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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