Karl Goldkamp   ND,  L.Ac., Dipl. Oriental Medicine The Center For Natural Medicine Family Practice 81 Halls Road, Old Lym...
What is Methylation <ul><li>It is the process by which a single carbon atom (a methyl group) is transferred from a methyl ...
Why is Methylation important <ul><li>The most important example is the epigenetic regulation of gene expression by DNA met...
Why is methylation important con’t <ul><ul><li>Since all cells contain the same DNA, then the differences between cell typ...
Why is methylation important con’t <ul><li>Development of tissues begins with the undifferentiated cells –stem cells </li>...
Why is methylation important con’t <ul><li>Abnormal methylation </li></ul><ul><ul><li>Then changes the development of the ...
Homocysteine & Methylation <ul><li>It was through the gradual acceptance of the  </li></ul><ul><li>Homocysteine theory of ...
Homocysteine Theory  of Arteriosclerosis <ul><li>Attributes one of the underlying causes of vascular disease to elevation ...
The Homocysteine story <ul><li>Homocysteine in the body derives from  methionine ,  </li></ul><ul><ul><li>an essential ami...
The Homocysteine story <ul><li>If there are adequate levels of vitamins B6, B12 and folic acid in the body, the homocystei...
The road to discovery <ul><li>Dietary deficiency of vitamin B-6 and folic acid and absorptive deficiency of vitamin B-12, ...
The road to discovery <ul><li>The homocysteine theory  took nearly 30 years  to be accepted in the U.S. medical community ...
The Road to Discovery <ul><li>At the time the proposal of the Homocysteine theory was in contrast to accepted theory of th...
Kilmer McCully get his due 1997 2000
The road to discovery <ul><li>Dr. McCully was the first to identify the connection between elevated homocysteine and vascu...
Other cases  <ul><li>In 1953 the amino acid methionine  inhibited  experimentally induced atherogenisis and eleveated chol...
Other cases con’t <ul><li>In 1962 children with  </li></ul><ul><ul><li>Mental retardation, dislocated ocular lens, acceler...
Other cases con’t <ul><li>1968, two month old boy with growth failure and pneumonia </li></ul><ul><li>Had  homocysteine , ...
Other cases con’t <ul><li>1976, a child with homocysteinuria, and atheriosclerotic plaques throughout the body was determi...
Putting the associations together   <ul><li>The previous cases suggested that somehow the three enzymes  </li></ul><ul><li...
This diagram represents both the folate cycle and the methylation cycle (aka the SAM or Methionine cycle).
Steps in the Methylation cycle <ul><li>Methionine is converted to SAMe  </li></ul><ul><ul><li>In the presents of magnesium...
Steps in the methylation cycle <ul><li>Methionine is converted to SAMe  (S-adenosylmethionine ) </li></ul><ul><ul><li>In t...
Steps in the Methylation cycle <ul><li>S-adenosylhomocysteine  is then metabolized to homocysteine by SAHH </li></ul><ul><...
Steps in the Methylation cycle <ul><li>Homocysteine is removed as an intermediate in three ways </li></ul><ul><li>A reveri...
Steps in the Methylation cycle <ul><li>Homocysteine is removed as an intermediate in three ways </li></ul><ul><li>A reveri...
The Methylation Cycle MTHFR Glutathione CBS MS MSR
The Betainehomocysteine-Methyltransferase (BHMT)  conversion of Homocysteine
A Function of Folate <ul><li>Folate is needed for the generation of SAM  </li></ul><ul><li>(s-adenosylmethionine) </li></u...
Dietary Folate & the Folate cycle <ul><li>The Folate cycle  (simply put)  : </li></ul><ul><li>Tetrahydrofolate (THF)  </li...
Dietary Folate & the Folate cycle <ul><li>Dietary folate is converted into Dihydrofolate ( DHF )  in the presence of B3.  ...
The Methylation Cycle MTHFR Glutathione CBS MS MSR
The Methylation cycle and the Folate cycle glutathione
Another way to view it MS / MSR MTHFR CBS Glutathione 5,10 methyleneTHF
Think of this as a coupling of different cycles Redox Rep 2003, 8(1): 57-63
Methylation  ->  Trans-sulfuration  –>  glutathionine synthesis Under conditions where homocysteine conversion to methioni...
During oxidative stress With oxydative stress the conversion of homocysteine to cysteine and  glutathione,is the dominant ...
Homocysteine regulation <ul><li>Homocysteine  is removed either  </li></ul><ul><li>1. by its irreversible conversion  </li...
Think of this as a coupling of different cycles Redox Rep 2003, 8(1): 57-63
Homocysteine regulation con’t <ul><li>There are two separate remethylation reactions:  </li></ul><ul><ul><li>1. Catalyzed ...
MTHFR ( methylenetratrahydrofolate reductase ) The  MTHFR  enzyme is an essential enzyme in the folate cycle.  It catalyze...
MTHFR con’t <ul><li>Methylenetetrahydrofolate exists in the cytoplasm of cells, except vascular tissue. </li></ul><ul><li>...
The Methylation cycle and the Folate cycle glutathione Sulfate
The polmorphisms <ul><li>A gene mutation is a permanent change in the DNA sequence that makes up a gene. </li></ul><ul><li...
Single nuclear polymorphism
SNPs of MTHFR <ul><li>There are approximately 24 known snps for this enzyme, however only two have primarily been studied ...
MTHFR C677T Polymorphism  and its role in disease <ul><li>A common SNP in  MTHFR  is at basepair 677 (a change from a  Cyt...
MTHFR C677T Polymorphism  and its role in disease <ul><li>It is interesting to note that 677TT individuals are at a decrea...
C677T MTHFR & Depression <ul><li>In a large population study from Norway increased plasma homocysteine was associated with...
MTHFR & depression <ul><li>Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to ...
Neural Tube Defect <ul><li>“ It is proven that folic acid supplied in the periconceptional period can lower the recurrence...
Where can we supplement
Testing 5 year old ASD (Austistic spectrum disorder) child Metametrix labs  www.metametrix.com
Oxidative Stress Indicators <ul><li>Lipid Peroxides  - Serum DNA/Oxidative Stress Marker  - Urine </li></ul><ul><li>Standa...
Intracellular testing  of antioxidant function <ul><li>Spectracell Total Antioxidant Function </li></ul><ul><li>isolated p...
Female 60 years old, Hx stroke,  meds lipitor with CoQ10, fish oil, vitamin D
 
 
Female 60 years old, hx stroke,  meds lipitor with CoQ10, fish oil, vitamin D
 
Female 56, Hx ulcerative colitis,  meds: sulfalazine, lipitor, Supplements: folate, fish oil, antioxidant drink, coQ10
 
 
See any patterns?
 
Female 68, recent dx of sarcoidosis
 
 
 
See any Patterns ?
 
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METHYLATION CYCLE AND IT\'S POLYMORPHISM

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  • I am grateful to the author for his willingness to share a presentation that is overall quite well done and very useful. Yes, the basic definition of methylation in slide two should be corrected - some misspellings, too (eg sles 22 and 23). But most of these slides are well worth reviewing for anyone lacking the mean-spirited MTHFR variant that causes overproduction of strong negative posts, which can epigenetically be moderated by supplementing thoughtfulness and humility.
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  • Is there any point in watching this at all? The second slide is wrong. A methyl group is NOT a single carbon atom. It is CH3 group on a larger molecule. If you get that wrong right off the bat what else is wrong?
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METHYLATION CYCLE AND IT\'S POLYMORPHISM

  1. 1. Karl Goldkamp ND, L.Ac., Dipl. Oriental Medicine The Center For Natural Medicine Family Practice 81 Halls Road, Old Lyme CT. The Methylation cycle and its common polymorphisms
  2. 2. What is Methylation <ul><li>It is the process by which a single carbon atom (a methyl group) is transferred from a methyl donor to another molecule. </li></ul>
  3. 3. Why is Methylation important <ul><li>The most important example is the epigenetic regulation of gene expression by DNA methylation. </li></ul><ul><ul><li>When DNA is methylated, it is incapable of being expressed, in other words it is turned off. </li></ul></ul>
  4. 4. Why is methylation important con’t <ul><ul><li>Since all cells contain the same DNA, then the differences between cell types </li></ul></ul><ul><ul><ul><li>(heart muscle vs brain neurons vs liver cells) </li></ul></ul></ul><ul><ul><ul><li>are the specific pattern of DNA methylation for that tissue. </li></ul></ul></ul>
  5. 5. Why is methylation important con’t <ul><li>Development of tissues begins with the undifferentiated cells –stem cells </li></ul><ul><li>Which are guided in changes by sequential shifts in their DNA methylations until they become the ultimate specific tissue (heart, brain, liver etc). </li></ul>
  6. 6. Why is methylation important con’t <ul><li>Abnormal methylation </li></ul><ul><ul><li>Then changes the development of the various tissues. </li></ul></ul><ul><ul><ul><li>This is process is thought to contribute to neurodevelopment disorders such as Autism and ASD. </li></ul></ul></ul><ul><ul><ul><li>Abnormal methylation has been considered a causative factor in Rett & fragile-X syndromes. </li></ul></ul></ul>Deth, Richard. Molecular Aspects of Thmerosal-induced Autism
  7. 7. Homocysteine & Methylation <ul><li>It was through the gradual acceptance of the </li></ul><ul><li>Homocysteine theory of arteriolsclerosis </li></ul><ul><ul><li>that the components of the Methylation cycle were identified </li></ul></ul>
  8. 8. Homocysteine Theory of Arteriosclerosis <ul><li>Attributes one of the underlying causes of vascular disease to elevation of blood homocysteine concentrations as the result of dietary, genetic, metabolic, hormonal, or toxic factors. </li></ul><ul><li>Homocysteine is a key by-product of the methylation cycle. </li></ul>McCully, Kilmer. Homocysteine, vitamins, and vascular disease prevention, 2007
  9. 9. The Homocysteine story <ul><li>Homocysteine in the body derives from methionine , </li></ul><ul><ul><li>an essential amino acid present in large amounts in protein from animal sources like meat, eggs and milk (but not in soy) </li></ul></ul>The Fall and Rise Of Kilmer McCully New York times Magazine, 8-7-1997
  10. 10. The Homocysteine story <ul><li>If there are adequate levels of vitamins B6, B12 and folic acid in the body, the homocysteine is broken down into harmless waste products or protein building blocks. But if there's a deficiency of those vitamins, the homocysteine begins its ravages on the blood vessels. </li></ul>The Fall and Rise Of Kilmer McCully New York times Magazine, 8-7-1997
  11. 11. The road to discovery <ul><li>Dietary deficiency of vitamin B-6 and folic acid and absorptive deficiency of vitamin B-12, which result from traditional food processing or abnormal absorption of B vitamins, are important factors in causing elevations in blood homocysteine. </li></ul>McCully, Kilmer. Homocysteine, vitamins, and vascular disease prevention, 2007
  12. 12. The road to discovery <ul><li>The homocysteine theory took nearly 30 years to be accepted in the U.S. medical community </li></ul><ul><li>it has been one of the factors that resulted for the dramatic decline in cardiovascular mortality since the 50s </li></ul><ul><li>And having B6 and folic acid added to the food supply </li></ul><ul><li> </li></ul>
  13. 13. The Road to Discovery <ul><li>At the time the proposal of the Homocysteine theory was in contrast to accepted theory of the day in the medical community: the cholesterol theory of arteriosclerosis </li></ul><ul><li>Its’ chief proponent, Dr. Kilmer Mccully eventually lost his job at Harvard because of his alternative theory. </li></ul>
  14. 14. Kilmer McCully get his due 1997 2000
  15. 15. The road to discovery <ul><li>Dr. McCully was the first to identify the connection between elevated homocysteine and vascular disease </li></ul><ul><li>Published a paper in 1969 </li></ul><ul><ul><li>Vascular disease which had reached it’s peak in 1955 in the US </li></ul></ul><ul><ul><li>He made the connection between the case of homocystinuria (from 1933) to a cobalamin C disease (1968) </li></ul></ul>
  16. 16. Other cases <ul><li>In 1953 the amino acid methionine inhibited experimentally induced atherogenisis and eleveated cholesterol level monkeys </li></ul><ul><li>suggesting an association between the sulfur amino acid vascular disease. </li></ul>Stare FJ. Experimental atherosclerosis in cebus monkeys. J Exp Med 1953; 98:195-218
  17. 17. Other cases con’t <ul><li>In 1962 children with </li></ul><ul><ul><li>Mental retardation, dislocated ocular lens, accelerated growth, osteoporosis, and a tendency to thrombosis of arteries and veins and increased homocysteine in their urine </li></ul></ul><ul><ul><li>Had an deficiency of cystathione synthase (an enzyme that links the methylation cycle to the transulfuration cycle requiring B-6). </li></ul></ul>Carson, NAJ. Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Arch Dis Child 1962
  18. 18. Other cases con’t <ul><li>1968, two month old boy with growth failure and pneumonia </li></ul><ul><li>Had homocysteine , cystathionine , and methylmalonic acid in the urine and advance atherioclerosis. </li></ul><ul><li>Also a deficiency of Methionine synthase ( MTR ) </li></ul><ul><ul><li>An enzyme dependent on B12 and methylenetetrahydrofolate </li></ul></ul><ul><li>was later called cobalamin C disease </li></ul>McCully, Kilmer. Homocysteine, vitamins, and vascular disease prevention, 2007
  19. 19. Other cases con’t <ul><li>1976, a child with homocysteinuria, and atheriosclerotic plaques throughout the body was determined to have a deficiency of methylenetetrahydrofolate reductase </li></ul><ul><ul><li>MTHFR </li></ul></ul>
  20. 20. Putting the associations together <ul><li>The previous cases suggested that somehow the three enzymes </li></ul><ul><li>methionine synthase (MTR) </li></ul><ul><li>methylenetetrahydrofolate reductase (MTHFR) </li></ul><ul><li>and cystathione synthase (CBS) </li></ul><ul><li>And Methionine deficiency all had something to do with elevated Homocysteine </li></ul><ul><ul><li>…… .. What? </li></ul></ul>
  21. 21. This diagram represents both the folate cycle and the methylation cycle (aka the SAM or Methionine cycle).
  22. 22. Steps in the Methylation cycle <ul><li>Methionine is converted to SAMe </li></ul><ul><ul><li>In the presents of magnesium, ATP (universal energy donor) by the enzyme methionine- adenosyltransferase (MAT) </li></ul></ul><ul><li>SAMe is considered the universal methyl donor </li></ul><ul><ul><li>It is the primary source of methyl groups for most other biochemical reactions including methylation of DNA, RNA, protein, neurotransmitters, creatinine </li></ul></ul>
  23. 23. Steps in the methylation cycle <ul><li>Methionine is converted to SAMe (S-adenosylmethionine ) </li></ul><ul><ul><li>In the presents of magnesium, ATP (universal energy donor) by the enzyme methionine- adenosyltransferase (MAT) </li></ul></ul><ul><li>SAMe is considered the universal methyl donor </li></ul><ul><ul><li>It is the primary source of methyl groups for most other biochemical reactions including methylation of DNA, RNA, protein, neurotransmitters, creatinine </li></ul></ul><ul><li>Once same donates its methyl group it becomes SAH S-adenosylhomocysteine </li></ul>
  24. 24. Steps in the Methylation cycle <ul><li>S-adenosylhomocysteine is then metabolized to homocysteine by SAHH </li></ul><ul><ul><li>If you need to know is called </li></ul></ul><ul><ul><ul><li>S-adenosylhomocysteinehydrogenase. </li></ul></ul></ul>
  25. 25. Steps in the Methylation cycle <ul><li>Homocysteine is removed as an intermediate in three ways </li></ul><ul><li>A reverible reaction that converts homocysteine back to methionine (folate cycle dependent). </li></ul><ul><li>An irreversible reaction through the trans-sulfuration to crystathione and on to glutathione </li></ul><ul><li>Converted back to methione independent of the folate cyle via betaine (aka trimethylglycine) BHMT (betainehomocysteinemethyltransferase) </li></ul>
  26. 26. Steps in the Methylation cycle <ul><li>Homocysteine is removed as an intermediate in three ways </li></ul><ul><li>A reverible reaction that converts homocysteine back to methionine (folate cycle dependent). </li></ul><ul><li>An irreversible reaction through the trans-sulfuration to crystathione and on to glutathione </li></ul><ul><li>Converted back to methione independent of the folate cyle via betaine (aka trimethylglycine) BHMT (betainehomocysteinemethyltransferase) </li></ul>
  27. 27. The Methylation Cycle MTHFR Glutathione CBS MS MSR
  28. 28. The Betainehomocysteine-Methyltransferase (BHMT) conversion of Homocysteine
  29. 29. A Function of Folate <ul><li>Folate is needed for the generation of SAM </li></ul><ul><li>(s-adenosylmethionine) </li></ul><ul><li>A deficiency of SAM is associated with congenital abnormalities, cancers, cardiovascular disease, neural tube defect, and peripheral neuropathies. </li></ul>
  30. 30. Dietary Folate & the Folate cycle <ul><li>The Folate cycle (simply put) : </li></ul><ul><li>Tetrahydrofolate (THF) </li></ul><ul><li>is converted to </li></ul><ul><li>5,10 methyleneTHF </li></ul><ul><li>which in turn gets converted to (with the help of B2 ) </li></ul><ul><li>5-methyl THF (aka MTHF and “Folapro”) </li></ul><ul><li>is then converted back to THF. </li></ul>
  31. 31. Dietary Folate & the Folate cycle <ul><li>Dietary folate is converted into Dihydrofolate ( DHF ) in the presence of B3. </li></ul><ul><li>DHF is then converted to THF with the help of B3. </li></ul><ul><li>THF is converted to 5,10 MTHF with the help of B6 and serine. </li></ul><ul><ul><li>THF get a CH2- (methylene group) from serine to become 5-10 MTHF </li></ul></ul><ul><ul><li>Folinic acid ( 5-formyl THF ) is also converted to 5,10 MTHF simultaneously </li></ul></ul>
  32. 32. The Methylation Cycle MTHFR Glutathione CBS MS MSR
  33. 33. The Methylation cycle and the Folate cycle glutathione
  34. 34. Another way to view it MS / MSR MTHFR CBS Glutathione 5,10 methyleneTHF
  35. 35. Think of this as a coupling of different cycles Redox Rep 2003, 8(1): 57-63
  36. 36. Methylation -> Trans-sulfuration –> glutathionine synthesis Under conditions where homocysteine conversion to methionine is dominant then folate and B12 are critical micronutrients.
  37. 37. During oxidative stress With oxydative stress the conversion of homocysteine to cysteine and glutathione,is the dominant flow and B6 is the critical micronutrient. While the transmethylation of homocysteine to methionine is inhibited.
  38. 38. Homocysteine regulation <ul><li>Homocysteine is removed either </li></ul><ul><li>1. by its irreversible conversion </li></ul><ul><li>to cysteine </li></ul><ul><li>(trans-sulfuration) or </li></ul><ul><li>2. to methionine </li></ul><ul><li>( remethylation ). </li></ul>
  39. 39. Think of this as a coupling of different cycles Redox Rep 2003, 8(1): 57-63
  40. 40. Homocysteine regulation con’t <ul><li>There are two separate remethylation reactions: </li></ul><ul><ul><li>1. Catalyzed by betaine (aka tri-methylglycine): homocysteine methyltransferase and </li></ul></ul><ul><ul><li>2. methionine synthase, respectively. </li></ul></ul><ul><li>The reactions that remove homocysteine are very sensitive to B vitamin </li></ul><ul><ul><li>Trans-sulfuration enzymes require pyridoxal phosphate (B6), </li></ul></ul><ul><ul><li>methionine synthase contains cobalamin (B12) and receives its methyl group from folic acid. </li></ul></ul>
  41. 41. MTHFR ( methylenetratrahydrofolate reductase ) The MTHFR enzyme is an essential enzyme in the folate cycle. It catalyzes 5,10-methylenetetrahydrofolate  5-methyltetrahydrofolate . The later serves as a methyl donor for the remethylation of homocysteine to methionine through B12 to methyl-B12. MTHFR is the most common SNP in the pathway .
  42. 42. MTHFR con’t <ul><li>Methylenetetrahydrofolate exists in the cytoplasm of cells, except vascular tissue. </li></ul><ul><li>It directs folate species either to DNA synthesis or to homocysteine remethylation to methionine. </li></ul><ul><li>MTHFR irreversibly reduces 5,10-methylenetetrahydrofolate (substrate) to 5-methyltetrahydrofolate. </li></ul><ul><li>5-Methyltetrahydrofolate is used to convert homocysteine (potentially toxic amino acid) to methionine by the enzyme methionine synthase. </li></ul>
  43. 43. The Methylation cycle and the Folate cycle glutathione Sulfate
  44. 44. The polmorphisms <ul><li>A gene mutation is a permanent change in the DNA sequence that makes up a gene. </li></ul><ul><li>Mutations range in size from a single DNA base to a large segment of a chromosome. </li></ul><ul><li>A Single Nucleotide polymorphism is a small genetic change, or variation. </li></ul><ul><ul><li>The genetic code is specified by four nucleotide “letters” A (adenine), C (cytosine), T (thymine), G (guanine). </li></ul></ul><ul><ul><li>SNP occurs when a single variation occurs when a single nucleotide is replaced by another one, eg C -> T or A -> G. </li></ul></ul><ul><li>It is a difference in the DNA sequence from that of the most common type in the population (the wild type). </li></ul>
  45. 45. Single nuclear polymorphism
  46. 46. SNPs of MTHFR <ul><li>There are approximately 24 known snps for this enzyme, however only two have primarily been studied </li></ul><ul><li>C677T (the most studied) and </li></ul><ul><li>A1298G </li></ul>
  47. 47. MTHFR C677T Polymorphism and its role in disease <ul><li>A common SNP in MTHFR is at basepair 677 (a change from a Cytosine to Thymine , C  T) that results in a enzyme with decreased enzymatic activity. </li></ul><ul><li>10% of North American population are homozygous for this polymorphism, estimated reduction in function is approx. 70% less then the wild type MTHFR. </li></ul><ul><li>Individuals of 677TT are predisposed to mild hyperhomocysteinemia because they have less – or slower functioning MTHFR -available to produce 5-methyltetrahydrofolate (which is used to decrease homocysteine). </li></ul><ul><li>Low dietary intake of the folic acid can also cause mild hyperhomocysteinemia. This polymorphism and mild hyperhomocysteinemia are associated with neural tube defects in offspring, arterial and venous thrombosis, and cardiovascular disease. </li></ul>Schwahn B, Rozen R (2002). &quot;Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences.&quot;. American journal of pharmacogenomics : genomics-related research in drug development and clinical practice
  48. 48. MTHFR C677T Polymorphism and its role in disease <ul><li>It is interesting to note that 677TT individuals are at a decreased risk for certain leukemias and colon cancer, but only when their dietary intake of folate is high. </li></ul><ul><li>The MTHFR gene could be one of the factors of overall schizophrenia risk. Schizophrenic patients having the risk allele (TT) show more deficiencies in executive function tasks. </li></ul>Schwahn B, Rozen R (2002). &quot;Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences.&quot;. American journal of pharmacogenomics : genomics-related research in drug development and clinical practice
  49. 49. C677T MTHFR & Depression <ul><li>In a large population study from Norway increased plasma homocysteine was associated with increased risk of depression but not anxiety. </li></ul><ul><li>There is now substantial evidence of a common decrease in serum/red blood cell folate, serum vitamin B12 and an increase in plasma homocysteine in depression. </li></ul>Coppen, A. J Psychopharmacol. 2005 Jan;19(1):59-65. Treatment of depression: time to consider folic acid and vitamin B12.
  50. 50. MTHFR & depression <ul><li>Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to be overrepresented among depressive patients… </li></ul><ul><li>On the basis of current data, we suggest that oral doses of both folic acid (800 microg daily) and vitamin B12 (1 mg daily) should be tried to improve treatment outcome in depression. </li></ul><ul><li>Coppen, A. J Psychopharmacol. 2005 Jan;19(1):59-65. Treatment of depression: time to consider folic acid and vitamin B12. </li></ul>
  51. 51. Neural Tube Defect <ul><li>“ It is proven that folic acid supplied in the periconceptional period can lower the recurrence and occurrence rate of neural tube defects (NTDs). </li></ul><ul><li>Preventable NTDs are partly based on hyperhomocystinemia and a genetic predisposition mutation of the methylenetetrahydrofolate-reductase gene (MTHFR) ……. </li></ul><ul><li>The bottom line: </li></ul><ul><li>This genetic metabolic defect can be overcome by treatment with folic acid and/or vitamin B12. </li></ul>Folates and the fetus, European Journal of Obstetrics & Gynecology and Reproductive Biology ,  Volume 71, Issue 2 ,  February 1997 , Pages 105-111
  52. 52. Where can we supplement
  53. 53. Testing 5 year old ASD (Austistic spectrum disorder) child Metametrix labs www.metametrix.com
  54. 54. Oxidative Stress Indicators <ul><li>Lipid Peroxides - Serum DNA/Oxidative Stress Marker - Urine </li></ul><ul><li>Standard testing offered by a number of labs </li></ul>
  55. 55. Intracellular testing of antioxidant function <ul><li>Spectracell Total Antioxidant Function </li></ul><ul><li>isolated peripheral blood mononuclear cells (lymphocytes, WBCs) that are </li></ul><ul><li>stimulated to grow in a chemically-defined, serum and protein-free media. </li></ul><ul><li>Cumene hydroperoxide is added to the media to provide an oxidative stress, </li></ul><ul><li>and after several days of incubation, lymphocyte growth is measured by </li></ul><ul><li>tritiated thymidine incorporation – this measures total cell proliforation </li></ul><ul><li>All factors that influence antioxidant status are taken into account since live, </li></ul><ul><li>metabolically active cells are used. </li></ul><ul><li>Since the function of antioxidants is to protect biomolecules from oxidative </li></ul><ul><li>damage, this test measures the net ability of antioxidants and repair </li></ul><ul><li>mechanisms of each individual's own cells, reporting a total assessment of </li></ul><ul><li>antioxidant function. </li></ul>http://www.spectracell.com
  56. 56. Female 60 years old, Hx stroke, meds lipitor with CoQ10, fish oil, vitamin D
  57. 59. Female 60 years old, hx stroke, meds lipitor with CoQ10, fish oil, vitamin D
  58. 61. Female 56, Hx ulcerative colitis, meds: sulfalazine, lipitor, Supplements: folate, fish oil, antioxidant drink, coQ10
  59. 64. See any patterns?
  60. 66. Female 68, recent dx of sarcoidosis
  61. 70. See any Patterns ?
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