DOCSLIB.ORG

Maternal Gene-Environment Interactions During Pregnancy: Risk

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Maternal Gene-Environment Interactions During Pregnancy: Risk Maternal Gene-Environment Interactions S. Jill James, PhD During Pregnancy: Risk of Autism and Potential for Prevention Reduced Folate Carrier (RFC1) variant G allele RFC1 Genotype Frequencies : Mother, Father, Child is increased in mothers: Metabolic Impact Case Methionine THF SAM Methyl acceptor MS DMG 5,10-CH2-THF MTase Folate Cycle MTRR MTHFR B12 DNA Methylation 5-CH3-THF SAH SAHH Homocysteine Adenosine Cell Membrane RFC1 G allele B6 CBS Cystathionine B6 RFC1 Cysteine GSH GSSG Redox Balance RFC1 Transmission Disequilibrium Test (TDT) MAXIMUM LIKELIHOOD RATIO TEST The LRT is capable of differenQang whether the geneQc risk is operang (relative transmission of G allele from each parent) through the case child and/or through the mother. Genetic 95% Confidence Overall Maternal transmission Paternal transmission Relative Risk p-value Interval R1 (offspring inheriting 1 G allele) 1.23 0.12 0.94, 1.73 Transmitted Not Transmitted Not Transmitted Not Transmitted R2 (offspring inheriting 2 G alleles) 1.18 0.38 0.81, 1.70 Transmitted Transmitted S1 (mother carrying 1 G allele) 1.60 0.007 1.13, 2.26 275 258 118 96 92 97 S2 (mother carrying 2 G alleles 1.52 0.02 1.07, 2.15 p=0.4883 p=0.1510 p=0.7712 Offspring Likelihood Ratio 2.71 NS Maternal Likelihood Ratio 7.76 0.02 Requires genotyping mother, father and child Genetic Relative Risk Folate-Methylation-Redox Pathways are a Continuum: Imbalance in one will affect activity of the others Genetic Relative Risk p Value Child RFC1 AG 1.2 NS Methionine Child RFC1 GG 1.1 NS THF SAM Methyl acceptor DMG 5,10-CH2-THF MS MTase Maternal RFC1 AG 1.60 0.007 Folate Cycle MTRR DNA Methylation MTHFR B12 5-CH3-THF SAH Maternal RFC1 GG 1.52 0.01 SAHH Homocysteine Cell Membrane Adenosine B6 CBS Offspring Effect 2.71 NS Cystathionine Maternal Effect 7.76 0.02 B6 RFC1 Cysteine For RFC1, the genotype of the mother, not the child, GSH GSSG is the RFC1 determinant of risk Redox Balance Maternal Gene-Environment Interactions S. Jill James, PhD During Pregnancy: Risk of Autism and Potential for Prevention 16% DECREASE IN DNA METHYLATION IN ASSOCIATION OF DNA METHYLATION AND SAM/SAH MOTHERS HOMOZYGOUS FOR RFC1 GG IN MOTHERS OF CHILDREN WITH AUTISM DNA Methylaon (% 5mC) P< 0.02 SAM/SAH rao P=0.005 P=0.01 n = 40 n = 40 Maternal Methionine Cycle Metabolites Maternal Transsulfuration Metabolites Control Mothers Autism Mothers p value Control Mothers Autism Mothers p value n=80 n=57 n=80 n=57 Methionine (µmol/L) 23.9 ± 4.4 21.0 ± 3.8 0.001 Homocysteine (µmol/L) 7.2 ± 1.3 9.2 ± 1.8 0.001 SAM (nmol/L) 70.0 ± 12 69.9 ± 21 NS Cysteine (µmol/L) 252 ± 20 247 ± 27 NS SAH (nmol/L) 23.9 ± 6.6 32.3 ± 10 0.001 fGSH (µmol/L) 2.0 ± 0.4 1.8 ± 0.4 0.05 SAM/SAH ratio 3.2 ± 1.0 2.4 ± 1.3 0.01 GSSG (µmol/L) 0.20 ± 0.08 0.26 ± 0.13 0.001 Adenosine (µmol/L) 0.27 ± 0.1 0.36 ± 0.2 0.01 GSH/GSSG ratio 11.1 ± 4.4 8.5 ± 4.5 0.01 Homocysteine (µmol/L) 7.2 ± 1.3 9.2 ± 1.8 0.001 Nitrotyrosine (µmol/L) 68 ± 22 104 ± 43 0.01 Folate (nmol/L) 17.4 ± 6.2 15.4 ± 4.0 0.01 24% of mothers had homocysteine levels > 10 µmol/L HOMOCYSTEINE: BRANCH POINT METABOLITE HOMOCYSTEINE: BRANCH POINT METABOLITE Methionine Methionine METHYLATION METHYLATION THF SAM THF SAM MTase Cellular MTase Cellular 5,10-CH2THF MS Methylation 5,10-CH2THF MS Methylation B12 SAH Reactions B12 SAH Reactions 5-CH3THF 5-CH3THF Purines and Adenosine Purines and Adenosine Thymidylate Thymidylate HOMOCYSTEINE HOMOCYSTEINE B6 B6 DNA SYNTHESIS Cystathionine DNA SYNTHESIS Cystathionine REDOX REDOX Cysteine HOMEOSTASIS Cysteine HOMEOSTASIS PROLIFERATION PROLIFERATION GSH GSSG GSH GSSG Maternal Gene-Environment Interactions S. Jill James, PhD During Pregnancy: Risk of Autism and Potential for Prevention HOMOCYSTEINE: BRANCH POINT METABOLITE HOMOCYSTEINE: BRANCH POINT METABOLITE Methionine Methionine METHYLATION METHYLATION THF SAM THF SAM MTase Cellular MTase Cellular 5,10-CH2THF MS Methylation 5,10-CH2THF MS Methylation B12 SAH Reactions B12 SAH Reactions 5-CH3THF 5-CH3THF Purines and Adenosine Purines and Adenosine Thymidylate Thymidylate HOMOCYSTEINE HOMOCYSTEINE B6 B6 DNA SYNTHESIS Cystathionine DNA SYNTHESIS Cystathionine REDOX REDOX Cysteine HOMEOSTASIS Cysteine HOMEOSTASIS PROLIFERATION PROLIFERATION GSH GSSG GSH GSSG Both genes and environment affect Homocysteine Maternal GeneQcs/EpigeneQcs Important Caveat PRE-NATAL Because the plasma metabolic profile was taken from Autism mothers 3- 10 years after the birth of their child, these results cannot be extrapolated to their PRE-NATAL ASDs metabolic profile during pregnancy. We recently measured the plasma metabolic profile in Child Genecs Environment high risk mothers (who already had one child with autism) /Epigenecs POST-NATAL in collaboration with the MARBLES study at UC Davis. Homocysteine is a commercially available biomarker of abnormal one-carbon metabolism Percent of Mothers with Functionally Significant Alterations in Methylation and Redox Metabolites During Pregnancy Interestingly, the percent of mothers with elevated homocysteine (~20%) in the third trimester is close the Functionally Significant 1st Trimester 2nd Trimester 3rd Trimester Change n=23 n=47 n=47 recent percent risk of a second autism outcome. SAM < 60 nmol/L 22% 27% 27% SAH > 32 nmol/L 4% 15% 25% SAM/SAH < 1.8 13% 13% 23% Homocysteine >10 µmol/L 17% 23% 23% We do not yet know if this metabolic imbalance GSH < 1.5 µmol/L 13% 13% 23% GSSG > 0.3 µmol/L 4% 21% 25% will be associated with an autism outcome. GSH/GSSG < 6.5 9% 23% 21% It will take 2-3 years before all siblings are evaluated Homocysteine levels normally drop during pregnancy to 6-7 μmol/L and we know final answers. Maternal homocysteine crosses the placenta and predicts fetal and neonatal homocysteine Maternal Gene-Environment Interactions S. Jill James, PhD During Pregnancy: Risk of Autism and Potential for Prevention Risk factors associated with elevated Homocysteine: Conditions associated with elevated Homocysteine: Common Polymorphisms in one-carbon metabolism (MTHFR, MTRR, MTR, TCN2, RFC1) Cardiovascular Disease Age Alzheimer’s Disease B vitamin insufficiency Bipolar Disorder Alcohol Schizophrenia Smoking Osteoporosis Diabetes Birth defects Preeclampsia Homocysteine levels are easily normalized by B vitamins: Potential for Autism Prevention: Folate, B12, B6, Riboflavin, Choline) We cannot control our genetic inheritance but we do have some control over environmental exposures that may increase risk of an autism Have your (total) homocysteine level checked: pregnancy (as they come to be known) Now Before conception As soon as you know you are pregnant Every trimester Fasting level should be between 7 and 8 μmol/L if you are under 35 RISK FACTORS DO NOT ACT IN ISOLATION Pu3ng it all into Perspec7ve……we see what we know Epigenetics SNPs Elevated Homocysteine Cellular Metabolic Pathways Mutations Dietary deficiencies Mitochondrial dysfunction You Are Here Estrogen Free radicals Testosterone Toxins Thyroxin Viral/Bacterial infections Genes Emotional stress Environment Hormones Oxidative Stress Epigenetic FINAL COMMON PATHWAY Dysfunction Timing, duration, developmental stage, severity Neuroinflammation Microbiome pathology Abnormal circuitry Gut dysfunction Immune Dysfunction Maternal Gene-Environment Interactions S. Jill James, PhD During Pregnancy: Risk of Autism and Potential for Prevention Acknowledgements Autism Metabolic Genomics Laboratory Stepan Melnyk, PhD Stefanie Jernigan Teresa Evans Tim Trusty Shannon Palmer Sarah Blossom, PhD Dr. Moms and Dads Lesya Pavliv Researchers Study Coordinators And Physicians Lisa Seidel, Laura Walters, Margaret Pauly Funding: NICHD, DoD, ACHRI Foundation Folate Receptor Autoimmunity in Dan Rossignol, MD Autism Spectrum Disorders: Research Update Disclaimer Folate Receptor Autoimmunity in While Dr. Rossignol has attempted to make the Autism Spectrum Disorders: information in this presentation as accurate as Research Update possible, the information is provided without any expressed or implied warranty. The purpose of this Dan Rossignol, MD FAAFP lecture is to provide information about different International Child Development Resource Center conditions or treatments that may affect individuals 321-259-7111 www.icdrc.org [email protected] with autism and other conditions. Please be advised that Dr. Rossignol is not giving medical www.danrossignolmd.com advice and that circumstances may dictate different ARI Conference treatments. All of the reviewed treatments in this October 16, 2011 lecture are considered off-label and not FDA- approved. Before beginning any treatment, please consult with your or your child’s physician. Types of Folate 5MTHF Transport into Brain . Folate = folic acid, inactive and oxidized form . 5MTHF binds to a Folate Receptor . 5-methyltetrahydrofolate (5MTHF): form of (FR1) in the choroid plexus and then folate that crosses the blood brain barrier undergoes endocytosis, storage and and is concentrated 2 to 4 times higher in then delivery into the CSF. It is then cerebral spinal fluid (CSF) than in the blood transported into neurons by the . Methylenetetrahydrofolate reductase reduced folate carrier (RFC) (MTHFR) converts folic acid into 5MTHF . 5-formyltetrahydrofolate (folinic acid) can . In this process, folate transport by FR1 also cross the blood brain barrier is ATP-dependent . There are over 100 folate analogues Folate Receptors (FR) . FR1: found at the luminal surface of intestinal cells, choroid plexus epithelium, pulmonary alveolar cells, thyroid cells (may play a role in hypothyroidism), and renal tubular cells (does not affect kidney function as antibodies do not cross there) . FR2: found in mesenchymal cells such as red blood cells Folate Receptor Autoimmunity in Dan Rossignol, MD Autism Spectrum Disorders: Research Update Reduced Folate Carrier (RFC) FR Autoantibodies . The Reduced Folate Carrier (RFC) carries . Autoantibodies to FR1 were first reported in folate into cells, including into neuronal 2005 and can be measured in the blood cells .
Load more

Recommended publications
  • Environmental Health Issue
    FIFTH EDITION 2006, Volume 45 R5 Environmental Health and Autism In thIs Issue: Time To GeT a Grip By martha r. Herbert, m.D., ph.D. Beyond Behavior—Biomedical Diagnoses in Autism spectrum Disorders By Margaret L. Bauman, M.D. transforming the Public Debate on neurotoxicants By Elise Miller, M.Ed. ADVERTISEMENT ADVERTISEMENT Autism does not have to be a life sentence You’re not about to give up on your child. Neither Are We. Since , the Autism Treatment Center of America™ has provided innovative training programs for parents and professionals caringifor children challenged by Autism Spectrum Disorders and related developmental difficulties. • Practical Tools • Powerful Results • Limitless Hope c Help your child improve in all areas of over p learning, development, communication and hoto skill acquisition. : © W I Join us for our internationally-acclaimed ll T ERR Son-Rise Program® Start-Up, a y comprehensive weeklong training program for parents and professionals. We don’t put limits on the possibilities for your child. Free 25-Minute Initial Call 877-766-7473 We’ll give you the keys to unlock their world. HOME OF THE SON-RISE PROGRAM® SINCE 1983 South Undermountain Road Sheffield, MA - USA Telephone: -- • E-mail: [email protected] www.autismtreatment.com Copyright © 2006 by The Option Institute & Fellowship. All rights reserved. 02.06-6 CONTENTS December 2006 page 18 SpOTlIGHT Time to Get A Grip By marTHa r. HerBerT, m.D., pH.D. Does an environmental role in autism make sense? How do we decide? And if environment is involved in autism, what do we do about it? These are challenging questions.
    [Show full text]
  • Association of MTHFR Gene Variants with Autism
    Association of MTHFR Gene Variants with Autism Marvin Boris, M.D.; Allan Goldblatt, P.A.; Clinically available testing for methylenetetrahydrofolate Joseph Galanko, Ph.D.; S. Jill James, Ph.D. reductase (MTHFR) gene mutations (polymorphisms) has recently become available and had been incorporated into our evaluation ABSTRACT process for developmentally delayed children. The MTHFR gene codes for an essential enzyme in folate metabolism. To further Autism is a complex neurodevelopment disorder with understand this condition, we retrospectively evaluated our numerous possible genetic and environmental influences. findings regarding the genomic variations in the gene. MTHFR We retrospectively examined the laboratory data of 168 children enzyme catalyzes the reduction of 5,10-methylenetetrahydrofolate sequentially referred to our facility with a confirmed diagnosis of to 5-methyltetrahydrofolate. Methyltetrahydrofolate is essential in autism or pervasive developmental disabilities (PDD). Since folate one-carbon-donor metabolism for the remethylation of and methylation (single carbon metabolism) are vital in homocysteine to methionine and the generation of metabolically neurological development, we routinely screened children for the active tetrahydrofolate in the methionine synthase reaction.1 common mutations of the methylenetetrahydrofolate reductase Common polymorphisms in the MTHFR gene have been gene (MTHFR), which regulates this pathway. All children had associated with reduced enzyme activity. A detailed review of polymerase chain reaction
    [Show full text]
  • 2 James Mif06sun Metabollic Biomarkers
    Pathologic Implications of Low Glutathione Levels And Oxidative Stress in Children with Autism: Metabolic Biomarkers and Genetic Polymorphisms S. Jill James, Ph.D. Department of Pediatrics Arkansas Children’s Hospital Research Institute University of Arkansas for Medical Sciences Little Rock, AR Overview Pathways of Folate/Methionine/Glutathione metabolism; Impact of Oxidative Stress Mechanisms and Functions of Glutathione Depletion of glutathione with Thimerosal in vitro Abnormal Methylation and Oxidative Stress in Autistic Children: Treatment with Methyl B-12, Folinic Acid, and TMG Selected Genetic Polymorphisms Associated with the Abnormal Metabolic Profile in Autism Implications of Oxidative Stress in the Pathogenesis of Autism Methionine Transsulfuration to Cysteine and Glutathione Methionine THF 5,10-CH 2THF 1 MS B12 MTHFR 5-CH 3THF Homocysteine B6 THF: tetrahydrofolate Enzymes Methionine Transsulfuration to Cysteine and Glutathione Methionine THF 5,10-CH 2THF 1 MS B12 MTHFR 5-CH 3THF Homocysteine B6 THF: tetrahydrofolate Enzymes Methionine Transsulfuration to Cysteine and Glutathione Methionine Methylation THF SAM Potential (SAM/SAH) MTase Cell Methylation 5,10-CH 2THF 1 MS BHMT 2 B12 SAH MTHFR Betaine 5-CH 3THF SAHH Choline Adenosine Homocysteine B6 THF: tetrahydrofolate Enzymes Methionine Transsulfuration to Cysteine and Glutathione Methionine Methylation THF SAM Potential (SAM/SAH) MTase Cell Methylation 5,10-CH 2THF 1 MS BHMT 2 B12 SAH MTHFR Betaine 5-CH 3THF SAHH Choline Adenosine Homocysteine B6B6 CBS Cystathionine 3 B6 Antioxidant
    [Show full text]
  • Autism Made Easy Therapeutic Nutritional Strategies in the Autistic Spectrum of Disorders
    Autism Made Easy Therapeutic Nutritional Strategies in the Autistic Spectrum of Disorders Peta Cohen, MS., RD. Star Academy Johannesburg, Nov 2011 www. PetaCohen .com Therapeutic Nutritional Strategies in ASD Defining the Problem • Autism is treatable, recovery is possible • Epigenetic Phenomenon (methylation) • Complex – Whole Body, Multi-System, Metabolic Disorder – Many targets for simultaneous treatments • Biological Heterogeneity • Chronic Dynamic Encephalopathy • Disorder that Affects the Brain www. PetaCohen .com 2 Autism- A Whole Body, Multi-System, Metabolic Disorder Systems Oxidative Stress Inflammation Methylation Transulfuration Mitochondrial Redoxstatus Function Biotransformation Excitation SNPs – Single Nucleotide Polymorphisms www. PetaCohen .com 3 Autism- A Whole Body, Multi-System, Metabolic Disorder Nervous System Gastro-Intestinal System Respiratory System Immune System Endocrine System Eco- System/Microbiome Cardiovascular System Oxidative Stress Impaired Methylation Inflammation Impaired Trans-Sulfuration Excitation Impaired Detoxification Mitochondrial Dysfunction Nutrient Insufficiencies/Excess pH Balance/Redox Status Cerebral Folate Deficiency SNP – Single Nucleotide Polymorphisms, Epigenetics Genomics Proteomics Metabolomics www. PetaCohen .com 4 Autism- A Whole Body, Multi-System, Metabolic Disorder Stressors Function Feed Forward Dysfunction - Systemic & Metabolic genetics immunity GI biotransformation www. PetaCohen .com 5 Stress Multiple Routes of Exposure – Environmental – Metabolic • Chemical/Toxic • Nutritional
    [Show full text]
  • Monday Morning Tools for Your Autism Treatment Toolbox
    Monday Morning Tools for Your Autism Treatment Toolbox Julie A. Buckley, MD FAAP 78th UWI/BAMP Annual Conference November 14, 2015 Disclaimer • I am not dispensing medical advice, information provided is without warranty • I have no financial relationships to disclose • Some of the discussed treatments are considered “off label” by the FDA Objectives • To become acquainted with autism as a complex medical disease • To understand its signs and symptoms in this context • To acquire treatment tools that are useful on Monday morning. • References are included here that will not be addressed during the live presentation due to time constraints. Suggested Pre-Reading • Buie, T et al. Evaluation, Diagnosis, and Treatment of Gastrointestinal Disorders in Individuals With ASDs: A Consensus Report. Pediatrics. 2010 Jan;125 (1):S1-S18. doi:10.1542/peds.2009-1878C • Whiteley, P et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2012 Nov; 6: 344. doi: 10.3389/fnhum.2012.00344 • Herbert, M and Buckley, J. Autism and Dietary Therapy: Case Report and Review of the Literature J Child Neurology. 2013 Aug;28(8):973 - 980. doi 10.1177/0883073813488668 • Rossignol, D et al. Hyperbaric oxygen treatment in autism spectrum disorders. Med Gas Res. 2012; 2:16. doi: 10.1186/2045-9912-2-16 • Agrawal, A et al.Thimerosal induces TH2 responses via influencing cytokine secretion by human dendritic cells. J Leukoc Biol. 2007 Feb;81(2):474-82. doi: 10.1189/jlb.0706467 • Rossignol, D and Frye R. Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism.Front.
    [Show full text]
  • Biomedicalhandbook.Pdf
    Congratulations and thank you for taking the first step down the road of biomedical treatment. I appreciate that you have chosen me to help support you and your child. As this may be a new treatment for your child, I would like to outline that some of the facets of biomedical care, challenges that may occur and some achievements that you can expect. I would also like to emphasize that this is not a “quick fix” and this is an ongoing process. Children who undergo long term biomedical treatment generally experience high levels of success and that is my ultimate goal in treating your child. We are a team! Biomedical Program Outline: Initial 60 – 90 minute assessment and individualized testing (see page 5 & 6) Supplements including: vitamins, minerals, amino acids, botanical medicines, probiotics, essential fatty acids, phospholipids and digestive enzymes Dietary intervention is a crucial part of biomedical treatment success. Follow up visits every 4-12 weeks based on re-assessment and protocol outcomes. Please note that follow up appointments are essential to treatment success Please note that B12 injections therapy requires follow up visits every 3 months in addition to supplementation with a B complex that contains folate or methyl folate and B6 Challenges often arise as we are trying to “repair” your child’s body and brain in order to recover as many neurotypical skills as possible. Challenges are short term and managed acutely as needed. These challenges will vary in terms of severity, and will be handled accordingly: Sleep changes
    [Show full text]
  • Folate Deficiency Disturbs Hepatic Methionine Metabolism and Promotes Liver Injury in the Ethanol-Fed Micropig
    Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig Charles H. Halsted*†, Jesus A. Villanueva*, Angela M. Devlin*, Onni Niemela¨ ‡§, Seppo Parkkila§, Timothy A. Garrow¶, Lynn M. Wallockʈ, Mark K. Shigenagaʈ, Stepan Melnyk**, and S. Jill James** *University of California, Davis, CA 95616; ‡EP Central Hospital Laboratory, Seina¨joki, Finland; §Institute of Medical Technology, University of Tampere, Tampere, Finland; ¶University of Illinois, Urbana, IL 61801; ʈChildren’s Hospital Oakland Research Institute, Oakland, CA 94609; and **National Toxicological Research Center, Jefferson, AR 72079 Communicated by Bruce N. Ames, University of California, Berkeley, CA, June 4, 2002 (received for review February 20, 2002) Alcoholic liver disease is associated with abnormal hepatic methi- ferase (MAT) reaction adds ATP to methionine for generation onine metabolism and folate deficiency. Because folate is integral of S-adenosylmethionine (SAM). Two different genes express to the methionine cycle, its deficiency could promote alcoholic liver different isoforms of MAT. MAT1A encodes the catalytic unit disease by enhancing ethanol-induced perturbations of hepatic that is expressed as a dimer, MATIII, and as a tetramer, MATI, methionine metabolism and DNA damage. We grouped 24 juvenile in the liver and is capable of converting liver methionine to 6–8 micropigs to receive folate-sufficient (FS) or folate-depleted (FD) g of SAM per day (17, 18). MAT2A encodes a different catalytic diets or the same diets containing 40% of energy as ethanol (FSE subunit and expresses MATII in fetal and extrahepatic tissues. and FDE) for 14 wk, and the significance of differences among the SAM is the principal methyl donor in methylation reactions, groups was determined by ANOVA.
    [Show full text]
  • Summary of Dietary, Nutritional, and Medical Treatments for Autism – Based on Over 150 Published Research Studies
    ARI Publication 40 – 2013 Version Summary of Dietary, Nutritional, and Medical Treatments for Autism – based on over 150 published research studies By James B. Adams, Ph.D. Director, ASU Autism/Asperger’s Research Program http://autism.asu.edu 2013 Version 1 ARI Publication 40 – 2013 Version Summary of Dietary, Nutritional, and Medical Treatments for Autism – based on over 150 published research studies By James B. Adams, Ph.D. 2013 Version see http://autism.asu.edu or www.autism.com for future updates. Overview This document is intended to provide a simple summary for families and physicians of the major dietary, nutritional, and medical treatments available to help children and adults with autism spectrum disorders. The discussion is limited to those treatments which have scientific research support, with an emphasis on nutritional interventions. This report excludes psychiatric medications for brevity. The dietary, nutritional, and medical treatments discussed here will not help every individual with autism, but they have helped thousands of children and adults improve, usually slowly and steadily over months and years, but sometimes dramatically. This summary is primarily based on review of the scientific literature, and includes over 150 references to peer-reviewed scientific research studies. It is also based on discussions with many physicians, nutritionists, researchers, and parents. This summary generally follows the philosophy of the Autism Research Institute (ARI), which involves trying to identify and treat the underlying causes of the symptoms of autism, based on medical testing, scientific research, and clinical experience, with an emphasis on nutritional interventions. Many of these treatments have been developed from observations by parents and physicians.
    [Show full text]
  • 2005, Vol. 19(4)
    Page 3 AUTISM RESEARCH REVIEW INTERNATIONAL Vol. 19, No.4, 2005 Guest Editorial: Jaquelyn McCandless, M.D. Clinical use of methyl-B12 in autism Dr. McCandless is a DAN! doctor who is in our afflicted children. We had been finding every three days is the optimal dose, volume, board-certified in psychiatry and neurology, more every day about how sulfhydryl (SH) reac- and frequency.) the grandmother of an autistic girl, and the tive metals such as mercury, lead, arsenic and 4) That the fat in the arm, abdomen, or author of Children with Starving Brains. cadmium appeared to be “triggers” for multiple thigh produces the same results as from the — disease symptoms in ASD. Dr. Deth’s studies fatty part of the buttocks. One of the most important treatment showed how thimerosal alters methionine Lowering the dose until side effects disap- modalities to come out of the strong focus synthesis activity with the potential to disrupt pear is a mistake, because the children with the on biomedical and metabolic aspects in au- normal development via its neurotoxic effect most side effects who stay with the course are tism in recent years is the use of injectable on DNA methylation and gene expression. the ones who make the most recovery. How- methylcobalamin, or methyl-B12. The evi- His studies lent tremendous credence to the ever, side effects must be dealt with. The most dence for transmethylation defects in autism importance of methylation disorders and their common are hyperactivity with or without disorders was already starting to accrue treatment in autism. increased stimming, changes in sleep pat- thanks to talented researchers helping us Prior to my DAN! presentation in Spring terns, and increased mouthing (not pica, to understand the basic science behind our 2005 I queried three of the more popular or eating of non-food item) of objects.
    [Show full text]
  • Autism References: Autism Research Directory Disclaimer: the Following
    Autism References: Autism Research Directory James A. Neubrander, MD James A. Neubrander, MD USAAA 2007 International Conference Methyl -B12: Doing It Right! Methylcobalamin Update Disclaimer: The following manuscript regarding methyl -B12 and related subjects is the work product from my practice. The majority of the concepts and conclusions are based on my cumulative clinical experiences since first using methyl -B12 in March, 2002. Much of the methylation, transsulfuration, and methyl -B12 biochemistry described is conventional wisdom. Much of the research mentioned is universally accepted. However, some of the biochemistry and research discussed represents newer thinking, one specifi c example being methionine synthase’s activity in the body vs. the brain. Many of the research ideas will be proven in time. Others will need to be updated and modified. So it is with my hypotheses and conclusions. Many will stand the test of time. Others I will modify as more data are accumulated. Many are shared by my colleagues; some are not. Nonetheless, there is fairly universal agreement among those of us who are using methyl -B12 that it is a powerful treatment for children on the autistic spectrum. OVERVIEW: In our practice we continue to see that methyl -B12, when used correctly , is still the single most predictable treatment we have to treat children on the autistic spectrum that gives numerous global benefits at the same time. At follow -up our aver age number of responses during the initial 1st six week methyl -B12 Initiation Phase is 30 to 45 or more. We have now monitored well over . million doses of methyl -B12 using numerous protocols.
    [Show full text]
  • Evidence for Metabolic Imbalance and Oxidative Stress in Autism by S
    BIoMeDICAL factoRs In AutIsM Evidence for Metabolic Imbalance and Oxidative Stress in Autism By S. JiLL JameS, pH.D. It is well accepted that both genetic and environmental factors The best index of methylation capacity is the ratio of two interact in the development of autism. The search for these substances, S-adenosylmethionine (SAM) to S-adenosylhomocys- factors, however, is proving challenging, with researchers report- teine (SAH). (This is called the SAM/SAH ratio.) When we tested ing little or no success in replicating findings. 95 autistic children and 75 age-matched control children, we found The metabolic aspects of autism have received much less that the autistic children’s SAM/SAH ratio was about 50 percent research attention, despite the fact that chronic biochemical that of unaffected control children (James et al., 2006). In addition, imbalance often plays a primary role in the development of many autistic children exhibited a threefold reduction in the ratio complex disease. The metabolism of an individual — that is, the of “active” glutathione (GSH) to “inactive” glutathione (GSSG). sum of the biochemical reactions in our cells that produce energy Cysteine, another substance needed for GSH synthesis, was also and form the materials we need to survive — is affected by both significantly reduced, suggesting that the building blocks for SG H genetic and environmental factors. As such, it gives us a window synthesis may be insufficient. through which we can view the interactive impact of genes and These new findings are of concern because they indicate a the environment, and identify relevant susceptibility factors. significant decrease in cellular methylation capacity and anti- Two metabolic impairments of particular interest, because of oxidant defense, and an increase in oxidative stress that could their association with many neurological disorders, are: contribute to the pathophysiology of autism.
    [Show full text]
  • 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.
    [Show full text]