Epigenetics in Autism and Other Neurodevelopmental Diseases

  • Kunio Miyake
  • Takae Hirasawa
  • Tsuyoshi Koide
  • Takeo KubotaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 724)


Autism was previously thought to be caused by environmental factors. However, genetic factors are now considered to be more contributory to the pathogenesis of autism, based on the recent findings of mutations in the genes which encode synaptic molecules associated with the communication between neurons. Epigenetic is a mechanism that controls gene expression without changing DNA sequence but by changing chromosomal histone modifications and its abnormality is associated with several neurodevelopmental diseases. Since epigenetic modifications are known to be affected by environmental factors such as nutrition, drugs and mental stress, autistic diseases are not only caused by congenital genetic defects, but may also be caused by environmental factors via epigenetic mechanism. In this chapter, we introduce autistic diseases caused by epigenetic failures and discuss epigenetic changes by environmental factors and discuss new treatments for neurodevelopmental diseases based on the recent epigenetic findings.


Neurodegenerative Disease Valproic Acid Epigenetic Mechanism Rett Syndrome Angelman Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Honda H, Shimizu Y, Imai MM. Cumulative incidence of childhood autism: a total population study of better accuracy and precision. Dev Med Child Neurol 2005; 47:10–18.PubMedCrossRefGoogle Scholar
  2. 2.
    Silverman JL, Yang M, Lord C. Behavioural phenotyping assays for mouse models of autism. Nature Review Neuroscience 2010; 490:490–502.CrossRefGoogle Scholar
  3. 3.
    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Diseases. 4th ed, APA, Washington DC, 1994.Google Scholar
  4. 4.
    World Health Organization. The ICD-10 Classification of Mental and Behavioural Diseases. Geneva, Switzerland, 1992.Google Scholar
  5. 5.
    Herbert MR. Contributions of the environment and environmentally vulnerable physiology to autism spectrum diseases. Curr Opin Neurol 2010; 23:103–110.PubMedCrossRefGoogle Scholar
  6. 6.
    Persico AM, Bourgeron T, Persico AM. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci 2006; 29:349–358.PubMedCrossRefGoogle Scholar
  7. 7.
    Zoghbi HY. Postnatal neurodevelopmental diseases: meeting at the synapse?. Science 2003; 302:826–830.PubMedCrossRefGoogle Scholar
  8. 8.
    Basic investigation report for handicapped children. report by Ministry of Health, Welfare and Labor, Japan. 2005 (in Japanese).Google Scholar
  9. 9.
    Yeargin-Allsopp M, Rice C, Karapurkar T. Prevalence of Autism in a US Metropolitan Area. JAMA 2003; 289:49–55.PubMedCrossRefGoogle Scholar
  10. 10.
    Holden C. Autism Now. Science 2009; 323:565.Google Scholar
  11. 11.
    Fombonne E. Epidemiology of pervasive developmental diseases. Pediatric Research 2009; 65:591–598.PubMedCrossRefGoogle Scholar
  12. 12.
    Hoekstra RA, Bartels M, Hudziak JJ. Genetics and environmental covariation between autistic traits and behavioral problems. Twin Res Hum Genet 2007; 10:853–860.PubMedCrossRefGoogle Scholar
  13. 13.
    Qiu J. Epigenetics: unfinished symphony. Nature 2006; 441:143–145.PubMedCrossRefGoogle Scholar
  14. 14.
    Guy J, Herndrich B, Hormes M. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 2001; 27:322–326.PubMedCrossRefGoogle Scholar
  15. 15.
    Kubota T, Das S, Christian SL. Methylation-specific PCR symplifies imprinting analysis. Nat Genet 1997; 16:16–17.PubMedGoogle Scholar
  16. 16.
    Kubota T, Nonoyama S, Tonoki H. A new assay for the analysis of X-chromosome inactivation based on methylation-specific PCR. Hum Genet 1999; 104:49–55.PubMedCrossRefGoogle Scholar
  17. 17.
    Xue F, Tian XC, Du F. Aberrant patterns of X chromosome inactivation in bovine clones. Nat Genet 2002; 31:216–220.PubMedCrossRefGoogle Scholar
  18. 18.
    Nolen LD, Gao S, Han Z. X chromosome reactivation and regulation in cloned embryos. Developmental Biology 2005; 279:525–540.PubMedCrossRefGoogle Scholar
  19. 19.
    Kubota T, Wakui K, Nakamura T. Proportion of the cells with functional X disomy is associated with the severity of mental retardation in mosaic ring X Turner syndrome females. Cytogenet Genome Res 2002; 99:276–284.PubMedCrossRefGoogle Scholar
  20. 20.
    Okano M, Bell DW, Habe DA. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999; 99:247–257.PubMedCrossRefGoogle Scholar
  21. 21.
    Shirohzu H, Kubota T, Kumazawa A. Three novel DNMT3B mutations in Japanese patients with ICF syndrome. Am J Med Genet 2002; 112:31–37.PubMedCrossRefGoogle Scholar
  22. 22.
    Kubota T, Furuumi H, Kamoda T. ICF syndrome in a girl with DNA hypomethylation but without detectable DNMT3B mutation. Am J Med Genet A 2004; 129:290–293.CrossRefGoogle Scholar
  23. 23.
    Amir RE, Van den Veyver IB, Wan M. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999; 23:185–188.PubMedCrossRefGoogle Scholar
  24. 24.
    Chunshu Y, Endoh K, Soutome M. A patient with classic Rett syndrome with a novel mutation in MECP2 exon 1. Clin Genet 2006; 70:530–531.PubMedCrossRefGoogle Scholar
  25. 25.
    Chen WG, Chang Q, Lin Y. Derepression of BDNF Transcription Involves Calcium-Dependent Phosphorylation of MeCP2. Science; 2003; 302:885–889.PubMedCrossRefGoogle Scholar
  26. 26.
    Martinowich K, Hattori D, Wu H. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 2003; 302:890–893.PubMedCrossRefGoogle Scholar
  27. 27.
    Horike S, Cai S, Miyano M. Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome. Nat Genet 2005; 37:31–40.PubMedCrossRefGoogle Scholar
  28. 28.
    Itoh M, Ide S, Takashima S. Methyl CpG-binding protein 2, whose mutation causes Rett syndrome, directly regulates Insulin-like Growth Factor Binding Protein 3 in mouse and human Brains. J Neuropathol Exp Neurol 2007; 66:117–123.PubMedCrossRefGoogle Scholar
  29. 29.
    Jiang YH, Sahoo T, Michaelis RC. A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A. Am J Med Genet A 2004; 131:1–10.PubMedCrossRefGoogle Scholar
  30. 30.
    Beaudet AL. Autism: highly heritable but not inherited. Nat Med 2007; 13:534–536.PubMedCrossRefGoogle Scholar
  31. 31.
    Beaudet AL. Allan Award lecture: Rare patients leading to epigenetics and back to genetics. Am J Hum Genet 2008; 82:1034–1038.PubMedCrossRefGoogle Scholar
  32. 32.
    Fombonne E. Epidemiology of pervasive developmental diseases. Pediatr Res 2009; 65:591–598.PubMedCrossRefGoogle Scholar
  33. 33.
    Bailey A, Le Couteur A, Gottesman I. Autism as a strongly genetic disease: evidence from a British twin study. Psychol Med 1995; 25:63–77.PubMedCrossRefGoogle Scholar
  34. 34.
    Zafeiriou DI, Ververi A, Vargiami E. Childhood autism and associated comorbidities. Brain Dev 2007; 29:257–272.PubMedCrossRefGoogle Scholar
  35. 35.
    Burdge GC, Lillycrop KA, Phillips ES. Folic acid supplementation during the juvenile-pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition. J Nutr 2009; 139:1054–1060.PubMedCrossRefGoogle Scholar
  36. 36.
    Jessberger S, Nakashima K, Clemenson GD. Epigenetic modulation of seizure-induced neurogenesis and cognitive decline. J Neurosci 2007; 27:5967–5975.PubMedCrossRefGoogle Scholar
  37. 37.
    Weaver IC, Cervoni N, Champagne FA. Epigentic programming by maternal behavior. Nat Neurosci 2004; 9:847–554.CrossRefGoogle Scholar
  38. 38.
    Tsankova NM, Berton O, Renthal W. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 2006; 9:519–525.PubMedCrossRefGoogle Scholar
  39. 39.
    Ma DK, Jang MH, Guo JU. Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 2009; 323:1074–1077.PubMedCrossRefGoogle Scholar
  40. 40.
    Kumar A, Choi KH, Renthal W. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 2005; 48:303–314.PubMedCrossRefGoogle Scholar
  41. 41.
    Pascual M, Boix J, Felipo V. Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat. J Neurochem 2009; 108:920–931.PubMedCrossRefGoogle Scholar
  42. 42.
    Renthal W, Nestler EJ. Epigenetic mechanisms in drug addiction. Trends Mol Med 2008; 14:341–350.PubMedCrossRefGoogle Scholar
  43. 43.
    Fraga MF, Ballestar E, Paz MF. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 2005; 102:10604–10609.PubMedCrossRefGoogle Scholar
  44. 44.
    Watanabe H, Fukuoka H, Sugiyama T. Dietary folate intake during pregnancy and birth weight in Japan. European J Nutr 2008; 47:341–347.CrossRefGoogle Scholar
  45. 45.
    Park JH, Stroffers DA, Nicholles RD. Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest 2008; 118:2316–2324.PubMedCrossRefGoogle Scholar
  46. 46.
    Kucharski R, Maleszka J, Foret S. Nutritional control of reproductive status in haneybees via DNA methylation. Science 2008; 319:1827–1830.PubMedCrossRefGoogle Scholar
  47. 47.
    Rimland B. Controversies in the treatment of autistic children: vitamin and drug therapy. J Child Neurol 1998; 3:68–72.CrossRefGoogle Scholar
  48. 48.
    James SJ, Cutler P, Melnyk S. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 2004; 20:1611–1617.Google Scholar
  49. 49.
    Moretti P, Sahoo T, Hyland K. Cerebral folate deficiency with developmental delay, autism and response to folinic acid. Neurology 2005; 64:1088–1090.PubMedCrossRefGoogle Scholar
  50. 50.
    Laird PW. Principles and challenges of genome-wide DNA methylation analysis. Nat Rev Genet 2005; 11:191–203.CrossRefGoogle Scholar
  51. 51.
    Varley KE, Mitra RD. Bisulfite Patch PCR enables multiplexed sequencing of promoter methylation across cancer samples. Genome Res 2010. [Epub ahead of print].Google Scholar
  52. 52.
    Ohtsuki A, Kimura MT, Minoshima M. Synthesis and properties of PI polyamide-SAHA conjugate. Tetrahedron Lett 2009; 50:7288–7292.CrossRefGoogle Scholar
  53. 53.
    Coufal NG, Garcia-Perez JL, Peng GE. L1 retrotransposition in human neural progenitor cells. Nature 2009; 460:1127–1131.PubMedCrossRefGoogle Scholar
  54. 54.
    Muotri AR, Chu VT, Marchetto MCN. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 2005; 435:903–910.PubMedCrossRefGoogle Scholar
  55. 55.
    Muotri AR, Zhao C, Marchetto MCN. Environmental Influence on L1 Retrotransposons in the Adult Hippocampus. Hypoocumpus 2009; 19:1002–1007.CrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  • Kunio Miyake
    • 1
  • Takae Hirasawa
    • 1
  • Tsuyoshi Koide
    • 2
  • Takeo Kubota
    • 1
    Email author
  1. 1.Department of Epigenetics Medicine, Faculty of Medicine, Interdisciplinary Graduate School of Medicine and EngineeringUniversity of YamanashiYamanashiJapan
  2. 2.Department of Mouse Genomics Resource LaboratoryNational Institute of GeneticsShizuokaJapan

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