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Maternal and Pediatric Implications
due to MTHFR and Methylation
Dysfunction
Presenter:
Benjamin Lynch, ND
ICA Pediatrics Conference
October 2014
Las Vegas, NV
(c) 2014: Benjamin Lynch, ND
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Disclaimer & Disclosures
The information presented here is for informational and educational purposes only. Docere, Inc 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.
President and CEO of SeekingHealth.com, SeekingHealth.org and founder of MTHFR.Net
(c) 2014: Benjamin Lynch, ND
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Why?
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Folate
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Source: Big Stock Photo
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Functions of Folate
“The functions of folate in human physiology are relatively simple,
but the implications of their activity (and dysfunction) can be
profound and far reaching.”
Functions:
• synthesis of nucleic acids (for DNA production/repair and tRNA)
• single carbon metabolism (methylation)
• interconversion of amino acids (for neurotransmitter production and
detoxification)
• formation and maturation of RBC, WBC and platelet production
(c) 2013: Benjamin Lynch, ND
Source: Herb, Nutrient and Drug Interactions by Stargrove et al
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Does Folic Acid = Folate?
Folic acid does NOT equal Folate.
Folic Acid is only ONE type of Folate.
Folic acid is not found in nature. Folate is.
Folic acid must undergo numerous biochemical transformations prior to utilization.
Must be specific when discussing folate. Use the appropriate term and form.
• Folic acid (unmetabolized folic acid)
• Folinic acid (5-FormylTHF)
• Methylfolate (5-MTHF)
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Comparing Folic Acid to 5-Methyltetrahydrofolate
FOLIC ACID 
CH3
METHYLFOLATE 
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MTHFR: Why now?
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Folic Acid
MTHFR increasing in the population.
• Folic acid fortification, artificial insemination, steroids, hormones
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↑ Full-Term Pregnancies
↑ Folate SNPs
↑ Methylation SNPs
↑ Inferior SNPs
↑ Metabolic Issues.
↑ Susceptibility to Environmental Exposures
UnNatural DeSelection:
Survival of the ‘Unfittest’
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“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.”
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“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”"
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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.”
(c) 2014: Benjamin Lynch, ND
http://learn.genetics.utah.edu/content/epigenetics/ and Epigenetics and the
developmental origins of inflammatory bowel diseases.
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Methylation
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Functions of Methylation
Several Functions of Methylation:
1. Turn on and off genes (gene regulation)
2. Process chemicals, endogenous and xenobiotic compounds (biotransformation)
3. Build neurotransmitters (norepinephrine  epinephrine, serotonin  melatonin)
4. Metabolize neurotransmitters (dopamine, epinephrine)
5. Process hormones (estrogen)
6. Build immune cells (T cells, NK cells)
7. DNA and Histone Synthesis (Thymine aka 5-methyluracil)
8. Produce energy (CoQ10, carnitine, creatine, ATP)
9. Produce protective coating on nerves (myelination)
10. Build and maintain cell membranes (phosphatidylcholine)
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How is Methylation Disturbed?
Methylation is often disturbed by various mechanisms
1. Lack of cofactors driving methylation forward (Zinc, B2, Mg, Choline, B6, B12)
2. Lack of substrate driving methylation forward (Methionine, Hcy)
3. Medications (antacids, methotrexate, metformin, nitrous oxide)
4. Specific nutrients depleting methyl groups (high dose Niacin)
5. Environmental toxicity, heavy metals, chemicals (acetylaldehyde, mercury, high copper)
6. Excessive end product (feedback inhibition – DMG, SAM, SAH, Hcy)
7. Genetic mutations/polymorphisms (MTHFR, GSTM1, PEMT, MAT, GAMT, SOD)
8. Mental state (stress, anxiety, lack of sleep, ‘can’t do it’, pessimist, optimist)
9. Receptor site blocking (folic acid, antibodies)
10. Carrier protein deficiency (transcobalamin, folate binding proteins)
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URACIL
ARSENIC
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Arsenic. Big Deal.
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Pregnancy
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Issues (some)
Mother:
• Infertility
• Miscarriage / Recurrent Pregnancy Loss
• Preeclampsia
• Gestational diabetes
• Postpartum depression
Newborn:
• Autism
• NTD
• Midline defects
• Down syndrome
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Patient Evaluation
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Screening
Team Care – Request Charts Prior to Treatment
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One Page Summary
History - thorough
Current Medications and Supplements (including OTC)
Diagnoses
Recent Lab Findings
Status of Children (autistic? DS? NTD?)
Labs (some)
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23andMe  MTHFRSupport.com / Genetic Genie
CBC
Full thyroid
CDSA (Doctors Data)
Urinary OAT (Great Plains)
Serum ferritin, vitamin D
RBC Fatty Acids and Plasma Amino Acids (Doctors Data)
Methylation Profile (Doctors Data)
ION Panel (Genova)
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Pregnancy Risk due to Methylation Dysfunction
Lifestyle
Conditions/History (some)
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Bile stagnation
IBD, Constipation
Diabetes
Obesity
Allergies / Asthma
Mental dysfunction
Cancer
Hispanic, Chinese, Italian descent
Reflux
Dental issues / Amalgams / Root Canals
Lyme, H pylori, Candida, EBV, Hep, Strep
Autoimmune
Eating disorders
Neurological disorders
Cardiovascular disorders
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Type A
Vegan
Vegetarian
Addictions
Hobbies
Commuter
Couch Potato
Premier Athlete
Occupational Exposures
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Take Caution with MTHFR (you already know to avoid Folic Acid)
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Antacids (deplete B12)
Cholestyramine (deplete cobalamin and folate absorption)
Colestipol (decrease cobalamin and folate absorption)
Methotrexate (inhibits DHFR)
Nitrous Oxide (inactivates MS)
High Dose Niacin (depletes SAMe and limits pyridoxal kinase = active B6)
Theophylline (limits pyridoxal kinase = active B6)
Cyclosporin A (decreases renal function and increases Hcy)
Metformin (decreases cobalamin absorption)
Phenytoin / Valproic acid (folate antagonist)
Carbamazepine (folate antagonist)
Oral Contraceptives (deplete folate)
Antimalarials JPC-2056, Pyrimethamine, Proguanil (inhibits DHFR)
Antibiotic Trimethoprim (inhibits DHFR)
Ethanol
Bactrim (inhibits DHFR)
Sulfasalazine (inhibits DHFR)
Triamterene (inhibits DHFR)
Source: Fischbach, Laboratory Diagnosis and BMJ http://heart.bmj.com/content/83/2/127/T1.expansion.html and
Herb, Nutrient and Drug Interactions by Stargrove
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At-Risk Populations for Methylation Dysfunction
Environment
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Zipcode (www.scorecard.org)
New construction
Remodeling
Office/Employment
Mold
Gas/Propane/Exhaust
Cleaning supplies
Gardening supplies
Food
Water
Bedroom location
House orientation
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Pregnancy Risks
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Spontaneous Abortion / RPL – Genetic Association
How many genes are associated with Spontaneous Abortion in PubMed?
• 289
What genes are most evaluated in PubMed for Spontaneous Abortion?
1. F5  94 papers  2 Meta Analysis
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Factor 5 Leiden
2. MTHFR  90 papers  5 Meta Analysis
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Genetics of recurrent miscarriage: challenges, current knowledge, future directions
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Neural Tube Defect – Genetic Association
How many genes are associated with NTD’s in PubMed?
• 166
What genes are most evaluated in PubMed for NTD’s?
1. MTHFR  119 papers  7 Meta Analysis
2. MTR  23 papers  4 Meta Analysis
3. MTRR  21 papers  4 Meta Analysis
4. CBS
5. MTHFD1
6. RFC1
7. BHMT
8. SLC19A1
9. DHFR
10. SHMT1
11. TCN2
12. TYMS
13. FOLH1
14. FOLR2
15. BHMT2
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Down Syndrome – Genetic Association
How many genes are associated with Down Syndrome in PubMed?
• 116
What genes are most evaluated in PubMed for DS?
1. MTHFR  50 papers  6 Meta Analysis
2. MTRR  21 papers  5 Meta Analysis
3. APOE  19 papers  1 Meta Analysis
4. MTR
5. RFC1
6. CBS
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Infertility – Genetic Association
How many genes are associated with Infertility in PubMed?
• 450
What genes are most evaluated in PubMed for Infertility?
1. AR  57 papers  3 Meta Analysis
2. CFTR  53 papers  1 Meta Analysis
3. MTHFR  49 papers  7 Meta Analysis
4. ESR1
5. GSTM1
6. GSTT1
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Autism – Genetic Association
How many genes are associated with Autism in PubMed?
• 463
What genes are most evaluated in PubMed for Autism?
1. SL6A4  27 papers  3 Meta Analysis
11. MTHFR  8 papers  0 Meta Analysis
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Autism – Prenatal Associated Risks
Methylation and detoxification systems are poorer in mothers of Autistic children
• SAH > 30 umol/L = 7.3 fold increased risk
• SAM:SAH ratio < 2.5 = 10.7 fold increased risk
• GSH:GSSG ratio < 20 = 15.2 fold increased risk
• Both SAM:SAH and GSH:GSSG ratios off = 46 fold increased risk
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“Geez. Now what?”
Support Pathways!
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Should we use folic acid?!
NTD Associated Genes:
1. MTHFR
2. MTR
3. MTRR
4. CBS
5. MTHFD1
6. RFC1
7. SLC19A1
8. DHFR
9. SHMT1
10. TCN2
11. TYMS
12. FOLH1
13. FOLR2
14. BHMT2
15. FOLR1
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Contribution from Adam Rinde, ND
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Diet
Stress
Diet
Diet
Stress
Diet
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Support Pathways
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ROS Key Points
From
mitochondria also
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Glutathione Key Points
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Systems Approach
Have to do it ALL. Cannot cherry pick.
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Interventions
Implement on all patients
• Breathing
• Sleep schedule
• Filtered water
• Caffeine free or greatly reduce
• Smaller yet more frequent whole food meals with protein, veggies, few good carbs
• Gluten and dairy free three week trial then challenge one at a time
• Chewing
• Read: The Metabolic Makeover
• CoQ10
• Boswelia AKBA or Liposomal Curcumin
• Liposomal Glutathione
• Choline
• Multi
• Probiotic
• D3
• Adaptogens
• Adrenal cortex
• Exercise – rebounder, weights, resistance, yoga, Zumba
• Sauna
• Potassium
• Magnesium
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(c) 2014: Benjamin Lynch, ND
Steps of Treatment
No Protocol – Think Systems – Do NOT Treat the SNP
• Remove causes and exposures
• Food, Lifestyle, Environment, Social, Hobby, Employment, Meds, Supplements
• Basic Foundational Support
• Food, Sleep, Hydration, Breathing, Exercise, Social, Nutritional
• Identify all areas of dysfunction
• GI, adrenals, mitochondria, liver, cell membranes
• Pathogens
• CDSA, OAT, Total IgG, IgM, IgE
• Labs
• CBC w chem panel, urinary hormones, serum ferritin, TNFa, ION
• Methylation profile
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Key Lab Findings
Common findings
• Lactate
• Ammonia
• Urinary MMA
• TNF alpha / Sed rate
• SAH
• SAM
• Cysteine
• MCV and MCH
• Serum ferritin
• Estrogens
• RBC magnesium
• RBC folate
• RBC zinc
• RBC manganese
• Arsenic
• Glutathione
• Homocysteine
• Vitamin D3
• Serum folate
• Serum B12
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Oxidative Stress & Mitochondrial
Screening
 Glutathione Levels
 Enzyme Upregulation
 Ammonia Levels
 Vitamin Levels
(c) 2013: Benjamin Lynch, ND
Test available through Doctors Data
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Test available through Health Diagnostics Lab
http://www.hdri-usa.com/tests/methylation/
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What else?
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Key Points to Take to the Clinic
1. Identify Obstacles and Remove
2. Foundation / Basics
3. Inform
4. Prepare
5. Team care
6. Test – Methylation Profile, 23andMe, MTHFR Support
7. Adrenals
8. Glutathione
9. GI
10. Pathogens
11. Inflammation
12. Mitochondrial support
13. Sulfur
14. Pathways and Systems – NOT Protocols or SNPs
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Three Points to Take to the Clinic
1. Balance Methylation by
• Reducing its workload
• Eliminating blockages
2. Screen for SNPs
3. Test Methylation and restore balance – after Foundation
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Key Supplements to Use at the Clinic
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Adaptogens
Liposomal Glutathione (start low)
Phosphatidylcholine
Multivitamin/mineral (to start - no folate, B12, Cu, Ca, Fe)
Methylfolate w/ methyl/adenosylcobalamin (after foundation)
Throw away Folic Acid
(c) 2014: Benjamin Lynch, ND
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Thank you
Great ways to stay informed:
• Newsletter Available at www.MTHFR.net
• Facebook: https://www.facebook.com/drbenjaminlynch
• October 2013 Nutrigenomics Conference www.SeekingHealth.org
• March 2014 Nutrigenomics Conference – www.SeekingHealth.org
• Pathway Planner Poster and Set – www.SeekingHealth.org
• Physician’s Forum for Collaboration – www.SeekingHealth.org
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