Transcript Methylation_Speech_Shortx

METHLYATION
A larger pathway than just
MTHFR
Betty Murray, CN, IFMCP, CHC
WHAT IS A GENE?
 A gene is the basic physical and functional unit of heredity.
 Genes, which are made up of DNA, act as instructions to
make molecules called proteins.
 Every person has two copies of each gene, one inherited
from each parent.
 Most genes are the same in all people, but some genes are
slightly different between people.
 These small differences contribute to each person’s unique
physical features.
GENE MUTATIONS
 Gene mutations can be classified in two major ways:
 Hereditary mutations are inherited from a parent and are
present throughout a person’s life in virtually every cell in the
body.
 Acquired mutations occur at some time during a person’s
life and are present only in certain cells, not in every cell in
the body. These changes can be caused by environmental
factors such as ultraviolet radiation from the sun, or can
occur if a mistake is made as DNA copies itself during cell
division. Acquired mutations in somatic cannot be passed
on to the next generation.
GENETIC DEFECTS
 Genetic defects are gene mutations that cause disease.
 Most inherited genetic diseases are recessive, which means
that a person must inherit two copies of the mutated gene
to inherit a disorder.
 Some well-known inherited genetic disorders include cystic
fibrosis, sickle cell anemia, Tay-Sachs disease,
phenylketonuria and color-blindness, among many others.
 All of these disorders are caused by the mutation of a single
gene.
FUNCTIONS OF METHYLATION
 Functions of Methylation:
1. Turn on and off genes (gene regulation)
2. Process chemicals and toxins (biotransformation)
3. Build neurotransmitters (dopamine, serotonin, epinephrine)
4. Process hormones (estrogen)
5. Build immune cells (T cells, NK cells)
6. DNA and RNA synthesis (Thymine aka 5-methyluracil)
7. Produce energy (CoQ10, carnitine, ATP)
8. Produce protective coating on nerves (myelination)
METHYLATION: CONTROLS EXPRESSION
CAUSES OF DEFICIENCY
 Nutritional
 - Deficient in food source
 Drug induced
 Malabsorption
 - Small bowel disease
 - IBS, tropical spure
 - Bacterial overgrowth
 - Nitrous oxide
 Disease states
 - Cancer
 - Liver disease
 - Hemodialysis
 Defects in utilization
 - Alcohol
 - Pregnancy & lactation
Dietary
insufficiency
 - Methotrexate
 - Anticonvulsants
 Inherited disorders (inborn errors)
 - MTHFR deficiency (severe forms)
 - MTHFR C677T polymorphism
 - Methionine synthetase deficiency
 Auto-antibodies to folate
receptor (FR- )
 - Cerebral folate deficiency
 Defect in folate receptor (FR- )
 - Cerebral folate deficiency
Genetics
Drug
Interactions
HOW METHYLATION IS REGULATED
 Methylation is regulated by Enzymes and Substrate (end product)
1. Many enzymes require cofactors to activate
• Cofactors are derived from minerals or vitamins.
2. Cofactors are required to complete methylation
3. Cofactors are required to turn off methylation
4. Excessive raw materials may turn off methylation (feedback
inhibition)
HOW IS METHYLATION DISTURBED
 Methylation is often disturbed by various mechanisms
1. Lack of cofactors driving methylation forward (zinc,
magnesium, B6)
2. Medications (antacids)
3. Specific nutrients depleting methyl groups (niacin)
4. Environmental toxicity, heavy metals, chemicals
(acetylaldehyde, arsenic, mercury)
5. Excessive raw materials (feedback inhibition)
6. Genetic mutations
CONDITIONS ASSOCIATED WITH METHYLATION
 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
New World Problem intersecting Old World Genetics
WHY ARE THESE CONDITIONS
SO PREVALENT
PREVALENCE IN ETHNIC
GROUPS
GENETICS IN THE PATHWAY
 MTHFR is easily available
 COMT and MAO A: processes neurotransmitter catabolism and
estrogens
 CBS: processes homocysteine and if upregulated, depletes methyl
groups, increases taurine
 MTR/MTRR: recycles B12 and processes B12 for methionine production
 GSTM1 and SOD: major detoxification enzymes
 GAD: transforms glutamate to GABA
 HNMT: processes histamine (secondary enzyme for histamine; primary is
DAO)
 QDPR: recycles BH4
 NOS: processes ammonia, forms nitric oxide from arginine
 SUOX: processs sulfites/sulfur and this mutation is made worse from CBS
upregulation
Adapted from seekinghealth.com
MOST COMMON SNPS TESTED IN FOLATE CYCLE
CONDITION RELATIONSHIPS
The Whole Enchilada
METHYLATION PATHWAY
Green Medicine – Replacing Pill for ill with “green pill” for ill
INTERCONNECTEDNESS OF
SYSTEMS AND CHEMISTRY
MECHANISM OF NEUROTOXICITY
Dr Robert Keller
COMMON DRUGS THAT DEPLETE
• 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)
• Niacin (depletes SAMe and limits pyridoxal kinase = active B6) useful during times of
over-methylation
• 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)
FUNCTIONAL TESTING
•Organic Acids
• Homocysteine (Vitamin Diagnostics)
• Biopterin and Neopterin
(Metametrix)
• Urea Breath Test (if FODMAP not
effective)
•Cystathionine, Cysteine,
phosphoserine
• GI Effects Stool Test
•Tryptophan, Tyrosine, Phenylalanine
• Methylmelonic Acid
• Formininoglutamic Acid
•SNP’s
• Ammonia
• Amino Acids (all)
• Nitrotyrosine
• Nitric Oxide
• Glutathione
• SAMe
• SAH (Vitamin Diagnostics)
• Minerals – zinc, copper,
molybdenum, selenium, magnesium,
calcium
• Pyroluria
• CBC with Chem Panel
POITENTIAL SUPPORTING NUTRIENTS
Main Support Nutrients for MTHFR
• Glutathione
• L-Methylfolate (good forms)
• Probiotics
• Sublingual Methylcobalamin
and/or Hydroxycobalamin
• Multivitamin with minerals and
complete B’s (if patient can
handle it)
• Vitamin E
• Krill Oil
• Fish Oil
• Silymarin
• Selenium
• Zinc
• Vitamin D3
• Vitamin C
• Electrolytes
• Magnesium
• Adaptogens (Ashwagandha)
• NAC, MSM, SAMe, Methionine, • Digestive Repair
Inositol, TMG, CoQ10, Alpha Lipoic • Potassium
Acid, L-Carnitine, Ribose
SIDE EFFECTS OF IMPROPER
METHYLATION
• Muscle Pain
• Vomiting
• Irritability
• Stomach Pain
• Anxiety
• Sweating
• Depression
• ‘Herxheimer Reaction’
• Joint Pain
• Rash
• Nausea
• Palpitations
• Headache
• Insomnia
• Seizures
POOR TOLERANCE?
Zero Tolerance to Methylfolate?
Not ready to take it yet. Stop.
• Heal the gut
• Change diet
• Do foundational steps first
• Check for H Pylori
• Consider further genetic testing for: COMT, CBS, MAO A
• Do lab testing as mentioned in Slide 26
Zero Tolerance to Methylcobalamin?
• Switch to Hydroxycobalamin – start low and work up.
• Heal the gut
• Change diet
• Do foundational steps first
• Check for H Pylori
• Consider further genetic testing for: COMT, CBS, MAO A
• Do lab testing as mentioned
More than just a mood modulator
STUDIES
SUMMARY OF CLINICAL DATA - PSY
CLINCAL STUDY DATA - DEMENTIA
QUESTIONS
METHLYATION
A larger pathway than just
MTHFR
Betty Murray, CN, IFMCP, CHC