Folate Metabolism and MTHFR:

Introductory Overview of an Essential Gene

Presenter:
Benjamin Lynch, ND

www.MTHFR.Net www.SeekingHealth.com
Disclaimer & Disclosures

The information presented here is for informational and educational purposes only. Seeking
Health, LLC and Benjamin Lynch, ND 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 Seeking Health, LLC

I am founder of MTHFR.Net

www.MTHFR.Net www.SeekingHealth.com
Overview of this Presentation
What is Folate?

Explain folate metabolism

Explain the importance of folate metabolism

Identify the necessary factors needed for folate metabolism

Define MTHFR

Identify the prevalence of MTHFR defects in the population and who is most at risk

Identify common associated conditions and disorders which are linked to MTHFR

Provide basic methods to support the MTHFR enzyme despite the defect

Identify the commonly prescribed medications and supplements for bypassing the MTHFR enzyme.

Identify the common side effects experienced by those supporting the MTHFR enzyme

How to lessen the side effects commonly seen with MTHFR support
What is Folate?

Folate comes from the Latin word ‘folium’ which means leaf

In 1946, folate was discovered by isolating the nutrient from 4 tons of

spinach leaves.

Folate is Vitamin B9

Found in uncooked leafy greens in high amounts.

Cooking rapidly destroys folate.

Source: Herb, Nutrient and Drug Interactions by Stargrove et al and Advanced Nutrition and Human Metabolism by Groff and Gropper

www.MTHFR.Net www.SeekingHealth.com
What is Folate? (cont’d)

Generic Term for the over 150 different forms of food folate

Folate consists of three similar components

1) Pterin molecule
2) PABA
3) Glutamic acid residues

www.MTHFR.Net www.SeekingHealth.com
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 and 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

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

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.

Folic acid must undergo various transformations prior to utilization.

Must be specific when discussing folate. Use the appropriate term and form.
• Folic acid
• Folinic acid
• Methylfolate

www.MTHFR.Net www.SeekingHealth.com
Comparing Folic Acid to 5-Methyltetrahydrofolate

CH3
Converting Folic Acid to
5-Methyltetrahydrofolate

Requires:
1) Two functioning enzymes
• MTHFD1
• MTHFR
2) Vitamins, Minerals and pH:
• B2
• B3
• B6
DIFFICULT TO DO!
• B12
• Vitamin C
• Zinc (for absorption)
• Acidic environment
(for absorption)

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

A Look at the Enzymes Needed for Conversion of Folic Acid to Methylfolate
Folic acid
DHF

www.MTHFR.Net www.SeekingHealth.com
Recap
1. Folate is vitamin B9
2. Critical regulator of methylation
3. Essential for DNA synthesis and repair
4. Essential for neurotransmitter production
5. Essential for WBC, RBC and platelet formation and maturation
6. Essential for detoxification of homocysteine
7. Folic acid is unnatural to the human body
8. There are over 150 forms of folate in food
9. Use the appropriate term – don’t just say ‘folate’ – be specific
10. Folic acid must undergo numerous steps in order for humans to utilize it
11. Various nutrients and enzymes are needed to convert folic acid into methylfolate
12. MTHFR is the last and final step from the conversion of folic acid into methylfolate

www.MTHFR.Net www.SeekingHealth.com
Terminology

Gene: inheritable material (DNA) from parents which has encoded data that must be read and translated. Produces proteins and
enzymes.

Enzymes: produced by genes. Enzymes are actively moving and functioning proteins which do work. Enzymes require specific
pH, substrates and cofactors in order to do work

Cofactor: typically a mineral or vitamin which enables an enzymes to function properly

Substrate: a molecule that is being converted into a different molecule by an enzyme

Nucleotide: building blocks of DNA bases.

Codon: comprised of three nucleotides and codes for a specific amino acid

Mutation: change in the nucleotide sequence which in turn alters the gene. It may or may not have an effect on the gene.

SNP: a single nucleotide base change in the gene. It may or may not have an effect on the gene. It may not change the codon
due to redundancy of our genetic code. A SNP may cause a mutation.

Redundancy: our genetic code has multiple nucleotide combinations to produce a single codon. Example: GAG and GAA
produce glutamic acid. If the last nucleotide base changes from a G to an A, the SNP has no effect.
MTHFR: Gene which produces the Methylenetetrahydrofolate Reductase Enzyme

MTHFR:
1) Produces the final form of folate – as 5-methyltetrahydrofolate (5-MTHF)
• 5-MTHF is the most abundant form of folate in the plasma circulation.
2) Provides the substrate for the transmethylation cycle
3) Found inside each cell – more so in certain areas such as testis, brain, kidney.
MTHFR: Gene which produces the Methylenetetrahydrofolate Reductase Enzyme

Without 5-MTHF, the transmethylation

pathway suffers and puts pressure on
the BHMT pathway. BHMT is only in
liver, kidney and eye whereas MTHFR is
in every cell – specifically the cytosol.

Source:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515933/ and
PMID: 11468972 and
Vitamin B2 http://www.ncbi.nlm.nih.gov/books/NBK6561/
MTHFR SNPs
SNPs in the MTHFR enzyme cause it to not work as well

Two commonly known MTHFR defects:

1) MTHFR C677T – at nucleotide 677, the cytosine changes to a thymine causing alanine to switch to valine.
2) MTHFR A1298C – at nucleotide 1298, the adenine changes to a cytosine causing glutamate to switch to
alanine.

The MTHFR enzyme is functional with these SNPs; albeit less so proportionately to the number of SNPs

Source: http://jmg.highwire.org/content/41/6/454.full.pdf
Loss of Function
The MTHFR enzyme is functional with these SNPs; albeit less so proportionately to the number of SNPs

Heterozygous = 1 copy of the gene from either parent

Homozygous = 1 copy of the gene from each parent (most commonly – some exceptions)

MTHFR C677T Heterozygous = 40% loss of function

MTHFR C677T Homozygous = 70% loss of function

MTHFR A1298C Heterozygous = No loss of function (debatable)

MTHFR A1298C Homozygous = No loss of function (debatable)

MTHFR C677T & MTHFR A1298C Compound Heterozygous = 50% loss of function

Source: http://jmg.highwire.org/content/41/6/454.full.pdf
What happens if we don’t have enough MTHFR activity?
1. 5-MTHF levels go down
2. Transmethylation cycle slows
3. BHMT enzyme activity increases but
this only supports liver and kidney
4. All tissues except liver and kidney
begin to suffer the effects of
decreased methylation
5. Decreased methylation leads to:
1. Deficient neurotransmitter
production
2. Deficiency in glutathione
6. As BHMT become depleted in
choline:
1. Homocysteine levels rise
2. Methylation in liver and
kidneys decrease
3. Phosphatidylcholine
production drops causing cell
membrane and myelin
instability
MTHFR Defects: Some Conditions They Cause

• Diabetes • Fibromyalgia
• Cancer • Chronic Fatigue Syndrome
• Pulmonary Embolisms • Depression
• Cleft Palette • Alcoholism
• Spina Bifida • Addictive Behaviors
• Autism • Insomnia
• Parkinson’s • Down’s Syndrome
• Neural Tube Defects • Chronic Viral Infection
• Atherosclerosis • Thyroid Dysfunction
• Immune Deficiency • Neuropathy
• ADD/ADHD • Recurrent Miscarriages
• Multiple Sclerosis • Infertility
• Alzheimer’s • Anxiety
• Dementia • Schizophrenia
• Chemical Sensitivity • Bipolar
• Congenital Heart Defects • Allergies
Who are at risk for MTHFR mutations?
Prevalence of homozygous TT genotype (two 677C>T alleles) among newborns by area and
ethnic background, ICBDMS 2003

Approximately 45% of the

population has 1 copy of the
MTHFR C677T

Wilcken B et al. J Med Genet 2003;40:619-625

www.MTHFR.Net
www.SeekingHealth.com
Testing for MTHFR
MTHFR Genetic Testing is available through:
• Spectracell
• Quest
• LabCorp
• Baylor Research Institute – excellent out of pocket option if insurance does not cover
• 23andMe - (provides only raw data which must be interpreted. Interpretation done by www.MTHFRSupport.com )

Insurance may cover MTHFR testing if one has experienced:

• Drug sensitivity – especially to methotrexate or nitrous oxide
• Recurrent blood clots
• Elevated homocysteine
• Recurrent miscarriage

www.MTHFR.Net
www.SeekingHealth.com
Testing for MTHFR

www.MTHFR.Net
www.SeekingHealth.com
Test Positive for MTHFR? Now What?

Supplement with:
L-5-MTHF

That’s enough right?

Methyl Trapping: Why more than L-Methylfolate is Needed

Supplement:
slow L-5-MTHF and
Methylcobalamin
(or Hydroxocobalamin)

Lozenge or Liposomal
Preferred for Best
Absorption

Those with digestive disorders

may not absorb or transport
either nutrient well.

www.MTHFR.Net
www.SeekingHealth.com
Unmetabolized Folic Acid

Increased levels may decrease NK cell activity. PMID: 16365081

Caused by excessive fortification programs and supplementation

May mask a vitamin B12 deficiency

Avoid Folic Acid

“Following absorption of physiological amounts of folic

acid into the enterocytes, a certain percentage
undergoes reduction.”

http://www.aacc.org/publications/cln/2011/january/Pages/FolateMetabolismFigure.aspx and Herb, Nutrient and Drug Interactions

Testing Levels of Methylfolate and UMFA

Test available through Metametrix Labs

Drugs to Avoid with MTHFR
Common Drugs to Avoid with MTHFR
• Antacids (deplete B12)
• Cholestyramine (deplete cobalamin and folate absorption) – common in gallbladder issues during
pregnancy!
• Colestipol (decrease cobalamin and folate absorption)
• Methotrexate (inhibits DHFR)
• Nitrous Oxide (inactivates MS)
• High Dose Niacin (depletes SAMe and limits pyridoxal kinase = active B6) Small doses are great.
• Theophylline (limits pyridoxal kinase = active B6)
• Cyclosporin A (decreases renal function and increases Hcy)
• Metformin (decreases cobalamin absorption)
• Phenytoin (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

www.MTHFR.Net
www.SeekingHealth.com
Nitrous Oxide and MTHFR

Nitrous oxide inhibits MTR enzyme.

Those with MTHFR and methylation

defects already have limited MTR
enzyme function so further reducing it
may cause significant neurological or
cardiovascular damage.

www.MTHFR.Net
Source: http://www.anesthesia-analgesia.org/content/105/1/83/F4.expansion.html
www.SeekingHealth.com
Common Meds used for MTHFR

Common Meds used with MTHFR

• Cerefolin
• CerefolinNAC
• Neevo
• NeevoDHA
• Metanx  personal favorite out of all of them but still don’t like it
• Deplin
• Folbee
• Folplex
• Folgard
• Foltx
• FABB

Common ‘Other Ingredients’ in MTHFR Meds

Dibasic Calcium Phosphate Dihydrate, Microcrystalline Cellulose 90, Microcrystalline Cellulose HD 90, Pyridoxal-5´-
Phosphate, Opadry II Purple 40L10045 (Polydextrose, Titanium Dioxide, Hypromellose 3cP, Hypromellose 6cP,
Glycerol Triacetate, Hypromellose 50cP, FD&C Blue #2, FD&C Red #40, Polyglycol 800), Microcrystalline Cellulose 50,
Opadry II Clear Y-19-7483 (Hypromellose 6cP, Maltodextrin, Hypromellose 3cP, Polyglycol 400, Hypromellose 50cP),
Lmethylfolate Calcium, Magnesium Stearate, Methylcobalamin, and Carnauba Wax.
Source: http://mthfr.net/comparison-of-homocysteine-support-products/2011/09/13/
www.MTHFR.Net
www.SeekingHealth.com
Which Methylfolate to use for MTHFR?

Quality forms of Methylfolate

• L-5-MTHF (L is important to avoid racemic R forms)
• Quatrefolic (glucosamine form)
• Metafolin (calcium form)
• L-Methylfolate
• (6S)-5-Methylfolate

Issues to Understand about Methylfolate

1. Maximum of 1,000 mcg of L-Methylfolate may be used solo
2. Maximum of 800 mcg of L-Methylfolate may be used in a formula
3. If no ‘L’ or (6S) or Quatrefolic or Metafolin is used on the label, avoid it!

Source: http://mthfr.net/l-methylfolate-methylfolate-5-mthf/2012/04/05/
www.MTHFR.Net
www.SeekingHealth.com
Primary Nutrients to Support MTHFR
1. L-5-MTHF
2. Riboflavin (B2)
3. Methylcobalamin or
Hydroxocobalamin
4. Zinc
5. DHA
6. Choline
7. TMG
8. Healthy Protein
9. Magnesium
10. SAMe
11. Pyridoxine (B6)
12. NAC
13. Vitamin E
14. Selenium
15. Glutathione
16. Vitamin C
17. Potassium
18. Probiotics
19. Molybdenum
20. Milk Thistle
Starting Supplementation

Start Slow and Evaluate

• One supplement or medication at a time – ideally one nutrient at a time vs formulations

• If sensitive to sulfur foods or sulfur supplements, do not start with L-5-MTHF.

• Use Molybdenum

• Increase slowly in dosage – don’t start high unless directed.

• Evaluate how you are feeling. Some days you need more support than other days. Adjust accordingly.

• More is not necessarily better

• Faster is not necessarily better

• More Methylation support is not necessarily better: BALANCE

www.MTHFR.Net
www.SeekingHealth.com
Common Side Effects with Methylfolate

Side Effects / Signs to Look For When Starting Methylfolate Meds or Supplements
• Muscle Pain
• Irritability
• Anxiety
• Depression
• Joint Pain
• Nausea
• Headache
• Insomnia
• Seizures
• Vomiting
• Stomach Pain
• Sweating
• ‘Herxheimer Reaction’
• Rash
• Hypokalemia
• Palpitations

Source: http://mthfr.net/methylfolate-side-effects/2012/03/01/
www.MTHFR.Net
www.SeekingHealth.com
Dealing with Side Effects from Methylfolate

Neutralize Side Effects from Methylfolate ASAP

There are two things to quickly quench most of the methylfolate side effects:
1. Consider 50 to 100 mg of nicotinic acid OR niacinamide every 30 minutes to 1 hour. Use as needed only.

2. Consider 250 mg of liposomal curcumin to help quench inflammation.

Note: Curcumin is a dose dependent MAO inhibitor so use caution in those with MAO snps.

3. Lowered potassium levels. Why? Increased folate increases DNA production which requires higher K+ demand.

Use Potassium Chloride powder or Potassium Gluconate or Neutralize. Consider 700 mg twice daily or as needed. Safest is
supplementing with high potassium foods (apricots, avocados, dates, carrot juice, almonds, baked beans, lima beans,
potatoes).

Source: http://mthfr.net/methylfolate-side-effects/2012/03/01/ and http://www.whfoods.com/genpage.php?tname=nutrient&dbid=90 and

http://www.ncbi.nlm.nih.gov/pubmed/18766332
Zero Tolerance to Methylcobalamin and/or Methylfolate?
MethylB12 and Methylfolate
combined support SAM
levels.

High SAM levels increase

transulfuration (CBS activity)
~ 5 fold which reduces the
transmethylation cycle thus
depleting methylation
production.

This leads to imbalanced

SAM:SAH ratio which induces
DNA methylation problems.

Combined with CBS 699 –

Source: http://www.ncbi.nlm.nih.gov/pubmed/16275737 even worse.
www.MTHFR.Net
www.SeekingHealth.com
High Dose Folic Acid Affects SAM:SAH Ratio

“Exposure of normal human cells to supra-physiological folic acid concentrations

present in commercial cell culture media perturbs the intracellular SAM:SAH ratio
and induces aberrant DNA methylation.”

Source: http://www.ncbi.nlm.nih.gov/pubmed/22617627
www.MTHFR.Net
www.SeekingHealth.com
Positive Ending: Epigenetic Influence on the MTHFR Mutation

“….data are consistent for Mexico and northern China, which not only have a very high
frequency of the TT genotype but also high rates of neural tube defect.”

“…In the United States, the rates of neural tube defects historically have been higher among
Hispanics, intermediate among non-Hispanic whites, and lower among African-Americans, a
trend that follows the relative frequency of the TT homozygous genotype.”

There are, however, notable exceptions.

“In southern Italy, the TT genotype is common, but the rate of neural tube defects is not
particularly high. Nevertheless, such exceptions are not entirely unexpected, because
environmental and nutritional factors are likely to modulate considerably the genetic risk.”

www.MTHFR.Net
www.SeekingHealth.com
 Thank You

www.MTHFR.Net
www.SeekingHealth.com