Cellular and Molecular Neurobiology

, Volume 30, Issue 2, pp 161–171 | Cite as

Understanding and Determining the Etiology of Autism

  • Salvatore A. Currenti
Review Paper


Worldwide, the rate of autism has been steadily rising. There are several environmental factors in concert with genetic susceptibilities that are contributing to this rise. Impaired methylation and mutations of mecp2 have been associated with autistic spectrum disorders, and related Rett syndrome. Genetic polymorphisms of cytochrome P450 enzymes have also been linked to autism, specifically CYP27B1 that is essential for proper vitamin D metabolism. Vitamin D is important for neuronal growth and neurodevelopment, and defects in metabolism or deficiency have been implicated in autistic individuals. Other factors that have been considered include: maternally derived antibodies, maternal infection, heavy metal exposure, folic acid supplementation, epigenetics, measles, mumps, rubella vaccination, and even electromagnetic radiation. In each case, the consequences, whether direct or indirect, negatively affect the nervous system, neurodevelopment, and environmental responsive genes. The etiology of autism is a topic of controversial debate, while researchers strive to achieve a common objective. The goal is to identify the cause(s) of autism to understand the complex interplay between environment and gene regulation. There is optimism that specific causes and risk factors will be identified. The results of future investigations will facilitate enhanced screening, prevention, and therapy for “at risk” and autistic patients.


Autism Vitamin D Methylation Folic acid Methyl-CpG-binding protein (mecp2) Methylenetetrahydrofolate reductase (MTHFR) Calcitriol Autoantibodies Glucocorticoids CYP27B1 MMR vaccine Heavy metals 



The author would like to acknowledge Egidio Currenti, Research Scientist at the New York State Department of Health/Wadsworth Center and David O. Carpenter, MD, Director of the Institute of Health and Environment at the State University of New York at Albany for their encouragement and support.


  1. Abrahams BS, Geschwind DH (2008) Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 9:1–15CrossRefGoogle Scholar
  2. Abraham IM et al (2001) Action of glucocorticoids on survival of nerve cells: promoting neurodegeneration or neuroprotection? Neuroendocrinology 13:749–760CrossRefGoogle Scholar
  3. Adams JB, Romdalvik J (2007) Mercury, lead, and zinc in baby teeth of children with autism versus controls. J Toxicol Environ Health 70:1046–1051CrossRefGoogle Scholar
  4. Adams JB et al. (2003) Exposure to heavy metals, physical symptoms, and developmental milestones in children with autism. Fall 2003 conference proceedings of defeat autism now! Portland, ORGoogle Scholar
  5. Almeras L et al (2007) Developmental vitamin D deficiency alters brain protein expression in the adult rat: implications for neuropsychiatric disorders. Proteomics 7(5):769–780CrossRefPubMedGoogle Scholar
  6. American Medical Association (1989) Harmful effects of ultraviolet radiation. Council on scientific affairs. JAMA 262(3):380–384CrossRefGoogle Scholar
  7. Ashwood P et al (2006) The immune response in autism: a new frontier for autism research. J Leukoc Biol 80(1):1–15CrossRefPubMedGoogle Scholar
  8. Bailey A et al (1995) Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 25:63–77CrossRefPubMedGoogle Scholar
  9. Ballatori N, Clarkson TW (1985) Biliary secretion of glutathione and of glutathione-metal complexes. Fundam Appl Toxicol 5:816–831CrossRefPubMedGoogle Scholar
  10. Bernard S et al (2001) Autism: a novel form of mercury poisoning. Med Hypothesis 56:462–471CrossRefGoogle Scholar
  11. Bhasin TK, Scendel D (2007) Sociodemographic risk factors for autism in a US metropolitan area. J Autism Dev Disord 37(4):667–677CrossRefPubMedGoogle Scholar
  12. Bird A (2008) The methyl-CpG-binding protein MeCP2 and neurological disease. Biochem Soc Trans 36:572–583CrossRefGoogle Scholar
  13. Bodnar LM et al (2007) High prevalence of vitamin D insufficiency in black and white pregnant women residing in the northern US and their neonates. J Nutr 137(2):447–452PubMedGoogle Scholar
  14. Bohm HV, Stewart MG (2009) Brief report: on the concordance percentages for autistic spectrum disorder of twins. J Autism Dev Disord 39:806–808CrossRefPubMedGoogle Scholar
  15. Boris MD et al (2004) Association of MTHFR gene variants with autism. J Am Phys Surg 9(4):106–108Google Scholar
  16. Braunschweig D et al (2008) Autism: maternally derived antibodies specific for fetal brain proteins. NeuroToxicology 22:6–231Google Scholar
  17. Burne TH, Feron F et al (2004) Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle. Physiol Behav 81(4):651–665CrossRefPubMedGoogle Scholar
  18. Cannell JJ (2008) Autism and vitamin D. Med Hypotheses 70:750–759CrossRefPubMedGoogle Scholar
  19. Centers for Disease Control and Prevention (2009) Autism information center. 27 May 2009
  20. Chang Q et al (2006) The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron 49:341–348CrossRefPubMedGoogle Scholar
  21. Chen WG et al (2003) Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302(5646):885–889CrossRefPubMedGoogle Scholar
  22. Comi AM et al (1999) Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol 14(6):388–394CrossRefPubMedGoogle Scholar
  23. Coy JF et al (1999) A complex pattern of evolutionary conservation and alternative polyadenylation within the long 3’-untranslated region of the methyl-CpG-binding protein 2 gene suggests a regulatory role in gene expression. Hum Mol Genet 8:1253–1262CrossRefPubMedGoogle Scholar
  24. Croen LA et al (2005) Maternal autoimmune diseases, asthma, and allergies, and childhood autism spectrum disorders. Arch Pediatr Adolesc Med 159:151–157CrossRefPubMedGoogle Scholar
  25. Cui X et al (2007) Maternal vitamin D deficiency alters neurogenesis in the developing rat brain. Int J Dev Neurosci 25:227–232CrossRefPubMedGoogle Scholar
  26. Deth R et al (2008) How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. NeuroToxicology 29:190–201CrossRefPubMedGoogle Scholar
  27. Egger G, Liang G, Aparicio A, Jones PA (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429:457–463CrossRefPubMedGoogle Scholar
  28. Epstein S, Schneider AE (2005) Drug and hormone effects on vitamin D metabolism. In: Feldman D, Pike JW, Glorieux FH (eds) Vitamin D. Elsevier, San DiegoGoogle Scholar
  29. Feron F et al (2005) Developmental vitamin D3 deficiency alters the adult rat brain. Brain Res Bull 65(2):141–148CrossRefPubMedGoogle Scholar
  30. Filipek PA, Accardo PJ, Ashwal S et al (2000) Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society. Neurology 55:468–479PubMedGoogle Scholar
  31. Fombonne E (1999) The epidemiology of autism: a review. Psychol Med 29:769–786CrossRefPubMedGoogle Scholar
  32. Fukushige S, Kondo E, Horii A (2008) Methyl-CpG targeted transcriptional activation allows re-expression of tumor suppressor genes in human cancer cells. Biochem Biophys Res Commun 377(2):600–605CrossRefPubMedGoogle Scholar
  33. Garcion E et al (2002) New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab 13(3):100–105CrossRefPubMedGoogle Scholar
  34. Gillberg C (1998) Chromosomal disorders and autism. J Autism Dev Disord 28:415–425CrossRefPubMedGoogle Scholar
  35. Gillberg C, Coleman M (2000) The biology of autistic syndromes, 3rd edn. Mac Keith, London (distributed by Cambridge University Press)Google Scholar
  36. Goetzl L et al (2002) Elevated maternal and fetal serum interleukin-6 levels are associated with epidural fever. Am J Obstet Gynecol 187(4):834–838CrossRefPubMedGoogle Scholar
  37. Hardell L, Sage C (2008) Biological effects from electromagnetic field exposure and public exposure standards. Biomed Pharmacother 62:104–109CrossRefPubMedGoogle Scholar
  38. Herbert MR et al (2006) Autism and environmental genomics. NeuroToxicology 27:671–684CrossRefPubMedGoogle Scholar
  39. Hertz-Piciotto I et al (2006) The CHARGE study: an epidemiological investigation of genetic and environmental factors contributing to autism. Environ Health Perspect 114:1119–1125CrossRefGoogle Scholar
  40. Holick MF (1987) Photosynthesis of vitamin D in the skin: effect of environmental and lifestyle variables. Fed Proc 46:1876–1882PubMedGoogle Scholar
  41. Holmes LB (1988) Does taking vitamins at the time of conception prevent neural tube defects? JAMA 260(21):3181CrossRefPubMedGoogle Scholar
  42. James SJ et al (2004) Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 80:1611–1617PubMedGoogle Scholar
  43. Kalueff AV et al (2006) The vitamin D neuroendocrine system as a target for novel neurotropic drugs. CNS Neurol Disord Drug Targets 5(3):363–371PubMedGoogle Scholar
  44. Kelleher RJ III, Bear MF (2008) The autistic neuron: troubled translation? Cell 135:401–406CrossRefGoogle Scholar
  45. Kern JK, Jones AM (2006) Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health Crit Rev 9(6):485–499CrossRefGoogle Scholar
  46. Li H, Yamagata T, Mori M et al (2005) Mutation analysis of Methyl-CpG binding protein family genes in autistic patients. Brain Dev 27:321–325CrossRefPubMedGoogle Scholar
  47. Liu J, Nyholt DR, Magnussen P et al (2001) A genome-wide screen for autism susceptibility loci. Am J Hum Genet 69:327–340CrossRefPubMedGoogle Scholar
  48. Liu L, Li Y, Tollefsbol TO (2008) Gene-environment interactions and epigenetic basis of human disease. Curr Issues Mol Biol 10(1–2):25–36PubMedGoogle Scholar
  49. Loat CS et al. (2008) Methyl-CpG-binding protein 2 polymorphisms and vulnerability to autism. Genes Brain Behav 7(7):754–760CrossRefPubMedGoogle Scholar
  50. Mahaffey KR et al (2004) Blood organic mercury and dietary mercury intake: National Health and Nutrition Examination Survey. Environ Health Perspect 112:562–570PubMedCrossRefGoogle Scholar
  51. Mariea TJ, Carlo GL (2007) Wireless radiation in the etiology and treatment of autism: clinical observations and mechanisms. J Aust Coll Nutr Env Med 26(2):3–7Google Scholar
  52. Martinowich K et al (2003) DNA methylation related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302:890–893CrossRefPubMedGoogle Scholar
  53. Marz P et al (1999) Role of interleukin 6 and soluble IL-6 receptor in region specific induction of astrocytic differentiation and neurotrophin expression. Glia 26:191–200CrossRefPubMedGoogle Scholar
  54. McGrath J et al (2001) Vitamin D: the neglected neurosteriod? Trends Neurosci 24(10):570–572CrossRefPubMedGoogle Scholar
  55. Miller E (2003) Measles-mumps-rubella vaccine and the development of autism. Semin Pediatr Infect Dis 14(3):199–206CrossRefPubMedGoogle Scholar
  56. Milunsky A, Jick H, Jick SS et al (1989) Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 262(20):2847–2852CrossRefPubMedGoogle Scholar
  57. Moore V, Goodson S (2003) How well does early diagnosis of Autism stand the test of time? Follow-up study of children assessed for autism at age 2 and development of an early diagnostic service. Autism 7:47–63PubMedGoogle Scholar
  58. Moore ME et al (2005) Evidence that vitamin D3 reverses age-related inflammatory changes in the rat hippocampus. Biochem Soc Trans 33(4):573–577CrossRefPubMedGoogle Scholar
  59. Mulinare J, Cordero JF, Erickson JD, Berry RJ (1988) Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 260(21):3141–3145CrossRefPubMedGoogle Scholar
  60. Nagarajan R, Hogart A, Gwye Y, Martin M, LaSalle J (2006) Reduced MeCP2 expression in frequent in Autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics 1:172–182Google Scholar
  61. Nan X et al. (1998) Gene silencing by methyl-CpG-binding proteins. Novartis Foundation symposium, vol 214, pp. 6–16 (discussion 16–21, 46–50)Google Scholar
  62. National Center for Biotechnology Information (2008) MeCP2 (human).
  63. Nuber UA et al (2005) Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome. Hum Mol Genet 14:2247–2256CrossRefPubMedGoogle Scholar
  64. Otto M, Von Mühlendahl KE (2007) Electromagnetic fields (EMF): do they play a role in children’s environmental health (CEH)? Int J Hyg Environ Health 210:635–644CrossRefPubMedGoogle Scholar
  65. Rassoulzadegan M et al (2007) Epigenetic heredity in mice: involvement of RNA and miRNA. J Soc Biol 201(4):397–399CrossRefPubMedGoogle Scholar
  66. Rice C et al (2007) Prevalence of autism spectrum disorders-autism and developmental disabilities monitoring network. CDC Survey Rep 56:12–28Google Scholar
  67. Rogers EJ (2008) Has enhanced folate status during pregnancy altered natural selection and possibly autism prevalence? A closer look at a possible link. Med Hypothesis 71:406–410CrossRefGoogle Scholar
  68. Rowland IR, Davies M, Evans J (1980) Tissue content of mercury in rats given methylmercury chloride orally: influence of intestinal flora. Arch Environ Health 35:155–160PubMedGoogle Scholar
  69. Samaco RC et al (2004) Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. Hum Mol Genet 13:629–639CrossRefPubMedGoogle Scholar
  70. Samaco RC et al (2008) A partial loss of function allele of methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome. Hum Mol Genet 17(12):1718–1727CrossRefPubMedGoogle Scholar
  71. Scriver CR et al (2000) The metabolic and molecular basis of inherited disease. McGraw-Hill, New YorkGoogle Scholar
  72. Shao Y, Wolpert CM, Raiford KL et al (2002) Genomic screen and follow-up analysis for autistic disorder. Am J Med Genet 114:99–105CrossRefPubMedGoogle Scholar
  73. Silva SC et al (2004) Autoantibody repertoires to brain tissue in autism nuclear families. J Neuroimmunol 152:176–182CrossRefPubMedGoogle Scholar
  74. Singer HS et al (2008) Antibodies against fetal brain in sera of mothers with autistic children. J Neuroimmunol 16:5–172Google Scholar
  75. Smalley SL et al (1998) A decade of research. Arch Gen Psychiatry 45:953–961Google Scholar
  76. Starmer J, Magnuson T (2009) A new model for random X-chromosome inactivation. Development 136(1):1–10CrossRefPubMedGoogle Scholar
  77. Steffenburg S et al (1989) A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry 30:405–416CrossRefPubMedGoogle Scholar
  78. Stuck B et al (2002) Concomitant administration of varicella vaccine with combined measles, mumps, and rubella vaccine in healthy children aged 12 to 24 months of age. Asian Pac J Allergy Immunol 20(2):113–120PubMedGoogle Scholar
  79. Szyf M (2009) Epigenetics, DNA methylation, and chromatin modifying drugs. Annu Rev Pharmacol Toxicol 49:243–263 CrossRefPubMedGoogle Scholar
  80. Thornton I (2006) Out of time: a possible link between mirror neurons, autism and electromagnetic radiation. Med Hypotheses 67(2):378–382CrossRefPubMedGoogle Scholar
  81. Torres AR (2003) Is fever suppression involved in the etiology of autism and neurodevelopmental disorders? BMC Pediatr 3:9CrossRefPubMedGoogle Scholar
  82. Urakubo A et al (2001) Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain. Schizophr Res 47:27–36CrossRefPubMedGoogle Scholar
  83. Wakefield AJ, Murch SH, Anthony A et al (1998) Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 351:637–641CrossRefPubMedGoogle Scholar
  84. Zhang L, Wong MH (2006) Environmental mercury contamination in China: sources and impacts. Environ Int 33:108–121CrossRefPubMedGoogle Scholar
  85. Zhao X, Pak C, Smrt R, Jin P (2007) Epigenetics and neural developmental disorders. Epigenetics 2(2):126–134PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Center for Nanoscale Science and Engineering (CNSE)State University of New York (SUNY)AlbanyUSA

Personalised recommendations