Mast Cell Activation Disorder (MCAD), Chronic Illness, and its Role in Methylation

mastcellWhat do chronic illnesses such as Autism, Chronic Fatigue Syndrome (CFS), Fibromyalgia Lupus, Chronic Lyme Disease, Interstitial Cystitis, Multiple Sclerosis, and more have in common? Well, these illnesses may have a lot of things in common, and a lot of overlapping symptoms, but many patients symptoms seem to be compatibled with Systemic Mast Cell Activation Disorder (MCAD).

So what is MCAD according to Mayo Clinic?

Systemic mastocytosis (mas-to-sy-TOE-sis) is a disorder caused by a genetic mutation that results in an excessive number of mast cells in your body. Mast cells normally help protect you from disease and aid in wound healing by releasing substances such as histamine and leukotrienes. But if you have systemic mastocytosis, excess mast cells can build up in your skin, around blood vessels, in your respiratory, gastrointestinal and urinary tracts, or in reproductive organs. When triggered, these mast cells release substances that can overwhelm your body and result in symptoms such as facial flushing, itching, a rapid heartbeat, abdominal cramps, lightheadedness or even loss of consciousness. Common triggers include alcohol, temperature changes, spicy foods and certain medications.

http://www.mayoclinic.org/systemic-mastocytosis/

A Slightly Better List of Triggers

The following “triggers” may influence a mast cell response: drug abuse, excessive alcoho consumption, preservatives, stress, sunlight, environmental toxins, bacteria/fungi/mold, artificial colors or flavorings, heat/cold, etc. Minimizing your exposure to these triggers may help redcuce you mastocytosis risk.

http://www.knowcancer.com/oncology/mastocytosis/

I know for a fact that many have trouble with one, many, or perhaps all of these triggers. From that list, I know alcohol, stress, sunlight, bacteria, mold, heat, and cold trigger my symptoms. The only thing I haven’t noticed as a trigger are artificial colors or flavoring, but maybe I am not paying close attention. Spicy food, which is not on this list can be another trigger for MCAD.

Mayo Clinic had a decent list at symptoms associated with Systemic Mastocytosis, but let’s look a little more in-depth of symptoms, since Systemic Mastocytosis has many of them.

The U.K. NHS has a pretty good list. The symptoms are a bit scattered throughout the article, so I’ll modify it a bit to make one complete list.

A Relatively Complete List of Associated Symptoms

  • hot flushing – described as a dry feeling of heat, rather than the sort of wet heat you experience when sweating
  • palpitations (irregular heartbeat)
  • lightheadedness
  • headache
  • shortness of breath
  • chest pain
  • nausea
  • diarrhoea
  • stomach pain caused by peptic ulcers
  • loss of appetite
  • weight loss
  • swelling of the liver, which can cause jaundice (yellowing of the skin and eyes) and make you feel lethargic
  • swelling of the spleen, which can cause abdominal (tummy) and shoulder pain
  • joint pain
  • swelling of the lymph nodes
  • weakness
  • fatigue
  • changes in mental state, such as confusion, irritability, poor attention span and impaired memory
  • urinary symptoms (needing to pass urine frequently, or pain when passing urine)
  • Low Blood Pressure (Hypotension)
  • dizziness
  • fainting (a sudden, temporary loss of consciousness)
  • blurred vision
  • general weakness

If you reach the state of anaphylaxis, you can even also have symptoms such as:

  • breathing difficulties
  • dizziness
  • swollen eyes, lips, genitals, hands, feet and other areas (called angio-oedema)
  • itchy skin or nettle rash (hives)
  • a strange metallic taste in the mouth
  • sore, red, itchy eyes
  • changes in heart rate
  • a sudden feeling of extreme anxiety
  • unconsciousness due to very low blood pressure
  • abdominal cramps, vomiting or diarrhoea
  • fever

While the NHS doesn’t mention hypertension, some patients may present with hypertension. Hyperadrenergic POTS can present in Mast Cell Activation Disorders. Hyperadrenergic POTS presents with orthostatic intolerance associated with an elevated heart rate (≥30 bpm within 5 minutes of standing) and hypertension (≥20 mm Hg increase in systolic blood pressure upon standing).

See Hyperadrenergic Postural Tachycardia Syndrome in Mast Cell Activation Disorders in the journal Hypertension.

Is There Research Connecting MCAD to Chronic Illness?

Ok, by now, you may be thinking, wow, I have many of the triggers and symptoms on this list, but is there research showing that this condition exists in various chronic illnesses? The answer to that question is yes. While there may not be a whole lot of research, Dr. Theoharides, the Director of the Molecular Immunopharmacology & Drug Discovery Laboratory, has put out quite a lot of research.

You can check out his huge amount of research here: http://www.mastcellmaster.com/publications.php

Treating Mast Cell Activation

While a lot of Dr. Theoharide’s research focuses on natural substances such as Luteolin for inhibiting mast-cell activation, and while he is the medical director of Algonot, it’s important to note that he receives no compensation from this company. I think it is important to note this fact because often when one has financial ties to companies or products, their research often becomes skewed or misleading. Algonot develops a supplement for MCAD called Neuroprotek that contains the bioflavonoids Luteolin, Quercetin, and Rutin.

There are pharmaceuticals for MCAD. Hydroxyzine preparations can be quite powerful, but usually require a prescription. Anecdotally, the combination of Zantac and Zyrtec (OTC at your local pharmacy) seems to work pretty well. Zyrtec is an H1 receptor inverse agonist and Zantac is a H2-receptor antagonist. However, even though these are over the counter, do not begin these medications without consulting with a qualified healthcare practitioner first.

Is MCAD connected to methylation?

This may be the million dollar question. There is not much information and MCAD and methylation, but I will end with a quote from the theory at mthfrheds.com.

MTHFR Polymorphism may be a predisposing factor to mast cell disease. 5-MTHF regulates biosynthesis of BH4. The A1298 mutation in the MTHFR enzyme effects the conversion of BH2 to BH4. Less amounts of BH4 inhibits NO formation resulting in increased mast cell degranulation. Inadequate BH4 formation also puts a strain on the conversion of tryptophan to serotonin and tyrosine to dopamine, leading to low levels of the neurotransmitters: dopamine, norepinephrine, serotonin and melatonin.

Low blood serotonin levels help define a sub-group of patients with mastocytosis that are more likely to present with neurological and gastrointestinal complaints. Human mast cells can express and be activated through multiple serotonin receptors, and synthesize and release serotonin. Low blood serotonin levels in such patients may be the result of low BH4 levels due to 5-MTHF deficiency, the result of long-term malabsorption from chronic inflammation of the gastrointestinal tract or both, as is the case with me.

BH4 is a critical factor in cellular activities such as cell proliferation, cell cycle regulation and differentiation. Could BH4 deficiency secondary to MTHFR polymorphism be one of the fundamental mechanisms that underlie mast cell proliferation?

So the question I am left with is what substances should we try, or how do we modify our methylation protocol when it seems that MCAD may play a large role in the clinical picture. In the absence of improvement of MCAD type symptoms (without taking antihistamines or Luteolin-based supplements), would taking BH4 directly help? Is BH4 deficiency really the issue?

If anyone has any comments on how to address MCAD with methylation supplements, or if they have tried taking BH4 directly, please comment.

By geneticgenie | January 31st, 2013 | Posted in Uncategorized |

63 Responses to “Mast Cell Activation Disorder (MCAD), Chronic Illness, and its Role in Methylation”

  1. julie gregory Says:

    Interesting. How about a variation of the MAO A R2974 gene (rs6323)? http://snpedia.com/index.php/Rs6323

    It is also involved in dopamine, norepinephrine, serotonin and melatonin levels. I am DXed with MCAD and I have the TT allele.

  2. julie gregory Says:

    Aha, I found the BH4 connection via the MAO defect!

    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.

  3. admin Says:

    I have MAO-A homozygous and I can’t handle epinephrine at the dentist, SSRIs, etc. I have high norepinephrine as well. Stuck in fight or flight a lot, tachycardia, etc. In a bad mood almost all the time – sorry, can’t help it!

    So I was searching for MAO-A agonist, and this is all I found. It’s called Respen-A. I think it’s a transdermal patch if I remember right.

    http://www.respen-a.com/

    I have never tried the RNA formulas because I never heard anybody using them and saying great things about them. Do they really work?

    You can only get it from a few pharmacies as prescription. They call it homeopathic, but it looks more like a diluted version of Resperine to me as the “homeopathic” has the same side effects and method of action according to their data.

    http://en.wikipedia.org/wiki/Reserpine

    As far as fixing the problem. I can’t figure that one out.

    I don’t understand the frequent doses of St. John’s Wort. Isn’t there too much Serotonin? SSRI’s either drive me up the walls or put me in the fetal position feeling like I am going to die.

    I think the stress from being so sick made that MAO-A gene express itself in a bad way.

  4. julie gregory Says:

    Or too little serotonin? MAO is involved in breaking it down. Perhaps it is present in great quantities, but we are unable to utilize it? Yasko’s suggestions might make sense then…

  5. julie gregory Says:

    More musings on how the MAO-A homozygous status interplays with serotonin…

    A few months ago, I ran my “23 & Me” raw data through Prometheus and I recall one warning that I would need to be on serotonin for an extended period before seeing results. Might that be further evidence that we have trouble breaking it down/using it appropriately? Does that apply to the other neurotransmitters as well?

  6. admin Says:

    Hmmm…

    Initial biochemical studies reported that St John’s wort is only a weak inhibitor of monoamine oxidase-A and -B activity but that it inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John’s wort extract demonstrated significant affinity for adenosine, GABAA, GABAB and glutamate receptors. In vivo St John’s wort extract leads to a downregulation of Beta-adrenergic receptors and an upregulation of serotonin 5-HT2 receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression.

    http://www.ingentaconnect.com/content/adis/cns/2003/00000017/00000008/art00001

    The science sounds a bit confusing if they got it right. My MAO-A may be downregulated (like most that have an epigenetic change in expression think) since I definitely have an excess of norepinephrine and since I can’t tolerate epinephrine. In theory, I think this should lead to too much serotonin.

  7. julie gregory Says:

    This is interesting. I found this blurb written by a woman, who is also an MAO-A homozygote:

    “I am MAO A ++, tested via Yasko. It means you break down serotonin much more slowly than most people. …But that also means that your levels can sometimes get too high temporarily and then too low in compensation.

    My serotonin shows up a bit low on tests, but this dysfunction means that I have to be VERY careful about any efforts to try to increase it. In particular, any interventions need to be very low dose, and spread out over the day (because too much at one time will spike me and cause my mood to plummet). I haven’ t experimented with little bits over the course of the day as Yasko suggests because by the time I got her results I had already balanced out my mood issues. I know that 5-htp and other serotonin boosters taken once per day made me really moody (which makes sense based on Yasko’s analysys). And my doctor’s attempts at prescription antidepressants were a disaster.

    This mutation seems to be part of what makes me naturally prone to mood swings – I can be perfectly happy one moment and then weepy the next (I’ve heard it can also cause aggression, though that doesn’t seem to be a big issue for me). I’ve pretty much eliminated that now through the supplements, etc. I take, but I know that my base state is much more moody than others. It also probably explains why I’m generally a very content type of person, though, so it’s not really a bad thing overall. And with my other mutations lowering my BH4 levels, this one may be part of what’s keeping me from getting depressed.

    In general, tiny tiny doses of most mood-affecting supplements, and spread out several times a day rather than all at once.

    The biggest differences in regulating my mood, personally, came from stable blood sugar (that’s my other issue, though, not necessarily related to this one. I was just made to be moody, apparently :Retro smile, Douglas Labs “Brain Calm” 2x/day, and dark chocolate in numerous small doses throughout the day. That last one seems to apparently be really critical for balancing me out, but I think that’s probably rare in the overall population. Can certainly tell when I’ve gone too long without my chocolate, though.

    For what it’s worth, Yasko’s observations based on my genetics have all lined up very, very closely with tendencies I was already noticing. I wasn’t sure how much to trust her at first, but I think she’s on to something. Not sure she actually knows how to truly cure things yet, but I give credit to her explanations of the reasons behind them.”

    So maybe rather than just being high or low in serotonin; it’s a dysregulation and we are prone to build-ups and shortages. THAT might explain why Yasko’s recommendations could work.

    Gotta LOVE the prescription for chocolate, but wouldn’t because of the sugar. Blood sugar issues are big for me too…

  8. Josie Says:

    Thankyou for this allowing me to understand how low B4 impacts – inhibits no production which leads to mast cell activation .

    High No also causes mast cell degranulation.

    http://www.jleukbio.org/content/83/5/1218.long- No protects mast cells from activation induced cell death .

    Immunol Rev. 2007 Jun;217:186-205.
    The role of reactive oxygen species and nitric oxide in mast cell-dependent inflammatory processes.
    Swindle EJ, Metcalfe DD.
    Source
    Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-6961, USA. [email protected]
    Abstract
    Reactive oxygen species (ROS) and reactive nitrogen oxide species (RNOS), including nitric oxide, are produced in cells by a variety of enzymatic and non-enzymatic mechanisms. At high levels, both types of oxidants are used to kill ingested organisms within phagocytes. At low levels, RNOS may diffuse outside cells where they impact the vasculature and nervous system. Recent evidence suggests that low levels of ROS produced within cells are involved in cell signaling. Along with these physiological roles, many pathological conditions exist where detrimental high-level ROS and RNOS are produced. Many situations in which ROS/RNOS are associated also involve mast cell activation. In innate immunity, such mast cells are involved in the immune response toward pathogens. In acquired immunity, activation of mast cells by cross-linking of receptor-bound immunoglobulin E causes the release of mediators involved in the allergic inflammatory response. In this review, we describe the principle pathways for ROS and RNOS generation by cells and discuss the existence of such pathways in mast cells. In addition, we examine the evidence for a functional role for ROS and RNOS in mast cell secretory responses and discuss evidence for a direct relationship between ROS, RNOS, and mast cells in mast cell-dependent inflammatory conditions.

    http://www.ncbi.nlm.nih.gov/pubmed/17498060

    sulphites activate mast cells in combination with NO – Biochim Biophys Acta. 1995 May 29;1267(1):41-4.
    Reaction of nitric oxide and its derivatives with sulfites: a possible role in sulfite toxicity.
    Harvey SB, Nelsestuen GL.
    Source
    Department of Biochemistry, University of Minnesota, St. Paul 55108, USA.
    Abstract
    The reaction between sulfites and nitric oxide or proposed carriers of nitric oxide (nitrosylated bovine serum albumin and S-nitrosoglutathione) was investigated as a potential source of the adverse effects of sulfites on biological systems. Rapid reaction occurred between sulfites and all of these reagents. Also, the ability of nitric oxide and these carriers of nitric oxide to inhibit platelet aggregation was reversed by low concentrations of sulfites. Counteraction of nitric oxide’s ability to function in cell signaling processes may be a major cause of sulfite toxicity.
    PMID: 7779867 [PubMed - indexed for MEDLINE]- http://www.ncbi.nlm.nih.gov/pubmed/7779867

    TNFalpha from mast cells also breaks down tryophan leading to clinically low serotonin and melotonin .

    In the study you quoted on serotonin in systemic mastocytosis . yes a sub set of patients were found to have low serotonin but actually most pts were found to have high serotonin due to a second release of serotinin later in the day which didnt happen in the normal controls .This is seen as an explination for mast cells pts being unable to get to sleep in the evening .
    So the Bh4 involvement would be limited to the pts with low serotonin so would explain this subset of patients .

    http://www.ncbi.nlm.nih.gov/pubmed/19021721

    This paper published last yr discusses the role of mast cell their triggers and chemicals relased in inflammatory conditions – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318920/

    I can see how changes in methylisation will fit into the pathophysiology of many conditions and this is an exciting development .But as yet doesnt completely explain mast cell activation .With the body being so complex this is not a surprise .Anything which advances our knowledge of how mast cells are activated and where the chemicals work will improve the lives of individuals me included ;-)

    my site covers most of the known routes of mast cell activation and research carried out on them and our knowledge of released chemicals .;-)

    Josie

  9. Mast Cell Disorder Says:

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  10. LD Says:

    could someone tell me what Prometheus is and where to go to run raw data through it?

    Thanks.

  11. Justine Says:

    Thanks for this great article. I know I am compound heterozygous for MTHFR from my Drs screening. We have 3 generations of MCAS and two of us have just sent away our samples for 23andme… Can’t wait to see what comes out of it.

  12. Justine Says:

    You can’t forget brain fog as a major symptom of MCAS. I was reading your article going wow how amazing to find this new article until I read the comments and realized I’d seen this back in March!

  13. shelley Says:

    I am a bit confused about the serotonin levels…can you take antidepressants to increase serotonin levels? My daughter has POTS and EDS and I believe MCAD…she is being tested soon for this and I have seen an improvement in her stomach issues with the histamine reducing diet and Neuroprotek ….thanks

  14. Lindsay Says:

    This article has some good info. However, the definition of Systemic Mastocytosis is quite different than MCAD/ MCAS. There are not excessive number of mast cells with MCAD/ MCAS like there is with Systemic Mastocytosis… There is a normal amount of mast cells with MCAD/ MCAS, they just are activated to degranulate by triggers. Here is a copy of the article my MCAD doctor sent to me. http://link.springer.com/article/10.1007%2Fs11882-012-0322-z#page-1

  15. Kathy Tomasic Says:

    My 12 year old has POTS (dysautonomia) and MCAD. He is very gifted, and lately, when he studies for long periods of time, writes a research paper, or takes tests, he becomes sick afterwards. His lung capacity is at about 70% overall, but he can’t tolerate Xopenex or most steroids. We’re trying Intal soon. I’m wondering if he isn’t low on oxygen when using brain power, but normally he is at 97-98%. If anyone has any advice or comments, please send them my way. Alec is on H1, H2 blockers, Gastrocrom, Midodrine (vasoconstrictor for POTS). He is getting headaches and episodes a few times a week, now. Will oxygen help? Any other suggestions?

  16. Carol W Says:

    Sometimes blood levels do not reflect the ability of the cells to use the chemical reported. I read somewhere the the folic acid in the bread and cereal we buy blocks the receptors so that the cells are not able to manufacture the chemicals we need. I have just started taking L-methylfolate in hopes of seeing some type of improvement. I think the sites I have visited are Dr. Yasko and the man whose name I can’t recall, but is the one who sells the Life Extension vitamins. I am usually skeptical of anyone who recommends a supplement, then manufactures them to sell to you. That is one downfall of the whole theory. But I have been able to find studies done by universities that are reviewed by other medical professionals and do say somewhat the same thing. I figure, B12 and folate probably won’t hurt me. It will probably take years for the well-known labs to come up with the same information. Adele Davis talked about hydrogenated fats before I was born, and she was only proven right in my adulthood. Anyhow, this is a complicated issue and requires either a knowledge of biochemistry and genetics or a trusted guide.

  17. Mast Cell Activation Disorder (MCAD), Chronic Illness, and its Role in Methylation | Genetic Genie | ChronicFatigue Fibromyalgia Says:

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  18. Shane Says:

    Chocolate contains the purine theobromine. I believe those getting a benefit from dark chocolate are benefitting from increased synthesis of BH4. I’ve noticed the same effect myself.

  19. nicole Says:

    hi there
    i stumbled upon this site after receiving an mthfr diagnosis for my young son. he has many of these issues/symptoms.
    i tried to order yaskos test the other day but it said it wasnt open to NY residents. is 23 and me similar? the same? is there a way around the NY issue?
    ANY information will be helpful!
    thanks

  20. Jandroid Says:

    Just want to be sure folks have clarity around the terms Systemic MCAD and Mastocytosis. MCAD (where D= disease OR disorder, variously) is used interchangeably with MCAS, which is related syndrome to Mastocytosis involving mast cells which are just more “trigger happy” (fire too easily) than they should/we’d like, but *do not appear in higher numbers throughout the body* as happens with Mastocytosis. This is a tricky distinction to make, and most doctors do not yet recognize MCAS, as word is still getting out on it. (Think of it as what you get when you’ve ruled out actual Masto, but still suffer like you have it). There’ also no single test or marker for it (unlike a nice juicy biopsy full of mast cells from either bone marrow, an endoscopy or your skin in the case of all forms of masto IFF the histologist stained the slide correctly with CD 117 or giemsa blue among other things – not commonly done, or an elevated serum tryptase level on even a good day for those with Masto – but usually only on a bad day with MCAS, if at all – not required!)

    A great resource to learn more about this is Dr. Afrin’s new chapter in a book I’ve yet to identify found here:

    https://www.novapublishers.com/catalog/product_info.php?products_id=42603

    Hope that helps. See also http://tmsforacure.org

  21. Lynn D Says:

    Was just about to ask what is diff between MCAD and mastocytosis and see the asnwer in post about mine.
    saw this info on mast cell activation syndrome- https://www.novapublishers.com/catalog/product_info.php?products_id=42603
    Had just thought lately was getting histamine rectiopns as have been reducing oxalates (slowly so dont get over reactions ) in the diet. Learned that can also create oxalates if bacterial, defic in B6,B1, fat malsorbtion.
    I had just started sneezing or nose running and since sneeze about once a year since stopped eating wheat, wondered why its starting back up . Learning theres more symptoms have that could be histamine reactions, stomach…Will see if can tell what sets them off more. was told dumping of oxalates does, wonder why it doesnt from eating them (really high in almonds ).
    Thanks for the ideas

  22. Jane Says:

    Nicole, order your kit and rebox it to send to someone you know in another state. They can open it, then drop the kit at the p.o. They are prepaid , fully labeled. NY sucks! You can do this test anywhere in the entire world except NY state. Unbelievable.

  23. Carolyn Tierney Says:

    Hi …I’m Carolyn I’m 52 years old and I’ve been sick for two years and every time I eat something my tongue would swell. I use to walk 35miles a week and go to the YMCA a couple times a week …as you can see I was very active.
    My eyes would tear all the time…I uses to be so nice now I tell people off. I do try not to now that I know it”s part of the Mast Cells….I finally just in the last 4 week got diagnose with Mast Cell disease my blood…I had so much histamine in my blood it was driving me crazy…The doctor gave me 5 pills a day and it was still coming throw….I want to tell you how my life has gotten better in the last 4 weeks…my girlfriend went online and found a doctor in Canada that wrote a book on mast Cells and to much histamine in your body Diet…And I”m tell you I have been taking my Meds and following the diet by the book …I FEEL SO MUCH BETTER…I used to wake up in the morning and have millions of little sissing pac men in my tongue arms and legs.And now I wake up and my body is really com. It”s not the wheat it’s the yeast…and so much more …Go on line and put in to much histamine in my body Diet and the Diet will come up …do it and you will feel so much better…It sucks but there is hope…XO Carolyn

  24. Carolyn Tierney Says:

    Hi it’s me again…I just went downstair to get the diet so you all will know how to get it..It’s amazing start going it right away….Dr.Joneja, by Mastocytosis Society canada It’s calledTHe Histamine& Tyramine Restriced Diet& Food Guideline for Mast Cell Disorders ….It a little hard at first because yu can’t eat any leftovers and you have to frezze alot of your food…you can’t eat annything with yeast at all…you can’t eat anything in a can. You can only drink water and coffee…Can you believe that I was drinking so much tea …you are going to dei when you see this diet …but you can eat vanilla ice cream…LOL I eat it every day.. Good luck …look it up right away and get creative….Alot of feeling better is the food you put in your mouth you won”t believe it….Carolyn

  25. jen Says:

    We use Neuro Biologix Neuro Immune Stabilizer Cream w/5 mthf and Calming Cream. My son is on h1&h2 blockers reg scheduled together & low histamine diet as well, he is 3 years old and also has 22q11deletion syndrome.

  26. Holly Glaser Says:

    Hello
    I have a mthfr mutation c667t homozygous and have had two anaphylaxic reactions that were life threatening after taking two drugs

    1. Deplin: Four days after starting it, initially itchy neck, suddenly difficult to swallow > ERtreatment

    2. Cyanocobalamin injected: felt lightheaded, went home, 3 hrs later to ER

    Reading about mast cells: My dad had huge mast cell
    After exposure to bug killers- inch dial circles with red raised center- his docs quarantined him (1964) and feared it was smallpox.

    I’m wondering if this was histamine intolerance and also if it it’s related to me winding up in the ER twice with anaphylaxis.
    Your thoughts?

  27. Frances Wisniowski Says:

    Hello everyone,

    it is great to see other people putting these puzzle pieces together.

    I wanted to mention a couple of things that were almost discussed on this post and thread.

    MTHFR mutation is a precursor for the expression of many diseases, in particular genetic mutations of the mast cell.

    The MTHFR gene regulates the most important processes that control cellular growth.

    The two SNPs that have the most influence on the effectiveness of the MTHFR gene are the A1298 SNP mentioned in the post and the C667T SNP mentioned by a commenter.

    Basically, these mutations reduce the effectiveness of the gene, slowing or stopping downstream processes such as histadine catabolism, folate regulated DNA synthesis and BH4 generation. Those are just a few of the processes relevant to this discussion.

    In the beginning someone with these mutations my present with fatigue, mood swings, histamine related symptoms in the absence of a true allergy and may react strongly to foods high in dietary histamine.

    The underlying and more insidious consequence of the mutation is that your cells are less able to recover if they are damaged. This mutation is a predisposing factor to adverse long term systemic events following exposure to cytogenic, tetrogenic or mutagenic compounds.

    I will explain where I am going with this on my next comment,
    gotta go back to work.

    Hang in there!

  28. Frances Wisniowski Says:

    Ok,

    So I left off with MTHFR SNPs make cells vulnerable to other mutations.

    So what is the big deal with mast cells? Why do they get messed up and stay messed up?

    Mast cells are extremely long lived cells that respond to and initiate a staggering number of processes in the body. They exist everywhere in the body, most notably in the bone marrow, brain, connective tissues, muscles, skin, organs and mucous membranes.

    They are a huge part of our innate immunity and ability to heal wounds.

    As such they are often exposed to virus and bacteria that can cause mutations in the infected cells DNA.

    Normally your body would repair that damage without incident. However, those of us with one of the two (or both) MTHFR mutations previously mentioned don’t have that ability or it is flawed.

    This means that after an immunization or an illness your mast cells may take a hit that they can’t recover from.

    The

  29. Frances Wisniowski Says:

    The mast cells do not always manifest the same mutation but the mutations that cause trouble are almost always on the c-KIT receptor of the mast cell. The c-KIT receptor is the stem cell ligand for the mast cell, controlling growth factor and is a major activating receptor for the mast cell.

    D816V is the c-KIT mutation seen in mast cell lukemia, mastocytosis and monclonal mast cell activation disease.

    Other activating c-KIT mutations that are as of yet unidentified cause GIST, vitiligo (there is a case study that suggests that vitiligo is caused by a somatic germline mutation on the mast cell c-KIT) and some cases of Mast Cell Activation Disease.

    These are typically treated with Imanitab (which bonds to the inactive configuration of the mast cell c-KIT, it doesn’t work with the D816V mutation because that mutation puts the c-KIT into a permanently active configuration).

  30. Frances Wisniowski Says:

    There are a number of viruses that cause cellular mutations, HPV, HIV, SV40 and any member of the poxvirus family.
    My own illness (Mast Cell Activation Disease, being successfully treated with Imanitab) began with a smallpox vaccine (live vaccina virus innoculation).

    Interestingly there is a paper that is referenced by the DOD vaccine safety board that shows that MTHFR mutations dramatically increase the risk of an adverse event following smallpox immunization, but the DOD review board decided that screening was not cost effective.

    Off the top of my head I personally know 9 individuals who have been damaged by vaccinia virus (various illnesses that all share that mast cell lineage) if you expand that out statistically that is potentially a huge population.

    Look at the sats for gulf war syndrome, just google search, and ponder what I’m pondering.

    Then add in all the spouses and kids who may have had secondary exposure.

    All it takes is the right combination of genetic predisposition and exposure

  31. Frances Wisniowski Says:

    to create the expression of a disease.

    Sorry for the odd breaks in my post.

    I post as bellagunn on inspire.com genetic alliance rare diseases support group; another resource for grassroots information.

    Cheers!

  32. Debbie McQueen Says:

    In case you’re not aware, the above contains inaccurate information. MCAD is not the same as SM. They are two different entities. MCAD is an allergy-like syndrome of unknown etiology; whereas SM is a myeloproliferative disorder involving heme. I bring this to your attention as erroneous information such as this only confuses the matter and perpetuates the misconception that SM and MCAD are one in the same, when in fact they are not.

    I have SM, have been off all mast cells meds for over 2 years now, and my reactivity is the lowest now that’s ever been in the 55 years I’ve been dealing w/this. I accomplished this by taking measures to alleviate the burden on my immune system which gave it the opportunity to balance (Th1/Th2) and heal. More specifically, that entailed reducing total body burden of toxins by addressing heavy metals and chronic infections once adequate methylation supports were in place, and through strict avoidance of environmental toxins including all processed foods. I imagine this same approach would work for MCAD.

  33. Eml256 Says:

    I would greatly appreciate if someone could list the “rs” number ( reference number) that corresponds to the c-Kit mutation associated with mast cell disorders.
    I attempted to discover the rs # to no avail so that I can check my 23andme report. Thanks

  34. Rebecca Says:

    Julie Gregory, was struck by your name, just finished a book by a Julie Gregory yesterday. :) My son has MCAD and is homozygous mthfr a1298c, along with a lot of other “bad” mutations. He is on a very full supplement protocol to help his methylation and detox. he also has a diagnosis of ulcerative colitis and EDS. My email is mdavis41 @aol.com, I added a space after the 1.

  35. eml256 Says:

    Does anyone know the “rs” # for the c-KIT D816V mutation? I have attempted looking for the info on my 23andme results. all SNPs are reported as “rs” #’s . thanks, madelyn

  36. Sue Says:

    I had a case if postpartum depression that lasted 6 1/2 years. Doctor said seratonin kevels were low. According to DNA tests I am homogeneous mthfr C677t and MAO.
    It is now, after 30 years, starting to make sense.
    Btw- I believe this was provoked my meds that were pumped into my body in hospital. I don’t think my body as able to methylate as I should have.

  37. John Says:

    I’m a 59 year old male and was diagnosed with Systemic Mastocytosis back in 1987. For many years, I experienced excessive bone pain (especially in my knees which I had to take cortisone shots to relieve the pain) headaches, pruritus and flushing just to mention a few issues I experienced constantly.
    In 2008 I was introduced to a dietary supplement – Prevennia which is a combination of four natural antioxidants. The doctors behind Prevennia have been focused on the prevention of cancer for over 40 years with over $38 million dollars of funding from the National Cancer Institute. They indicated that Prevennia could help me.
    I started taking Prevennia “twice a day” religiously since 2008. Last year I went to my doctor for my annual checkup and blood work. I was informed that my test results were the best results I’ve experienced since diagnosed with Systemic Mastocytosis back in 1987. As of October 2013, all my symptoms of my decease are “totally gone!!!!” I asked my doctor if I was cured which he refused to confirm but I can truthfully tell you, that ALL my pain is gone along with headaches, pruritus and flushing. I’m experiencing great energy and haven’t felt this good in years!!!! I believe I’m “CURED!!!”
    I recommend strongly that you research this incredible new dietary supplement with over 40 years of research and start taking it daily. This product is incredible and is natural!!!!
    Go to http://www.Prevennia.com for all the information along with how to order.

  38. Elisabeth Says:

    Wow! I have been sick for three years and have been to a dozen doctors and no one can figure it out. I have many of these symptoms. What type of doctor should I go to? What type of tests should I request? I have been searching for an answer for so long. I am very ill. Thank you.

  39. Frances Wisniowski Says:

    @ Debbie McQueen, I appreciate your opinion but the general consensus is that MCAD which stands for Mast Cell Activation Disease or Disorder (depending on which paper you read) is an umbrella term

    “Mast cell activation disease comprises disorders characterized by accumulation of genetically altered mast cells and/or abnormal release of these cells’ mediators…..”

    perhaps you would enjoy reading the paper I have quoted, you can find it here

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069946/

    Perhaps you should fact check before you jump on the high horse.

    Also, I would like to mention that I never said I had MCAS (mast cell activation syndrome) which what you clearly thought I was talking about.

    I said Mast Cell Activation Disease, I don’t typically post in detail the exact specifics of my diagnosis unless I feel that it relevant; ie someone is asking about experience with a particular form of mast cell disease for support purposes.

    I sympathize with your difficulties having SM but your attitude towards other mast cell suffering is repugnant in my opinion.

  40. Frances Wisniowski Says:

    @ EML256

    you can search the database by SNP

    http://www.ncbi.nlm.nih.gov/snp

    but to answer your question the it’s

    rs121913507

    here is the entry for it

    http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=121913507

    keep in mind this is not the only activating mutation that can cause KIT malignancy, its just the most common one associated with SM.

    when you are going through the 23 bad me raw data use the link to go to the dbSNP database for rs #s that you show as being mutated, keep an eye out for the yellow OMIM and yellow or red variant view flags.

    You can click those flags in dbSNP and it will bring up a detailed view of the pathogenicity of that SNP.

  41. Frances Wisniowski Says:

    @ John

    I’m a bit wary of over the counter miracle cure products but in all fairness our entire drug industry is a bit suspect, if it works for you and does what it says than awesome sauce.

    That just underlines the validity of treating the abnormal gene expression directly to shut down the abhorrent mast cell behavior.

    I have been switched from Gleevec to Sutent (which fits my particular KIT mutation better) and so far it is fantastic.

    The Gleevec was a huge improvement (0 anaphylactic reactions while on it until my doc lowered my dose and stress tested to justify the Sutent) but with Sutent I have my anaphylaxis under control AND have been able to add some food triggers/ high histamine foods back into my diet.

    So far so good. :)

  42. Tomato Says:

    Debbie McQueen, I am sorry you have systemic and hope you are healing. But I wanted to also correct you in saying MCAS is an allergy. That’s pretty dismissive. I have issues with my liver, my kidney’s, my autonomic system from it, so I would hardly call it an allergy. You were correcting one thing but sort of damaging another. Maybe you did not mean to come out that way. I know we all have good intentions.

    John@ Can you tell me more about Prevennia? Also am curious-since you are cured, do you still research or join these blogs to help out? Or are you still in the healing process?
    Thanks So Much,
    Tomato

  43. Lisa Says:

    Dear Frances Wisniowski,

    Is there any possibility that I can get in contact with you?

    You have got amazing knowledge which I would love to use for my health and my film!

    Kind regards
    Lisa Klit
    MTHFR mutation/MCAD/
    Documentary film maker
    Denmark

  44. tom miler Says:

    i have mast cell disease i started getting little dots on my skin now my body is covered with them i take zantec and zertec every day if i miss a dose the dots turn into hives i get aheadache is there anything that will make the red dots go away also 2 years ago i had black stool i had been bleeding in my intestine the jujunim they did sergery and found a growth as big as a tennis ball in there they said it was amast cell and removed it no one wants to help me my docter said i will have to take zertec and zantec for the rest of my life is there anyone who can refer me to a docter in colorado springs that can help me

  45. Annette Baker Says:

    The dr/researcher who developed Z & Z (H1 & H2 blockers) also developed NeuroProtek, NeuroProtek LP, FibroProtek & others especially for MCAD continues to do research. The NeuoProtek has helped many children with autism, as well as others. They have lessened the number & severity of my migraines.

    Annette

  46. Audrey Says:

    Francis, I tried to search for rs121913507 in the browse raw data section and got this response:

    No SNPs matching ‘rs121913507′ found in the data from your chip.

    Am I not doing it right?

  47. Audrey Says:

    Does anyone know how to intrepret HNMT raw data or can you direct me to someone who does?

    Thanks!

  48. eml256 Says:

    Frances Wisniowski , THANK YOU.

  49. Things That Plague Us: Mast Cell Activation and Histamine • MTHFR Living Says:

    [...] MCAD, genetically altered mast cells are overabundant, building up in the skin, gastrointestinal tract, reproductive organs or other places where they can cause trouble. Certain triggers then cause them to degranulate [...]

  50. courtney5168 Says:

    So happy I cam across this!

  51. Brandon Says:

    I have recently had issues with MCADS. Specifically to a medicine I had been taking for many years previously which was giving me anyphylaxis. I do get mast cell symptoms from other things like mold but nothing is as severe as to that one medicine. Any reason why I could start reacting like that all of the sudden?

    Also, I have been on a methylation protocol for about a year now. I never had anaphylaxis before starting the methylation protocol. This makes me question if this has something to do with BH4. Would supplementing BH4 perhaps lessen MCADs symptoms? Could adequate BH4 supplementation fix the issues of MCADs? Are there any methods of increasing BH4 without high doses of methylfolate or supplementing BH4 directly? I have been having troubling finding a source for pure bh4 and I cannot tolerate high doses of methylfolate.

  52. John Kelleher Says:

    I’m also MAO-A homozygous and have trouble with both serotonin and dopamine– me I become homocidal. Personality probably plays big role in how this mutation express itself. I lack emotions and empathy (like 6% of the population) so I lack the mood swings even though I suffered from paranoia, psychosis and cognitive disorder. I’ve actually been diagnosed with schizoid personality disorder which is perhaps the only thing psychiatry got right which I’m sure was an accident. Thing is the paranoia and psychosis was organic. I’m on methylprednisolone, an immune suppressant which makes these symptoms autoimmune dementia. Something to consider when plagued by out of control emotions.

    Much of methylation takes place in the liver and a toxic inflamed liver can cause organic mental disorder. Toxic overload can also lead to cognitive disorder. I notice some relief from aphasia after using activated charcoal to detox. My biggest trigger for aphasia is environmental– noise can send me right into receptive aphasia. A constant productive aphasia is usually always present though. Any relief is a welcome thing.

    Methylprednisolone and activated charcoal can be had relatively easily and may provide a positive indication for organic mental disorder. Something to consider?

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  55. Cindy Says:

    I read through all the comments. 2x’s people have asked what type of Doctor treats this illness. I am curious too. What type of doctor would one go to if they suspect they have this? An allergist? I know for a fact that normal practitioners would look at you cross eyed if you brought this up. Even a hematologist at the Cancer center wouldn’t have a clue. All I see instead are folks who want to talk about themselves… So tell me – who or what type of doctor did everyone go to for their diagnosis?

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  58. Frances Wisniowski Says:

    @ Audrey:

    If the rsID does not come up in the 23andme raw data search it means that there was no information for the SNP in your test, or they did not test for it.

    23andme is not very reliable to genetic testing (it is a bit like taking a fuzzy Polaroid) but for many of us it is the best option available.

    My colleagues and I were able to use 23andme test data to justify the use of sutent but it is not very firm data (my geneticist friend does not agree with my predictive model and wants a full KIT sequence performed, I can’t say I blame him as I am using a novel approach based on computational data derived from a series of papers that tested lab created SNP’s against a panel of TKIs, there is more to the picture than one SNP!)

    So in the meantime we are trying to manifest the funds for a full KIT sequence (wish us luck with the insurance provider…..at this point I am considering crowd sourcing, LOL!), science plods forward, one step at a time.

    Check the phoenixrising forum for HNMT info, there are a lot of good threads there!

    @ Lisa

    You can drop me a friend invite on Inspire, my screen name is bellagunn

    or you can message me through facebook (Fran Wisniowski)

    I would like to hear about your project.

    @ Cindy

    It takes a village……… there is no such thing as a ‘mast cell doctor’, the closest thing is a hematologist/oncologist and even then only if you are lucky and that particular doc has an interest in mast cell disorders.

    To date I have seen an allergist, GI doc, hematologist/oncologist and dermatologist.

    Other people have told me they have seen an immunologist, geneticist, rheumatologist, naturopath, psychiatrist (some meds that are used for mental heath disorders are efficacious for MCAD).

    Getting a diagnosis is often a harrowing and difficult journey as patients get bounced around from one specialist to another.

    I got really, really lucky to see an allergist who right off the bat suspected mast cell disease (he thought mastocytosis) and referred me to a hematologist oncologist friend of his who suspected MCL (thank goodness he was wrong) but it still took us a another 2 years to get to a diagnosis (all this time the actual field of mast cell research has been changing dramatically and new diagnosis are becoming possible thanks to the efforts of Dr. Afrin et al).

    @ eml256

    Cheers!

    @ Brandon

    Good question, difficult to answer, low BH4 can lead to increased mast cell degranulation, it may be with trying to push a supplement, however I am not sure how bio-effective it would actually be as I have no experience with those types of supplements

  59. Christy Says:

    I have had 2 24 urine tests done and my histamine levels are off the charts!! 2600! I have had anaphlix shock since April and many ct scans and lab work done all negitive except extremely high white cells in my urine. Drs here won’t do anything and left in limbo!! I have left side pain and swell an double in size all the time. The only thing keeping me going is massive doses of presidone. I’m weak dizzy fatigued yellow around my eyes can’t catch my breath and my blood pressure is high. I have a constant joint pain numbness in my face head and neck and no appetite and stay nauseaus! Please help I don’t know what else to do

  60. Terry Blinkenberg Says:

    thank you so much for this website! I feel like I have wasted over 10 years of my life with specialist after specialist and you guys were here all along to help where no one else could. I forwarded this website to my allergist who has been at her wits end along with my rheumatologist (and GI, endocryn, cardio) to figure this things out.
    I am homozygous MTHFR C677T and MAO-A…. But what has been baffling everyone chronic low grade temps and constant anaphylactic reactions. My food lists keep dwindling every year.

    My latest blood-work showed depleted Seratonin (which no one knew what to do with) even though I’m on 2 antidepressants (high doses). Reading the information here, it’s all making sense.

    But I was wondering if anyone knows of any correlation between Chromogranin A levels and MTHFR/Mast Call Activation Disorder? My levels are 4x higher than the normal high. But no tumors have been found and my H1AA are normal and I’m not on any Proton inhibitors at all. Any help would be greatly appreciated.
    Thank you all so much
    Terry

  61. SeekingHelp Says:

    Hello!

    I am searching for some answers and based on these comments I hope that someone can help me.

    I am heterozygous for MTHFR gene A1298C. I have had unexplained gastrointestinal issues for the past 4 years, headaches, chronic pain, etc. All of my GI tests come back normal. My symptoms started after a chicken pox vaccine booster and a mono infection. I am wondering if anyone else has had an experience like this?

    I think I may have mastocytosis or something in that family because of the way that my body responds after eating. I have done serum and skin allergy testing and no foods came back as triggers. I have been gluten free, egg free, milk free, etc. but that has also no alleviated my symptoms.

    When I eat, I experience a state almost like someone has drugged me. It is primarily with larger meals involving meat/chicken, but sometimes even a salad can cause it. My head hurts but in a non migraine way. It’s more like a hollow, tense feeling, I can’t think straight, I feel incredibly nauseous, my nose, mouth, and eyes get incredibly dry and I can barely function. I normally have to lay down for at least two hours after eating-not because I am tired but because I can’t think straight and I am lethargic. I don’t have any spots on my skin that would aid in mastocytosis diagnosis. If I do have mastocytosis, I think it may be systemic.

    I am sorry if this post seems disjointed. I am just trying to find someone who has perhaps had a similar experience.

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  63. MKW Says:

    I have all the triggers and symptoms of SM (Systemic Mastocytosis). It has made me incredibly sick, so sick I thought I was dying my my more dramatic moments before I found out what was wrong with me. I’m now incredibly better due to various treatments including Gastrocrom, Diamine Oxidase (ingested histamine metabolizer), DHA, D3 and Glutamine.

    However, as regards diagnosis… my allergist says SM is extremely serious, “as serious as cancer” in his words… so he is only willing to diagnose me with MCAD.

    This makes no sense to me. I’ve read the comments above about the differences between SM and MCAD. And when I read the UK government page about SM/MCAD linked above, reading the list of triggers and symptoms was like reading about myself, word for word, every single thing.

    I know that in the end, whichever I have (SM or MCAD) it’s incurable, and the treatment in my case will be the same, which thankfully is really quite effective in mitigating the many symptoms, which had made my life almost unlivable for a number of years. (My new nickname since starting treatment is “Lazarus” I’m so much better).

    So I guess my question is… does accurate diagnosis matter in the long term? For my own peace of mind it does matter. I’m almost sure I have SM. I’d love to hear comments and thoughts from others about what I’ve written, thanks.

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