Maternal and Pediatric Implications due to MTHFR and Methylation Dysfunction

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2 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 2

8 Source: Big Stock Photo 8

9 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 9

10 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) (c) 2013: Benjamin Lynch, ND 10

15 Folic Acid MTHFR increasing in the population. Folic acid fortification, artificial insemination, steroids, hormones Full-Term Pregnancies Folate SNPs Methylation SNPs Inferior SNPs Metabolic Issues. Susceptibility to Environmental Exposures UnNatural DeSelection: Survival of the Unfittest (c) 2014: Benjamin Lynch, ND 15

16 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 16

17 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 17

19 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 and Epigenetics and the developmental origins of inflammatory bowel diseases. 19

22 Functions of Methylation Several Functions of Methylation: 1. Turn on and off genes (gene regulation) 2. Process chemicals, endogenous and xenobiotic compounds (biotransformation histamine, arsenic) 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) (c) 2013: Benjamin Lynch, ND 22

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24 How is Methylation Disturbed? Methylation is often disturbed by various mechanisms 1. Lack of cofactors supporting methylation (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) 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) 9. Receptor site blocking (folic acid, antibodies) 10.Carrier protein deficiency (transcobalamin, folate binding proteins) 11.Inflammation (TNF-alpha) 12.Hormones (estrogen, cortisol) (c) 2013: Benjamin Lynch, ND 24

25 URACIL ARSENIC 25

28 Issues (some) Mother: Infertility Miscarriage / Recurrent Pregnancy Loss Preeclampsia Cholestasis Gestational diabetes Postpartum depression Newborn: Autism NTD Midline defects Down syndrome (c) 2014: Benjamin Lynch, ND 28

30 Screening Team Care Request Charts Prior to Treatment One Page Summary History - thorough Current Medications and Supplements (including OTC) Diagnoses Recent Lab Findings Status of Children (autistic? DS? NTD?) Labs (some) 23andMe MTHFRSupport.com / Genetic Genie CBC Full thyroid with antibodies CDSA (Doctors Data) Urinary OAT (Great Plains) Serum ferritin, vitamin D, fasting insulin, DHEA-S RBC Fatty Acids and Plasma Amino Acids (Doctors Data) Methylation Profile (Doctors Data) ION Panel (Genova) (c) 2014: Benjamin Lynch, ND 30

31 Pregnancy Risk due to Methylation Dysfunction Conditions/History (some) Bile stagnation IBD, Constipation Diabetes Obesity Fatty Liver (NASH) 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 Lifestyle Type A Vegan Vegetarian Addictions Hobbies Commuter Couch Potato Premier Athlete Occupational Exposures (c) 2014: Benjamin Lynch, ND 31

32 Take Caution with MTHFR (you already know to avoid Folic Acid) 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 and Herb, Nutrient and Drug Interactions by Stargrove (c) 2014: Benjamin Lynch, ND 32

33 At-Risk Populations for Methylation Dysfunction Environment Zipcode ( New construction Remodeling Office/Employment Mold Gas/Propane/Exhaust Cleaning supplies Gardening supplies Food Water Bedroom location House orientation (c) 2014: Benjamin Lynch, ND 33

35 What should you be asking?? 35

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40 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 Factor 5 Leiden 2. MTHFR 90 papers 5 Meta Analysis (c) 2014: Benjamin Lynch, ND 40

45 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 (c) 2014: Benjamin Lynch, ND 45

47 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 (c) 2014: Benjamin Lynch, ND 47

50 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 (c) 2014: Benjamin Lynch, ND 50

51 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 (c) 2014: Benjamin Lynch, ND 51

53 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 Medications Corticosteroids Valproic acid SSRI (c) 2014: Benjamin Lynch, ND 53

55 55 Contribution from Adam Rinde, ND

56 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 (c) 2014: Benjamin Lynch, ND 56

58 58 Contribution from Adam Rinde, ND

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60 PET scans (show) diminished serotonin synthesis in children with ASD between the age of 2-5 years. The short-term depletion of L- tryptophan exacerbate(s) repetitive behaviour and elevate(s) anxiety in autistic individuals. Rose Meyer Molecular Autism 2013 (c) 2014: Benjamin Lynch, ND 60

65 Interventions Prior to Pregnancy Implement on all patients Breathing Sleep schedule Filtered water Caffeine free or greatly reduce Whole food meals with healthy fat, grass-fed protein, veggies, few good carbs Gluten and dairy free three week trial then challenge one at a time Chewing Read: The Metabolic Makeover CoQ10 Liposomal Glutathione Choline Prenatal Probiotic D3 Adaptogens Adrenal cortex Exercise rebounder, weights, resistance, yoga, Zumba Sauna Potassium Magnesium (c) 2014: Benjamin Lynch, ND 65

66 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, (Precision Analytical) Serum ferritin, TNFa Methylation Profile RBC Fatty acids RBC Essential and Toxic Elements Fasting insulin DHEA-S (c) 2014: Benjamin Lynch, ND 66

67 Key Lab Findings Common findings Lactate Ammonia Urinary MMA TNF alpha / Sed rate SAH SAM Cysteine Choline MCV and MCH Serum ferritin Estrogens / Progesterone RBC magnesium RBC folate RBC zinc RBC manganese Arsenic Glutathione Homocysteine Vitamin D3 Serum folate Serum B12 (c) 2014: Benjamin Lynch, ND 67

Oxidative Stress & Mitochondrial Screening Glutathione Levels Enzyme Upregulation Ammonia

70 Test available through Health Diagnostics Lab 70

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75 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 / Adapt 8. Glutathione 9. GI 10. Pathogens 11. Inflammation 12. Mitochondrial support 13. Sulfur tolerance (SUOX blocked?) 14. Pathways and Systems NOT Protocols or SNPs (c) 2014: Benjamin Lynch, ND 75

76 Three Points to Take to the Clinic 1. Balance Methylation Remove blockages Reduce workload Restore nutritionally 2. Screen for SNPs 3. Test Methylation and restore balance after Foundation (c) 2014: Benjamin Lynch, ND 76

77 Key Supplements to Use at the Clinic 1. Adaptogens 2. Liposomal Glutathione (start low) 3. Phosphatidylcholine 4. Multivitamin/mineral (to start - no folate, B12, Cu, Ca, Fe) 5. Methylfolate w/ methyl/adenosylcobalamin (after foundation) Throw away Folic Acid (c) 2014: Benjamin Lynch, ND 77

81 Thank you Great ways to stay informed: Newsletter Available at Facebook: October 2013 Nutrigenomics Conference March 2014 Nutrigenomics Conference Pathway Planner Poster and Set Physician s Forum for Collaboration (c) 2014: Benjamin Lynch, ND 81

Bonus The Expert Panel

Practical Clinical Application of Methylation and Epigenetics Bonus The Expert Panel CAM Genomic Conference April 11, 2015 London, UK 1 Disclaimer & Disclosures The information presented here is for informational