Mold-Induced Illness

(work in progress)

Significant exposure to mold and related organisms, usually prolonged, can cause a wide range of symptoms and conditions.  This is a common cause or exacerbating factor for MCAS.  Common symptoms of mold illness include fatigue, headaches, digestive problems, respiratory problems (including asthma and shortness-of-breath), cough, sore throat, allergies and reactions that look like allergies (such as sneezing, hives, rashes), excessive thirst, muscle cramps, joint pain, stiffness in the morning, sleep problems, night sweats, brain fog and related cognitive issues (such as problems with memory and executive function), light sensitivity, blurred vision,  numbness, tingling, and tremors.

Mold illness can be diagnosed as many things, including- ME/CFS, Fibromyalgia, MS, Somatization disorders, anxiety, depression, PTSD, ADHD, dementia, Irritable Bowel Syndrome, and more.  That is to say that you may meet criteria for one or more of these diagnoses, but mold exposure is the reason that you have the symptoms in the first place.  For some people, treating and healing from the mold illness allows them to heal and lose the diagnosis.  Whether or not they "actually had" the illness then becomes a semantic issue rather than a scientific one.

The Basics of Mold Illness and Toxicity
Mold Toxicity - Depression, Anxiety, Fatigue, Brain Fog & Inattention 
Mold "can contribute to Pyrrole Disorder due the stress it puts on the body.  It can lead to elevated copper by overwhelming one of the antioxidants in the body that regulates copper.  Because it interferes with the immune system, it can lead to a susceptibility to candida/yeast, Lyme and its co-infections.  It also frequently worsens mast cell activation."

Mold can thrive in water damaged buildings or anywhere indoors where there is retained moisture, including AC units and ductwork.  The mold thrives because it has the ideal conditions for growth and because it doesn't have the competition that keeps it in check outdoors.  Additionally, mold spores and toxins build up inside without the natural ventilation that exists outside.  Mold can poison us with toxins and it can also colonize our bodies, such as our sinuses and GI tract.  Some people also have mold allergy.

"Seemingly 25% of people are unable to make antibodies to mold toxins. Add to that the 50% of buildings that have water damage, and you have a lot of people who are unknowingly becoming toxic while spending time in affected homes, schools, workplaces, cars, dorms, and nurseries."

"Mold toxins basically go from the body, to the liver and gallbladder where they are bound to bile and sent out into the gastrointestinal tract. The bile, however, is recycled (as a means of conservation), and thus take toxins back into the body."  

Some of the symptoms that she lists that I don't see listed often include: electric shock sensations, ice-pick pains, Atypical Parkinson's Disease, Atypical ALS, Psychogenic seizures or pseudo-seizures​​, Tics, spasms and seizure like events; Sensitivity to light touch, Suspected or Diagnosed PANS/Pediatric Acute-Onset Neuropsychiatric Syndrome, Rapid weight gain, Body temperature dysregulation, and diagnosis of fibromyalgia, or chronic fatigue.  
Detection of Mycotoxins in Patients with Chronic Fatigue Syndrome
"Urine specimens from 104 of 112 patients (93%) were positive for at least one mycotoxin (one in the equivocal range). Almost 30% of the cases had more than one mycotoxin present. OTA was the most prevalent mycotoxin detected (83%) with MT as the next most common (44%). Exposure histories indicated current and/or past exposure to WDB in over 90% of cases. Environmental testing was performed in the WDB from a subset of these patients. This testing revealed the presence of potentially mycotoxin producing mold species and mycotoxins in the environment of the WDB. Prior testing in a healthy control population with no history of exposure to a WDB or moldy environment (n = 55) by the same laboratory, utilizing the same methods, revealed no positive cases at the limits of detection."

Most doctors who specialize in mold illness use urinary mycotoxin testing to figure out which mycotoxins a patient is dealing with, as treatment consists largely of the use of binders and different ones bind different toxins  

Comprehensive Guide to Mycotoxin Binders

MCAS & Mold: Fungal Colonization of the Sinuses (video)

Mold often co-occurs with other organisms, such as bacteria, in water-damaged buildings.
Aerobic Actinomycetes of Clinical Significance

CIRS (Chronic Inflammatory Response Syndrome)
There is another condition called CIRS (Chronic Inflammatory Response Syndrome) which seems to me to be essentially another name for MCAS, but was recognized and described without as thorough an understanding of the underlying immunological mechanisms.  CIRS-WDB refers specifically to the condition when developed after prolonged exposure to the inside of water-damaged buildings.  According to this 2024 study, CIRS is "an acquired medical condition characterized by innate immune dysregulation following respiratory exposure to water-damaged buildings (WDB).", and states that ME/CFS is "a common misdiagnosis of CIRS".  MedicineNet gives a more detailed description of CIRS "a multisystem and multi-symptom illness that occurs when a person gets exposed to toxins such as mold spores or biotoxins found in tick or spider bites. These toxins get attached to the immune system to trigger an inflammatory response and induce hormonal changes. The immune system produces an excess of cytokines that can lead to the immune system attacking its tissues, causing inflammation and other associated symptoms."  This source further defines biotoxins as "fat-soluble molecules that travel from cell to cell without entering the bloodstream" and further states that "measuring biotoxins in the blood is difficult, but doctors usually identify them by the damage inflicted on various organs."

According to Dr Shoemaker, there are some HLA-DR/DQ haplotypes (combinations of genes that are inherited together) that make a person less able to clear biotoxins, such as mold toxins, from their bodies, making them more likely to develop CIRS when exposed to mold, which then cause the innate immune system to overreact and lead to chronic inflammation.  These include:
HLA-DR4-3-53
HLA-DR7-2/3-53
HLA-DR11-3-52B
HLA-DR13-6-52A/B/C
HLA-DR17-2-52B
HLA-DR18-4-52A

Diagnostic Process for Chronic Inflammatory Response Syndrome (CIRS): A Consensus Statement
Report of the Consensus Committee of Surviving Mold
"Clinical management of patients with a complex, multisystem, multi-symptom illness identified as a chronic inflammatory response syndrome (CIRS) has expanded. Often associated with illness due to exposure to low molecular weight biotoxins and inflammagens found (i) inside water-damaged buildings (WDB); (ii) following exposure to blooms of cyanobacteria; (iii) following consumption of ciguatoxic fish; and (iv) following confirmed acute Lyme disease, persistent despite reasonable use of antibiotics, CIRS is increasingly recognized. A need for a formal case definition and case management protocol has arisen. Patients with CIRS will have abnormalities in innate responses, reduced levels of
regulatory neuropeptides MSH and VIP, elevated inflammatory markers of C4a, MMP9 and TGF beta-1.  Systemic illness, based on abnormal gene activation and suppression, as shown by RNA Seq and transcriptomics, requires a multi-factorial, rigorous diagnostic assessment to assist in both differential diagnosis and monitoring response to therapy. A consensus statement is herein provided to assist practitioners in case identification and management."

Chronic inflammatory response syndrome: a review of the evidence of clinical efficacy of treatment

Dr. Scott McMahon, a board-certified pediatrician and CIRS specialist (Podcast)

Treatment for Mold Illness
The Shoemaker Protocol is widely recognized as the best treatment for mold-induced illness, whether or not you call it CIRS.  

Doctors who specialize in treating people with mold-induced illness tend to use urinary mycotoxin testing to identify which mycotoxins a person is dealing with, and prescribe substances that bind and remove those specific toxins as part of the treatment protocol.  Examples of binders include bentonite clay, activated charcoal, chlorella, cholestyramine, and colesevelam HCI. 

Finding and Remediating Mold in Your Environment
Consensus Statement for Microbial Remediation 2020
(Indoor Environmental Professional Panel of Surviving Mold)

Dr Jill Carnahan is considered by many to be an authority on cleaning mold and mold remediation.  This page from her website has the basics:
How to Get Rid of Mold – Definitive Mold Removal Guide

"Michael Rubino provides valuable resources and professional guidance on safely addressing mold issues in your home. His website offers detailed information on proper mold cleaning techniques, prevention, and the importance of air quality in maintaining a healthy living environment."

This is information given to me by someone with specialized knowledge of building materials:
"MDF is Medium-Density Fiberboard. There is also OSB, or Oriented Strand Board, and there are number of other building products like particle board made with the tailings or trash from milling lumber, held together by resins. The wood millings are damp from cutting, lay around in damp piles, and develop mold. The mold in this wood is fed by the resins used to make it into building materials. The paper backing on drywall has the same issue. I understand that there is now third-party certified mold-free OSB and MDF made differently."

ImmunoLytics swab tests

Resources Regarding Mold and Mold Illness:
Dr Ritchie Shoemaker's "Surviving Mold" website

International Society For Environmentally Acquired Illnesses / ISEAI website

American Academy for Environmental Medicine 
(database of practitioners who treat environmentally acquired illnesses including mold)

Dr Neil Nathan, MD is an expert in mold illness.  This book from him is highly regarded:
Toxic: Heal Your Body from Mold Toxicity, Lyme Disease, Multiple Chemical Sensitivities, and Chronic Environmental Illness

Dr Jill Crista, ND is a highly respected mold doctor.  "Dr. Jill focuses on conditions that cause injury to the brain and nervous system, including mold, PANS/PANDAS, Lyme disease, and concussion."
Dr Jill Crista online courses about mold 

Dr. Efrat Lamandre focuses on integrative and functional medicine, offering solutions for mold toxicity, chronic illnesses, and environmental health issues. Her practice emphasizes a holistic approach to diagnosing and treating mold-related conditions. Her website provides information and support for those navigating mold toxicity and other environmental health concerns.
Toxic Overload and Chronic Illness: How Mold, Plastics and Pesticides Make You Sick

#moldfinders: RADIO (Podcast)
Mold expert Brian Karr shares his secrets on how to find and remove mold and mycotoxins from your home,

The Virginia Center for Health and Wellness (has video series from Dr Andrew Heyman 

National Institute of Environmental Health Sciences Mold Information

CDC Information About Mold 

EPA Information About Mold

RealTime Laboratories, Inc. (RTL)
"RealTime Laboratories, Inc. (RTL) is a CAP and CLIA accredited clinical and environmental diagnostic laboratory that specializes in testing for and identifying hazardous mold, toxins, and infectious diseases."  They have a free e-book called:
Mycotoxins 101: An Introduction to Crucial Facts

MyMycoLab provides mycotoxin testing

Mold prevention strategies and possible health effects in the aftermath of hurricanes and major floods

The Hidden Connection: COVID, Mold Exposure, and Viral Reactivation 

A comprehensive review of mold research literature from 2011 - 2018

Legal Resources
Well.Law is a legal practice that understands the complexities of mold-related and environmental illness cases. They support clients navigating housing issues, disability rights, and toxic exposure with compassion and legal expertise. She started the personal injury firm she couldn't find.

How to get the most insurance money for mold remediation
"Learn the secrets insurance companies don’t want you to know that will maximize your insurance coverage amount."

Mold Insurance Playbook with Corey Levy (Podcast)
"It can be really expensive... But what if you didn’t have to pay full price for remediation? That’d be awesome! Today we share our entire playbook on how to maximize your coverage! Here is the quick overview... and we go in depth on each one of these in the episode: 1) DON’T CALL YOUR INSURANCE COMPANY! 2) STOP the water 3) Mold Inspection 4) Get Remediation Bids 5) Hire a public adjuster 6) Now you can contact your insurance company... If you go out of order you can literally cost yourselves tens of 1,000s of dollars!"

Gallbladder Disease- the Connection Between MTHFR, Methylation, and Digestion

These are my notes for a post and video done by Dr Andrew Rostenberg, DC which can be found here.

While there doesn't seem to be a direct relationship between poor methylation and poor digestion, the two often occur together, which can be caused by the effects of poor methylation on the functioning of the liver and gallbladder, resulting in the gallbladder not being able to perform it's important role in proper digestion and detoxification. He says that the gallbladder is the most methylation-sensitive organ in the body. The liver needs the enzymes involved in methylation to make bile, which is made from cholesterol. If you can't make adequate bile, you can't excrete fats out of your body. There are some things that hinder the release of bile, which include "High stress lifestyles, low stomach acid, estrogen dominance, toxin and pesticide exposure can all stop the bile from being released. All these things hurt our methylation cycle, which in turn hurts the gallbladder."

Bile is critical for proper digestion of fats.  It is an emulsifier and a detergent so it breaks fat up into smaller pieces which can then be absorbed.  If there isn't enough bile, deficiencies of fat-soluble vitamins can occur.  Bile also works like soap in that it "rinses out" particles of food and bacteria from the walls of the small intestines, the same way that detergent rinses these things off of your dishes.  If this process doesn't work properly than bacteria can grow too high up in the intestines and cause SIBO.  If insufficient bile is excreted it can also lead to leaky gut.  Without adequate gallbladder function,  there are more cracks and spaces between the cells lining the gut.  The gallbladder concentrates the toxins and junk that the liver is trying to get rid of, so if it gets emptied less and less frequently and fully problems can occur.  The liver is trying to get rid of things like pesticides, flame retardants, heavy metals, food additives, and medications.  A major part of detoxification is simply producing bile when we eat.  Bile is also important for clearing excess estrogen so hormonal balance can also be affected.

Poor methylation means poor detoxification.  If methylation, sulfation, and glutathione aren't working well (oxalate can reduce sulfation even more) the body switches to an alternative pathway called UGT (glucoronidation), in which things are detoxified by being "stuck" to glucose.  Unfortunately this results in thick and sticky bile which can hinder it's function and even keep it from leaving the gallbladder.   The bile should have a relatively thin consistency, like that of dish detergent, rather than the more molasses-like thickness that it can take on when a lot of sugar is used for detox.  There is research showing that giving taurine and sulfur to mice with thick bile corrected the problem.  Estrogen must also be detoxed via the bile, so increased estrogen levels (such as pregnancy) or the taking of birth control pills and/or hormone replacement therapy can exacerbate this problem.  This also explains why gallbladder disease seems to occur more often during pregnancy.

Choline (as phosphatidyl choline) removes excess cholesterol but if the gallbladder isn't working right it may not be able to do this, so in some cases high cholesterol is simply the result of the gallbladder being unable to remove it.  Phosphatidyl choline also protects the gut lining from irritation caused by bile in the GI tract.  Without enough phosphatidyl choline fat cannot be removed from the liver which then leads to liver disease.

This is what he has to say about correcting the problem "So the way we prevent this is through optimizing methylation by increasing taurine, phosphatidylcholine, folate, B12, and TMG. Taurine is produced by the methyl cycle, and when taurine is given to rats with gallbladder sludge, their bile gets slippery again and rescues their liver from damage.5 The methylation genes PEMT and BHMT are found in the liver and they make choline phospholipids which are necessary to keep the bile flowing. Choline protects the liver and gallbladder against damage from the detergent action of bile and it promotes movement of cholesterol into the bile so it can be removed from the body. When we run out of choline, cholesterol and fat literally get stuck in our liver and muscles, leading to fatty liver disease and muscle damage."  (On an interesting and possibly related note, I recently read a theory that suggests that insulin-resistance and diabetes may be caused by bits of fat being inside the cells and "mucking up" the insulin receptors.  At the bottom of this post is a more detailed list of the supplements that Dr Rostenberg recommends.

SNP testing

The term SNP stands for Single Nucleotide Polymorphism, and refers to variation in genes that arise from a single substitution of one nucleotide for another at a specific point along a gene.  Genes are segments of our DNA that are coposed of long sequences of base pairs, which are two of these nucleotides, one from each side of the DNA double helix, that "fit together" like the teeth on a zipper.  A SNP (pronounced "snip") is a variant of a gene that alters the function of the protein that is coded for by the gene.  These proteins can be enzymes, in which case the SNP will alter the rate at which the enzyme works in many cases,  or can be components of cells and tissue, in which case the function of the cell or tissue can be altered.  

Dr Amy Yasko pioneered the use of a person's SNP profile to guide biomedical intervention, which allows dietary, supplement, and other interventions to be more customized and to avoid many potential side effects or poor outcomes.  This testing was very expensive however so not accessible to many.  The company 23andMe has brought the cost way down and provides information on many more SNPs than Yasko testing has.  23andMe has stopped giving out what they call "health info" due to an order from the FDA.  This DOES NOT affect your access to your SNP data which is usually the reason to do the testing.  You can order the test here.  For some basic FAQs about suing 23andMe go here.  Many people feel uncomfortable about having this information about them "out there" so they choose to submit the test kit under a false name.  Forbes has just run an article giving an update about 23andMe's business plan and a possible sale to Genentech, which provides a little more information about what is being done with the data they are collecting.  Once the test is processed, you are sent a link to access your information online.  To find out your SNPs, download your raw data from the 23andMe website, and then run it through one of a number of apps available to generate a SNP report.

Here are some options:

Genetic Genie is free with a suggested donation of $10.  It provides a modest report with some good information about the SNPs found.  You can choose a methylation report or a detox report.

Promethease is another option, it costs $5.  There is a video on the site that gives more information about the service.

I prefer an app called LiveWello, that is more expensive at $19.95 (these costs are all per person, so if you are running 3 people's data from your family you will have to pay for each person).  LiveWello generates a much more comprehensive report, and has a sandbox feature where you can look up your SNPs in any of the raw data by typing in the gene name or rs number (a tutorial for using this feature can be found here).  You also have access to smaller reports made by other users that identify SNPs associated with specific issues, such as Parkinson's, Crohn's Disease, allergies, even production of oxytocin.  If you don't see a template that fits your needs, you can go to google and search for "risk alleles associated with ___" whatever you are interested in.  Then you can copy and paste the rs number into the sandbox feature and find out which SNPs you have for that gene.

BASIC TOOLS TO UNDERSTAND YOUR SNPs

There are a lot of tools available online to help you understand the meaning of your SNPs.  Honestly, I have found Wikipedia to be one of the most helpful resources.  The first step is often to figure out what the gene does, the second step is figure out what affect your variation has on it's function.  In addition to these sources, you can simply google your SNP and look for scientific articles that mention it.

A Catalog of Published Genome-Wide Association Studies

Genetics Home Reference

Tales From The Human Genome is a class presented by Udacity and 23andMe for beginners

SNPedia

Genopedia

dbSNP

OMIM

METHYLATION PATHWAY MAPS AND RESOURCES

Basic map from Heartfixer

Basic map from Dr Yasko

Dr Yasko's methylation maps

Methylation basics from Wikipedia

The Role of Methylation in Gene Expression

RESOURCES FROM DR AMY YASKO

Know Your Genetics will provide a Yasko Methylation Protocol Analysis

This sample MPA (from above) can help you begin to process your SNP information

Amy Yasko's book Autism: Pathways to Recovery

The workbook for Pathways to Recovery

Genetic Bypass by Dr. Amy Yasko

Articles by Dr Yasko

Videos of presentations by Dr Yasko

Slides from Dr Yasko's presentations

Dr Yasko's work

This talk was given at AutismOne and its an introduction to her approach and philosophy.  It is an excellent place to start if you are interested in her protocol.  I will expand this post soon and add additional ones with more specific resources of hers.  She is one of the pioneers in using genetic information to guide autism treatment, and her work is extremely valuable as a guide for people interested in pursuing this whether or not they choose to use her protocol specifically or her services.  Many families now are using 23andMe testing, which is much less expensive, and then using her resources (many of which are available for free) to develop an approach themselves.

An Individualized approach: Introduction to the Yasko Protocol

An Individualized Approach: Introduction to The Yasko Protocol from Holistic Health on Vimeo.

Summary:

Dr Yasko's approach is to base treatment on the genotype of an individual, rather than the usual emphasis on phenotype (how the individual presents, what symptoms they exhibit). This is not because there is no value in phenotype-based treatment, it is more about being able to individualize the treatment to the unique needs of the individual.  She primarily looks at what are called SNPs, which stand for Single Nucleotide Polymorphisms.  These are small changes in our DNA, caused by the substitution of one nucleotide for another at a specific place along a gene, and which results in altered functioning of that gene.  Many SNPs are common variants of genes and the results of having these variants are studied.  By taking these SNPs into account, treatment can target the specific underlying causes of symptoms, which is especially important when there are many possible underlying causes.  Additionally, potential side effects and pitfalls are easier to avoid this way.  Part of her protocol is also to do regular biometric testing (such as urine and blood tests) to measure actual progress in an individual.

She says that she sees autism as a multifactorial disorder, in which "a number of components need to come together in the wrong way".   The main components are genetic, environmental, infectious disease, and stress related.  More specifically, these factors include increased glutamate receptors, methylation defects, chronic bacterial and viral infection, heavy metal burden, vaccine injury, and issues of cell membrane fluidity and function.  From a genetic standpoint, it's not about "an autism gene"...it's not about finding one or a few genes that cause the whole picture, rather more a question of many genetic alterations in key metabolic and other pathways that add up to a person's unique form of autism, in combination with other factors.  These are genes that are influenced by the environment, and which influence how our environment affects us.

According to the genetic information based on the several thousand people with autism, who are working with her, certain SNPs come up frequently and not others (these are discussed beginning at 20:35).  She describes following the program as being more focused on making meaningful improvement, not just a focus on recovery.  Improvements can be very significant in a person's  quality of life.  She also says the journey is more like a marathon than a race, and also much like a rollercoaster with the ups and downs.

Dr Ben Lynch on MTHFR Genetic Variance and Methylation

These are my notes for Dr Ben Lynch's presentation about MTHFR and methylation (which can be viewed here). The first 30 minutes of this presentation covered the basics of methylation, and my notes for that part can be found here.


-Disorders related to under-methylation, which therefore can also be associated with MTHFR, include: Autism, MS, Fibromyalgia, Diabetes, Parkinson's, Chronic Fatigue Syndrome, Alcoholism and other addictive problems, ADHD, Insomnia, Alzheimer's, Cancer, Allergies, Bipolar, Schizophrenia, Depression, Anxiety, Neural Tube Defects including Spina Bifida, Cleft Palate, frequent miscarriages, Infertility, Tongue Tie, Tethered Spinal Cord, Chiari Malformation, Pulmonary Embolisms, Atherosclerosis, Immune Deficiency, Chronic Viral Infection, Congenital Heart Defects, Chemical Sensitivity, Thyroid Dysfunction, Neuropathy, Down's Syndrome, and mercury poisoning.
-In his list of who to screen for MTHFR variants, in addition to people based on the list of disorders above, there is also people with cervical dysplasia, elevated cobalamin, cardiovascular risk, and newborns and people hoping to conceive.
-MTHFR is very common.  The frequency varies tremendously between different ethnic groups and in different locations.  The two groups with the highest rates appear to be Mexicans and people from southern Italy.  Rates of neural tube defects tend to correlate to rates of MTHFR (except in the case of southern Italy).
-Testing looks for the two common variants, called C667T (what Roo has) and A1298C.  There are at least 40 other variants that are known, but not tested for.


Problems associated with C677T variant, also know as A222V or rs1801133 include-


Cardiovascular function, Homocysteine regulation, DNA regulation, glutathione production, and low methylfolate levels.  1 copy of this variant results in a 40% loss of function of the MTHFR enzyme, 2 copies results in a 70% decrease.  Normal is having two Cs at this spot on the gene, not a T.

 Problems associated with A1298C variant, also known as E429A or rs1801131 include-

Neurological issues, regulation of neurotransmitters, low BH4 levels, and elevation of nitric oxide.  These people may not have deficiencies in methylfolate levels, it appears that this variant may cause issues via production of biopterin.   Normal is having two As at this spot, not a C.

Metabolism of Folic Acid and Folate

Folic acid is the non-natural form of this nutrient that is added to fortified foods.  It is converted by an enzyme called DHFR into the next form along the pathway (dihydrafolate or DHF), which is a slow process.  If folic acid is consumed at a faster rate than the conversion takes place, unmetabolized folic acid builds up in the system which leads to lower levels of NK (natural killer) cells.  Dr Lynch suggests that this is the mechanism for why folic acid can lead to cancer, by suppressing NK cells, which are critical in fighting cancerous cells at the very beginning before they become large tumors.

The end product of the chain of transformations is 5-MTHF.  This nutrient can be purchased from Thorne and is also available in uncooked leafy greens.  Nutrients that are needed to make methylfolate (other than simply eating it straight from leafy greens) are vitamins B2 and B6.  These vitamins are necessary cofactors, so even people who do not have a genetic variation and produce a fully functioning enzyme will still be deficient in methylfolate if they do not have adequate B2 and B6.

For 5-MTHF to be used, there needs to be adequate cobalamin levels for the methyl group from the 5-MTHF to go to to make methylB12.  Cobalamin levels must be adequate for the 5-MTHF to be used.  That is very important as many doctors will address low methylfolate levels without making sure enough cobalamin is present for the 5-MTHF to do anything.  Once the methyl group is transferred to the cobalamin to make mB12, it enters the methionine- homocysteine cycle that results in the production of SAM-e which is the body's primary methyl donor.  In this way, sufficient methylation capacity is dependent on the functioning of the MTHFR enzyme as well as the list of cofactors (B2, B6, B12, magnesium, etc).  Additionally, the SAM-e then is converted to homocysteine, which is then converted to glutathione, which is the body's primary anti-oxidant and a person's glutathione level is largely what determines their susceptibility to metal toxicity (mercury in particular). 

The above describes the impact of the C677T variant because it impacts the amount of folate that is converted to methylfolate.  The A1298C leads to different issues because it seems to impact the production of BH4 (tetrahydrabiopterin).  C677T also affects BH4 levels because methylfolate is needed for the DHFR enzyme to convert BH2 to BH4.  Because the mechanism is different, associated symptoms are also different with the 1298 variant.  Issues associated with 1298 tend to have more to do with neurological and mental health issues, addictions, chronic pain such as fibromyalgia, and nerve pain.  BH4 is needed to convert tyrosine into dopamine, tryptophan into serotonin, and arginine into nitrous oxide and citramine. 

Methods for Lowering Homocyteine

One common result of an MTHFR mutation is elevated homocysteine levels.  Vitamin B6 supports the conversion of homocysteine to glutathione, which is really important so this is an excellent way to lower it.  MethylB12 will convert homocysteine to methionine.  Betaine (also called TMG) is very effective at converting homocysteine to methionine as well.  TMG is very similar to DMG, and the two are often confused, although for some reason he says that DMG inhibits this conversion while TMG supports it (he also says that giving HCl supplements inhibits the body from producing HCl itself, which is not consistent with mine and many other people's experiences.  Giving HCl tends to lead to a person actually making enough on their own).  Beets are an excellent food source of betaine.  Lastly, riboflavin (B2) also supports the breakdown of excessive homocysteine.

He says not to supplement with glutathione directly because it shuts down the CBS pathway (which is how homocysteine is converted to glutathione).  If the CBS enzyme is defeicent, which is also common, then glutathione will already be low (this is very common in kids with autism).  Under functioning CBS also results in elevated ammonia, which is problematic for several reasons including that coping with the excess ammonia strains the body's ability to balance neurotransmitters. 

A Few Notes About Testing Homocysteine Levels

Most labs do not test properly for homocysteine levels, according to both Dr Lynch and the American Pathology Association.  He says home tests are not accurate and should not be used.  COnsumption of high methionine foods can give false results on the test.  The patient needs to fast for 12 hours prior to having blood drawn.  The sample must be put on ice immediately, or the red blood cells need to be spun out right away. 

Drugs to Avoid When MTHFR is present

There is a really long list, so I will just list the ones here that I recognize or seem relevant (if you want to see the whole list it's at 1:02 in the presentation).  Antacids should be avoided because they deplete B12.  Nitrous Oxide inactivates MS (methionine synthase, an important enzyme) and needs to be avoided.  This can actually be quite dangerous, even fatal.  Oral contraceptives deplete folate.  Metformin decreases B12 absorption.  Methotrexate and Bactrim reduce the function of important enzymes.

Supplements and Drugs to Address MTHFR

Of the prescription forms of methylfolate, Dr Lynch's favorite is Metanx.  He says that Deplin, which ranges from 7.5 mg to 15 mg, is so high that it can cause many problems.  He generally does not prefer meds to address MTHFR.

As for supplements, there are many options that are on the market and it is confusing.  Choose one that either has an L at the beginning of the name (as in L-methylfolate), a 6S (such as (6s)-5-methylfolate), Quatrefolic, or Metafolin.  Avoid forms that begin with an R- (racemic forms, they inhibit absorption of the L-form).  Companies are not allowed to put more than 1,000 mcg of L-methylfolate per serving into their products if it is on it's own, or 800 mcg if in a combo formula. 

Supps to take to support MTHFR include: L-methylfolate, methylB12 and/or hydroxyB12 (methyl- if the person under methylates, hydroxy- if they over methylate), vitamin E, Krill Oil (better for crossing BBB), Fish Oil, sylimarin (from milk thistle, if oxalate sensitive avoid this), selenium, zinc, glutathione (start low), a strong probiotic (a healthy gut spares the methylation cycle a lot of work), multivitamin with complete B complex and minerals, vitamin D3, vitamin C, electrolytes, magnesium, adaptogens (ashwaghanda is good), potassium. 

Protocol to Support MTHFR

The most important thing is to address lifestyle issues to reduce the strain on the body and the methylation pathway.  Eat Paleo or GAPS (he recommends people read "The Paleo Solution" by Rob Wolf), reduce toxic exposures, get enough sleep, digestion must be in good shape so that gut is healthy and nutrients can be absorbed, should be having several formed bowel movements per day, try to remove medications that are folic acid antagonists, make sure no folic acid or niacin in supps, test for MTHFR.  Specific supps with doses for each MTHFR SNP is at 1:20 in the presentation.  Potassium can help reduce side effects from methylcobalamin or methylfolate (due to alkalinizing?).  If symptoms are due to over-methylation, give 50 mg of niacin (timed release) to slow down excessive methylation.  To avoid pushing methylation too far to cause over-methylation, start low and work up slowly. 

The Basics of the Methylation Pathway

These are my notes for a presentation given by Dr Ben Lynch about identifying and supporting methylation issues in patients with MTHFR (which you can watch here).  It is a great place to start to learn about methylation.  This post covers the first 30 minutes of the presentation, which focus on methylation chemistry.  The last 60 minutes is specifically about MTHFR and can be seen in this post.

What is methylation?

Methylation is basically the biochemistry surrounding the giving of a methyl group from one substance to another to alter it (a methyl group is one carbon atom with 3 hydrogen atoms attached, CH3).  The recipient of the methyl group can include DNA, RNA, chemicals from our environment that have made it into our bodies, neurotransmitters and hormones, our immune system, and our nerves.  For example, thymine is what you get when a methyl group is added to uracil.  Without adequate methylation, there will not be adequate thymine for DNA synthesis. 

The Functions of Methylation Include:

-Gene regulation (turning genes off and on)
-Transforming harmful chemicals in our bodies into less harmful and water soluble forms so that they can be excreted in the urine, or in some cases making it fat soluble and storing it in our bodies (our bodies sometimes use fat cells to store harmful chemicals until our bodies are able to detoxify them safely.)
-Making neurotransmitters and regulating their level in the blood.
-Breaking down excess estrogen.
-Building some immune cells, especially T-cells and NK cells.
-DNA and RNA synthesis
-Producing energy (CoQ10, carnitine, ATP).
-Production of myelin coating on nerves.

How Is Methylation Regulated?

It is regulated by how much substrate is available (the end product of methylation), and the amount of enzymes available.  Too much of a substrate can "turn off" methylation as a feedback mechanism.  Methylation is "done" by enzymes.  Enzyme function may be inhibited by a lack of needed cofactors (vitamins and/or minerals needed to make the enzyme work), or because the DNA that codes for the enzyme is mutated such that the enzyme is misshapen and not able to function adequately (such as in the case of an MTHFR variance).

How is Methylation Disturbed?

-Deficiency of the vitamins and minerals that function as cofactors, such as zinc, magnesium, and vitamin B6.  (This is how Pyroluria leads to under-methylation)
-Certain medications, such as antacids can disrupt methylation.  Antacids casue B12 deficiency, and without adequate B12 methylation is limited.
-Some nutrients, such as niacin, use up methyl groups and thus suppress methylation.
-Environmental toxicity from chemicals such as aldehydes (common in perfumes), chemicals used in building and remodeling, heavy metals such as mercury and arsenic, alcohol, all require methylaiton to be processed so they place a strain on the methylation system.  Candida (yeast) also produces acetylaldehyde and this page discusses how it interrupts methylation in more detail.
-Too much substrate limits methylation, such as too much SAM-e, or glutathione, or cysteine.  All of these "shut down" methylation.  This is mostly an issue from over supplementation.  (People with high plasma cyteine who are mercury poisoned are often sensitive to foods containing a form of sulfur called thiols, I wonder if this is why?)
-Genetic mutations.  There are many possible ones.  (Yasko testing seems to me to be the best way to find out about these).

Disorders That Are Related to Under-Functioning of the Methylation System

Autism, MS, Fibromyalgia, Diabetes, Parkinson's, Chronic Fatigue Syndrome, Alcoholism and other addictive problems, ADHD, Insomnia, Alzheimer's, Cancer, Allergies, Bipolar, Schizophrenia, Depression, Anxiety, Neural Tube Defects including Spina Bifida, Cleft Palate, frequent miscarriages, Infertility, Tongue Tie, Tethered Spinal Cord, Chiari Malformation, Pulmonary Embolisms, Atherosclerosis, Immune Deficiency, Chronic Viral Infection, Congenital Heart Defects, Chemical Sensitivity, Thyroid Dysfunction, Neuropathy, Down's Syndrome, and mercury poisoning.

Why Are Disorders of Under-methylation Increasing?

-Changes in food supply resulting in less nutrition in foods and more chemical contaminants such as pesticides.
-Increased stress from fast pace of modern living (I think this is quesitonable, I think human life has always had its stresses, but I do think the modern ones are different and perhaps we are less resilient to them as we are not adapted yet).
-Our environment is saturated with chemicals- in our water, food, air, clothing, toys, electronics, cookware, etc.
-Exposures from pharmaceuticals (drugs and vaccines).

How Can Under-methylation Be addressed and Reversed?

-A multifaceted approach is needed, that looks at lifestyle, diet, environment, mental outlook, and nutrition.  This is a lot, but still not enough for many people.  For these people it is necessary to take genetics into account as well.  He believes that MTHFR is the most common genetic cause.  There are many others as well.
-The list of mutations that he has in his presentation is long, but the ones that jump out at me as likely relevant to Roo and I are GAD (which transforms glutamate to GABA), HNMT (secondary enzyme for processing histamine, after DAO), MTR/MTRR (recycling of B12), CBS (processes homocysteine), and for Roo NOS which processes ammonia, and for both of us GSTM1 which produces glutathione.  This list is really worth looking at.
-As an interesting aside, he says that DAO, which is the primary enzyme that breaks down histamine, if more often damaged or down regulated by environmental factors than be inherited genetics.  Alcohol in particular suppresses it's function.

Dr Rawlins on MTHFR

These are my notes for a 4-part presentation on YouTube by Dr Rawlins about MTHFR
(be sure to watch all 4 parts!)

According to Dr Rawlins, MTHFR mutations were first discovered in 1995 as the result of The Human Genome Project.  The 677 mutation was the first one discovered and many studies only account for this one.  The other common mutation, 1298, was discovered in 2001.  The people who are most affected have both the 677 and 1298 and so they have only been recognized within the past 10 years.  The population with the highest incidence of this gene defect is Italy, the population with the lowest level is sub-Saharan Africa.  MTHFR variants are usually called polymorphisms, or SNiPs for single nucleotide polymorphisms.

He references the book MTHFR Polymorphisms and Disease
(I will definitely look into getting this book from the library)

Dietary folate is dihydrofolate, which becomes tetrahydrofolate, which becomes 5, 10 methylene THF, which is THEN converted to the active form L-methylfolate.  The C to T polymorphism limits that last conversion.  Folinic acid doesn't work around the blockage.  People with this issue will test as having enough folic acid, which they do- it's just not getting into the active form. 

If your body can't convert folic acid into it's active form, you can't make adequate neurotransmitters, which can result in anxiety, depression, irritable bowel syndrome, fibromyalgia, CFS, and migraines.  Low methylfolate levels means low levels of serotonin, dopamine, norepiniphrine, glutathione (needed for protection from toxicity and for memory function), and low BH4 which is needed for nerve protection and serotonin function.

30% of people have both genes defective (10-15% of normal function of the enzyme), 40% have one gene defective (55-70% of normal function).  When the function of the enzyme is limited, it can't increase at times of increased need such as infection, puberty, and toxic exposure).

BPA blocks the same pathway.  This means it blocks the making of glutathione.
 

Folic acid blocks l-methylfolate from crossing the blood-brain-barrier.


MTHFR is an enzyme with two functions, it is necessary for the production of both methylfolate as well as BH4, which is important for protecting nerves from damage from toxins.

When this pathway is partially blocked, heavy metals build up, BPA and other toxins build up.  He mentions mercury in our fillings, also oral contraceptives decrease our levels of methylfolate, as do some diabetes medications. Mercury blocks methionine synthase, the step right after MTHFR in the pathway.

Studies show that when people lose lots of weight, the levels of toxins in their blood skyrockets, and if they can't clear the toxins they often put the weight back on as a way to protect their nerves from the damage of the toxins.  He says one theory of Fibromyalgia is that some people are genetically not able to excrete certain toxins.

A study in India found that low levels of arsenic (within the range considered safe) were found to lead to a 4-fold increase in diabetes, heart disease, stroke and high blood pressure. 

A study showed that 98% of kids with autism have at least one MTHFR gene SNiP.  Two studies that show how important the folate pathway is are one that found that women who did not take prenatal vitamins right before or during pregnancy were twice as likely to have a child with autism, and women with an MTHFR who didn't take folate were 7 times as likely to have a child with autism.  

Berries have the active form of folate.

Recommendations- get rid of as many toxins as possible.  This includes having a water filter, improve metabolism by improving diet.  Take supplements that support your body.  Detox by sweating, sweating gets rid of environmental toxins.  Might be worth testing to see if there is a high mercury load.

Supplement both methylfolate and BH4.  He also suggests taking P5P (active B6) 25 mg per day, he says that if you take too much you get the feeling that there is a tight band around your head.  Also 1 gram of vitamin C per day, 200-250 mg of DMG or TMG every day, 20-40 mg per day of zinc, omega-3s every day, 400 IU of vitamin E.  (I would warn that the vitamin C and DMG/TMG can be problematic for people who are oxalate sensitive).  He also recommends

Interestingly, he says that mathematics and music help to soothe parts of the brain that are thrown off by not having enough serotonin.  This is interesting because so often in families of kids with autism, there are many musicians, engineers and mathematicians.  The Anterior Cingulate Cortex, which is known as your "gear shifter", is regulated by serotonin.  He says that when it's not well regulated it can lead to compulsive behavior.  I wonder about ADHD as well?

Interview With Dr Lynch About the MTHFR Gene Mutation

These are my notes from an interview with Dr Lynch of MTHFR.net with Starlene Stewart on her blog Radio Show GAPS Diet Journey.  You can listen to it here.

Conditions that have been linked to MTHFR include autism, IBS, Schizophrenia, addictions, Type 1 Diabetes, many cancers, Fibromyalgia, MS, Chronic Fatigue Syndrome, many fertility issues and birth defects including cleft palate, tongue tie, tethered cord, and congenital heart defects.  A longer list is available on Dr Lynch's site.  This genetic mutation was discovered in the 80s because people started seeing many things like strokes in young children and identified high homocysteine levels as the cause, and the new focus on the human genome allowed the connection to be made.  Dr Lynch himself came across MTHFR by researching the underlying causes of bipolar disorder.

The MTHFR gene is about 20,000 base pairs.  The terms C677T or A1298C refer to where on the gene the mutation occurs and which nucleotides are switched with each other.  The order of the nucleotides determines the shape and therefore function and effectiveness of the enzyme called MTHFR that the gene codes for.  One mutation in a specific spot (being heterozygous for that one mutation) results in the enzyme being somewhat misshapen, having two copies of the mutation at a given spot (being homozygous) means that the enzyme is more affected and even less functional.  The order of mutation combos from least severe to most severe is: one copy of 1298, 2 copies of 1298, one copy of 677 (what Roo has), one copy of each, 2 copies of 677.  With 2 copies of 677, there is about  a70% reduction in the function of the enzyme.  2 copies of 1298 results in a 40% reduction.  In the research, kids with autism seem to often have one of each, which is called compound heterozygous. 

Here is Dr Lynch's list of the 16 things that he is doing to help his own family, who have many variations of MTHFR: gluten-free diet, dairy-free diet, probiotics, sauna for detoxing at least 20 times per year, filtered water, no carpets in the house, air purification, organic food, very limited processed foods, no artificial soaps, odors, or perfumes, no cleaning products aside from natural soap and vinegar, limited pressboard in the home, organic bedding and mattresses, multivitamin with methylfolate, pure fish oil, CoQ10, cal/mag, vitamin D3, limited sugar intake, and no soda.  This genetic mutation is not "fate"- lifestyle choices can make a huge difference on how much we are impacted.  Dr Lynch gives the example of two populations with high levels of the 677 mutation, people in Mexico and people in southern Italy, and yet the rate of neural tube defects is very different between the two groups, presumably from lifestyle and dietary differences.  Another way of saying this is that environmental factors matter in how much having this gene affects our daily lives.

MTHFR causes undermethylation, which means that the process of methylation is under functioning.  Methylation does many things, including detoxification.  The reason that many things are on the above list, such as avoiding artificial scents, is because methylation is required to process them.  He feels that the expression of MTHFR is very high in the US now because of our poor food supply, stressful lifestyles, high use of chemicals and plastics, etc. MTHFR also makes it harder for us to regulate our blood sugar, which is why there is a connection with diabetes.  It also causes us to have trouble regulating our hormones and this can lead to many problems. 

To learn more about methylation, he recommends watching the MTHFR and Methylation video on YouTube:



Dr Lynch has a company called Seeking Health that can assist with testing.  Dr Lynch also provides consultations.  He says that if your doctor will order the test insurance usually pays for it.  It may be important to look at your lab report yourself, as some doctors don't know how to read the tests.  He suggests NOT treating yourself, or allowing your doctor to treat you, by just giving high amounts of methylfolate such as taking methylfolate supps or drugs such as Deplin.  He says this can cause seizures, mood swings, and other unpleasant side-effects.  He suggests treating by focusing on the GAPS protocol type stuff, which is the list above of how he helps his family.  He also says new information shows that we can get the active form of folate, methylfolate, from leafy greens.  He says to start treatment by going on GAPS, or eating paleo, basically putting as little demand on the methylation system.  This frees up the methylfolate that we do make to do what it needs to do- to detoxify, regulate neurotransmitters, etc.  He also says that folic acid needs to be avoided.

Some tidbits from the phone questions:

There are 200-400 different types of folate that occur naturally.  The type of folate that occurs naturally in greens is okay to eat if you have MTHFR.

Sedation- people with MTHFR are more sensitive to certain kinds of anesthetic, especially nitrous oxide.  He said people with the 677 mutation (the form Roo has) are more sensitive and should never be given nitrous oxide.  This is because it inhibits the enzyme Methionine Synthase, which can lead to very high levels of homocysteine. 

Dr Lynch has a few modifications that he suggests from the GAPS diet.  He says that raw eggs bind to biotin and deplete it.  Biotin inhibits the reproduction of yeast.  He encourages cooked eggs, just not raw.  He also says that we need to consider A1 vs A2 milk, when having milk, rather than assuming that all milk is okay if raw or fermented.  You need to address MTHFR in order to really heal the gut.  The intestines are supposed to regenerate quickly, the whole thing in 7 days, MTHFR needs to be working well in order for that to happen.  

(As an aside, he says that krill oil is better at supporting the brain than fish oil because it is a phospholipid whereas fish oil is a triglyceride, and the brain is made of phopholipid).

"Medicine is supposed to be 80% history" (and 10% labs/diagnostics, and 10% physical exam). ..the doctor is supposed to listen first, then ask questions.  Testing has taken on too large of a role and tests are fraught with problems and can be inaccurate.  Testing is also a snapshot in time.