Metabolic Function and Role of Dimethylglycine DMG in Reversing Autism

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

• Roger V. Kendall, Ph.D.
• NAA Conference
• Myrtle Beach, SC
• November 2005

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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

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What is Autism?

• A complex multifactorial neurological
  developmental disorder along the spectrum (ASD).

Aspergers Syndrome
ADHD
PDD
Tourettes
Autism

• Each child with autism has a unique set of
  biological abnormalities that require a unique
  set of biomedical interventions.

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Possible Causes of Autism

• Metabolic Dysfunction/Imbalances
• Immune Dysfunction/Infection
• Oxidative Stress
• Environmental Factors/Toxins
• Genetic Predisposition
• Vaccinations

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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

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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.

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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.

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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.

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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

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Dr. Kuns 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.
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Results of Controlled DMGStudy 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.
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Biochemical Metabolic Role of DMG
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WHAT IS DMG?

• DMG is the dimethylated derivation of the
  simplest protein amino acid glycine.

Structure of glycine
Structure of N,N-Dimethylglycine (DMG)
N-CH2-CO
H
N-CH2-CO
CH3
OH
H
CH3
OH
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Where is DMG found in the metabolic pathway?

• DMG is one of the key metabolic intermediates of
  the choline/one carbon cycle.

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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-CO
CH3
CH3
OH
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Choline/One Carbon Cycle
Choline
TMG
Dimethyl Ethanolamine
Methyl Group Pool
DMG
Methyl Ethanolamine
Sarcosine
Glycine
Ethanolamine
Serine
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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.

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Methionine
ATP
Supplemental DMG
Choline
TMG/Betaine
Methyl Pool
SAMe
Reactions including building and modifying
choline, vitamins, hormones, antibodies, and
neurotransmitters.
Over 41 Transmethylation Reactions
DMG (CH3)2N-CH2CO2H
DonatesCH3
S-Adenosylhomocysteine
Sarcosine CH3NH-CH2CO2H
Donates CH3
Adds CH3
Adenosine
ATP
Homocysteine
Glycine NH2-CH2-CO2H
Serine
Cysteine
Methyl (CH3) transfer Requires Folic Acid,
Vitamin B 12, FAD, and NAD
Glutathione
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Can form GSH, the primary antioxidant of the cell
Can be used to form Phosphocreatine the primary
energy source for muscles
Glycine
Acts as an inhibitory neurotransmitter
Methionine
Essential amino acid
Can be used to make SAMe, the primary methylating
agent in the body
Serine
Helps convert homocysteine to cysteine, which can
be used to make GSH
DMG
SAMe
The primary methylating agent in the body
GSH is the bodys primary antioxidant
Glutathione
Cysteine
Can be used to form GSH
Indirect methyl donor
Sarcosine
Breaks down into glycine
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DMG SUPPLEMENTATION BENEFITS

• Methylation Pathway
• Immune System
• Neurological Pathways
• Detoxification

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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

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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

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DMG/One Carbon Cycle
Homocysteine
Choline
TMG/Betaine
Methyl-THF
B12
Methionine Synthase
Betaine Homocysteine Methyl Transferase
Methionine
S-Adenosylmethioine (SAM)
Methyl Transfer Reactions DNA methylation for
gene expression Lipid membrane methylation
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Research on DMG
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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,
  143101, 1981.
• Kendall, R.V., and Graber, C.D.
  N,N-Dimethyglycine and Use In Immune Response,
  U.S. Patent 4,385,068, May 1983.

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Lymphocyte (T-cell) increase before and after DMG
1-3 Normal 4-6 Sickle Cell Patients 7-9
Diabetic Patients
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Human PneumovaxImmunization Study
Test and Control Average of Antibody Production
Conclusion DMG fed group demonstrated a 4.5
fold increase in antibody production versus the
controls
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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. 115481, 1990.

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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. 115481 (1990).
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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

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Reduction of Seizure Activity with DMG
Roach, S. and Carlin, L. N,N-Dimethylglycine for
epilepsy. The New England Journal of Medicine,
October 21, 1982 307(17)1081-1082
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Reduction in Strychnine- Induced Seizures and
Mortality in Mice Given Methylglycines
Percent of Seizures
Percent Deaths
Conclusion Methylated glycines effective
whereas glycine was not.
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TMG Versus DMG

• In
• Methylation Pathway Impairment

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Dietary Supplemental Sources of Methyl Groups

• Methionine, Choline
• Methyl B-12, 5-Methyl THF
• TMG, DMG, Sarcosine, Serine
• SAMe

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Results of Intervention
With TMG, Folinic Acid Methyl B-12
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
80611.
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Methionine
ATP
Supplemental DMG
Choline
TMG/Betaine
Methyl Pool
SAMe
Reactions including building and modifying
choline, vitamins, hormones, antibodies, and
neurotransmitters.
Over 41 Transmethylation Reactions
DMG (CH3)2N-CH2CO2H
DonatesCH3
S-Adenosylhomocysteine
Sarcosine CH3NH-CH2CO2H
Donates CH3
Adds CH3
Adenosine
ATP
Homocysteine
Glycine NH2-CH2-CO2H
Serine
Cysteine
Methyl (CH3) transfer Requires Folic Acid,
Vitamin B 12, FAD, and NAD
Glutathione
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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

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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)

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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.

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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.

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Supplementation Options

• With DMG and other participants in the
  methylation pathway

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Trimethylglycine/Betaine
Dimethylglycine
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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

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