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Bridging the biochemistry of Down syndrome to that seen in autism

Bridging the biochemistry of Down syndrome to that seen in autism. Implications for the understanding of autism in the general population. Laurette Janak Autism One May 2008 Email: laurette.janak@verizon.net. Overview. Description of Down syndrome

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Bridging the biochemistry of Down syndrome to that seen in autism

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  1. Bridging the biochemistry of Down syndrome to that seen in autism Implications for the understanding of autism in the general population. Laurette Janak Autism One May 2008 Email: laurette.janak@verizon.net

  2. Overview • Description of Down syndrome • Why discuss Down syndrome at an autism conference? • Might Down syndrome children be more sensitive to mercury? • Down syndrome and mitochondrial dysfunction. • Cancer and vaccines; is there a connection?

  3. Common knowledge about DS • Characteristic facial features • Learning challenges • Increased risk of leukemia • Advanced aging with early development of Alzheimer’s disease But what actually IS Down syndrome?

  4. Genetics of Down syndrome Extra chromosome 21

  5. Why shed light on DS at an autism conference? • A 1979 study was published showing the extremely rare condition of having both DS and autism. • J Autism Dev Disord. 1979 Mar;9(1):31-6 • Twenty years later in 1999, a new study found at least 7% of DS children had autism. • Dev med Child Neurol 1999 Mar;41(3):153-8 • By 2001 a study reported that autism in DS is “by no means rare”. • Dev Med Child Neurol 2001 Nov;43(11):750-4

  6. Why shed light on DS at an autism conference? Because the incidence of autism is so elevated in the DS population it is worth asking if there are any similarities between children with autism and DS. It is also interesting to ask what changed in the 20 years from a 1979 report of autism being rare in DS to the 1999 report of a 7% co morbidity.

  7. Comparing DS and Autism Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004 Dec;80(6):1611-7. “The current study was prompted by a serendipitous observation in a previous study that the metabolic profiles of dizygotic twins---one with Down syndrome and one with autism---were virtually identical with respect to methionine cycle and transulfuration metabolites.”

  8. Comparing DS and Autism Gloria’s twins Gloria’s twins Justin has autism Kyle has DS

  9. Comparing DS and Autism • Homocysteine metabolism in Children with Down Syndrome: In Vitro Modulation. • Am J. Hum Genet. 69:88-95, 2001 • Full text available at: • http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=11391481 • Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. • Am J. Clin Nutr 2004;80:1611-7 • Full text available at: • http://www.ajcn.org/cgi/reprint/80/6/1611

  10. Gene located on Chr 21 methionine L THF SAM L B12 MS SAH CH3-THF (Methyl THF) homocysteine L CBS “L” represents decreased levels in both DS and ASD children compared to controls. cystathionine cysteine GST SOD L H2O2 GSH GR GPx GSSG H2O

  11. Comparing DS and Autism Important notes Both the DS study and the ASD study looked at the biology of these two disorders. Both studies looked at biological interventions and were not designed to investigate improvement in DS or autism behaviors. Neither the DS or Autism study was designed to look at issues having to do with mercury. (more on the mercury issues shortly)

  12. Chicken or the Egg Oxidative stress Autism

  13. Chicken or the Egg Early oxidative stress in amniotic fluid of pregnancies with Down syndrome. Clin Biochem. 2007 Feb;40(3-4):177-80 Tested the hypothesis that oxidative stress occurs early in DS pregnancies. Measured Isoprostanes (IPs) in the amniotic fluid of DS pregnancies as a marker of free radical damage to lipids. A 9-fold increase in IPs was found in the amniotic fluid of pregnancies with DS fetuses.

  14. Chicken or the Egg Conclusion: “The study reveals that oxidative stress occurs early in pregnancy and supports the idea of testing whether prenatal antioxidant therapy may prevent or delay the onset of oxidative stress diseases in the DS population.” Early oxidative stress in amniotic fluid of pregnancies with Down syndrome Clin Biochem. 2007 Feb;40(3-4):177-80

  15. Chicken or the Egg • Might oxidative stress in pregnant woman contribute to the risk of autism in their offspring? • To investigate this possibility we will first look at DS moms then mothers of children with autism.

  16. Comparing DS and Autism • “A significant increase in plasma homocysteine concentrations and lymphocyte methotrexate cytotoxicity was observed in the mothers of children with Down syndrome, consistent with abnormal folate and methyl metabolism.” • Am J Clin Nutr. 1999 Oct;70(4):495-501. • Increased homocysteine is a risk factor for having a child with Down syndrome. • Full text available at: • http://www.ajcn.org/cgi/reprint/80/6/1611

  17. methionine THF SAM B12 MS SAH H CH3-THF (Methyl THF) homocysteine H “H” represents an increase in DS moms compared to controls. “?” = not measured. cystathionine cysteine GST ? SOD H2O2 GSH GR GPx ? GSSG H2O

  18. Comparing DS and Autism • Elevated homocysteine is a risk factor for neural tube defects. • Report of increase in NTD in DS families • Lancet. 2003 Apr 19;361(9366):1331-5. • This lends support to the idea that the mothers may have had elevated homocysteine (a marker of functional folate deficiency) prior to the conception of their DS baby.

  19. Comparing DS and Autism • Let’s compare the biochemistry of the moms of children with DS to that of the moms with autistic children. • 86 autism parents differ from 200 controls in the following: • Higher homocysteine • Higher SAH • Lower GSH (glutathione) • Increased GSSG (oxidized glutathione) • Unpublished data from the lab of Dr. Jill James

  20. methionine THF SAM B12 MS SAH H CH3-THF (Methyl THF) homocysteine H High and low values of ASD parents compared to controls. cystathionine cysteine GST L SOD H2O2 GSH GR GPx H GSSG H2O

  21. Comparing DS and Autism Personal correspondence with Dr. Jill James

  22. Comparing DS and Autism • Is there any indication the elevated homocysteine found in the moms of autistic children may have existed prior to her pregnancy? • Elevated homocysteine is associated with depression. • Family histories of depression in autism. • Am J Psychiatry 1999 Apr;156(4):557-63

  23. Comparing DS and Autism • Is there any evidence that alterations in homocysteine metabolism can increase the risk of having a child with autism? • The antiepileptic drug Valproate has been used to induce an animal model of autism. • What does valproate do and how does this compare to the chemistry seen in the moms?

  24. methionine THF SAM B12 MS H SAH CH3-THF (Methyl THF) homocysteine H Arrows indicate increases or decreases seen with valproate. Letters indicate increase or decrease in autism moms compared to control moms. cystathionine cysteine GST L SOD H2O2 GSH GR GPx H GSSG H2O

  25. Comparing DS and Autism • There are many similarities between autism and the anticonvulsant syndrome seen in children whose mothers took valproate during pregnancy. • Fetal valproate syndrome and autism: additional evidence of an association • Characteristics of fetal anticonvulsant syndrome associated autistic disorder. • A clinical study of 57 children with fetal anticonvulsant syndromes. • A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate. • Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism.

  26. Comparing DS and Autism • I hypothesize the abnormal homocysteine metabolism seen in the moms of autistic children was present during her pregnancy and may act in a similar manner as valproate exposure. • If so, I further suggest that this may have provided an in-utero environment of increased oxidative stress which might predispose toward autism when combined with additional postnatal oxidative stressors.

  27. Mitochondria in Moms • Maternal hyperhomosysteinemia in animal models: • Alters fetal brain development • Significantly reduced learning abilities in offspring • Caused increased lipid peroxidation in the brain of offspring (oxidative stress) • Increased brain DNA fragmentation in offspring • Folate deprivation promotes mitochondrial oxidative decay: DNA large deletions, cytochrome c oxidase dysfunction, membrane depolarization and superoxide overproduction in rat liver. • Br J Nutr. 2007 May;97(5):855-63.

  28. Mitochondria in Moms • J Biol Chem. 1998 Nov 13;273(46):30808-17. • Study done in-vitro with human cells • “In this study, we demonstrate that homocysteine alters mitochondrial gene expression, function, and structure and provide evidence that homocysteine and H2O2 act synergistically to enhance mitochondrial damage.” • Inracellular glutathione was able to protect mitochondria from homocysteine and H2O2 induced damage. • Were study doses of homocysteine relevant? • Mitochondrial dysfuntion is well documented with valproate exposure. • Elevated homocysteine • Low glutathione • Similar set up in moms of children with DS and/or ASD • Environmental exposures and infections can increase H2O2 production.

  29. Genetics While you cannot have a genetic epidemic, dietary deficiencies can unmask a genetic predisposition to injury from an environmental exposure. Environment Nutrition The percentage of energy from eating energy dense, nutrient poor foods was an independent positive predictor of serum homocysteine in adult Americans. Serum concentrations of vitamins A, E, C, and folate were inversely related to consumption of energy dense, nutrient poor foods. Am J Clin Nutr 2000;72:926-36

  30. Comparing DS and Autism Justin Kyle Autism, tethered cord, tongue tied and hypothyroidism Down syndrome and hypothyroidism Lauren Celiac and JRA

  31. Comparing DS and Autism • Twinning • Increased in both DS and ASD • Biochemistry • In DS and ASD children • Decreased Methionine, SAM, Hcy, GSH • Increased GSSG • In DS and ASD moms • Increased SAH and Hcy • Similar pattern seen in valproate exposure • Celiac • 1 in 14 DS individuals have celiac • Reports of increased celiac in ASD families • Does not appear to be supported by current studies

  32. Comparing DS and Autism • Autoimmune disorders • In DS - increased occurrence of autoimmune disorders with target organs including pancreas, thyroid, joints, adrenal gland, gastric mucosa and brain. • In autism there is a familial presence of autoimmune diseases including pancreas, thyroid, joints, brain. • Zinc status • Reports of low zinc status in both DS and ASD • Thyroid disorders • High occurrence of antibodies to thyroid gland in DS • Familial autoimmune thyroid disease is a risk factor for ASD regression • J Autism Dev Disorder 2006 Apr;36(3):317-24

  33. Comparing DS and Autism • Altered immune system • DS • Immune suppression • Decreased NK cell activity • Disruptions in CD4, CD8, and CD26 • Decreased IL-2 • T and B cell derangement • Autism • Immune system skewed toward Th2 • Decreased NK cell activity • Abnormal CD4/CD8 ratios

  34. Comparing DS and Autism • Response to MethylB12 • DS - in vitro study shows a positive metabolic response to MeB12 • Autism - shows positive metabolic response to MeB12 • MeB12 has been shown to: • Be useful in RA • Increase NK cell activity • Positively alter the CD4/CD8 ratio • Increase methionine synthase activity

  35. DS and environmental exposures • My discussion on mercury can be extended to the many environmental exposures our high tech society has brought into our life. • This should not be construed into thinking I believe mercury is the sole cause of autism; as I do NOT believe that to be true. • I further believe that other components in vaccines (especially viruses) may be problematic for children with DS. • Additional material is included for your consideration after my closing slide.

  36. IOM 2004 With respect to the hypothesis that there may be a subgroup of children who are genetically more sensitive to the toxic effects of thimerosal (a mercury preservative found in vaccines), the IOM had this to say: “This hypothesis cannot be excluded by epidemiological data from large population groups that do not show an association between a vaccine and an adverse outcome. Depending upon the frequency of the genetic defect, a rare event caused by genetic susceptibility could be missed even in large study samples.”

  37. Glutathione Utilization Over expressed in Down syndrome cysteine GST Detoxification of drugs and chemicals L SOD H2O2 GSH GR GPx H2O GSSG Up-regulated by metal exposure GST: glutathione transferase SOD: superoxide dismutase H2O2: hydrogen peroxide GSH: glutathione GSSG: oxidized glutathione GR: glutathione reductase GPx: glutathione peroxidase

  38. DS and Mercury • Studies showing the overexpression of SOD and increased oxidative stress in Down syndrome are plentiful and predated the IOM 2004 investigation. • The fact that heavy metals (including mercury) increase oxidative stress and upregulate SOD was known prior to the IOM 2004 investigation.

  39. DS and Mercury • Studies showing decreased levels of GSH in DS predated the IOM 2004 investigation. • J Pediatr. 2003 May;142(5):583-5. • Am J Hum Genet. 2001 Jul;69(1):88-95. • It is a well established fact that mercury and other metals deplete GSH in a dose dependent manner. This fact has been shown in many studies that predated the IOM 2004 investigation. • Immunopharmacol Immunotoxicol. 1993 Mar-Jun;15(2-3):273-90.

  40. DS and Mercury • An animal model of DS which showed decreased GSH in hippocampal neurons stated: • “Additional lowering of GSH levels led to enhanced cell death…..Based on these results we suggest that a GSH level which is decreased under a specific threshold by increased consumption, reduced synthesis or lack in precursor contributes to cell loss and neurodegneration in Down syndrome.” • Brain Res 1997 Aug 15;765(2):313-8

  41. DS and Mercury • Animal models and human studies have found cholinergic dysfunction in DS. • Eur J Neurosci. 2000 Sep;12(9):3259-64. • Brain Res. 1994 Sep 26;658(1-2):27-32. • Neurosci Lett. 1997 Feb 7;222(3):183-6. • It has been shown that exposure to mercury can induce cholinergic dysfunction. • J toxicol Sci 1979 Nov;4(4):351-62 • Res Commun Chem Pathol Pharm 1980 Nov;30(2):381-4 • Brain Res Dev Brain Res 1995 Mar 16;85(1):96-109

  42. Mitochondria in DS • It is extremely well documented that Down syndrome individuals have mitochondrial dysfunction. • The nature of this dysfunction is multifactorial & includes: • Impaired mitochondrial enzyme activities • Cytochrome oxidase (complex IV) • Isocitrate dehydrogenase (Krebs cycle enzyme) • Decreased protein levels of complex I • Decreased gene expression of ATPase6 (effects functioning of complex V)

  43. Mitochondria in DS • Accumulation of toxic free radicals • Begins in-utero (Clin Biochem. 2007 Feb;40(3-4):177-80) • Studies on fetal DS brain and in fetal DS amniocytes demonstrate mitochondrial dysfunction occurs prior to birth. • J Neural Transm Suppl. 2001;(61):109-16. • Mol Cells. 2003 Apr 30;15(2):181-5. • DS mitochondria have a lower mitochondrial membrane potential which, is “underlying the presence of an increasing susceptibility of these organelles to damaging agents”. • FEBS Lett. 2007 Feb 6;581(3):521-5. Epub 2007 Jan 17.

  44. Mitochondria in ASD • Nov. 9, 2007 the US. government conceded a vaccine-autism case in the Court of Federal Claims. • Claim: vaccinations aggravated an underlying mitochondrial disorder resulting in features of ASD. • Media Spin: this was an unusual case and mitochondrial disorders are rare.

  45. Mitochondria in ASD • As early as 1998, mitochondrial dysfunction was hypothesized to be related to autism. • Autism: a mitochondrial disorder? Med Hypotheses. 1998 Jun;50(6):497-500 • Since that time, a number of other studies have noted this association in a subset of children with autism. • J Child Neurol. 2002 Jun;17(6):435-9. • Ann Neurol. 2003 Jun;53(6):801-4. • J Child Neurol. 2004 May;19(5):379-81. • J Autism Dev Disord. 2004 Dec;34(6):615-23. • Dev Med Child Neurol. 2005 Mar;47(3):185-9. • J Autism Dev Disord. 2006 Nov;36(8):1137-40. • J Child Neurol. 2007 Sep;22(9):1121-3. • Dev Med Child Neurol. 2007 Oct;49(10):726-33.

  46. Mitochondria in ASD • “data suggest that further metabolic evaluation is indicated in autistic patients and that defects of oxidative phosphorylation might be prevalent.” • Developmental regression and mitochondrial dysfunction in a child with autism. • J Child Neurol. 2006 Feb;21(2):170-2. • Poling JS, Frye RE, Shoffner J, Zimmerman AW. • It is estimated that up to 20% of children with autism may have mitochondrial disease. http://osdir.com/ml/culture.autism/2005-07/msg00093.html

  47. Mitochondria in DS/ASD • What about DS children who are all known to have mitochondrial dysfunction that exists even before birth? • Are vaccines also aggravating the underlying mitochondrial dysfunction in DS children? • Might this explain the vastly higher incidence of autism among DS children?

  48. Mitochondria in DS/ASD • Recall from an earlier slide: • DS mitochondria have a lower mitochondrial membrane potential which, is “underlying the presence of an increasing susceptibility of these organelles to damaging agents”. • FEBS Lett. 2007 Feb 6;581(3):521-5. • Can thimerosal be one of the “damaging agents” described above?

  49. Mitochondria, mercury and homocysteine • Mercury induces SOD and increases H2O2. • The presence of homocysteine and H2O2 combined has been shown to cause mitochondrial damage. • Are study doses relevant to in-vivo findings? • J Biol Chem. 1998 Nov 13;273(46):30808-17. • Who might have elevated homocysteine? • Persons who use valproate • Mothers of Down syndrome children • Mothers of autistic children • Persons with depression • Persons with cardiovascular disease, etc. etc….

  50. Mitochondria, mercury and homocysteine • Has thimerosal (the mercury component found in flu vaccines) been tested for its ability to cause mitochondrial damage? • Thimerosal induces neuronal cell apoptosis by causing cytochrome c and apoptosis-inducing factor release from mitochondria. • Int J Mol Med. 2005 Dec;16(6):971-7. • Have thimerosal studies looked at vulnerable subsets such as Down syndrome children or persons with elevated homocysteine?

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