Biological Trace Element Research

, Volume 144, Issue 1–3, pp 475–486

Altered Heavy Metals and Transketolase Found in Autistic Spectrum Disorder

  • Mark E. Obrenovich
  • Raymond J. Shamberger
  • Derrick Lonsdale
Article

Abstract

Autism and autism spectrum disorder (ASD) are developmental brain disorders with complex, obscure, and multifactorial etiology. Our recent clinical survey of patient records from ASD children under the age of 6 years and their age-matched controls revealed evidence of abnormal markers of thiol metabolism, as well as a significant alteration in deposition of several heavy metal species, particularly arsenic, mercury, copper, and iron in hair samples between the groups. Altered thiol metabolism from heavy metal toxicity may be responsible for the biochemical alterations in transketolase, and are mechanisms for oxidative stress production, dysautonomia, and abnormal thiamine homeostasis. It is unknown why the particular metals accumulate, but we suspect that children with ASD may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations. Accumulation or altered mercury clearance, as well as concomitant oxidative stress, arising from redox-active metal and arsenic toxicity, offers an intriguing component or possible mechanism for oxidative stress-mediated neurodegeneration in ASD patients. Taken together, these factors may be more important to the etiology of this symptomatically diverse disease spectrum and may offer insights into new treatment approaches and avenues of exploration for this devastating and growing disease.

Keywords

Transketolase Hair Heavy metal Copper Iron Mercury Arsenic Divalent cation Transport Autistic spectrum disorder Mitochondria Oxidative stress 

References

  1. 1.
    Aliev G, Liu J, Shenk JC, Fischbach K, Pacheco GJ, Chen SG, Obrenovich ME, Ward WF, Richardson AG, Smith MA, Gasimov E, Perry G, Ames BN (2009) Neuronal mitochondrial amelioration by feeding acetyl-L-carnitine and lipoic acid to aged rats. J Cell Mol Med 13(2):320–333PubMedCrossRefGoogle Scholar
  2. 2.
    Aliev G, Obrenovich ME, Reddy VP, Shenk JC, Moreira PI, Nunomura A, Zhu X, Smith MA, Perry G (2008) Antioxidant therapy in Alzheimer's disease: theory and practice. Mini Rev Med Chem 8(13):1395–1406PubMedCrossRefGoogle Scholar
  3. 3.
    Aliev G, Obrenovich ME, Smith MA, Perry G (2003) Hypoperfusion, mitochondria failure, oxidative stress, and Alzheimer disease. J Biomed Biotechnol 2003(3):162–163PubMedCrossRefGoogle Scholar
  4. 4.
    Aliev G, Smith MA, Obrenovich ME, de la Torre JC, Perry G (2003) Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Azheimer disease. Neurotox Res 5(7):491–504PubMedCrossRefGoogle Scholar
  5. 5.
    Bettendorff L, Wins P (1994) Mechanism of thiamine transport in neuroblastoma cells. Inhibition of a high affinity carrier by sodium channel activators and dependence of thiamine uptake on membrane potential and intracellular ATP. J Biol Chem 269(20):14379–14385PubMedGoogle Scholar
  6. 6.
    Brin M (1962) Effects of thiamine deficiency and of oxythiamine on rat tissue transketolase. J Nutr 78:179–183PubMedGoogle Scholar
  7. 7.
    Di Noia MA, Van Driesche S, Palmieri F, Yang LM, Quan S, Goodman AI, Abraham NG (2006) Heme oxygenase-1 enhances renal mitochondrial transport carriers and cytochrome C oxidase activity in experimental diabetes. J Biol Chem 281(23):15687–15693PubMedCrossRefGoogle Scholar
  8. 8.
    Fido A, Al-Saad S (2005) Toxic trace elements in the hair of children with autism. Autism 9(3):290–298PubMedCrossRefGoogle Scholar
  9. 9.
    Geier DA, Kern JK, Garver CR, Adams JB, Audhya T, Geier MR (2008) A prospective study of transsulfuration biomarkers in autistic disorders. Neurochem Res 34(2):386–393PubMedCrossRefGoogle Scholar
  10. 10.
    Gibson GE, Zhang H (2002) Interactions of oxidative stress with thiamine homeostasis promote neurodegeneration. Neurochem Int 40(6):493–504PubMedCrossRefGoogle Scholar
  11. 11.
    Gorgoglione V, Laraspata D, La Piana G, Marzulli D, Lofrumento NE (2007) Protective effect of magnesium and potassium ions on the permeability of the external mitochondrial membrane. Arch Biochem Biophys 461(1):13–23PubMedCrossRefGoogle Scholar
  12. 12.
    Hanson DR, Gottesman II (1976) The genetics, if any, of infantile autism and childhood schizophrenia. J Autism Child Schizophr 6(3):209–234PubMedCrossRefGoogle Scholar
  13. 13.
    Holmes AS, Blaxill MF, Haley BE (2003) Reduced levels of mercury in first baby haircuts of autistic children. Int J Toxicol 22(4):277–285PubMedCrossRefGoogle Scholar
  14. 14.
    James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA (2004) Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 80(6):1611–1617PubMedGoogle Scholar
  15. 15.
    Jeyasingham MD, Pratt OE, Shaw GK, Thomson AD (1987) Changes in the activation of red blood cell transketolase of alcoholic patients during treatment. Alcohol Alcohol 22(4):359–365PubMedGoogle Scholar
  16. 16.
    Karuppagounder SS, Xu H, Shi Q, Chen LH, Pedrini S, Pechman D, Baker H, Beal MF, Gandy SE, Gibson GE (2008) Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model. Neurobiol Aging 30(10):1587–1600PubMedCrossRefGoogle Scholar
  17. 17.
    Ke ZJ, DeGiorgio LA, Volpe BT, Gibson GE (2003) Reversal of thiamine deficiency-induced neurodegeneration. J Neuropathol Exp Neurol 62(2):195–207PubMedGoogle Scholar
  18. 18.
    Kern JK, Grannemann BD, Trivedi MH, Adams JB (2007) Sulfhydryl-reactive metals in autism. J Toxicol Environ Health A 70(8):715–721PubMedCrossRefGoogle Scholar
  19. 19.
    Kim JS, Hamilton DL, Blakley BR, Rousseaux CG (1991) The effects of thiamin on lead metabolism: whole body retention of lead-203. Toxicol Lett 56(1–2):43–52PubMedGoogle Scholar
  20. 20.
    Kolevzon A, Gross R, Reichenberg A (2007) Prenatal and perinatal risk factors for autism: a review and integration of findings. Arch Pediatr Adolesc Med 161(4):326–333PubMedCrossRefGoogle Scholar
  21. 21.
    Lombard J (1998) Autism: a mitochondrial disorder? Med Hypotheses 50(6):497–500PubMedCrossRefGoogle Scholar
  22. 22.
    Lonsdale D (2007) Dysautonomia, a heuristic approach to a revised model for etiology of disease. Evid Based Complement Alternat Med 6(1):3–10PubMedCrossRefGoogle Scholar
  23. 23.
    Lonsdale D (2007) Three case reports to illustrate clinical applications in the use of erythrocyte transketolase. Evid Based Complement Altern Med 4(2):247–250CrossRefGoogle Scholar
  24. 24.
    Lonsdale D, Shamberger RJ, Audhya T (2002) Treatment of autism spectrum children with thiamine tetrahydrofurfuryl disulfide: a pilot study. Neuro Endocrinol Lett 23(4):303–308PubMedGoogle Scholar
  25. 25.
    Massod MF, McGuire SL, Werner KR (1971) Analysis of blood transketolase activity. Am J Clin Pathol 55(4):465–470PubMedGoogle Scholar
  26. 26.
    Newschaffer CJ, Croen LA, Daniels J, Giarelli E, Grether JK, Levy SE, Mandell DS, Miller LA, Pinto-Martin J, Reaven J, Reynolds AM, Rice CE, Schendel D, Windham GC (2007) The epidemiology of autism spectrum disorders. Annu Rev Public Health 28:235–258PubMedCrossRefGoogle Scholar
  27. 27.
    Ogier de Baulny H, Gerard M, Saudubray JM, Zittoun J (1998) Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr 157(Suppl 2):S77–S83PubMedCrossRefGoogle Scholar
  28. 28.
    Oliveira G, Diogo L, Grazina M, Garcia P, Ataide A, Marques C, Miguel T, Borges L, Vicente AM, Oliveira CR (2005) Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Dev Med Child Neurol 47(3):185–189PubMedCrossRefGoogle Scholar
  29. 29.
    Olkowski AA, Gooneratne SR, Christensen DA (1991) The effects of thiamine and EDTA on biliary and urinary lead excretion in sheep. Toxicol Lett 59(1–3):153–159PubMedCrossRefGoogle Scholar
  30. 30.
    Quig D (1998) Cysteine metabolism and metal toxicity. Altern Med Rev 3(4):262–270PubMedGoogle Scholar
  31. 31.
    Saxena P, Saxena AK, Cui XL, Obrenovich M, Gudipaty K, Monnier VM (2000) Transition metal-catalyzed oxidation of ascorbate in human cataract extracts: possible role of advanced glycation end products. Invest Ophthalmol Vis Sci 41(6):1473–1481PubMedGoogle Scholar
  32. 32.
    Schanen NC (2006) Epigenetics of autism spectrum disorders. Hum Mol Genet 15(Spec No 2):R138–R150PubMedCrossRefGoogle Scholar
  33. 33.
    Schenk G, Duggleby RG, Nixon PF (1998) Properties and functions of the thiamin diphosphate dependent enzyme transketolase. Int J Biochem Cell Biol 30:1297–1318PubMedCrossRefGoogle Scholar
  34. 34.
    Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT (2004) Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119(1):19–31PubMedCrossRefGoogle Scholar
  35. 35.
    Splawski I, Yoo DS, Stotz SC, Cherry A, Clapham DE, Keating MT (2006) CACNA1H mutations in autism spectrum disorders. J Biol Chem 281(31):22085–22091PubMedCrossRefGoogle Scholar
  36. 36.
    Wang X, Wang B, Fan Z, Shi X, Ke ZJ, Luo J (2007) Thiamine deficiency induces endoplasmic reticulum stress in neurons. Neuroscience 144(3):1045–1056PubMedCrossRefGoogle Scholar
  37. 37.
    Waring RH, Ngong JM, Klovzra L (1997) Biochemical parameters in autistic children. Dev Brain Dysfunction 10:40–43Google Scholar
  38. 38.
    Wells DG, Baylis EM, Holoway L, Marks V (1968) Erythrocyte-transketolase activity in megaloblastic anaemia. Lancet 2(7567):543–545PubMedCrossRefGoogle Scholar
  39. 39.
    Whang R, Whang DD (1990) Update: mechanisms by which magnesium modulates intracellular potassium. J Am Coll Nutr 9(1):84–85PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Mark E. Obrenovich
    • 1
    • 2
    • 3
    • 4
  • Raymond J. Shamberger
    • 2
  • Derrick Lonsdale
    • 3
    • 4
  1. 1.Department of ChemistryCleveland State UniversityClevelandUSA
  2. 2.King James Medical LaboratoryClevelandUSA
  3. 3.Private PracticeClevelandUSA
  4. 4.The American Institute For Complementary Alternative MedicineClevelandUSA

Personalised recommendations