Methylation & Clinical Nutrigenomics, Part 2:

Latest Findings, Establishing Treatment Plans & SNPs

Presenter:
Benjamin Lynch, ND

Bastyr University
Kenmore, WA
March 15 - 16, 2014

PowerPoint Slides:
http://www.seekinghealth.com/media/MethylationPart2.pptx
(c) 2014: Benjamin Lynch, ND 1
Disclaimer & Disclosures

The information presented here is for informational and educational purposes only. Seeking Health,
LLC and Benjamin Lynch will not be liable for any direct, indirect, consequential, special, exemplary, or
other damages arising from the use or misuse of any materials or information published.

I am President and CEO of SeekingHealth.com and founder of MTHFR.Net

(c) 2014: Benjamin Lynch, ND 2

Part 1: October 2013 Conference
How Everything Works
• Folate Cycle
• Methionine Cycle
• Transsulfuration Cycle
• Detoxification
• ROS
• Mitochondria
• Testing
• Brief Treatment

(c) 2014: Benjamin Lynch, ND 3

(c) 2014: Benjamin Lynch, ND 4
Oxidative Stress: Degree Is Everything
“When oxidative stress is severe, or when the function of protective enzymes is deeply
compromised, cells may ‘sacrifice themselves’ by apoptosis, which protects the surrounding
healthy tissue from further damage. Only under the most severe oxidative stress conditions
and when adaptation mechanisms fail will cells then undergo necrotic death, which exposes
the surrounding non-damaged cells to immune responses.”

“In contrast to apoptosis, necrosis can result from extensive damage to the plasma
membrane with disturbance of ion transport, dissolution of membrane potential, cell
swelling and eventual rupturing of the cell. During necrosis, the cell liberates breakdown
products, including lipid peroxides, aldehydes and eicosanoids triggering an inflammatory
response. Apoptosis is energy dependent and is considered to be a protective mechanism
that prevents cells from oncotic necrosis, which often promotes more damage to surrounding
cells through the involvement of the immune system. In the presence of ATP, cell death can
proceed by apoptosis, but when mitochondria are de-energised, cell death proceeds by
necrosis.”
(c) 2013: Benjamin Lynch, ND http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3704158/ 5
6
Part 2: More Underlying Causes & How to Fix

Think ‘Big Picture’ using Biochemical/Gene Pathway Interactions

Identify pathogens, mitochondrial dysfunction, detoxification imbalances

Understand the interactions between folate, methionine, transsulfuration, sulfation

and biopterin

Identify and evaluate key genes which help regulate these cycles

Understand cofactors and substrate for each major pathway

Starting treatment with the patient methodically

Identify ‘hiccups’ in treatment and how to restore

Case Studies
(c) 2014: Benjamin Lynch, ND 7
How are these linked?

• Viral Infections and Asthma

• Air Pollution and Hypertension
• MTHFR and Thrombus
• Viral Infections and HTN
• NAC and Bad Behavior
• Methylfolate and Itchiness/Rash
• Depression and Chronic Disease
• High MCV/MCH, High Serum B12, High Serum Folate

(c) 2014: Benjamin Lynch, ND 8

(c) 2014: Benjamin Lynch, ND 9
Why?

(c) 2014: Benjamin Lynch, ND 10

Treat the Patient. Not the SNPs
Key Points about SNPs and Clinical Use
• Most SNPs not clinically relevant
• Optimizing pregnancy
• Increases compliance
• Fantastic for disease prevention
• Ability to optimize patient’s wellness
• Identify possible nutrient deficiencies
• Identify predispositions and risks
• Ability to create a long-term plan
• Forces a need to understand the normal function and interactions.
• Identify reasons why patient responds poorly/favorably to treatment.
(c) 2014: Benjamin Lynch, ND 11
Treat the Patient. Not the SNPs
SNPs are not to be used:
• Alone
• To design a treatment plan (some exceptions)
• For recommending supplementation (some exceptions)

(c) 2014: Benjamin Lynch, ND 12

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Testing Levels of Various Folate Forms

mislabeled

Test available through Health Diagnostics Lab

http://www.hdri-usa.com/tests/methylation/
(c) 2014: Benjamin Lynch, ND 18
(c) 2014: Benjamin Lynch, ND 19
(c) 2014: Benjamin Lynch, ND 20
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Genetics: Nuclear DNA
Folate Methyltransferases Detoxification
Nuclear DNA (nDNA)
• DHFR • COMT • Cyt P450’s
• Paternal and Maternal Sets
• MTHFD • PEMT • SULT
• Histones = Protection
• MTHFR • BHMT • NAT
• Repair mechanisms
• SHMT • GAMT
• FOLR • HNMT Additional:
• TYMS • GNMT • APOE
• SLC19A1 • PNMT • BCMO1
• FUT2
B12 Glutathione • GAD
• TCN2 and TCN3 • GSTM1 • MAOA
• MMAB (aka cblB) • GCS • PON1
• GPX1 • SOD2
Methionine Cycle • GR • DAO
• MTR/MTRR • G6PD
• MAT1 • NOS1, 2 and 3
• AHCY
(c) 2014: Benjamin Lynch, ND • CBS
http://www.ornl.gov/sci/techresources/Human_Genome/project/info.shtml
23
Genetics: Mitochondria
Mitochondrial DNA (mtDNA)
• Inherited only from Maternal side (family hx Important)
• Majority of ATP produced in mitochondria
• Require importing nDNA gene products to function
• SNPS/mutations in mtDNA may be pathological
• Cancer
• Diabetes
• Cardiovascular Diseases
• Neurodegenerative Diseases
• Aging Mitochondrial
• Degenerative Diseases • SOD
• Lack of Histones = high rate of mtDNA mutagenesis (10x nDNA) • CAT
• Mitochondrial Transcription Factor A (TFAM) = Protective coating and regulation • NDUF
• mtDNA copy number ↑ cell survival and function • ATP
• COX
http://cshperspectives.cshlp.org/content/5/5/a012641.full.pdf and http://www.nature.com/scitable/topicpage/mtdna-and-mitochondrial-diseases-
903 and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753274/pdf/pone.0074513.pdf
(c) 2014: Benjamin Lynch, ND 24
(c) 2014: Benjamin Lynch, ND 25
Genetics: Mitochondria
Mitochondrial DNA (mtDNA)
• Sperm – 700 molecules of mitochondria
• Oocytes – 200,000 molecules of mitochondria

Cell Division and Mitochondria:

• Mitochondria ‘float’ in cytoplasm
• Lack of Spindles
• Randomized

Acton B et al. Mol. Hum. Reprod. 2004;10:23--‐32 European Society of Human Reproduction and Embryology
(c) 2014: Benjamin Lynch, ND 26
Cell Division and Replication of ‘Sick’ Cells?

Stimulate DNA Bases and ↑ Cell Proliferation

• “New” cells created:
• ↓ Glutathione
• Oxidized cell membrane
• ↓ Potassium
• ↑ ROS
• ↑ Cell death

Flare of Patient Symptoms with

addition of Folate / B12.

Necessitates Treatment Flow

(c) 2014: Benjamin Lynch, ND 27

Epigenetics
“As an organism grows and develops, carefully orchestrated chemical
reactions activate and deactivate parts of the genome at strategic times
and in specific locations.

Epigenetics is the study of these chemical reactions and the factors that
influence them.”

“Epigenetic changes are environmentally responsive mechanisms that can

modify gene expression independently of the genetic code.”

http://learn.genetics.utah.edu/content/epigenetics/ and Epigenetics and the

(c) 2014: Benjamin Lynch, ND developmental origins of inflammatory bowel diseases. 28
Most stable
epigenetic
alteration at
CpG islands

29
Epigenetic Example: Inflammatory Bowel Disorders
High monozygotic twin discordant rates in Crohn disease and UC.
70+ loci associated with CD. 40+ for UC = epigenetic control.

High monozygotic twin concordant rates in Celiac disease.

Single HLA locus linked to 40% of heritability = genetic control

Epigenetic Control in Crohn’s Disease and UC

Source: Epigenetics and the developmental origins of inflammatory bowel diseases.

(c) 2014: Benjamin Lynch, ND 30

Epigenetic Example: Rheumatoid Arthritis

800+ genes associated with RA = epigenetic control.

Common Researched Genes in RA

• HLA-DRB1
• TNF
• PTPN22
• HLA-B
• STAT4
• HLA-DQB1
• CTLA4
• IL-1B
• MTHFR
• IL-10
• PADI4
• IL1RN

(c) 2014: Benjamin Lynch, ND Pubmed 31

Tale of Two Mice
Genetically Identical. Epigenetically Different.
• Prone to diabetes, yellow fur, cardiovascular disease and obesity
• After birth and throughout life:
• One mouse fed additional folate, choline, B12, genestein in chow
• Other mouse fed standard chow

(c) 2014: Benjamin Lynch, ND 32

(c) 2014: Benjamin Lynch, ND 33
Queen Bee vs Worker Bee
Genetically Identical. Epigenetically Different.
• Worker Bee:
• Life of hard work
• Inferior food
• Susceptible to outside environment and stressors
• Live 3 to 6 weeks
• Queen Bee:
• Safer from outside environment
• Highly nutritious food: Royal Jelly
• 20x longer lifespan

(c) 2014: Benjamin Lynch, ND http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1000532 34

35
 Clinical Approach

(c) 2014: Benjamin Lynch, ND 36

Key ‘Typical’ Disturbances
• Inflammation
• Free Radicals
• Immune
• Hormone
Body works as a Complete System
• Neurotransmitter
Treat it as such
• Infectious
• Cardiovascular
• Pulmonary
• Nutritional
• Genetic

(c) 2014: Benjamin Lynch, ND 37

Typical Case Presentation
• Male, Age 18
• Vegetarian
• State Champion 2 yrs ago – 500 m sprint - Track athlete
• Dry skin
• Difficulty focusing in school
• Difficulty breathing at times when exercising
• Often irritable
• Difficulty sleeping
• Recurring apthous ulcers
What’s causing these symptoms?
What should you be thinking?
(c) 2014: Benjamin Lynch, ND 38
 Epigenetics 1st

(c) 2014: Benjamin Lynch, ND 39

MTHFR and Patient Response

I have been using the MTHFR protocols you detailed at the October weekend conference
with patients, and so far have not seen any clinical response I could say was specific to the
treatment itself.

Of course I have been doing naturopathic support for all these patients and can see
benefit from that.

I have read and re-read information from your website, class notes, and done considerable
research on my own regarding MTHFR and other SNPs, at this time I am feeling that the
research doesn't match the clinical presentation or results of treatment and have a hard
time recommending testing and treatment that I cannot make a change with.

Am I wrong? What else is missing?

(c) 2014: Benjamin Lynch, ND 40
Key ‘Big Picture’ Disturbances
• Environment
• Lifestyle
• Diet
• Pathogens
System-Wide Dysfunction
• Heavy Metals
• Xenobiotics
• Oxidative Stress
• Nutrient Deficiencies
• Nutrient Excess
• SNPs

(c) 2014: Benjamin Lynch, ND 41

Immediate Support (commonly)
1. Adaptogens
2. Adrenal
3. Thyroid (indirect ideally)
4. B vitamins (no folate/B12)
Reduces Catabolism & Burden
Supports many Pathways
Supports:
• Balanced Neurotransmission
• FAD Synthesis

http://booksite.elsevier.com/brochures/conap2/PDFs/Vol7Flavin-DependentEnzymes.pdf and
(c) 2014: Benjamin Lynch, ND http://lpi.oregonstate.edu/infocenter/vitamins/riboflavin/ 42
“Steps” to Repair
1. Goals
2. History!
3. Environment
4. Lifestyle
System-Wide Restoration
5. Diet
6. GI
7. Mitochondria
8. Detoxification
9. Pathogens
10. Cell Membranes
11. Neurotransmission
12. Methylation
13. SNPs
(c) 2014: Benjamin Lynch, ND 43
Step 1: Goals
“Basics”
• Realistic
• Committed Goal Setting
• Expectation Prepared by Patient Before First Visit
• Outcome Reviewed w/ pt at FOC
• Short Term
• Mid Term
• Long Term

(c) 2014: Benjamin Lynch, ND 44

Step 2: History
“Basics”
• Family Hx – trends
Time Line
• Travel Prepared by Patient Before First Visit
• Siblings Reviewed w/ pt at FOC
• Medications / Supplements
• All Symptoms / Complaints
• Life Timeline
• Pre-conception Parent History
• Pregnancy
• Zipcode
• Exposures
• All Health Events
• Significant Stressors
(c) 2014: Benjamin Lynch, ND 45
Step 3: Environment
“Basics”
• Awareness
• Prevention Open-Ended Questions
• Home Prepared by Patient Before First Visit
• Office Reviewed w/ pt at FOC
• Water
• Food
• Hobbies
• Transportation
• Exposures

(c) 2014: Benjamin Lynch, ND 46

Step 4: Lifestyle
“Basics”
• Addictions
• Activity
• Sleep
• Social Open-Ended Questions
• Passion Prepared by Patient Before First Visit
• Awareness Reviewed w/ pt at FOC
• Pace
• Convenience
• ‘Drive-Through Medicine’
• Restaurants
• Prepared Foods
• WiFi / Cell Phones

(c) 2014: Benjamin Lynch, ND 47

Step 5: Diet

“Basics”
• Gluten-Free
• Dairy-Free
Journal: 3 Days all meals/snacks
• Organic
Prepared by Patient Before First Visit
• Non-GMO
Reviewed w/ pt at FOC
• Whole Foods
• Expansive Menu
• Limited Processing
• Local / Home Grown
• Home-Cooked Meals
• Elimination Diet / Food Allergy Testing
(c) 2014: Benjamin Lynch, ND 48
Step 6: GI
“Basics”
• Awareness
• Breath
• Tongue Open-Ended Questions
• Gums / Teeth Prepared by Patient Before First Visit
• Stomach Reviewed w/ pt at FOC
• Pancreas
• Liver / Gall Bladder
• Small Intestine
• Large Intestine
• Elimination
• Gas

Testing Considerations
• CDSA
(c) 2014: Benjamin Lynch, ND
• Pathogens 49
Step 7: Mitochondria
“Basics”
• Fatigue Open-Ended Questions
• Exercise Prepared by Patient Before First Visit
• Stimulants
Reviewed w/ pt at FOC
• Syndromes
• Maternal Hx
• Multiple Conditions
• Post-Workout Soreness

Testing Considerations
• Oxidative Stress Panels
• Urinary Organic Acids (Lactate)
• Urinary Amino Acids (Ammonia)
(c) 2014: Benjamin Lynch, ND 50
Step 8: Detoxification
“Basics”
• GI Open-Ended Questions
• Skin
Prepared by Patient Before First Visit
• Sweating
• Sensitivities
Reviewed w/ pt at FOC
• Syndromes
• Immune Dysfunction
• Hormone Dysfunction
• Mitochondrial Dysfunction

Testing Considerations
• Hepatic Detox Profile
• Hormone Metabolism
• Heavy Metals / BPA / Pthalates
(c) 2014: Benjamin Lynch, ND 51
Step 9: Pathogens
“Basics”
• Travel Open-Ended Questions
• Bites Prepared by Patient Before First Visit
• Syndromes
Reviewed w/ pt at FOC
• Chronic Conditions

Testing Considerations
• Viral
• Bacterial
• Mold
• Lyme
• H Pylori

(c) 2014: Benjamin Lynch, ND 52

Step 10: Cell Membranes
“Basics”
• Diet Open-Ended Questions
• Lifestyle Prepared by Patient Before First Visit
• Exposures Reviewed w/ pt at FOC

Testing Considerations
• RBC Fatty Acids
• Lipid peroxidation
• Cholesterol Subfraction (VAP)

(c) 2014: Benjamin Lynch, ND 53

Step 11: Neurotransmission
“Basics”
• Mood Open-Ended Questions
• Sleep Prepared by Patient Before First Visit
• Attention Reviewed w/ pt at FOC
• Adrenals
• Response to Stressors
• Diet / Lifestyle / GI …

Testing Considerations
• Urinary Organic Acids
• Urinary Amino Acids
• Urinary Neurotransmitters (maybe)
• Methionine Cycle vs BHMT
(c) 2014: Benjamin Lynch, ND 54
Step 12: Methylation
“Basics”
• Age Open-Ended Questions
• Medications Prepared by Patient Before First Visit
• Infections Reviewed w/ pt at FOC
• Midline Defects (at birth)

Testing Considerations
• Methylation Profile

(c) 2014: Benjamin Lynch, ND 55

Step 13: SNPs
“Basics”
• 23andMe Prepared by Patient Before First Visit
• MTHFR Support Reviewed w/ pt at FOC
• Genova
• Doctor’s Data
• Specialty Labs

(c) 2014: Benjamin Lynch, ND 56

Labs
“Basics”
• 23andMe
• MTHFR Support
• Fasting CBC with chem panel and GGT
• TSH, T4, T3, rT3, anti-TPO, anti-TG
• Cytokine panel – IL-1B, IL6, IL8, TNFα, INFα
• Serum ferritin
• Fasting insulin
• Fasting homocysteine Screening Labs for Many Patients
• VAP Cholesterol subfraction
• ADMA
Blood drawn from pt at FOC
• Urinary amino acids
• Urinary organic acids
• Methylmalonic acid
• Holotranscobalamin
• CDSA
• Viruses / Bacteria / Parasite / Mold / Lyme (if history warrants)
• Provoked Heavy Metals (in time…)
(c) 2014: Benjamin Lynch, ND 57
Labs - Pathogens
• EBV (4 part panel)
• Candida / C diff / Parasites
• H Pylori
• Mycoplasma & Chlamydia pneumonia
• Strep (ASO)
Screening Labs for Many Patients
• HHV Family
Chronic disease
• HSV 1 & 2 (HHV-1 and HHV-2)
• Parvovirus B-19 (if rheumatic)
• Adenovirus
• Coxsackie B
• Lyme
• Molds
• Hepatitis A, B, C
• CMV
• HHV-6

(c) 2014: Benjamin Lynch, ND Paul Anderson, ND 58

(c) 2014: Benjamin Lynch, ND 59
 MTHFR: Why now?

(c) 2014: Benjamin Lynch, ND 60

61
Folic Acid  GMH
MTHFR increasing in the population.
• Folic acid fortification
• ↑ Full-Term Pregnancies
• ↑ Folate SNPs
• ↑ Methylation SNPs
• ↑ Inferior SNPs
• ↑ Metabolic Issues

↑ Susceptibility to Environmental Exposures

Natural DeSelection:
Survival of the ‘Unfittest’
(c) 2014: Benjamin Lynch, ND 62
Has enhanced folate status during pregnancy altered natural selection and
possibly Autism prevalence? A closer look at a possible link
“It is hypothesized here that the enhancement of maternal folate status before and during
pregnancy in the last 15 years has altered natural selection by increasing survival rates during
pregnancy of infants possessing the MTHFR C677T polymorphism, via reduction in
hyperhomocysteinemia associated with this genotype and thereby miscarriage rates.

This also points directly to an increased rate of births of infants with higher postnatal
requirements for folic acid needed for normal methylation during this critical
neurodevelopmental period.

If these numbers have increased then so have the absolute number of infants that after birth fail
to maintain the higher folate status experienced in utero thus leading to an increased number of
cases of developmental disorders such as Autism. Detection of the C677T polymorphism as well
as other methionine cycle enzymes related to folate metabolism and methylation at birth as part
of newborn screening programs could determine which newborns need be monitored and
maintained on diets or supplements that ensure adequate folate status during this critical
postnatal neurodevelopment period.”

(c) 2014: Benjamin Lynch, ND 63

Is folic acid good for everyone?
“In Spain, the prevalence of the MTHFR 677TT genotype has reportedly approximately doubled
in the population since the introduction in 1982 of folic acid supplements for women in early
pregnancy”…

“Folic acid fortification and supplement use might be “a genetic time bomb.” The first premise of
this dramatic claim, that folic acid use increases the proportion of children born with the T allele
of MTHFR, is as yet poorly documented and is clearly in urgent need of further study.

Studies of the MTHFR genotype frequencies in children before and after fortification should be
carried out in countries planning fortification of food with folic acid. Thus, saving fetuses that
have a genetic constitution that favors abortion or nonsurvival could lead to children being born
with genotypes that favor increased disease during life”"

(c) 2014: Benjamin Lynch, ND 64

(c) 2014: Benjamin Lynch, ND 65
 Juice Flowing
What’s Up?

(c) 2014: Benjamin Lynch, ND 66

Hair Loss d/t Methotrexate. Folic Acid works. MTHF doesn’t?!
Had a patient on methotrexate whom I switched from regular folic acid to
5MTHF and she says her hair is falling out which was controlled by 2 mg
regular folic acid; would it be better to have her on that again to replenish
methotrexate folic acid depletion or up the 5MTHF - in other words was is
wrong to switch her?

What happened? Think it through.

(c) 2014: Benjamin Lynch, ND 67

Sulfur vs Methylation?
I am a psychiatrist who does not practice integrative Psychiatry but have started to
take an in interest in the field.

Although MTHFR and Methylation intuitively make sense as culprits in mental illness,
there is still no evidence as to the efficacy of Methylation protocols.
Additionally there seems to be dissent as to Methylation fundamentals. In particular I
have reviewed the work of Hinz and was wondering what your opinion was. In a
nutshell he postulates that correcting Methylation must begin with fortification of the
Sulphur Amino Acids (Cysteine 4500mg D) with simultaneous administration of
Dopamine and Serotonin precursors and cofactors. 5MTHF,B6 B12, B2 in his opinion
are far lesser factors to be concerned with.

I was wondering what you felt about the Sulphur issue as it seems to be a departure
from the MTHFR researchers protocols.

Wrong again? Why not?

(c) 2014: Benjamin Lynch, ND 68
Elevated Serum B12 levels
I have a quick question. Twice I have been asked a question about elevated
serum B12 levels and genetic defects. I know of all the classic associations
(e.g. cirrhosis, myeloproliferative disorders, hepatitis, liver cancer). There is
certainly a lot less info about genetic associations I have run across a little bit
concerning the FUT2 gene and a few references to more severe, and early
symptomatic disorders from the MTR, MTRR and MMADHC genes.

Only genetics here? What else?

(c) 2014: Benjamin Lynch, ND 69

MTHFR is about Homocysteine
I do think it is not very helpful to just do a MTHF gene test without first
checking on homocysteine. If someone has a homocysteine of 7, say, then
why care about genes, really, when they are able to get around some gene
mutation and methylate as they should? I think we should check
homocysteine first, and B12/MMA and then if a problem, do the gene test.

MTHFR, I think it's being blown out of the water a bit, especially if
homocysteine is doing fine

Thoughts?

(c) 2014: Benjamin Lynch, ND 70

MTR/MTRR and Oxidative Stress
The MTR/MTRR block with ROS is significant in Lyme clients. We have many
who have this concern so its great to start learning how to manage it.

Steps to optimize MTR/MTRR?

(c) 2014: Benjamin Lynch, ND 71

IBS and Acute Gastroenteritis
After experiencing acute gastroenteritis, IBS sets in. Methane-producing
bacteria take over. Antibiotics help eliminate the symptoms for up to
three months or more. Then, without restricted diets or routine
antibiotic use, symptoms come back.

Why? What is the solution?

(c) 2014: Benjamin Lynch, ND 72

23andMe and Bogged Down
I’ve been analyzing 23&me raw data, as well as running the Doctors Data Methylation
reports. Sometimes the methylation panels have been quite helpful, but I still get bogged
down in SNPs due to the complexity it sometimes reveals. Used MTHFR Support in the
past, but haven’t used it in it’s new iteration because patients usually don’t run it through
themselves and don’t want to shell out $20 every time I do it. Hopefully you are working
on building better ways to critically analyze SNPs and related support, as I know this can
be powerful to tailor treatment.

I’m also working to identify and address mitochondrial trouble, heavy metals, digestive
and immune trouble. Have always treated pathogens by changing the environment for
them in the body (and some supplementary help) but realizing more recently that I may
have to address pathogens more directly since I’m seeing they my often be the initial
triggers of inflammation/autoimmune, etc.
Bingo.
(c) 2014: Benjamin Lynch, ND 73
74
 Methylation Glimpse Diet
Diet
 Lifestyles
 Meat & Potatoes
 Vegan, Vegetarian
 Obesity
 Athletes
 Type ‘A’ Diet
 Addictions
 Alcohol Diet Diet
 Smoking
 Environment
Diet
 Heavy Metals
 Pesticides/Herbicides
 Xenobiotics
 Medications
 Acetaminophen
 Antacids
 Nitrous Oxide
Diet

(c) 2014: Benjamin Lynch, NDhttp://nutritiondata.self.com/tools/nutrient-search

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Methylation Glimpse
 Key Genes (sampling)
 MTHFR
 MTR
 MAT
 CBS
 GSTM1
 Cyt P450’s
 BHMT
 PEMT
 PON1
 DAO
 FOLR
 GAD
 GAMT
 MAO
 COMT
 TCN2
 SUOX
 SULT

(c) 2014: Benjamin Lynch, ND 76

 Homocysteine

(c) 2014: Benjamin Lynch, ND 77

Homocysteine
• Methionine = Methyl-Homocysteine

• Breakdown product of SAM  SAH via AHCY

Methionine
(c) 2014: Benjamin Lynch, ND 78
Homocysteine Metabolism (Routes)
Three Possible Routes:
1. MTR/MTRR (50%)
 (B12 & MTHF)
2. BHMT
 (TMG & Zn)
3. CBS (50%)
 (B6)
 Only eliminating route
Low homocysteine is
an important finding

(c) 2014: Benjamin Lynch, ND 79

Homocysteine Metabolism
Tissue Specific

Plasma homocysteine is a ‘gross’ average.

Not tissue specific.

Ex. CBS Ex. BHMT Ex. MTR

• Brain • Liver • Brain
• Liver • Oocyte • Oocyte
• Pancreas • Kidney
• Muscle
Support ALL Routes

Regulation of homocysteine metabolism and methylation in human and mouse tissues and
(c) 2014: Benjamin Lynch, ND http://www.procrelys.fr/telechargement/publications/hcy_fertil_steril.pdf 80
(c) 2014: Benjamin Lynch, ND 81
What did the doctor do? What happened here?

(c) 2014: Benjamin Lynch, ND 82

Here is the consequence. What happened? How to restore?

(c) 2014: Benjamin Lynch, ND 83

Homocysteine Kinetics
• Methionine cycle  low Km for sulfur-containing substrate
• ↑ methionine (sulfur) ↓ methionine cycle

• Betaine-Homocysteine Methyltransferase (BHMT)  low Km for Hcy

• Transsulfuration cycle  high Km for sulfur-containing substrate

• ↑ methionine (sulfur) ↑ transsulfuration cycle
• ↑ GSH
• ↑ H2S
• ↑ Taurine
• ↓ Hcy
• ↑ demand of P5P and serine
(c) 2014: Benjamin Lynch, ND 84
Homocysteine Testing
• Fasting Plasma Homocysteine
• Passive – not as functional

• Post-Methionine Loading (100 mg/kg)

• Active
• Identifies potential blockages
• Vitamin B6
• Betaine
• Zinc
• Choline
• Serine
(c) 2014: Benjamin Lynch, ND 85
Addressing Elevated Homocysteine
Homocysteine-lowering Nutrients
• Cobalamin (Hydroxo, Methyl)
• Methylfolate
• TMG
• Zinc
• Riboflavin
• Pyridoxine May retest in 2 Weeks
• Phosphatidylcholine

Choline supplemented as phosphatidylcholine decreases fasting and

(c) 2014: Benjamin Lynch, ND postmethionine-loading plasma homocysteine concentrations in healthy men 86
Addressing Elevated Homocysteine
Phosphatidylcholine ↓ Hcy
• Why?
• Supports BHMT
• Preserves SAM (and thus stores of B12 and MTHF)
• Supports Folate pathway (indirectly)
• Choline  Betaine (TMG)  DMG  remethylates THF

(c) 2014: Benjamin Lynch, ND 87

(c) 2014: Benjamin Lynch, ND 88
Phosphatidylcholine Side Effects

Increased acetylcholine
• choline + acetyl-CoA = acetylcholine + coenzyme A
• ↑ Acetylcholine may ↓ Serotonin and vv

Depression?
• Tryptophan deficiency
• Upregulated Kyurenine Pathway
• Intake
• Absorption
• Biopterin deficiency
• Vitamin B6
• Niacin

(c) 2014: Benjamin Lynch, ND Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis 89
Serotonin Increase: CARBS Dopamine/Norepinephrine Increase: 40% PROTEIN
90
 Folate Cycle

(c) 2014: Benjamin Lynch, ND 91

 92
(c) 2014: Benjamin Lynch, ND
Converting Folic Acid to
Folinic acid and MTHF

Requires:
1) Uncooked Leafy Greens
2) Functioning Enzymes
3) Available Receptors
4) Transport

5) Vitamins, Minerals and pH:

• B2
• B6
• B12
• Acidic environment
(for absorption)

Source: Herb, Nutrient and Drug Interactions by Stargrove et al 93

Folate

• Ferritin levels influence folate catabolism

• TNF, IL-6 and IFN-γ ↑ Ferritin levels

Inflammation Destroys Folate?

Folate in Health and Disease, Second Edition and ‘INFLUENCE OF INFECTION AND INFLAMMATION ON BIOMARKERS OF
NUTRITIONAL STATUS’
(c) 2014: Benjamin Lynch, ND 94
Gene Variant rsID & (orientation) Risk Allele Issue
SLC19A1 80A>G Rs1051266 (-) G ↑ Serum folate levels (↓ RBC Folate)
MTHFD1 1958G>A Rs2236225 (-) C ↓ Stability and Activity
MTHFR C677T Rs1801133 (-) T ↓ One carbon metabolism
MTHFR A1298C Rs1801131 (-) C ↓ One carbon metabolism (with 677)

http://www.genecards.org Abnormal Folate Metabolism and Maternal Risk for Down Syndrome
(c) 2013: Benjamin Lynch, ND 95
 GG
GA
GA
GA

Orientation (+) = do nothing Orientation (-) = Flip the Base

AT GC
TA CG

(c) 2014: Benjamin Lynch, ND 96

 Methionine Cycle

(c) 2014: Benjamin Lynch, ND 97

(c) 2014: Benjamin
(c) 2014:
Lynch,
Benjamin
ND Lynch, ND 98
Methionine
• Protein
• MTHFR + MTR/MTRR
via Hcy (B12 + MTHF)
• BHMT via Hcy (Zn + TMG)
• Provides SAM (Mg + ATP)
via MAT

99
Nitric Oxide
Nitrous Oxide

(c) 2014: Benjamin Lynch, ND 100

S-Adenosylmethionine (SAM): Functions
• Cofactor for Methyltransferases
• COMT, PEMT, PNMT, GNMT, GAMT, DNMT
• Maintains normal liver function
• Induces apoptosis in liver cancer cells
• Modulates iNOS synthesis
• ↓ NFk-B
• ↑ CBS  cysteine and glutathione

Dietary Choline and Betaine Intakes and Risk of Cardiovascular Diseases: Review of Epidemiological Evidence and
http://emergency.doctorsonly.co.il/wp-content/uploads/2011/03/SAMe-therapy-in-liver-disease-J-HEP-11.12.pdf
(c) 2014: Benjamin Lynch, ND 101
Gene Support Function Issue
MTHFR B2 Provides substrate for MTR/MTRR ↓ MTHF = ↓ MTR/MTRR
MTR B12 / Zinc Transfers CH3- from MethylB12  to Hcy = ↓ THF, ↑ Hcy, ↓ SAM,
(methionine cob(I)alamin + methionine. Then, remethylates ↑ ROS
synthase) the cob(III)alamin with MTHF.
MTRR B2 (FAD) Remethylates the cob(I)alamin with MTHF. 2 ↑ reduced Cb(I), ↓ MTR,
(methionine [methionine synthase]-cob(II)alamin + NADPH ↑ Hcy, ↓ SAM, ↑ ROS
synthase + 2 SAM = 2 [methionine synthase]-
reductase) methylcob(III)alamin + 2 SAH + NADP(+)
MAT1A Magnesium, Catalyzes the formation of SAM from ↓ SAM, ↑ Hcy
Cobalt, K methionine and ATP
AHCY NAD catalyzes reversible hydrolysis of SAH (AdoHcy) ↑ SAH, ↑ Adenosine  ↑
to adenosine (Ado) and homocysteine uric acid. ↑ MethylT inhibition

CBS P-5-P, ↑SAM Hcy  Cystathionine. Regulates H2S. Start of ↑ or ↓ Hcy and H2S (when
Glutathione production. Brain. cysteine used)

CTH (CGL) P-5-P Cystathionine  Cysteine. Regulates H2S. Start ↑ or ↓ Hcy and H2S (when
of ND
(c) 2013: Benjamin Lynch, Glutathione production. Vascular. cysteine used) 102
http://www.genecards.org
Gene Variant rsID & (orientation) Risk Allele Issue
MTR A2756G Rs1805087 (+) G ↑ MTR function
MTRR A66G Rs1801394 (+) G ↑ Oxidation of B12
CBS 833T>C Rs5742905 (-) C ↓ Homocysteine

http://www.genecards.org Effects of methionine synthase and methylenetetrahydrofolate reductase gene

(c) 2013: Benjamin Lynch, ND polymorphisms on markers of one-carbon metabolism 103
Methionine – Potential Causes of Low Levels Methionine – Potential Causes of High Levels
↓ Protein intake ↑ Protein intake
↓ B12 SAM Supplementation
↓ Methylfolate Methionine Supplementation
↓ Zinc ↓ Magnesium
↓ Choline ↓ ATP
↓ SAM ↓ CBS Activity
↓ Homocysteine ↑ MATI/III Inhibition
↑ CBS Activity
↑ B12 Oxidation
SNPS: MTHFR, MTRR/MTR, BHMT, CBS SNPS: MAT
Trisomy

(c) 2013: Benjamin Lynch, ND http://www.genecards.org 104

SAM Deficiency via MATI/III Inhibitors
Oxidative Stress
• NO
• TNFα
• IL-6

Causes vicious cycle

↓ SAM  ↓ CBS activity  ↓ Glutathione

Methionine intake may NOT ↑ SAM

http://emergency.doctorsonly.co.il/wp-content/uploads/2011/03/SAMe-therapy-in-liver-disease-J-HEP-11.12.pdf

(c) 2014: Benjamin Lynch, ND 105

(c) 2014: Benjamin Lynch, ND 106
ADA: Adenosine Deaminase
Adenosine + Zinc  Inosine + NH3 
Hypoxanthine + Molybdenum 
Uric acid + Superoxide

ADA upregulated in CAD, AI

• ↓ Adenosine =
• ↓ ATP formation
• ↑ Inflammation

DPP IV = Potent Inhibitor of ADA

(c) 2014: Benjamin Lynch, ND 107
 Choline Cycle

(c) 2014: Benjamin Lynch, ND 108

(c) 2014: Benjamin Lynch, ND 109
 Transsulfuration Cycle

(c) 2014: Benjamin Lynch, ND 110

(c) 2014: Benjamin Lynch, ND 111
112
113
CBS and CDO

CBS CDO
• Cofactor: B6 • Cofactor: Iron & Zinc
• Requires: Serine or Cysteine & Hcy • Requires: Cysteine
• Inhibited by: NO • Inhibited by: α-ketoglutarate, TNFα
• Promoted by: SAM • Promoted by: Sulfur/Cysteine
• Product: H2S & Cystathionine • Product: H2S & Cystathionine

CDO Inhibition may lead to Cysteine Excitotoxicity

- Support CDO - Support COMT - Remove Pathogens
- Support IDO - Support MAO - Remove Metals

Signs (sensitive to cysteine intake):

↑ Cysteine:Sulfate ↑ Cysteine:Taurine ↑ Sulfite:Sulfate ↑ Hydrogen Sulfide

http://www.wikigenes.org/e/gene/e/1036.html and
http://www.ncbi.nlm.nih.gov/pubmed/11059810 and
(c) 2014: Benjamin Lynch, ND http://ajpendo.physiology.org/content/early/2011/06/15/ajpendo.00151.2011 114
 Neurotransmission

(c) 2014: Benjamin Lynch, ND 115

 116
(c) 2014: Benjamin Lynch, ND
Neurotransmission: More than SNPs

• Diet SNPs
• Lifestyle • COMT
• PAPS (Sulfonation) • MAOA
• IDO (Kyurenine – Tryptophan) • GAD1
• Th1/Th2 (Cytokines) • GAD2
• Methylation (SAM) • HNMT
• PNMT
• Cofactors • MAOB
• Substrate
• Infections
• Heavy Metals

(c) 2014: Benjamin Lynch, ND 117

Gene Cofactor Function Variant Issue
COMT SAM, Mg Catalyzes catecholamine and rs4680, Downregulation
catechol hormones rs769224, ↑ Catechols/Catecholamines
rs4633
MAOA B2 (FAD) Catalyzes deamination of amines rs6323 and Downregulation
(dopa, serotonin, epi/norepi) rs10548363 ↑ amines
GAD1 and 2 Mg, B6 Glutamate  GABA many Downregulation
↓ GABA, ↑ Glutamate

118
http://www.genecards.org (c) 2013: Benjamin Lynch, ND
119
120
121
122
123
124
 Neurotransmission:
Biopterin Cycle
NOS, ADMA, DHFR, PAPS, IDO

(c) 2014: Benjamin Lynch, ND 125

Urine

126
Urine

127
Tetrahydrobiopterin
Substrate
• Phenylalanine
• Tyrosine
• Tryptophan

and

Nitric Oxide Formation

• Arginine

128
129
Gene Cofactors Function Issue Regulation
NOS1 Neurotransmitter. Expressed Neurotoxicity
Neuronal in many tissues. Regulates
smooth muscle, peristalsis,
penile erection.
NOS2 Innate Immune Function ↑ Damage. ↑ Pathogens induce iNOS.
Inducible BH4, (Macrophages) Autoimmune Risk. ↑ NOS Eliminate pathogens. See
Calcium, • Antibacterial Uncoupling. next slide for more.
FAD, FMN, • Antiviral
NADPH • Antifungal
• Tumoricidal
NOS3 Promotes vascular endothelial Coronary spasm. ↓ ADMA
Endothelial growth factor. Angiogenesis. Rs2070744. 786T  C (↓)
Cardiovascular homeostasis.
DHFR NADPH Recycles BH2  BH4, DNA base synthesis ↓ Folic Acid. Uncooked
precursor to folate pathway reduction, NOS leafy greens OR 5-MTHF
from dihydrofolate uncoupling with B12

130
http://www.genecards.org (c) 2013: Benjamin Lynch, ND
NOS2 Promoters NOS2 Inhibitors NOS2 SNPs
LPS TGF-beta Not significant
NF-KappaB IL-4 It’s about expression
INF-gamma IL-10
HIF-1 IL-13
Calcium Aspirin
TNF Candida
IL-1B Coccidioides
Influenza
EBV
Klebsiella
Chlamydia
HSV-1
Helicobactor pylori
(c) 2014: Benjamin Lynch, ND http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877599/pdf/BMRI2013-696317.pdf 131
and PMID 20950359 and 18997441 and 10193423 and 12439755 and 10191185
132
DHFR
Initial enzyme in folate metabolism
• ↓ activity in fetus
• ↓ activity in normal adult tissues
• ↑ activity in proliferating cells such as:
• cancer
• microbial pathogens

Inhibited by:
• Methotrexate
• ECGC
• Folic acid
• Grape Seed Extract
PMID 21756052, 21402147, 10856255
(c) 2014: Benjamin Lynch, ND 133
134
135
136
Neurotransmitter and Cardio
Problems
No point in increasing BH4
recycling until oxidative stress
is reduced. In fact, worsens the
situation due to vicious loop
cycle.

Supplement directly with

nutrients to bypass BH4
deficiency initially.
• 5-HTP
• Tyrosine
• Melatonin
• SAM

Can try L-5-MTHF if

NO not elevated
137
BH4 Bioavailability
“Restoration of BH4 bioavailability therefore represents a
promising approach to recoupling NOS for the treatment of
cardiovascular disease. However, early clinical trials of oral
synthetic BH4 (sapropterin) thus far generally have failed to
demonstrate efficacy in the treatment of diseases characterized by
endothelial dysfunction.

These disappointing results may result from failure to improve

the ratio of BH4 to BH2 highlighting the need for further research
on cellular and systemic BH4 oxidation, trafficking and recycling.
The clinical efficacy of improving BH4 bioavailability also may
depend on other biochemical determinants of NOS uncoupling,
including cellular concentrations of L-arginine, methylarginines,
and oxidized glutathione.”
http://link.springer.com/content/pdf/10.1007%2Fs11897-012-
0097-5.pdf (c) 2014: Benjamin Lynch, ND 138
139
140
Restoration of NOS Coupling
• NAC
• Vitamin C
•
•
Vitamin B6
Methylfolate
Exercise
• Melatonin
• Arginine balance
• DHFR Support
• Stop EGCG, Grape Seed Extract, Folic Acid
• Eliminate Pathogens – especially viral
• H Pylori VERY common
• Glutathione (reduced)
• Selenium, B2, B3

PMID 21756052, 21402147, 10856255, 19361795, Cardiovascular diseases: protective

(c) 2014: Benjamin Lynch, ND effects of melatonin 141
142
ADMA
• Created by proteins being methylated by SAM
• Concentration elevated by oxidized LDL
• Eliminated by dimethylarginine dimethylaminohydrolase (DDAH)
• Homocysteine downregulates DDAH
• High ADMA levels inhibit eNOS
• Inhibited eNOS increases cardiovascular disease

(c) 2014: Benjamin Lynch, ND 143

(c) 2014: Benjamin Lynch, ND 144
 Superoxide
inhibits

(c) 2014: Benjamin Lynch, ND 145

ADMA Testing

Readily Available
• NOS function
• Arginine levels
• Monitor treatments

(c) 2014: Benjamin Lynch, ND 146

ADMA Lowering
• ↑ Melatonin
• ↑ Vitamin E
• ↓ SAM (if elevated)
• ↑ Transsulfuration Cycle
• ↑ NAC
• ↑ B6
• ↓ ROS

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877599/pdf/BMRI2013-696317.pdf and
(c) 2014: Benjamin Lynch, ND PMID 20950359 and http://ndt.oxfordjournals.org/content/18/11/2415.full.pdf+html 147
 Neurotransmission:
PAPS and Sulfation

(c) 2014: Benjamin Lynch, ND 148

Sulfation Functions
Substrate for many enzymes
• ↓ Serotonin
• ↓ Dopamine
• ↓ Thyroid hormones
• ↓ Estrogen hormones
• ↓ Bile acid toxicity and ↑ excretion
• Produce homocysteine
• ↑ Glutathione
• Process medications (Tylenol, Salicylates)
• Process food coloring

(c) 2014: Benjamin Lynch, ND 149

Sulfur Kinetics
• Methionine cycle  low Km for sulfur-containing substrate
• ↑ methionine (sulfur) ↓ methionine cycle

• Transsulfuration cycle  high Km for sulfur-containing substrate

• ↑ methionine (sulfur) ↑ transsulfuration cycle
• ↑ GSH
• ↑ H2S
• ↑ Taurine

• Phenol Sulfotransferase (SULT1A)

• PAPS as cofactor
(c) 2014: Benjamin Lynch, ND 150
Sulfur Kinetics
SUOX  high Km for sulfur-containing substrate, low capacity
• Cofactor: Molybdenum
• Inhibitor: Tungsten, Arsenic

Sulfate-Reducing Bacteria
• Dominate over
• Methanogenesis-producing bacteria
• Lactose fermentation
• Produce Hydrogen Sulfide

Microbial pathways in colonic sulfur metabolism and links with health and disease and
(c) 2014: Benjamin Lynch, ND http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1817665/pdf/ehp0115-000158.pdf 151
Sulfur Kinetics
Before pushing sulfur: Sulfur Caution:
• Sulfur tolerance • Down’s Syndrome
• Sulfur flatulence • Inflammatory Bowel Disorders
• Sulfite tolerance • Giardia
• Homocysteine > 6.5 umol/L • CFS
• Urinary Thiosulfate (Quest) • Upregulated CBS
• Blood sulfate • Sulfite Sensitivity
• Monitor and support T3 and T4 • ↑ Tungsten
• Monitor and support Estrogens
• (if elevated, Calcium-D-Glurarate, DIM)

(c) 2014: Benjamin Lynch, ND 152

Restoring Sulfur Tolerance = Fix Phenol sulfontransferase (PST)
Remove: Add:
• Amines • Butyrate
• Chocolate • Mitochondrial support (ATP)
• Salad Bars • Magnesium, CoQ10, NADH
• Vanillin • Molybdenum (prn)
• Wine • Vitamin B6
• Flavonoids • Vitamin B2
• Salicylates • Vitamin B1 (sulfites)
• Tylenol • Hydroxocobalamin (if H2S excess)
• Sulfur (1-3 days) • Adaptogens
• BPA • Calcium-D-Glucarate
• Triclosan

PMID: 17976885 and 21396232 and Susan Costan Owens and “The Detoxification System Part III: Sulfoxidation and Sulfation pdf”
and http://dmd.aspetjournals.org/content/32/10/1162.full.pdf+html
(c) 2014: Benjamin Lynch, ND 153
(c) 2014: Benjamin Lynch, ND 154
Sulfur and Molybdenum
Molybdenum Side Effects:
• ↑ Uric Acid (Xanthine Oxidase)
• ↑ Superoxide (Xanthine Oxidase)

Molybdenum Side Effects Antidotes:

• Stop Molybdenum
• ↑ Glutathione
• ↓ Homocysteine (SAH specifically with P-5-P)

(c) 2014: Benjamin Lynch, ND 155

PAPS: 3'-phosphoadenosine 5'-phosphosulfate

• Utilized as cofactor for many sulfation pathways

• Player in degradation of many neurotransmitters

Requires:
1. ATP
2. Sulfate

(c) 2014: Benjamin Lynch, ND 156

(c) 2014: Benjamin Lynch, ND 157
(c) 2014: Benjamin Lynch, ND 158
PAPS: Support
Optimize:
• Mitochondria (ATP)
• Sulfate
• Sodium sulfate > Cysteine > Methionine (GI)
• NAC (Lung)
• Molybdenum (SUOX)
• Exposures
• Neurotransmission
• Reabsorption
• Adrenals (sodium)
• Thyroid
• Vitamin D
• Potassium
• Gut Flora
(c) 2014: Benjamin Lynch, ND 159
Sulfate Excretion
Depends on:
• Dietary intake (saturable)
• Renal sodium-dependant sulfate transport system
• ↑ Excretion:
• Acetominophen
• Salicylates
• Menopause
• pH 7.49
• Low T3

Sulfate-Reducing Bacteria
• Only bacteria can reduce thisulphate
 urinary thiosulfate
 Quest Diagnostics Test Code: 117892
PMID: 10900245
(c) 2014: Benjamin Lynch, ND 160
Sulfate Reducing Bacteria

Depend on:
• Sulfate

Dominant
• Out compete methanogenic bacteria

SIBO
Excessive Methane and Hydrogen Gas
False negatives d/t SRB? Low SRB?
PMID: 10900245, 1855683
(c) 2014: Benjamin Lynch, ND 161
(c) 2014: Benjamin Lynch, ND 162
(c) 2014: Benjamin Lynch, ND 163
(c) 2014: Benjamin Lynch, ND 164
 Psychoneuroimmunology
Immune System – Neurotransmitter Connection

(c) 2014: Benjamin Lynch, ND 165

(c) 2014: Benjamin Lynch, ND 166
Th1 and Th2
Th1: Cell mediated immunity Th1 Th2
• Intracellular IFN-gamma IL-4
• Viruses IL-2 IL-5
• Cancer
TNF-alpha IL-6
IL-1 IL-10
Th2: Humoral mediated immunity IL-12 IL-13
• Extracellular NK cells Mast cells
Macrophages Eosinophils

(c) 2014: Benjamin Lynch, ND http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386509/pdf/CN-10-97.pdf 167

Indoleamine 2,3-Dioxygenase 1 (IDO1)
• NAD Synthesis
• T reg cell synthesis
• Requires Tryptophan
• Upregulated in Inflammation Oxidative Stress
• SNPs not relevant

(c) 2014: Benjamin Lynch, ND 168

(c) 2014: Benjamin Lynch, ND 169
 Protective

Destructive

(c) 2014: Benjamin Lynch, ND 170

(c) 2014: Benjamin Lynch, ND 171
Indoleamine 2,3-Dioxygenase 1 (IDO1)
Support Mental Health AND Immune Tolerance:
• NOS coupling
• Tryptophan
• Niacin
• Eliminate Pathogens

(c) 2014: Benjamin Lynch, ND 172

IDO Promoters IDO Inhibitors IDO SNPs
IFN-alpha IL-4 Not significant
IFN-gamma IL-10 It’s about expression
TNF-alpha
LPS
IL-1B
IL-6

(c) 2014: Benjamin Lynch, ND Kynurenines in CNS disease: regulation by inflamatory cytokines 173
 COMT
“Executive Function”
and . . . Stressed out.

(c) 2014: Benjamin Lynch, ND 174

COMT: Function
Transfers methyl group from SAM to catecholamines: Cofactor: Magnesium
• Dopamine
• Norepinephrine
• Epinephrine

Transfers methyl group from SAM to catechol hormones:

• Estrogen

Transfers methyl group from SAM to catechol drugs:

• L-Dopa

(c) 2014: Benjamin Lynch, ND http://genecards.org/cgi-bin/carddisp.pl?gene=COMT&search=comt 175

COMT

Wildtype (Val/Val) SNP (Met/Met)

rs4680 (G allele) rs4680 (A allele)
Normal dopamine removal Slow dopamine removal
Tolerance to pain Intolerant to pain
Decreased concentration Better memory & attention
More tolerant Quick to anger
Anxiety

http://genecards.org/cgi-bin/carddisp.pl?gene=COMT&search=comt and
Genetic association between the COMT genotype and urinary levels of
tea polyphenols and their metabolites among daily green tea drinkers
(c) 2014: Benjamin Lynch, ND http://snpedia.com/index.php/Rs4680 176
(c) 2014: Benjamin Lynch, ND 177
Phenylalanine Sources (Foods chosen > 1000 mg per 100 grams)
Vegetables Legumes Fish Dairy and Egg
Seaweed Soy Protein Cod Dried Eggs
Spirulina Peanut Flour Mollusks Dried Milk
Peanuts Roe Cheese
Nuts/Seeds Mung Beans Tuna
Sesame Seed Flour Kidney Beans Salmon Other
Pumpkin Seeds Lima Beans Red Meat Gelatin
Almonds Lentils Top Round Beef
Sunflower Seeds Bacon
Pistachio Poultry Pork Loin
Walnuts Turkey Bison, Lamb, Deer, Elk
Chia Seeds Chicken

(c) 2014: Benjamin Lynch, ND http://nutritiondata.self.com/foods-011086000000000000000-w.html?maxCount=1 178

(c) 2014: Benjamin Lynch, ND 179
Tyrosine Sources (Foods chosen > 1000 mg Tyrosine per 100 grams)

Vegetables Legumes Fish Dairy and Egg

Seaweed Soy Protein Cod Dried Eggs
Spirulina Peanut Flour Mollusks Dried Milk
Peanuts Roe Cheese
Nuts/Seeds Tuna
Sesame Seed Flour Salmon
Pumpkin Seeds Poultry Red Meat
Turkey Top Round Beef

Chicken Bacon
Pork Loin
Bison, Lamb, Deer, Elk

(c) 2014: Benjamin Lynch, ND http://nutritiondata.self.com/foods-012087000000000000000-w.html?maxCount=15 180

 Vitamin C

Norepinephrine
B1
B3
Vit C

(c) 2014: Benjamin Lynch, ND 181

COMT: Inhibition – Side Effects of ↑ Dopamine
Cardiovascular Respiratory Neurological Endocrine
Arrhythmias Dyspnea Headache ↓ Prolactin
Angina Impair T Lymphocyte
Bradycardia ↓ DHEAS
Ectopic Beats Psychiatric Dermatological ↓ TSH release
Conduction Issues Anxiety Piloerection ↓ T4 to T3 conversion
Palpitations Apprehensiveness ↓ LH and GH
Hypotension Restlessness ↑ BUN
Hypertension
Tachycardia Gastrointestinal
Vasoconstriction Nausea
Wide QRS Complex Vomiting

(c) 2014: Benjamin Lynch, ND http://www.rxlist.com/dopamine-drug/side-effects-interactions.htm and 182

http://www.drugs.com/sfx/dopamine-side-effects.html
(c) 2014: Benjamin Lynch, ND 183
COMT: Inhibition – Side Effects of ↑ Epinephrine
Cardiovascular Respiratory Neurological Endocrine
Arrhythmias Dyspnea Dizziness ↑ Blood glucose
Angina Lightheaded ↑ Insulin
Hypertension Tingling ↓ Potassium
Pallor Psychiatric Tremor ↓ TSH release
Palpitations Agitation Weakness ↓ T4 to T3 conversion
Tachycardia Disorientation ↓ LH and GH
Vasoconstriction Impaired Memory ↑ BUN
Aggressive
Assaultive Gastrointestinal
Hallucinations Nausea
Psychosis Vomiting

http://www.rxlist.com/dopamine-drug/side-effects-interactions.htm and 184

(c) 2014: Benjamin Lynch, ND
http://www.drugs.com/sfx/epinephrine-side-effects.html
Low Epinephrine
↓ Epinephrine with ↑ Norepinephrine
• Evaluate cortisol levels
• Adrenal fatigue
• Methylation deficiency

Symptoms of ↓ Epinephrine
• Adrenal fatigue
• Weight gain
• Depression
• Low concentration

https://www.neurorelief.com/index.php?p=cms&cid=148&pid=20 and Dunwoody Labs

(c) 2014: Benjamin Lynch, ND 185
COMT: Drugs Metabolized and Inhibitors
Drugs Metabolized by COMT: COMT Inhibitors
• Alpha-methyl DOPA • Entacapone
• Apomorphine • Tolcapone
• Benserazide • Nitecapone
• Bitolterol • Quercetin
• Dihydroxyphenylserine • Tea catechins
• Dobutamine • Coffee
• Dopamine • SAH
• Epinephrine
• 2-Hydroxyestrogens
• 4-Hydroxyestogens
• Isoetherine
• Isoprenaline
• Isoproterenal
• Norepinephrine
• Rimiterol
http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/83301
(c) 2014: Benjamin Lynch, ND 186
(c) 2014: Benjamin Lynch, ND 187
 Leptin TNFα Leptin TNFα
SAM TNFα TNFα
1. 1. SAM
Magnesium
Magnesium
3. 3.
anti-proliferative
TNFα TNFα
FAD / NADH FAD / NADH
2. 2.
rs1800566
609 C > T
2-HE less risky – 4-HE more risky –
weak binding to receptor stronger binding to DNA

Glutathione H2O2
2 x H20

188
(c) 2014: Benjamin Lynch, ND Effect of tumour necrosis factor-alpha on estrogen metabolic pathways in breast cancer cells
Current Gene Function

(c) 2014: Benjamin Lynch, ND 189

 Minus Orientation: Flip the Base. Ex. GG  CC
(c) 2014: Benjamin Lynch, ND Orientation: Just read it.
Plus 190
Breast Cancer Risk Scenario
TNF G308A = (rs1800629)
CYP1B1 119Ser = 3x more active (rs1056827)
CYP1A1 Val462Ile = 2x more active (rs1048943)
COMT Met/Met = 3x less active (rs4680)
NQO1 609C>T = hetero 3x less active // homo 4% activity (rs1800566)
Lower Risk More Risk Most Risk
TNF -/- TNF -/+ TNF +/+
CYP1B1 -/- CYP1B1 -/+ CYP1B1 +/+
CYP1A1 -/- CYP1A1 -/+ CYP1A1 +/+
COMT -/- COMT -/+ COMT +/+
NQO1 -/- NQO1 -/+ NQO1 +/+

Relative Risk: Obesity, Smoking, Alcohol

COMT > CYP1A1 Total Years of Estrogen Exposure
Polycyclic aromatic hydrogens (PAH): Fried, broiled, well-done meat
Catechol-O-Methyltransferase (COMT)-mediated Metabolism of Catechol Estrogens Comparison of Wild-Type
and Variant COMT Isoforms and http://cebp.aacrjournals.org/content/15/5/979.full.pdf+html and
Breast Cancer Risk Associated with Genotype Polymorphism of the Estrogen-metabolizing Genes CYP17,
CYP1A1, and COMT A Multigenic Study on Cancer Susceptibility and Effect of tumour necrosis factor-alpha on
(c) 2014: Benjamin Lynch, ND estrogen metabolic pathways in breast cancer cells 191
COMT Downregulation: Symptoms Match SNP?
What is issue? ↑ Dopamine? ↑ Norepi? ↓ Epi? ↑ Estrogen?

Support COMT:
• Molybdenum (prn)
• Magnesium
• Vitamin B6
• Vitamin C
• Niacin
• SAM
• Adaptogens
• Watch Phenylalanine and Tyrosine Intake
• MSM, NAC or sulfur-containing foods (if tolerated)
• Blood sugar stabilization (diet, sleep, exercise, chromium)

(c) 2014: Benjamin Lynch, ND 192

In urine.

193
 MAO
“The Warrior Gene”

(c) 2014: Benjamin Lynch, ND 194

MAO: Function
MAOA and MAOB
• Cofactor: FAD
• Metabolizes biogenic amine hormones
• Dopamine, Norepinephrine, Serotonin
• Metabolizes xenobiotic amines
• Heterocyclic amines (meat)
• Tyramines
• Histamine

http://biocyc.org/META/NEW-IMAGE?type=ENZYME&object=CPLX-33
(c) 2014: Benjamin Lynch, ND 195
(c) 2014: Benjamin Lynch, ND 196
Tryptophan Sources (Foods chosen > 550 mg Tryptophan per 100 grams)

Vegetables Legumes Fish Dairy and Egg

Seaweed Soy Whitefish Dried Eggs
Spirulina Salmon = 350 mg Dried Milk
Parsley Poultry Cheese
Nuts/Seeds 400 mg
Sesame Seed Flour
Pumpkin Seeds Red Meat
Chia Seeds Most ~ 400 mg
Elk = 545 mg

(c) 2014: Benjamin Lynch, ND http://nutritiondata.self.com/foods-000079000000000000000-w.html 197

 B1
B3
Vit C

(c) 2014: Benjamin Lynch, ND 198

 B1 B1
B3 B3
Vit C Vit C

(c) 2014: Benjamin Lynch, ND 199

(c) 2014: Benjamin Lynch, ND 200
MAO:
Support:
• Adaptogens Inhibitors:
• Tryptophan Balance • Buproprion (Wellbutrin)
• Adrenal/Thyroid • Duloxetine (Cymbalta)
(FAD) • IL-6
• Glucuronidation • High dose niacin (without methyl support)
(backup for amines)
• Sleep Patterns
• Retinoic Acid
• More Protein
• Less Carbs
• Eliminate Amines
• Aged cheeses
• Sausages
• Grilled Meats https://www.unifr.ch/biochem/assets/files/albrecht/publications/Hampp08.pdf
and http://www.jbc.org/content/284/25/16723.full.pdf
(c) 2014: Benjamin Lynch, ND http://www.ncbi.nlm.nih.gov/pubmed/22906985 201
(c) 2014: Benjamin Lynch, ND 202
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MAO Support

Amine Resources:
• http://www.mc.vanderbilt.edu/documents/neurology/files/Tyramine%20Menu%20Book%2006227101.pdf
• http://www.millhousemedical.co.nz/files/docs/factsheet_7_amines_in_foods.pdf
• http://www.chempap.org/file_access.php?file=591a70.pdf

(c) 2014: Benjamin Lynch, ND 204

MAO snps

Gene Variant rsID & (orientation) Risk Issue

Allele
MAOA VNTR rs10548363 (+) ? ↓ activity
MAOA R297R rs6323 (+) T ↓↑ activity

CORRECTION:
Was stated that R297R was a
downregulation. It is an
upregulation.

http://snpedia.com/index.php/Rs6323
(c) 2013: Benjamin Lynch, ND 205
(c) 2013: Benjamin Lynch, ND 206
 Macrocytic Anemia

(c) 2014: Benjamin Lynch, ND 207

MCV/MCH - Elevated
Macrocytic Anemia (Megaloblastic Anemia)
• Lack of DNA synthesis
• Block in mitosis
• Cell cycle cannot move from G2 growth stage  M stage
• Cell gets big but cannot divide

(c) 2014: Benjamin Lynch, ND 208

MCV/MCH - Elevated
Macrocytic Anemia
• ↓ Vitamin B12
• ↓ Folinic acid
• MTR/MTRR downregulation
• Oxidative stress
• Metals
• Acetylaldehyde
• Medications

(c) 2014: Benjamin Lynch, ND 209

(c) 2014: Benjamin Lynch, ND 210
 Testing

(c) 2014: Benjamin Lynch, ND 211

(c) 2014: Benjamin Lynch, ND Benjamin Lynch, ND
(c) 2014: 212
Testing Levels of Various Folate Forms

mislabeled

Test available through Health Diagnostics Lab

http://www.hdri-usa.com/tests/methylation/
(c) 2014: Benjamin Lynch, ND 213
Identifying Detox Pathway Issues

(c) 2014: Benjamin Lynch, ND 214

 Glutathione Levels
• Support GSR with B2, B3
• Support GPX with Selenium
• SGS or Liposomal Glutathione
• Cysteine, Glycine, Glutamine
 SOD Levels
• Support with Mn, Zn, Cu
 Ammonia Levels
• Butyrate
• Carnitine
• B1, B2, B3, B5, B6
• Eliminate pathogens
 Lipid Peroxides
• Vitamin E
• Vitamin C
• Glutathione
• RBC Fatty Acids
• Phosphatidylcholine
 Sulfate
• MSM
• Sulfate Foods
• Molybdenum
• Calcium D Glucarate

(c) 2014: Benjamin Lynch, ND 215

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(c) 2014: Benjamin Lynch, ND 217
 SNPs

(c) 2014: Benjamin Lynch, ND 218

 BCMO1
Beta Carotene  Vitamin A

Future evaluation: α-Tocopherol

(c) 2014: Benjamin Lynch, ND 219

BCMO1: Function
Vitamin A Production
• Beta-carotene  Trans-retinol
• Process 35% to 90% of beta carotene
• Cofactor: Iron
• Location: cytosol of enterocytes

Vitamin A Roles (500+ enzymes)

• T regulatory cells / Immune function
• Embryonic development
• Reproduction
• Cell growth and differentiation
• Eye health

Mammalian carotenoid-oxygenases: key players for carotenoid function and homeostasis

(c) 2014: Benjamin Lynch, ND and Molecular and dietary regulation of beta-carotene 15, 15′-monooxygenase 1 (BCMO1) 220
BCMO1: SNPs
May cause:
• ↑ plasma beta-carotene
• ↓ plasma retinol
RS ID Variant Variant Allele Frequency Effect
rs12934922 R267S T 44% None seen
rs7501331 A379V T 29% 32% ↓ conversion
Both 36% 69% ↓ conversion
rs11645428 G 25% - 100% 51% ↓ conversion
rs6564851 G (hetero sig) 10% to 67% up to 59% ↓ conversion
rs6420424 A 12% to 71% up to 59% ↓ conversion

Orientation: +
Mammalian carotenoid-oxygenases: key players for carotenoid function and homeostasis
(c) 2014: Benjamin Lynch, ND and Molecular and dietary regulation of beta-carotene 15, 15′-monooxygenase 1 (BCMO1) 221
BCMO1: Support

Inhibitors/Slowed Promoters
Iron chelators Iron
EDTA (~) Glutathione
Sulfhydryl alkylating agents Omega 3 Fatty Acids
↓ Protein Protein
Quercetin
Curcumin
Catechols (ECGC)
BHT

(c) 2014: Benjamin Lynch, ND Mammalian carotenoid-oxygenases: key players for carotenoid function and homeostasis 222
 HNMT / DAO / APB1
Histamine Issues

Future evaluation: Histamine Receptors

(c) 2014: Benjamin Lynch, ND 223

HNMT & DAO/ABP1: Function
DAO extracellular histamine metabolism
putrescine
spermine, spermidine
• ↑ DAO expression during luteal phase
• ↓ DAO expression during follicular phase
• ↑ DAO expression during pregnancy

HNMT  intracellular histamine metabolism

• Metabolize histamine

PMID: 23099198 and http://www.doiserbia.nb.rs/img/doi/0042-

(c) 2014: Benjamin Lynch, ND 224
8450/2010/0042-84501004286T.pdf
 225
(c) 2014: Benjamin Lynch, ND
 226
(c) 2014: Benjamin Lynch, ND
 B1
B3
Vit C

B1
B3
Vit C

227
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 228
(c) 2014: Benjamin Lynch, ND
 Pregnancy

↑ DAO

↑ DAO

↓ DAO

229
(c) 2014: Benjamin Lynch, ND
 230
(c) 2014: Benjamin Lynch, ND
HNMT & DAO/ABP1: SNPs
HNMT HNMT ABP1 ABP1 ALDH2
rs11558538 rs1050891 rs10156191 rs1049793 rs671
rs1801105
T allele = risk C allele = risk T allele = risk G allele = risk A allele = risk

Orientation = - Orientation = - Orientation = + Orientation = + Orientation = +

Thr105Ile 16Met His645Asp 12G>A

314C/T T939C 4107C>G

Asthma ADHD NSAID sensitivity ↓ DAO Alcohol Flush

Atopic Derm Chronic Urticaria ↑ UC Sx Severity ↑ Mito dys

Polymorphisms of two histamine-metabolizing enzymes genes and childhood allergic asthma: a

case control study and The role of histamine degradation gene polymorphisms in moderating the
(c) 2014: Benjamin Lynch, ND effects of food additives on children's ADHD symptoms and PMID 19178400 231
Histamine
Foods
• Aged, Spoiled, Leftovers Histidine Histamine
• Alcohol
• Fish • Pseudomonas aeruginosa
• Pickled foods • Haemophilus spp.
• Canned foods • Enterobacter aerogenes
• Aged cheeses • Clostridium perfringes
• Smoked meats
• Shellfish
• Beans
• Nuts – walnuts, cashews
• Chocolate / cocoa
• Citrus
• Wheat
• Vinegar

http://jmm.sgmjournals.org/content/35/6/363.full.pdf
(c) 2014: Benjamin Lynch, ND 232
 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022763/pdf/FNR-
(c) 2014: Benjamin Lynch, ND 233
55-5572.pdf
 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022763/pdf/FNR-
(c) 2014: Benjamin Lynch, ND 234
55-5572.pdf
 235
(c) 2014: Benjamin Lynch, ND
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 238
(c) 2014: Benjamin Lynch, ND
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(c) 2014: Benjamin Lynch, ND
 PON1
Shouldn’t be significant….but nowadays – it is VERY significant

(c) 2014: Benjamin Lynch, ND 240

Paraoxonase (PON1): Functions
• Associated with HDL
• Inhibits oxidation of LDL and HDL by hydrolysis of lipid peroxides
• ↓ atherosclerotic process
• Protection against homocysteine-thiolactone
• Protection against organophosphates

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237359/pdf/ehp.1003296.pdf

(c) 2014: Benjamin Lynch, ND 241

Paraoxonase (PON1): Organophosphates
[T]he human enzyme paraoxonase (PON1) detoxifies various organophosphate pesticides with
different efficiency depending on single nucleotide polymorphisms (SNPs) at various position on the
PON1 gene. We analyzed blood samples from mothers and children participating in the CHAMACOS
cohort to determine their PON1 genotype and activity.

We found that PON1 activity is very low in newborns, suggesting that they are more susceptible to
adverse effects of pesticides than adults.

PON1 activity was particularly low in newborns with vulnerable PON1 genotype.

Based on their PON1 status, some newborns may be 26 to 50 times more susceptible to exposure to
certain organophosphate pesticides than other newborns.

The most susceptible newborns may be 65 to 130 times more sensitive to organophosphate
pesticides than the least susceptible some adults.

(c) 2014: Benjamin Lynch, ND http://www.dailykos.com/story/2011/02/21/947919/-New-Study-Exposes-Link-Between-Pesticides-and-ADHD 242

Glyphosate Function

Glyphosate's mode of action is to inhibit an enzyme involved in the synthesis of the

aromatic amino acids tyrosine, tryptophan and phenylalanine. It is absorbed
through foliage and translocated to growing points. Because of this mode of action,
it is only effective on actively growing plants.

SERIOUSLY? Ok. I believe that.

What enzyme does it sound like it inhibits in humans?

(c) 2014: Benjamin Lynch, ND http://en.wikipedia.org/wiki/Glyphosate 243

244
PON1 Promoters PON1 Inhibitors PON1 SNPs Conditions
↑ Selenium Age - Infants rs662 ADHD
↑ HDL Age - Older rs705379 ALS
Vitamin C ↓ Selenium rs854560 Autism
Vitamin E ↓ HDL Developmental Delay
Quercetin Mercury Alzheimers
Resveratrol Lead LDL Oxidation
EGCG Organophosphates
Blueberries ROUNDUP
Curcumin
Pomegranate juice
Taurine
Acai
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237359/pdf/ehp.1003296.pdf
http://alsn.mda.org/article/als-research-roundup-may-2008
(c) 2014: Benjamin Lynch, ND http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077125/pdf/nihms253678.pdf
245
(c) 2014: Benjamin Lynch, ND 246
(c) 2014: Benjamin Lynch, ND 247
(c) 2014: Benjamin Lynch, ND 248
Glyphosate Everywhere

2007: 185,000,000 pounds applied – Agriculture

15,000,000 pounds applied – Industry, Commerce, Government
8,000,000 pounds applied – Home and Garden
> 200,000,000 pounds applied

2008: Glyphosphate Resistant Crops: 80% of the 120 million hectares

• Soybean
• Corn
• Cotton
• Canola
• Sugarbeet

(c) 2014: Benjamin Lynch, ND http://en.wikipedia.org/wiki/Glyphosate and United States EPA 2007 Pesticide Market Estimates 249
(c) 2014: Benjamin Lynch, ND 250
(c) 2014: Benjamin Lynch, ND 251
 Case Studies

(c) 2014: Benjamin Lynch, ND 252

Typical Case Presentation - Revisited
• Male, Age 18
• Vegetarian
• State Champion 2 yrs ago – 500 m sprint - Track athlete
• Dry skin
• Difficulty focusing in school
• Difficulty breathing at times when exercising
• Often irritable
• Difficulty sleeping
• Recurring apthous ulcers
What’s causing these symptoms?
What should you be thinking?
(c) 2014: Benjamin Lynch, ND 253
Case Review: Complex Multisystem Dysfunction

(c) 2014: Benjamin Lynch, ND 254

Current Symptom Picture

Neuropathic pain – generalized Fatigue

Intolerance to clothing or things touching General muscle weakness
Generalized pruritus Generalized panic disorder - extreme
Pain agnosia Psychosis – intermittent
Myalagia/arthralgias Self mutilatory behavior
Abdominal pain – recurrent Insomnia
Tics Mood instability
Intermittent oromotor paralysis Intolerance to environmental toxins
Speech, motor development delay Rashes
No tolerance of vegetables – only meat Vertigo

(c) 2014: Benjamin Lynch, ND 255

Current Supplementation and Protocols

Many sulfur based

Magnesium
Riboflavin
Detoxification protocol
Methylcobalamin
Methylfolate
GAPS Diet
Epsom salt baths
Glutathione creams

(c) 2014: Benjamin Lynch, ND 256

Methylation Lab Findings
Nitrotyrosine 22.4 (high)
Nitric oxide 93.1 (very high) Homo
Glutathione
(oxidized .55) - high MTR
(reduced 3.2) - low CBS 699
S Adenosylmethionine (RBC) 212 (low) MAO A
S Adenosylhomcysteine (RBC) 52.7 (high)
5 CH3 THF 8.0 (low)
10 Formyl THF 3.4 (normal) Hetero
5 Formyl THF 3.9 (normal) MTHFR C677 and 1298
THF 0.48 (low) COMT V158M
Folic Acid 8.9 (low normal)
Folinic Acid (WB) 9.3 (low normal) MTRR A66G
Folic Acid active (RBC) 319 (low)
Kryptopyrrol 7.5
Adenosine 23.8 (high)
Ammonia – (off the chart high)
Lactate - elevated
(c) 2014: Benjamin Lynch, ND 257
Key Issues Identified

Mitochondrial dysfunction
Oxidative stress
Methylation inhibited
Candida overgrowth - significant
Possible additional pathogen involvement
Sulfur overload (CBS upregulation, SULTs overloaded, not taking Molybdenum)
Neurotransmitters negatively affected
Intolerance to vegetables – possibly nitrates

(c) 2014: Benjamin Lynch, ND 258

Unknowns

Pathogens
Hormone levels
Detoxification blocks
Other key SNPs
Urinary amino acids
Urinary organic acids
GI health

(c) 2014: Benjamin Lynch, ND 259

Changes in Supplementation and Protocol

No sulfur-based
Molybdenum
Sodium Butyrate
Acetyl-L-Carnitine
Pantothenic Acid
Niacin PRN
CoQ10
Magnesium with P5P
Anti-Candida Protocol
Sunset Lamp

(c) 2014: Benjamin Lynch, ND 260

Changes in Symptoms

Quickly:
Decreased outbursts
Better sleep
Tolerating clothing
Home schooling 20 minutes a day
Outbursts managed with niacin prn, butyrate, molybdenum, riboflavin
Faster recovery from outbursts

(c) 2014: Benjamin Lynch, ND 261

Current Status

Had very fast improvement initially

Not much improvement since last consult
Managing

(c) 2014: Benjamin Lynch, ND 262

Next steps?
Identify further SNPs
Functional testing
Amino acids
Organic acids
Fatty acids
Detox pathway
GI
Pathogen screen
Methylation
CBC with thyroid, serum ferritin
Hormone panel
Support biopterin recycling
Support all neurotransmitter cofactors
Support all Kreb cycle cofactors
Test NAC, Glutathione
After tolerance of all above, add in B12 and Folates
(c) 2014: Benjamin Lynch, ND 263
Keep to the Basics

• History
• Lifestyle
• Diet
• Compliance
• Motivation
• Mindset
• Environment
• Water
• Exercise

(c) 2014: Benjamin Lynch, ND 264

Stay Informed

Great ways to stay informed:

• Free Newsletter Available. Register at www.MTHFR.net
• Facebook: https://www.facebook.com/drbenjaminlynch
• October 2013 Nutrigenomics Conference www.SeekingHealth.net

(c) 2014: Benjamin Lynch, ND 265

 Thank You

(c) 2014: Benjamin Lynch, ND 266