Maternal and Pediatric Implications due to MTHFR … and Pediatric Implications due to MTHFR and Methylation Dysfunction Presenter: ... reactions activate and deactivate parts of the

Maternal and Pediatric Implications due to MTHFR and Methylation

Dysfunction

Presenter:

Benjamin Lynch, ND

ICA Pediatrics Conference

October 2014

Las Vegas, NV

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

Stress – likely worse with menses

Depression / Insomnia

Folate

8Source: Big Stock Photo

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.”

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

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

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)

Comparing Folic Acid to 5-Methyltetrahydrofolate

FOLIC ACID

METHYLFOLATE

MTHFR: Why now?

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’

“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.”

“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”"

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.”

developmental origins of inflammatory bowel diseases.

“Epigenetic changes are environmentally responsive mechanisms that can

modify gene expression independently of the genetic code.”

Methylation

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)

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)

ARSENIC

URACIL

Arsenic. Big Deal.

Pregnancy

Issues (some)

Mother:• Infertility• Miscarriage / Recurrent Pregnancy Loss• Preeclampsia• Cholestasis• Gestational diabetes• Postpartum depression

Newborn:• Autism• NTD• Midline defects• Down syndrome

Patient Evaluation

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)

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

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 http://heart.bmj.com/content/83/2/127/T1.expansion.html and Herb, Nutrient and Drug Interactions by Stargrove

At-Risk Populations for Methylation Dysfunction

Environment• Zipcode (www.scorecard.org)• New construction• Remodeling• Office/Employment• Mold• Gas/Propane/Exhaust• Cleaning supplies• Gardening supplies• Food• Water• Bedroom location• House orientation

Pregnancy Risks

What should you be asking??

Spontaneous Abortion / RPL – Genetic Association

What genes are most evaluated in PubMed for Spontaneous Abortion?1. F5 94 papers 2 Meta Analysis

• Factor 5 Leiden2. MTHFR 90 papers 5 Meta Analysis

How many genes are associated with Spontaneous Abortion in PubMed?• 289

Genetics of recurrent miscarriage: challenges, current knowledge, future directions

Neural Tube Defect – Genetic Association

What genes are most evaluated in PubMed for NTD’s?1. MTHFR 119 papers 7 Meta Analysis2. MTR 23 papers 4 Meta Analysis3. MTRR 21 papers 4 Meta Analysis4. CBS5. MTHFD16. RFC17. BHMT8. SLC19A19. DHFR10. SHMT111. TCN212. TYMS13. FOLH114. FOLR215. BHMT2

How many genes are associated with NTD’s in PubMed?• 166

Down Syndrome – Genetic Association

What genes are most evaluated in PubMed for DS?1. MTHFR 50 papers 6 Meta Analysis2. MTRR 21 papers 5 Meta Analysis3. APOE 19 papers 1 Meta Analysis4. MTR5. RFC16. CBS

How many genes are associated with Down Syndrome in PubMed?• 116

Infertility – Genetic Association

What genes are most evaluated in PubMed for Infertility?1. AR 57 papers 3 Meta Analysis2. CFTR 53 papers 1 Meta Analysis3. MTHFR 49 papers 7 Meta Analysis4. ESR15. GSTM1 6. GSTT1

How many genes are associated with Infertility in PubMed?• 450

Autism – Genetic Association

What genes are most evaluated in PubMed for Autism?1. SL6A4 27 papers 3 Meta Analysis11. MTHFR 8 papers 0 Meta Analysis

How many genes are associated with Autism in PubMed?• 463

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

Support Pathways!

“Geez. Now what?”

55Contribution from Adam Rinde, ND

Should we use folic acid?!

NTD Associated Genes:1. MTHFR2. MTR3. MTRR4. CBS5. MTHFD16. RFC17. SLC19A18. DHFR9. SHMT110. TCN211. TYMS12. FOLH113. FOLR214. BHMT215. FOLR1

Stress

58Contribution from Adam Rinde, ND

“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

Support Pathways

1. Remove2. Reduce3. Restore

ROS Key Points

From mitochondria also

Glutathione Key Points

Systems Approach

Have to do it ALL. Cannot cherry pick.

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

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

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

Oxidative Stress & Mitochondrial Screening Glutathione Levels Enzyme Upregulation Ammonia Levels Vitamin Levels

Test available through Health Diagnostics Lab

http://www.hdri-usa.com/tests/methylation/

What else?

Key Points to Take to the Clinic

1. Identify Obstacles and Remove2. Foundation / Basics3. Inform4. Prepare5. Team care6. Test – Methylation Profile, 23andMe, MTHFR Support7. Adrenals / Adapt8. Glutathione9. GI10. Pathogens11. Inflammation12. Mitochondrial support13. Sulfur tolerance (SUOX blocked?)14. Pathways and Systems – NOT Protocols or SNPs

Three Points to Take to the Clinic

1. Balance Methylation• Remove blockages• Reduce workload• Restore nutritionally

2. Screen for SNPs3. Test Methylation and restore balance – after Foundation

Key Supplements to Use at the Clinic

1. Adaptogens2. Liposomal Glutathione (start low)

3. Phosphatidylcholine4. Multivitamin/mineral (to start - no folate, B12, Cu, Ca, Fe)

5. Methylfolate w/ methyl/adenosylcobalamin (after foundation)

Throw away Folic Acid

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

Thank you

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