This blog is a way of sharing the information and resources that have helped me to recover my son Roo from an Autism Spectrum Disorder. What I have learned is to view our symptoms as the results of underlying biological cause, which can be identified and healed. I say "our symptoms" because I also have a neuro-immune disorder called Myalgic Encephalomyelitis.

And, of course, I am not a doctor (although I have been known to impersonate one while doing imaginative play with my son)- this is just our story and information that has been helpful or interesting to us. I hope it is helpful and interesting to you!


Wednesday, December 3, 2014

Mast Cell Disease Links

Mast cells have a central role in many functions of the immune system, including inflammatory responses, fighting pathogens, and autoimmunity.  They regulate many other immune cells.  They are one of several immune cell types called "sentinel" cells because they are "on guard" for threats (and potential threats) from the environment, and  are found in high numbers in areas of the body that have contact with the "outside world", including the skin, the GI tract, the respiratory system, the vagina, and the mucous membranes including the eyes.  Once the mast cells perceive something as a threat (whether or not it actually is), they begin to orchestrate an immune system response.  An allergy is one clear example of this process, but it plays out in many other ways as well.  Mast cell disorders occur when the cells experience a genetic change triggered by an environmental insult, which can cause the mast cells to either be too reactive, called Mast Cell Activation Syndrome, or for too many to be made (which leads to them building up in high numbers in parts of the body), called Systemic Mastocytosis.  Mast cells originate in the bone marrow and fat tissue.

I will add more explanations and commentary in the future, but for now I want to make this information available, so I am posting this as a sorted list of links.

Spectrum of Mast Cell Activation Disorders
"Mast cell (MC) activation disorders present with multiple symptoms including flushing, pruritus, hypotension, gastrointestinal complaints, irritability, headaches, concentration/memory loss and neuropsychiatric issues. These disorders are classified as: cutaneous and systemic mastocytosis with a c-kit mutation and clonal MC activation disorder, allergies, urticarias and inflammatory disorders and mast cell activation syndrome (MCAS), idiopathic urticaria and angioedema. MCs are activated by IgE, but also by cytokines, environmental, food, infectious, drug and stress triggers, leading to secretion of multiple mediators. The symptom profile and comorbidities associated with these disorders, such as chronic fatigue syndrome and fibromyalgia, are confusing. We propose the use of the term 'spectrum' and highlight the main symptoms, useful diagnostic tests and treatment approaches."

Mastocytosis by Metcalfe and Brockow
In this video by Dr Theo, called "My Mystery Symptoms and Mast Cells", he talks with 2 Mast Cell Disease patients about their experiences with the disease, including symptoms, diagnosis, treatments, and what life with the disease is like.
Immunology and clinical manifestations of Non-Clonal Mast Cell Activation Syndrome
Autoimmune Urticaria (autoimmune chronic hives)
Cold Urticaria
Autoimmune progesterone anaphylaxis.
One of the ways that MCAS has been differentiated from SM (Systemic Mastocytosis) has been whether or not a mutation has been found in the C-KIT gene.  This has resulted in SM and one rare form of MCAS being considered "monoclonal" disorders, while MCAS has not been seen this way.  In a presentation given by Dr Afrin he explains that current evidence points to MCAS also being a clonal disorder of the c-kit gene.  This is significant because it means there may not be "one" MCAS, but many different related disorders that differ in symptoms and treatment needs.

"What Dr. Molderings discovered back in 2007, and there was a follow-up paper just last summer (2010) confirming and further extending these findings, is that just as systemic mastocytosis is a clonal disease largely of the D816V mutation in KIT, mast cell activation syndrome is a clonal disease, too, but it is a pool of many different clones. There are many different mutations. Dozens of mutations have been found, and they are scattered across all pieces of KIT [slide 37]. Each mutation leads KIT to behave in a different way, driving the cells to produce different aberrant mediator expression patterns leading to different clinical presentations. And it gets worse (with respect to trying to understand MCAS as a single entity): most patients have multiple KIT mutations, and so far there has been little apparent linkage amongst the different mutations. And then there’s another twist that makes the situation worse yet: we’ve also learned that most of these patients also have mutations in other genes and proteins that are integral to mast cell function."

These cells produce and express dozens of mediators. One mutation leads to aberrant expression of maybe not all mediators in the mast cell but probably a sizable subset. But there are multiple mutations in most patients with mast cell disease including mast cell activation syndrome. How any one mutation might interact with any other one or multiple mutations remains to be determined. And there are multiple genes beyond just KIT that are mutated in most myeloproliferative disease
patients. And when you go to that “COPE with Cytokines” website, it will really hit this home for you. Each mediator doesn’t cause just one problem. Each mediator has an entire array, a unique array, of effects – direct effects, indirect effects, local effects, and remote effects – so when you do all the multiplying implicit in all of this biology math, you begin to understand why this disease could present with such extreme heterogeneity."

Mast Cells:  versatile gatekeepers of pain

What Causes Mast Cell Disease?

The genetic basis of mast cell activation disease
Transgenerational transmission of systemic mast cell activation disease—genetic and epigenetic features
Genetic cause of Vibratory Urticaria found and here

Testing and Diagnosis of Mast Cell Diseases

The Physician's Guide to Laboratory Testing for Mast Cell Disorders
24-hour N-methylhistamine urine test
"NMH levels may be depressed in individuals who have a polymorphism in the histamine-N-methyl transferase gene, which encodes the enzyme that catalyzes NMH formation. This polymorphism results in an amino acid change that decreases the rate of NMH synthesis."
Testing for Prostaglandin D2 in urine
Bone Marrow Biopsies for the Diagnosis of Systemic Mastocytosis
(found that one biopsy is not sufficient to detect SM in all cases)

What triggers mast cells to react (degranulate)?

List of common mast cell triggers from the site MastoKids
Prostaglandins in inflammation
More on prostaglandins and how to inhibit them
Neural circuitry engaged by prostaglandins during the sickness syndrome

Treating mast cell disease

Medications used to help mast cell patients tend to address symptoms rather than cause, such as antihistamines and the anti-leukotriene med Singulair.  There are 4 known histamine receptors, labeled H1 through H4.  The antihistamine meds that most of us are familiar with, such as Benadryl, Claritin and Zyrtec are examples of H1 blockers.  H2 receptors are associated with stomach acid production when stimulated, which is why H2 blockers are used to reduce acid fro treatment of acid reflux.  These receptors are also involved in smooth muscle relaxation, antibody production,

Pharmacological treatment options for mast cell activation diseaseSeveral heart meds have recently been found to be H3 blockers
Antihistamines by Receptor Activity
The use of continuous benadryl infusion via pump to control severe MCAS

What stabilizes mast cells so they react less:

 The prescription medications that are commonly used to stabilize mast cells include Cromolyn Sodium (also called Gastrocrom) and Ketotifen (which is not FDA approved and needs to be obtained through a compounding pharmacy).  Other medications including medical cannabis and the benzodiazepines are thought to also stabilize mast cells but the exact mechanism isn't fully understood.  They do bring a lot of relief to a lot of mast cell patients.

Immunomodulation of mast cells by nutrients
Mast cells and mast cell mediators as targets of dietary supplements
Quercetin more effective than Cromolyn
How quercetin and luteolin help brain inflammation from mast cells
Green tea contains a mast cell stabilizer
Chondroitin sulphate inhibits connective tissue mast cells
Chondroitin Sulfate as a mast cell stabilizer
Mast cell stabilizing potential of Camel milk
Anti-inflammatory and anti-oxidative effect of curcumin in connective tissue type mast cell
Antihistamine foods (be aware that many of these foods can also be potent mast cell triggers)
Progesterone may stabilize mast cells
Vitamin D stabilizes mast cells

Emergency Room Information and Resources

Emergency Care for Patients with Mast Cell Disorders
Emergency Room Protocols
A handy reference guide to provide everything you need for emergency room visits as a patient with a Mast Cell Disorder (from The Mastocytosis Society)

Mast cell involvement in other diseases and disorders"
"Recent evidence indicates that neuro-inflammation could contribute to seizures. We hypothesize that brain mast cell activation due to allergic, environmental and/or stress triggers could lead to focal disruption of the blood-brain barrier and neuro-inflammation, thus contributing to the development of seizures."
“Allergic Symptoms” in Children with Autism Spectrum Disorders. More than Meets the Eye?Activated mast cells excrete mitochondrial components, triggering autoimmunity
Children with autism have elevated levels of mast cell mediators in their blood
Mercury causes mast cells to release pro-inflammatory mediators
Is a subtype of autism an allergy of the brain?
Focal Brain Inflammation in Autism
Neuroinflammation and Autism

In the gut:
MCAS and RCPS (Regional Complex Pain Syndrome)
Mast Cells- the key to Multiple Sclerosis?
Mast Cells, histamine, and hydroxyzine in MS
Mast cells may lead to abnormal nerve growth such as Neurofibromatosis
Mast cells are involved in the pathogenesis of neurofibromas

In the heart
Cardiovascular symptoms in patients with systemic mast cell activation disease
Evidence for a Role of Mast Cells in the Evolution to Congestive Heart Failure
"These observations suggest that mast cells play a critical role in the progression of heart failure. Stabilization of mast cells may represent a new approach in the management of heart failure."
Cardiac mast cells: the centerpiece in adverse myocardial remodelling
Cardiac mast cells cause atrial fibrillation through PDGF-A–mediated fibrosis in pressure-overloaded mouse hearts