Metabolic Function and Role of Dimethylglycine DMG in Reversing Autism

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

2. 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

3. What is Autism? A complex multifactorial neurological developmental disorder along the spectrum (ASD).

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

5. 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

6. 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.

7. 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.

8. 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.

10. 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

11. Dr. Kun�s Autism Study

13. Results of Controlled DMGStudy in Autism Reduction in Irritability, Lethargy and Hyperactivity Better Verbal Communication Reduction of Stereotypical ASD Characteristics

14. Biochemical & Metabolic Role of DMG

15. WHAT IS DMG? DMG is the dimethylated derivation of the simplest protein amino acid glycine.

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

17. 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.

18. Choline/One Carbon Cycle

19. 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.

22. DMG SUPPLEMENTATION BENEFITS Methylation Pathway Immune System Neurological Pathways Detoxification

23. 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

24. 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

26. Research on DMG

27. 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.

28. Lymphocyte (T-cell) increase before and after DMG

29. Human PneumovaxImmunization Study

30. 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.

32. 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

33. 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

35. Reduction in Strychnine- Induced Seizures and Mortality in Mice Given Methylglycines

37. TMG Versus DMG In Methylation Pathway Impairment

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

41. 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

42. 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)

43. 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.

44. 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.

45. Supplementation Options With DMG and other participants in the methylation pathway

47. 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