very low in sulfate, so that your Phase II sulfation detox

pathway is suppressed, and then when you add sulfate, it begins to

mobilize some stored toxins. If you are low in sulfate, you should

be experiencing some joint problems also, I think. Sulfate should

not cause you the same types of problems as other forms of sulfur,

because it does not have to pass through the sulfite oxidase enzyme.

I don't know why direct sunlight wears you out. One possibility

would be a porphyria, but I think you were tested for at least some

of them, and it was negative, right?

Magnesium shots help you, which suggests that you are low in

intracellular magnesium, and I think that results from glutathione

depletion.

I think I've dealt with most of the issues you've reported over the

past four years or so, and I think we now have a somewhat better

understanding of what's behind them.

One more thing, I want to acknowledge another mistake on my part.

When I was analyzing your urine amino acids report a while back, I

got confused and thought that I had a previous organic acids report

from you. You wrote back that you didn't recall ever having such a

test. When I went back through my file on you this time, I looked

more carefully, and I found that the organic acids test I had put in

your file was actually from another person, also a " F., "

also living in Canada, also on this list! However, the F. stands

for a different last name! Sorry about that. So please disregard

everything I said related to that organic acids test. You mentioned

that you were thinking about getting one yourself, and I would

certainly be interested in seeing the results if you do.

O.K., now, what about treatment?

Well, first, as I mentioned in my earlier email to you, I encourage

you to join the group at http://www.autismanswer.com. Amy Yasko has

set up a special section called " parents and adults, " and she is

currently working on a simplified treatment program for adults and

is writing a book about how her approach applies to adults. Also,

in the book " Genetic ByPass, " of which I think you have a copy, the

particular pages that refer to your set of SNPs are pages 211-214

and 233-239. I suggest that you read pages 233-239 first, because

they will trump everything else in your case.

In view of your CBS and reverse MTHFR SNPs, I think it is clear that

you should limit your protein intake (I realize that this won't be

easy for you, because your body is intolerant to so many foods), do

the ammonia support program, which involves taking activated

charcoal and yucca to bind ammonia in the gut and carry it out, and

take supplements to encourage the secondary pathway from

homocysteine to methionine, such as trimethylglycine (betaine),

phosphatidyl serine and phosphatidyl choline. Also limit your

intake of sulfur-containing substances, which I'm sure you already

do. The purpose of these actions is to slow the flow into the

transsulfuration pathway and encourage the flow back to methionine,

as well as to minimize the production of sulfite and ammonia, and

help your body get rid of excess ammonia.

Amy Yasko also has a gut program, and I would suggest that you look

into doing that early on, too.

It may take some time to get these flows going in the right

direction again, so you will need to be patient with this approach.

The next things to do will be to build up your B12 and folate.

Because of your heavy downregulation of COMT, the form of B12 that

you should use is hydroxocobalamin. Both folinic acid and FolaPro

would likely be helpful to you as well, especially until the

methionine synthase reaction gets going well again. After that, you

probably won't need folinic.

After you have built your B12 and folate up, you can add DMG to slow

the alternate pathway and encourage the methionine synthase

reaction.

These actions will start to increase your detoxing and that will be

unpleasant, but you can track what's going on with urine toxic

metals tests. There are some particular things Amy Yasko recommends

for females to help with the detox, including horsetail grass, EDTA,

and some others.

There is more detail on all of this in the book and on Amy Yasko's

websites. I realize that all of this is very complicated, but I do

think it is the right path to follow, in view of the facts that it

appears to explain the other observations associated with your case,

and that it seems to be getting down to the rock bottom causes of

what has been going on in your body all these years.

I hope this is helpful. Please let me know what you think about it,

and especially tell me if you see anything here that you know is not

correct.

Rich