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.

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julie gregory
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julie gregory

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.

julie gregory
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julie gregory

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… Read more »

julie gregory
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julie gregory

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…

julie gregory
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julie gregory

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?

julie gregory
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julie gregory

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… Read more »

Josie
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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. ejswindle@niaid.nih.gov Abstract Reactive oxygen species (ROS) and reactive nitrogen oxide species (RNOS), including nitric oxide, are produced in… Read more »

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[…] as it is reported to be. Here is a link to help you understand more about this disorder: Mast Cell Activation Disorder (MCAD), Chronic Illness, and its Role in Methylation | Genetic Genie There is so much research going on in this area, it is mind boggling. A really great site to […]

LD
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LD

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

Thanks.

Justine
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Justine

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.

Justine
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Justine

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!

shelley
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shelley

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

Lindsay
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Lindsay

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

Kathy Tomasic
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Kathy Tomasic

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… Read more »

Carol W
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Carol W

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… Read more »

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[…] Mast Cell Activation Disorder (MCAD), Chronic Illness, and its Role in Methylation | Genetic Genie. […]

Shane
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Shane

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.

nicole
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nicole

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

Jandroid
Guest

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… Read more »

Lynn D
Guest

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… Read more »

Jane
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Jane

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.

Carolyn Tierney
Guest

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… Read more »

Carolyn Tierney
Guest

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… Read more »

jen
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jen

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.

Holly Glaser
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Holly Glaser

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… Read more »

Frances Wisniowski
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Frances Wisniowski

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… Read more »

Frances Wisniowski
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Frances Wisniowski

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… Read more »

Frances Wisniowski
Guest
Frances Wisniowski

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… Read more »

Frances Wisniowski
Guest
Frances Wisniowski

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… Read more »

Frances Wisniowski
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Frances Wisniowski

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!

Debbie McQueen
Guest

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… Read more »

Eml256
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Eml256

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

Rebecca
Guest
Rebecca

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.

eml256
Guest
eml256

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

Sue
Guest
Sue

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.

John
Guest

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… Read more »

Elisabeth
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Elisabeth

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.

Frances Wisniowski
Guest
Frances Wisniowski

@ 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… Read more »

Frances Wisniowski
Guest
Frances Wisniowski

@ 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… Read more »

Frances Wisniowski
Guest
Frances Wisniowski

@ 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… Read more »

Tomato
Guest
Tomato

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… Read more »

Lisa
Guest

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

tom miler
Guest
tom miler

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… Read more »

Annette Baker
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Annette Baker

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

Audrey
Guest
Audrey

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?

Audrey
Guest
Audrey

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

Thanks!

eml256
Guest
eml256

Frances Wisniowski , THANK YOU.

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[…] 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 […]

courtney5168
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courtney5168

So happy I cam across this!