kendall

Metabolic Function and Role of Dimethylglycine (DMG) in Reversing Autism: 

Metabolic Function and Role of Dimethylglycine (DMG) in Reversing Autism Roger V. Kendall, Ph.D. NAA Conference Myrtle Beach, SC November 2005

LEARNING OBJECTIVES: 

LEARNING OBJECTIVES Specific Benefits of DMG in ASD Biochemical & Metabolic Role of DMG Review of DMG Research Comparison Between TMG & DMG Supplementation Options for ASD

What is Autism?: 

What is Autism? A complex multifactorial neurological developmental disorder along the spectrum (ASD). ADHD Asperger’s Syndrome PDD Tourette’s Autism Each child with autism has a unique set of biological abnormalities that require a unique set of biomedical interventions.

Possible Causes of Autism: 

Possible Causes of Autism Metabolic Dysfunction/Imbalances Immune Dysfunction/Infection Oxidative Stress Environmental Factors/Toxins Genetic Predisposition Vaccinations

Defects in Biochemical Pathways/Metabolic Function: 

Defects in Biochemical Pathways/Metabolic Function Methylation Pathway Sulfation Pathway Neurological Function Immune System Detoxification Antioxidant Defense System Digestion/GI Tract Health Energy Production Genetic Expression

SUMMARY:: 

SUMMARY: Autism is associated with defects and imbalances in the biochemical pathways of the body giving rise to a large range of symptoms and responses.

Biomedical Intervention: 

Biomedical Intervention Role of Biomedical Intervention is to identify and correct metabolic, functional and biochemical defects and imbalances by use of dietary modification and nutritional supplementation to optimize the total well being of individuals with ASD.

DMG & ASD RESEARCH: 

DMG & ASD RESEARCH DMG is associated with what the Russians in 1967 referred to as Calcium Pangamate/ Pangamic Acid (Vitamin B-15) Dr. Alan Cott reported benefits of Calcium Pangamate in children on the spectrum with behavior and language problems. DMG is the active metabolite behind Calcium Pangamate. Starting in 1969 Dr. Bernard Rimland began to evaluate the impact of DMG on children with ASD.

DMG BENEFITS THOSE WITH ASD: 

DMG BENEFITS THOSE WITH ASD ARI has recommended DMG for those with ASD since 1990. Areas where parents and teachers have noted improvement with DMG on those with ASD include: Better verbal communication Better eye contact Improved affection Better social interaction Reduction in seizures Improved quality of sleep

Dr. Kun’s Autism Study: 

Dr. Kun’s Autism Study Improved Verbal Communication, Cooperation, Eating and Bathroom Habits Conclusion: 80% of autistic children showed improvement. Reference: Rimland, B. Dimethylglycine, a nontoxic metabolite, and autism. Research Rev. Int. 4(#3), 1990.

Results of Controlled DMGStudy in Autism: 

Results of Controlled DMG Study in Autism Reduction in Irritability, Lethargy and Hyperactivity Better Verbal Communication Reduction of Stereotypical ASD Characteristics Reference: Jung, S., M.D. Taipei Springtide Foundation, Taipei, Taiwan, R.O.C.

Biochemical & Metabolic Role of DMG: 

Biochemical & Metabolic Role of DMG

WHAT IS DMG?: 

WHAT IS DMG? DMG is the dimethylated derivation of the simplest protein amino acid glycine. Structure of glycine N-CH2-C=O H OH Structure of N,N-Dimethylglycine (DMG) N-CH2-C=O H CH3 CH3 OH

Where is DMG found in the metabolic pathway?: 

Where is DMG found in the metabolic pathway? DMG is one of the key metabolic intermediates of the choline/one carbon cycle.

Choline/One Carbon Cycle: 

Choline/One Carbon Cycle One carbon cycle provides one and two carbon metabolites including methyl groups (-CH3) for methylation reactions and other substrates for metabolic pathways which can have impact on behavior and cognitive activity associated with Autism. N-CH2-C=O CH3 CH3 OH

Choline/One Carbon Cycle: 

Choline/One Carbon Cycle Choline TMG DMG Sarcosine Glycine Ethanolamine Serine Methyl Ethanolamine Dimethyl Ethanolamine Methyl Group Pool

Metabolic Role of DMG: 

Metabolic Role of DMG Supports Methylation Pathways Indirect Methyl Donor – Transmethylation Source of Two Carbon Species Chemical Messenger on Cell Receptor Sites Adaptogen / Antistress Provides Building Blocks for Biosynthesis of Many Bioactive Molecules including SAMe, Glutathione, and Creatine.

Slide20: 

Methyl Pool DMG (CH3)2N-CH2CO2H Sarcosine CH3NH-CH2CO2H Glycine NH2-CH2-CO2H Methionine SAMe Over 41 Transmethylation Reactions ** S-Adenosylhomocysteine Homocysteine Cysteine Glutathione ** Reactions including building and modifying choline, vitamins, hormones, antibodies, and neurotransmitters. Serine Adenosine ATP ATP *DonatesCH3 *Donates CH3 *Methyl (CH3) transfer Requires: Folic Acid, Vitamin B 12, FAD, and NAD+ Supplemental DMG Choline Adds CH3 TMG/Betaine

Slide21: 

DMG Glycine Methionine SAMe Glutathione Cysteine Serine Can form GSH, the primary antioxidant of the cell Can be used to form Phosphocreatine the primary energy source for muscles Acts as an inhibitory neurotransmitter Essential amino acid Can be used to make SAMe, the primary methylating agent in the body Helps convert homocysteine to cysteine, which can be used to make GSH The primary methylating agent in the body GSH is the body’s primary antioxidant Can be used to form GSH Sarcosine Breaks down into glycine Indirect methyl donor

DMG SUPPLEMENTATION BENEFITS: 

DMG SUPPLEMENTATION BENEFITS Methylation Pathway Immune System Neurological Pathways Detoxification

Methylation is Crucial for:: 

Methylation is Crucial for: Healthy SAMe/Homocysteine Levels Detoxification/Liver Function RNA, DNA Synthesis & Repair Neuronal Network Hormone/Vitamin Synthesis Phosphocreatine Production Neurotransmitter Production Immune Function Gene Expression Cell Membrane Fluidity, Permeability & Transmembrane Signaling

Impaired Methylation linked to ASD: 

Impaired Methylation linked to ASD Polymorphisms in methylation transfer reactions are higher in ASD Methylation intermediates are abnormal in ASD Toxic metals known to inhibit methylation Supplements that support methylation result in improvement in ASD James study on impaired methylation (2004) Methylation dysfunction can affect synchronized coordination of neuronal processes related to cognitive and learning ability

Slide25: 

Homocysteine Methionine S-Adenosylmethioine (SAM) Methyl Transfer Reactions DNA methylation for gene expression Lipid membrane methylation Choline TMG/Betaine DMG/One Carbon Cycle Methyl-THF B12 Betaine Homocysteine Methyl Transferase Methionine Synthase

Research on DMG: 

Research on DMG

The Immune System & DMG: 

The Immune System & DMG Medical University of South Carolina Improved Immunity in Rabbits Given Typhoid Vaccine Enhanced Lymphocyte Production in Humans Humoral and Cellular Immunity Potentiation in Humans Given Pneumovax Vaccine References: Graber, C.D., Goust, J.M. Glassman, A.D., and Kendall, R.V. Journal of Infectious Disease, 143:101, 1981. Kendall, R.V., and Graber, C.D. N,N-Dimethyglycine and Use In Immune Response, U.S. Patent #4,385,068, May 1983.

Lymphocyte (T-cell) increase before and after DMG: 

Lymphocyte (T-cell) increase before and after DMG 1-3 = Normal 4-6 = Sickle Cell Patients 7-9 = Diabetic Patients

Human PneumovaxImmunization Study: 

Human Pneumovax Immunization Study Conclusion: DMG fed group demonstrated a 4.5 fold increase in antibody production versus the controls Test and Control Average of Antibody Production

The Immune System & DMG: 

The Immune System & DMG Clemson University Improved Cellular Mediated and Humoral Immunity in Rabbits Increased Hybridoma Monoclonal Antibody Production Anti-Tumor Activity in B-16 Melanoma Study in Mice Anti-Inflammatory Activity in Rat Arthritic Study References: Reap, E.A. and Lawson, J.W. Stimulation of the Immune Response by Dimethylglycine. A Non-Toxic Metabolite. Journal of Laboratory and Clinical Medicine. 115:481, 1990.

Summary of DMG & the Immune Response: 

Summary of DMG & the Immune Response DMG has been shown to impact the Immune Response in the following areas: Enhances humoral and cellular mediated response of B-cells, T-cells & Macrophages Enhances antibody and lymphocyte production Modulates cytokine production Reference: Lawson, J. and Reap, E. J. Lab. And Clinical Med. 115:481 (1990).

Immune System Abnormalities in ASD: 

Immune System Abnormalities in ASD Cell-mediated immunity Abnormal T-cell subsets & activation Lower lymphocyte proliferative response Humoral immunity Auto-antibodies to neuronal antibodies IgA & IgG deficiency Abnormal cytokine profiles Th2 skewing Prevalence of allergic disorders

Slide34: 

Roach, S. and Carlin, L. “N,N-Dimethylglycine for epilepsy.” The New England Journal of Medicine, October 21, 1982: 307(17):1081-1082 Reduction of Seizure Activity with DMG

Reduction in Strychnine- Induced Seizures and Mortality in Mice Given Methylglycines: 

Reduction in Strychnine- Induced Seizures and Mortality in Mice Given Methylglycines Percent of Seizures Percent Deaths Conclusion: Methylated glycines effective whereas glycine was not.

TMG Versus DMG: 

TMG Versus DMG In Methylation Pathway Impairment

Dietary & Supplemental Sources of Methyl Groups: 

Dietary & Supplemental Sources of Methyl Groups Methionine, Choline Methyl B-12, 5-Methyl THF TMG, DMG, Sarcosine, Serine SAMe

Slide39: 

James, S., Cutler, P., Melayk, S., et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Amer. J. of Nut., 2004: 80:611. Results of Intervention With TMG, Folinic Acid & Methyl B-12

Slide40: 

Methyl Pool DMG (CH3)2N-CH2CO2H Sarcosine CH3NH-CH2CO2H Glycine NH2-CH2-CO2H Methionine SAMe Over 41 Transmethylation Reactions ** S-Adenosylhomocysteine Homocysteine Cysteine Glutathione ** Reactions including building and modifying choline, vitamins, hormones, antibodies, and neurotransmitters. Serine Adenosine ATP ATP *DonatesCH3 *Donates CH3 *Methyl (CH3) transfer Requires: Folic Acid, Vitamin B 12, FAD, and NAD+ Supplemental DMG Choline Adds CH3 TMG/Betaine

Both TMG & DMG Support: 

Both TMG & DMG Support Methylation Pathway Anti-Seizure Activity Enhanced Cognition/Behavior Reduces Hyperactivity with Folic Acid Enhanced Social Interaction/Eye Contact Improved Energy Supply Improved Sleep Quality

DMG versus TMG in Support of the Methylation Pathway: 

DMG versus TMG in Support of the Methylation Pathway DMG- May be best used for over methylators (High methionine levels, low homocysteine levels) TMG- May be best used for under methylators (High homocysteine and low methionine levels)

DMG versus TMG in Support of the Methylation Pathway: 

DMG versus TMG in Support of the Methylation Pathway From 14 to 20% of autistics get worse on TMG (hard/direct methylation) supplementation and those individuals may do better with DMG (soft/indirect methylation) 7% of DMG users get worse. This may indicate a folic acid deficiency or may do better on TMG. TMG and DMG are both effective and the choice may come down to biochemical individuality or individual preference.

TMG & DMG: 

TMG & DMG DMG has been shown to enhance the immune response whereas TMG may not be as effective. TMG has been shown to boost Glutathione (Sulfation) pathway whereas a study with DMG has not been done.

Supplementation Options: 

Supplementation Options With DMG and other participants in the methylation pathway

Slide46: 

Trimethylglycine/Betaine Dimethylglycine

Suggested Supplementation to Support Methylation: 

Suggested Supplementation to Support Methylation Folinic Acid 1600-3200 mcg Methyl B-12 (sublingual) 2,000-4,000 mcg Magnesium 400-800 mg Zinc 15-30 mg B6/P-5-P (Pyridoxal-5-Phosphate) 50-100 mg TMG (Under Methylators) 500-1500 mg DMG (Over Methylators) 250-750 mg TMG/DMG 800/400 mg Phosphatidylcholine 100-500 mg Methionine 400-800 mg SAM-e 400-800 mg