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What You Need to Know About Methylation and How to Get Started

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What You Need to Know About Methylation and How to Get Started What You Need To Know About Methylation and How To Get Started Copyright© 2016, Kurt N. Woeller, D.O. and Educational Resource Association. This material may not be reprinted, distributed or used without permission. 1 Content Disclaimer The material contained within this document/presentation is not intended to replace the services and/or medical advice of a licensed health care practitioner, nor is it meant to encourage diagnosis and treatment of disease. It is for educational purposes only. Kurt N. Woeller, D.O. (or associates) does not accept legal responsibility for any problems arising from experimentation with the information described herein. Any application of suggestions set forth in the following portions of this document/presentation is at the reader's discretion and sole risk. Implementation or experimentation with any supplements, herbs, dietary changes, medications, and/or lifestyle changes, etc., is done so at your sole risk and responsibility and should be discussed with your (or your child’s) personal physician first. 2 Lecture Overview • What is Methylation? • Methylation Problems and Autism • Testing Options For Methylation Assessment • Treatment Options for Methylation YOUR LOGO 3 Support Documents for Module #6 • Methyl-B12 Injection Prescription Form (must be signed by licensed physician). • Methyl-B12 Subcutaneous Injection Information Sheet. • Dr. Woeller’s Methyl-B12 for Autism eBook (pdf) • Lecture slides for Methylation and Autism (pdf) • Lecture slides for Methylation and Autism: note taking (pdf). YOUR LOGO 4 Between The Wheels YOUR LOGO 5 What Is Methylation? YOUR LOGO 6 A methyl group contains one carbon (C) atom and three hydrogen (H) atoms. The process of methylation is transferring this ‘methyl’ group for the purpose of modifying a variety of chemical reactions throughout the body. YOUR LOGO 7 Why Is Methylation So Important? • Key biochemical process commonly altered in many neurodevelopmental disorders like Autism, and neurological diseases such as Alzheimer’s. • The chemistry of methylation, and its impairment, explains a lot with regards to altered brain and cellular function seen in autism: • Memory retention and recall • Poor language development • Diminished environmental awareness • Multiple neurochemistry imbalances • Detoxification problems • Immune dysfunction YOUR LOGO 8 Methylation Cycle Diagram Methionine The cycle constantly spins from homocysteine DMG to methionine. Methyl- SAMe Methyl-B12 B12 has the greatest (Methionine influence through the TMG Synthase) enzyme complex called Methionine Synthase. Homocysteine P5P Glutathione (Potent Antioxidant) The overall effect of methylation is to regulate gene activity for proper cell function, as well as activate various enzymes in their role for biochemical conversions. 9 YOUR LOGO Methylation • Proper immune response to i.e. TB DNA synthesis • New blood cell formation • Helps control gene expression mutations, i.e. mental retardation, Schizophrenia • T cells • Supports detoxification Involved in DNA regulation and Immune Function • Membrane fluidity & phospholipid methylation – attention issue Myelination and pruning • Multiple enzymatic reactions requiring Glutathione production methylation: Prevents homocysteine trapping, i.e. • Melatonin cardiovascular implications • Neurotransmitter levels : dopamine Supports intestinal mucosa and norepinephrine • Tryptophan methylation: serotonin YOUR LOGO 10 Methylation is involved in cell membrane function YOUR LOGO 11 Regulation of neurotransmitter conversion such as Norepinephrine to Epinephrine is dependent on methylation. YOUR LOGO 12 The Role of Histamine • Inflammatory response • Sleep-wake cycle • Increases capillary • Body temperature permeability to white regulation. blood cells and various • Appetite immune proteins. • Erections • Gastric acid secretion • Learning and memory • Regulates various neurochemicals such as serotonin, norepinephrine and acetylcholine. YOUR LOGO 13 DNA methylation is a process in which methyl groups are added to DNA. In humans, we can methylate two nucleotides – Cytosine and Adenine. Methylation’s primary role is to modify DNA activity by suppression of DNA transcription. YOUR LOGO 14 YOUR LOGO 15 Melatonin Issues In Autism • The Pineal Gland produces Acetyl Serotonin Methyl-Transferase (ASMT) which converts serotonin to melatonin. • Dating back to the 60s, studies in autism have reported elevated levels of serotonin in the blood. • In the past 15+ years, various reports have shown abnormally low levels of melatonin in the blood or urine of people with autism. • Some children with autism obtain restful sleep after taking over-the- counter melatonin. • In 2008, a study analyzed ASMT and melatonin and found autism individuals tend to carry certain mutations in ASMT, and have significantly less melatonin and less ASMT in their blood compared with controls (Melke J. et al. Mol. Psychiatry, 90-98). • ASMT gene - there are two identical copies, one of which resides on the X chromosome and the other on the Y chromosome. YOUR LOGO 16 Methylation Problems In Autism YOUR LOGO 17 Methylation Cycle Diagram Methionine The cycle constantly spins from homocysteine DMG to methionine. Methyl- SAMe Methyl-B12 B12 has the greatest (Methionine influence through the TMG Synthase) enzyme complex called Methionine Synthase. Homocysteine P5P Glutathione (Potent Antioxidant) The overall effect of methylation is to regulate gene activity for proper cell function, as well as activate various enzymes in their role for biochemical conversions. 18 YOUR LOGO Jill James, Ph.D Research on Methylation Problems in Autism Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism1,2 S Jill James, Paul Cutler, Stepan Melnyk, Stefanie Jernigan, Laurette Janak, David W Gaylor and James A Neubrander From the Department of Pediatrics, University of Arkansas for Medical Sciences, and the Arkansas Children's Hospital Research Institute, Little Rock, AR (SJJ, SM, and SJ); Niagara Falls, NY (PC); Colden, NY (LJ); Gaylor and Associates, LLC, Eureka Springs, AR (DWG); and Edison, NJ (JAN) Results: Relative to the control children, the children with autism had significantly lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of SAH, adenosine, and oxidized glutathione. This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with autism. The intervention trial was effective in normalizing the metabolic imbalance in the autistic children. “An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.” YOUR LOGO 19 Methylation Altered By Environmental Toxins Neurodevelopmental Toxins Deplete Glutathione and Inhibit Folate and Vitamin B12- Dependent Methionine Synthase Activity: A Link between Oxidative Stress and Autism MOSTAFA IBRAHIM-AHMED WALY and RICHARD DETH PHARMACEUTICAL SCIENCES, NORTHEASTERN UNIVERSITY, BOSTON, MA Ethanol, arsenic, lead, mercury, aluminum and the vaccine preservative thimerosal are suspected to be etiological factors for neurodegenerative and neurodevelopmental disorders. Autism is a neurodevelopmental disorder characterized by oxidative stress and impaired methylation status, including decreased activity of the folate and vitamin B12-dependent enzyme methionine synthase (MS). MS-mediated conversion of homocysteine to methionine is crucial for neurons and all mammalian cells to sustain normal methylation status, involving more than 100 different reactions. Glutathione (GSH) protects MS from oxidative inactivation by reactive oxygen species, while MS inactivation increases GSH synthesis by augmenting transsulfuration. Utilizing SH-SY5Y cultured human neural cells, we found that a 1 hour pre-incubation of cells with arsenic, lead, mercury, aluminum and thimerosal potently decreased both hydroxycobalamin (OHCbl) and methylcobalamin (MeCbl)-based MS activity, although OHCbl exhibited greater sensitivity than MeCbl. At a concentration of 100 nmol, each of these neurodevelopmental toxins caused a 60–70% reduction of intracellular GSH levels. 22 mM (0.1%) ethanol caused a similar inhibition of OHCbl- and MeCbl-based MS activity and a similar decrease in GSH levels. “Our findings suggest that heavy metals and ethanol may contribute to the occurrence of neurodevelopmental disorders such as autism via a mechanism that involves oxidative stress and inhibition of Methionine Synthase activity.” YOUR LOGO 20 Thimerosal Blocks GSH-dependent Synthesis of Methyl-B12 Hydroxycobalamin Cyanocobalamin GSH GSH Thimerosal Thimerosal Glutathionylcobalamin S-adenosyl methionine 5-MethylTHF Methylcobalamin Methionine Homocysteine Methionine Synthase D4RMET D4RHCY YOUR LOGO 21 Testing Options For Methylation Assessment YOUR LOGO 22 The Methylation Pathway: Health Diagnostics and Research Institute www.hdri-usa.com YOUR LOGO 23 YOUR LOGO 24 Single Nucleotide Polymorphism SNP (aka. SNiP) YOUR LOGO 25 YOUR LOGO 26 YOUR LOGO 27 • Adenine • Thymine • Cytosine • Guanine YOUR LOGO 28 DNA is double stranded: two polynucleotides twisted into a double helix • Consists of four types of nucleotides: – Adenine pairs to Thymine – Cytosine pairs with Guanine Base pair The sequence of
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