More Methylation

[kim]

opps didn't mean to send that yet

[MomWithOCDSon]

Discovery of new antibodies (24.3.1)

 

In 2003, Kirvan and Swedo published the landmark Nature paper entitled Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea which pulled together all the above papers into a finding that there were three distinct antibodies that cross-reacted with Lysogangliosides in the brain. In addition, they found one of these antibodies caused significant CaM Kinase II activation in sera.During this time, Dale , Church and others were making similar observations regarding anti-basal ganglia-antibodies (ABGA).

 

and

 

 

Clarifying the presentation differences of PANDAS (sudden onset, episodic course)

 

In 2006, Kirvan and Cunningham published their finding that children from the Swedo studies were distinct from Tourettes and traditional OCD/ADHD patients in that the Sydenham Chorea and PANDAS children had elevated CaM Kinase II activation in their sera.In 2007, Kirvan further showed that Tubulin is a target of the anti-neural antibodies in patients with sydenham chorea.

 

Okay, we never had Cunningham's CamK test done, so I don't know definitively whether or not my DS has ever had high CamK.

 

But . . . again, strictly from a self-described "science dummy," isn't it possible that they found elevated CamK activation in PANDAS kids because they were looking for it, and they were looking for it because of Cunningham's previous work regarding SC?

 

Does anyone know if there's ever been any studies of "Tourettes and traditional OCD/ADHD patients" looking for the level of CamK activity? Or, is it one of those things that would "turn up" somehow in some other form of blood testing? Just from a reading of Kirvan, et. al., it seems to me that they're assuming the absence of elevated CamK activity in non-PANDAS patients, but assumption, of course, isn't fact. If those populations have never been studied for it, how do we know that it doesn't play a role in non-PANDAS behaviors, as well?

 

And if it does, in some way play a role, then what does that say about all the other potential players in these maladies?

Edited December 3, 2011 by MomWithOCDSon

[MomWithOCDSon]

Laura --

 

Honest to Pete, you have to be the undisputed Queen of Wonderful Metaphors and Imagery! I am in awe!

[LNN]

Nancy - the metaphors are only useful if they're accurate - and I have no idea if that's the case! Someone may pull up this thread two years from now and I'll groan at how wide of the mark I was. I can weave sentences together, but get totally lost when we start talking about basic chemistry.

 

But re: your question on studies of TS kids and CaMKII = I think Leckman started sending selected TS kids to Cunningham about 2 yrs ago to have their blood run thru her lab. I think she found elevated numbers in them too. But I don't know if anything got published on it - and bear in mind this is when Leckman was just getting pulled back more and more into the Pandas domain, so he may have been hand-picking the kids he felt had the TS label but might have had infection-triggered causes. I think it was a testing the waters thing and not a full blown study. I also don't know which numbers out of the 5 Cunningham looked at were more often elevated.

 

Kim - I think I'm still missing your point. You need to spell it out for me. I'm not disagreeing that anti-neuronal antibodies probably signal CaMKII and trigger inflammation and screw up neuronal signalling in the basal ganglia. Somewhere in her DVD, Yasko touches on her theory of how autoimmunity happens as a result of methylation blocks (hate to keep referencing her, as I'm not trying to hold her out as THE authority on everything - she's just my only source on this stuff at the moment).

 

But from a treatment/coping in the middle of an episode perspective, or from a keep it from happening again perspective, I still go back to "ok, let's say autoimmunity has happened and this mis-firing is happening. How do you stop the chain reaction?" You mention MSR A and I don't know much more on that than what you've already cited. But I'm thinking supplementing that would be helpful. But maybe another option is to regulate NMDA receptors. Sorry to quote Wiki again, but it's the only thing on the topic I can remotely hope to understand...

 

"CaMKII is activated by calcium/calmodulin, but it is maintained by autophosphorylation. CaMKII is activated by the NMDA-receptor-mediated Calcium elevation that occurs during LTP induction. Activation is accompanied by phosphorylation of both the alpha and beta-subunits and Thr286/287"

So one thing is to regulate Calcium to begin with (with zinc/B6 or reducing glutamate in the diet). But if the horse is out of the barn, what if you look at regulating NMDA receptors (which also get activated by glutamate). "Calcium/ calmodulin dependent protein kinase II is also heavily implicated in long-term potentiation (LTP) – the molecular process of strengthening active synapses that is thought to underlie the processes of memory. It is involved in many aspects of this process. LTP is initiated when the NMDA receptors allow Ca2+ into the post synaptic neuron."

 

Aside from Namenda, which a few people have had good experience with, NMDA receptors can be modulated with magnesium, sodium, K, zinc, copper. Plus "NMDA receptor function is also strongly regulated by chemical reduction and oxidation, via the so-called "redox modulatory site."[26] Through this site, reductants dramatically enhance NMDA channel activity, whereas oxidants either reverse the effects of reductants or depress native responses. It is generally believed that NMDA receptors are modulated by endogenous redox agents such as glutathione, lipoic acid, and the essential nutrient pyrroloquinoline quinone."

 

Glutathione is huge in terms of detox and anti-oxidation, clearing the body of used junk and free radicals that can do damage. I can't tell you how many times I come across glutathione both in treating lyme and in my methylation research. Oral glutathione is poorly absorbed and liposomal oral glutathione, which might be slightly better absorbed, is expensive. Alpha lipoic acid isn't an option for us right now because we may have a mercury problem and ALA is a mercury chelator that crosses the BBB (which could move mercury into, as well as out of, the brain), so I don't want to go there right now. So my wallet has brought me back to encouraging the body to make more of its own glutathione, which brings me back to unblocking the methylation pathway.

 

From my guinea pig experiment on one little boy, it seems that unblocking methylation points that are unique to him (either from genetic inability to synthesize certain nutrients or from poor diet which creates a nutrient deficiency) have made the whole system work better. It seems to be helping his brain chemistry and helping his body fight chronic infection - the source of any autoimmune trigger that's there. So geekiness aside, I still come back to shoring up the foundational, basic pathways to prevent car accidents and bad gas in the first place. My guinea pig still needs to get rid of some mercury (which I'm dreading) and still has to address biofilms. These things are probably still getting in the way of proper signalling/functioning.

 

So to come back full cycle to Nancy's original article, I think you can look at the methylation/trans-sulfuration pathways and either do genetic tests or infer from family history or individual behavior where you may have pre-dispostions to blockages (my family struggles at Reno and Chicago). So I'm supplementing with folate to improve seratonin (don't need methyl-folate because DS's MTHFR gene is normal) and zinc/B6 for pyroluria and deficiency at the point where the immune system is supplied with weapons and soldiers. (sorry to mix metaphors). I'm hoping that once the body is cleared of remaining obstacles (metals and borellia) we no longer need to manage hyper-activation of CaMKII and co. because the body will be able to balance itself. I know it's popular belief that you can't reverse auto-immunity. I'm no longer sure about that. I don't have anything other than my guinea pig, who's on mutliple abx, so I can't say whether he'll ever be able to handle a strep infection without intervention. But he's getting so much better with supplements that for the first time, I'm willing to entertain the hope that he'll be able to leave his PANS label behind him someday (albeit he may always need to take certain supplements - I'm ok with that trade-off).

Edited December 3, 2011 by LLM

[LNN]

One more thing I thought was worth mentioning - we started supplementing magnesium 2 months ago based on Dr Burrascano's "Guidelines for Treating Lyme" where he notes many lyme patients are magnesium deficient. Magnesium is a calcium agonist, so it's possible some of the improvements we're seeing are from the magnesium, not just the zinc/B6 for pyroluria. Magnesium is also a poop-inducer (too much gives you diarrhea), which is good for detox when you're killing bacteria that release toxins when they die (e.g. lyme and strep). Calcium is also an ingredient in biofilms and some biofilm busting protocols use EDTA as a cheltor. EDTA chelates aluminum (thought to be hoarded by bacteria in the biofilms) as well as calcium. When you use EDTA and/or magneisum, you need to keep an eye on calcium so you don't deplete too much, especially in growing bodies.

 

So it's all connected. Nancy's totally right - it's absolutely about balance. The right balance for each unique body. For us, doing things that reduce calcium have been helpful. For Nancy Fcxfer, adding calcium with her current protocol is helping her son. But it seems that when you do things intended to help brain chemistry, by supplementing nutrients the body needs (as opposed to a pharmaceutical supplement), you could end up supplementing/bypassing a methylation block, and vice versa. Clog-free highways are good all the way 'round. It's "simply" a matter of knowing where the clogs are likely to happen - like anything about this is "simple."

 

Yasko does such a better job of connecting these dots. All I can say is for anyone trying to look beyond antibiotics, this is really a topic worth exploring. Ok, off my soapbox - time to pull up a mold-harboring rug and replace it with wood flooring this weekend.

[MaggiesMoons]

One more thing I thought was worth mentioning - we started supplementing magnesium 2 months ago based on Dr Burrascano's "Guidelines for Treating Lyme" where he notes many lyme patients are magnesium deficient. Magnesium is a calcium agonist, so it's possible some of the improvements we're seeing are from the magnesium, not just the zinc/B6 for pyroluria. Magnesium is also a poop-inducer (too much gives you diarrhea), which is good for detox when you're killing bacteria that release toxins when they die (e.g. lyme and strep). Calcium is also an ingredient in biofilms and some biofilm busting protocols use EDTA as a cheltor. EDTA chelates aluminum (thought to be hoarded by bacteria in the biofilms) as well as calcium. When you use EDTA and/or magneisum, you need to keep an eye on calcium so you don't deplete too much, especially in growing bodies.

 

So it's all connected. Nancy's totally right - it's absolutely about balance. The right balance for each unique body. For us, doing things that reduce calcium have been helpful. For Nancy Fcxfer, adding calcium with her current protocol is helping her son. But it seems that when you do things intended to help brain chemistry, by supplementing nutrients the body needs (as opposed to a pharmaceutical supplement), you could end up supplementing/bypassing a methylation block, and vice versa. Clog-free highways are good all the way 'round. It's "simply" a matter of knowing where the clogs are likely to happen - like anything about this is "simple."

 

Yasko does such a better job of connecting these dots. All I can say is for anyone trying to look beyond antibiotics, this is really a topic worth exploring. Ok, off my soapbox - time to pull up a mold-harboring rug and replace it with wood flooring this weekend.

 

 

I have a very simple question (lol)...........

What tests do you start with to figure out the methylation, histamine, MTHFR, and so on?

We have tested with Dr. T, the basics I am assuming, diagnosed PANS now, lyme negative, myco and strep positive in 3 other adult family members but not DS. I read one place where certain B vits are good and others are bad and vice versa. Doing ABX 21 days now for DS, family finished 10 days ABX.

Could someone give me the "List" of what else to have tested? I think we need to look further like metals etc just don't know what to ask for.

[kim]

LLM,

 

I think I'm still missing your point.

 

That's probably because there really isn't one!

 

I guess I just wanted to discuss the more "natural side" of something that might be helpful. I had a lot of respect for the info that was coming out of Yasko's site. There isn't anything that you or Nancy have said that I don't basically agree with, except I am a little perplexed about " the loss of two neighboring methiones."

 

If CamK II is strictly being elevated by an antibody in a PANDAS situation, well maybe I'm way off base, but something that I had read a really long time ago was kind of stuck in my head

 

http://www.alternativementalhealth.com/articles/walshMP.htm

 

One thing that is absolutely certain is that methionine and/or SAMe usually harm low-histamine (overmethylated persons)..... but are wonderful for high-histamine (undermethylated) persons. The reverse in true for histadelic (undermethylated) persons, who thrive on methionine, SAMe, Ca and Mg..... but get much worse if they take folates & B-12 which can increase methyl trapping.

 

I wonder what can be learned from children here who had those high CamK II levels that don't strictly fit the PANDAS criteria that were used for the study?

 

 

Nancy,

 

If you look at this paper

http://intramural.nimh.nih.gov/pdn/pubs/pub-19.pdf

 

There was no elevation in 10 sera from non-PANDAS

tics, six sera from non-PANDAS OCD, 10 sera from ADHD,

or five age-matched normal control sera when compared to

PANDAS

 

I don't know if there is more in the research or not?

[JAG10]

A little bit more copied from the article Kim provided above:

 

Elevated histamine and/or elevated basophils indicate undermethylation. Review of symptoms and medical history can bolster the diagnosis. For example, most undermethylated persons exhibit seasonal allergies,

perfectionism, strong wills, slenderness, OCD tendencies, high libido, etc. Overmethylated persons generally exhibit anxiety, absence of seasonal allergies, presence of food/chemical sensitivities, dry eyes, low perspiration, artistic/music interests/abilities, intolerance to Prozac and other SSRI's, etc.

 

Conditions associated with undermethylation: Anorexia, Bulemia, shopping/gambling disorders, depression, schizo-affective disorder, delusions, oppositional-defiant disorder, OCD.

 

Conditions associated with overmethylation: Anxiety/Panic disorders, anxious depression, hyperactivity, learning disabilities, low motivation, "space cadet" syndrome, paranoid schizophrenia, hallucinations. (Oct 3, 2003)

 

 

Do we find this to be true? Or are we again a mixed bag not ever fitting neatly in any category? Kim, I am likely way off base, no doubt, but are you getting at that over or under methylation is a base-condition that may only be apparent after the "bad antibodies" from PANDAS are mopped up and then you can see the methylation backdrop that contributed to setting the stage in the first place? Seems most of our kids would symptomatically cross categories as they are described here.

 

Another novice question.....when histamine is referenced, that is neuronal histamine, yes? which isn't the same as other measurements of histamine, I thought......

[JAG10]

I've been trying to make sense of methylation on a very rudimentary level with only my dd11 is mind. Very rudimentary........

 

I was getting confused differentiating undermethylation and overmethylation; we'll say UM and OM. But I think what you have to do is look at what is left over when you're done mopping up the PANDAS antibodies. I mean, OCD and anorexia is associated with UM and the ADHD/learning/fog stuff is associated with OM....so how can you be both??? Well, looking only at clinical symptoms and no labs for my dd, I would say what were the symptoms that disappeared almost immediately with very first IVIG? restrictive eating, picking/trichotillomania w/skin, overt OCD, tics. These symtpoms were very impairing on quality of life. 75% of overall symptoms resolved with 1st ivig. What have been those lingering 25% symptom type; add, fog, attention, focus stuff. Not sure where immaturity/behavioral regression fits in, but I'm going to say with the ADD type.

 

So, once you've "mopped up the mess" of pandas antibodies, you're left with an over-mythylated girl? Now ivig & steroids must have been having some impact on that process as well because we have seen slow improvement in those areas too, but leaves a fragile state of wellness, perhaps. I looked through dd's records and I don't have any histamine measurements. I always thought that because she had this terrible reaction to bug-bites (as do I and my mom) that it was a hyper-histaminic response and she made too much histamine. Perhaps that is unrelated to histamine production or neuronal histamine, idk. She does not exhibit seasonal allergies. The only related lab I could find was Absolut Basophils measured 3 times at 11, 12, & 28 with a reference range of 0-200, but pretty low which is associated with OM.

 

Do you think this is why some kids look so "classic pandas" and some don't? Maybe the more "classic pandas" looking kids are UM?

 

But didn't Dr. T say he thought all of our kids were low-histamine which would be OM?

 

So....maybe some of the symptoms we are associating with PANDAS aren't really related to the PANDAS anti-neuronal antibody phenomena at all, but the underlying condition that helped make the child susceptible to PANDAS? I apologize if some of you are like...duh!

[trggirl]

Ok, tying the Camkinase II and methylation together, if a patient has a high Camkinase II, pubmed studies show it releases Glutamate and Norepinephrine. Now you have all this high Norepinephrine and Glutamate floating around. Theoretically, this is one place where the methylation would come into play. Methylation by SAMe is one way Norepinephrine is metabolized to Epinephrine. So if you have high Norepinephrine due to High Camkinase II, what effect would you have if you start supplementing Methionine or SAMe for methylation???? If I remember correctly, Nancy reported anxiety effects with her son on SAMe. Was this because supplementation was methylating the Norepinephrine and producing Epinephrine????? I think Chemar's son did well on SAMe. I wonder what the difference is???? And I know I am only talking about one area where methylation occurs and therefore probably oversimplifying the problem. How would you ever know what to give?

 

As far as overmethylation vs. undermethylation, we never fit perfectly into either category. I think there is a lot to be learned from their theories though.

 

One last thing, while I think the methylation stuff could definitely help with symptoms if you could figure it out, I love that this thread is bring ing up the question of why the CamKinase II is high in the first place. If phosphorylation activates the CamKinase, there has to be something that would make phosporylation conditions less prevelant and thereby decreasing the Camkinase!!??

[LNN]

Kim - not sure I have the same understanding on what is good/bad for under-methylators...you wrote "One thing that is absolutely certain is that methionine and/or SAMe usually harm low-histamine (overmethylated persons)..... but are wonderful for high-histamine (undermethylated) persons. The reverse in true for histadelic (undermethylated) persons, who thrive on methionine, SAMe, Ca and Mg..... but get much worse if they take folates & B-12 which can increase methyl trapping."

 

I agree on all except the folate piece. My understanding is that if you're an under-methylator (which my DD is), folate is critical - that either you don't have enough or perhaps genetically you can't convert folate into SAMe and therefore need methyl-folate, but in either case, some type of folate supplementation would be recommended. I do share your impression on the B12 and am struggling when Yasko says B-12 is good for everyone. Can you help me understand your comment on the folate? It seems to be helping my kids (one is clearly an UM and one is possibly an UM but clearly not an OM).

 

Jill - "So....maybe some of the symptoms we are associating with PANDAS aren't really related to the PANDAS anti-neuronal antibody phenomena at all, but the underlying condition that helped make the child susceptible to PANDAS?" - yes, 3 pages into this thread, you summed it up

 

I personally don't take Welch's article as absolute. Both my kids cross over his descriptions of UM and OM, particularly on the "soft" traits like being musically inclined. DD is clearly an UM - allergies galore, drama queen, OCD - yet is incredibly artistic and tons of anxiety. DS is likely UM but has big anxiety, adhd and what looks on the outside like learning disabilities that are clearing up with methylation support. So we are a mixed bag. From what I gather from other reading about Welch and Pfeiffer, Pfeiffer has created 26 categories of methylators and feels you can be an UM at some points in the cycle and OM at others (tho this is only an impression - I'm not well read on Pfeiffer).

 

Oh - and I don't know the answer to your histamine question - I never knew there was any difference between regular histamine and neuronal histamine. And if Dr T believes our kids are generally low histamine, I would respectfully disagree - at least in my house.

 

TrgGirl - "How would you ever know what to give?" - That's where Pfeiffer or Yasko come in. For a certain amount of money, either group will run tests to tell you where your weak points are and what you should supplement. After 3 years of pursuing big gun treatments, I am too strapped to go this route and am doing my own "educated guessing" based on very selective/incomplete testing.

 

"If phosphorylation activates the CamKinase, there has to be something that would make phosporylation conditions less prevelant and thereby decreasing the Camkinase!!?? " - this is sort of where I was trying to go with all my quotes from Wiki yesterday. For me, in my over-simplification of things, the "something" you mention could be calcium/glutamate and glutathione.

 

And finally, to the very practical Maggie's Moon, to whom I owe a ton of gratitude for opening my eyes to this whole methylation topic by making me look up the word "histadelia", what tests? Depends on what guru. Yasko has two dozen genes she tests, genes that effect the methylation points she feels are most telling/important. The whole test panel can be ordered for $500 http://www.holisticheal.com/health-tests/nutrigenomic-testing. Or you can pick and chose the genes that you think are most likely suspects. I had both kids' MTHFR gene tested last month and just got the EOB - Quest charged $450, Cigna's "negotiated/discounted rate" (what a racket this whole thing is) was $50 and my portion was $10. You can get Yasko's book/DVDs and get the full list of things she tests and what they mean. But since your doctor is already tuned into this stuff, he/she may have other ideas that are more practical or targeted for you. I'm also looking at family history as a guide.

 

I know some people are following this thread and aren't really sure why I'm so excited about all this. But it comes down to how Jill summed it up and what Suzan on the lyme forum posted yesterday - supporting the basics and supplementing at unique, genetically predisposed weak points - can really really help our kids get healthier and offer a bridge/bypass around the points that seem to fall apart and send our kids into "episodes". I think it's the same thing Stephanie2 and Fxcfer are finding, in their own ways. For me, treating methylation weak points is a way to prevent future episodes instead of relying on suppressive treatments once an episode is underway. It's not a one time fix. It could be a lifelong form of "medication" (albeit with vitamins and minerals) that puts our kids on a more permanent path of good health. I've been taking some of the same supplements and feel better than I have in 20 years. I know that sounds "infomercial hokey". But it's an OMG feeling - it's a complicated topic, but the result is an incredibly simple solution. Probably too simple. I'm sure there's more to good health than "just" methylation support. But it feels like I've found a really important piece we were missing.

Edited December 4, 2011 by LLM

[JAG10]

Kim - not sure I have the same understanding on what is good/bad for under-methylators...you wrote "One thing that is absolutely certain is that methionine and/or SAMe usually harm low-histamine (overmethylated persons)..... but are wonderful for high-histamine (undermethylated) persons. The reverse in true for histadelic (undermethylated) persons, who thrive on methionine, SAMe, Ca and Mg..... but get much worse if they take folates & B-12 which can increase methyl trapping."

 

 

Laura, this came directly from that Walsh article/link above.

 

I'm not sure about different types of histamine either. I do remember reading once about neuronal histamine, but I'll have to try and look it up again. Have you had your children's histamine levels tested? Was it one measurement? I don't even know what the name of that lab test is called. Do you know your kid's absolut basophil numbers? Does that jive with Walsh's article? Of course, I think it did say "elevated histamine +/- elevated absolut basophils"

[LNN]

Re: folate - folate is what gets converted into SAMe, so how can folate be bad for an under-methylator? I'm not arguing about the quote, I just don't get how this can be true. Unless your MTHFR genetic mutation makes it difficult to convert folate, in which case you'd use methyl-folate. But I'm just not getting how folate belongs in the list of bad things for UMs. Can anyone help me on this??

 

Have never had histamine levels tested - at least not that I know of, unless it's one of those things Dr B tests in his initial panels - that was 2 yrs ago. I'll have to check on the basophils - I don't recall their levels ever being out of range but it wasn't something I was focused on - will have to pull their labs.

[trggirl]

LLM, I believe it is Methionine that is converted to SAMe. The folate is used to convert homocysteine back to Methionine.

[LNN]

Oops - you're right.

Homocysteine=>B-12 & folate => methionine or homocysteine =>TMG/betaine=>methionine

Methionine=>ATP & magnesium => SAMe=>homocysteine

 

I got myself twisted around there. Thanks! Guess I'll be tweeking my guinea pigs' pills...and re-watching the DVDs to set myself straight again.