Current Neurology and Neuroscience Reports

, Volume 11, Issue 4, pp 428–434 | Cite as

Epilepsy and Autism: Neurodevelopmental Perspective

Article

Abstract

Epilepsy and autism coexist in up to 20% of children with either disorder. Current studies suggest that a frequent co-occurring condition in epilepsy and autism is intellectual disability, which shows a very high prevalence in those with both autism and epilepsy. In addition, these recent studies suggest that early-onset seizures may index a group of infants at high risk for developing autism, usually with associated intellectual deficits. In this review we discuss recent advances in the conceptualization of shared anatomical and molecular mechanisms that may account for the coexistence of epilepsy, autism, and intellectual disability. A major contribution to our improved understanding of the relationship among these three phenotypes is the discovery of multiple genomic variants that cut across them as well as other neurobehavioral phenotypes. As these discoveries continue they are very likely to elucidate causal mechanisms for the various phenotypes and pinpoint biologic pathways that may be amenable to therapeutic interventions for this group of neurodevelopmental disorders.

Keywords

Epilepsy Seizures Autism Autism spectrum disorders Intellectual disability Genetics Neurodevelopmental disorders Molecular pathways 

Notes

Acknowledgment

M. Cuccaro has received a grant from the National Institutes of Health supporting his work in autism.

Disclosure

Conflicts of interest: R. Tuchman: receives royalties as a co-editor for the book Autism: A Neurological Disorder of Early Brain Development, and he serves on the Scientific Advisory Committee for Autism Speaks; M. Cuccaro: none.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Spence SJ, Schneider MT. The role of epilepsy and epileptiform EEGs in autism spectrum disorders. Pediatr Res. 2009;65:599–606.PubMedCrossRefGoogle Scholar
  2. 2.
    • Tuchman R, Cuccaro M, Alessandri M. Autism and epilepsy: historical perspective. Brain Dev. 2010;32:709–18. This is a comprehensive review of studies on epilepsy and autism.PubMedCrossRefGoogle Scholar
  3. 3.
    Jensen FE. Epilepsy as a spectrum disorder: implications from novel clinical and basic neuroscience. Epilepsia. 2011;52 Suppl 1:1–6.PubMedCrossRefGoogle Scholar
  4. 4.
    • Amiet C, Gourfinkel-An I, Bouzamondo A, et al. Epilepsy in autism is associated with intellectual disability and gender: evidence from a meta-analysis. Biol Psychiatry. 2008;64:577–82. This meta-analysis establishes a clear association between intellectual disability, autism, and epilepsy.PubMedCrossRefGoogle Scholar
  5. 5.
    Turk J, Bax M, Williams C, et al. Autism spectrum disorder in children with and without epilepsy: impact on social functioning and communication. Acta Paediatr. 2009;98:675–81.PubMedCrossRefGoogle Scholar
  6. 6.
    Hara H. Autism and epilepsy: a retrospective follow-up study. Brain Dev. 2007;29:486–90.PubMedCrossRefGoogle Scholar
  7. 7.
    Danielsson S, Gillberg IC, Billstedt E, et al. Epilepsy in young adults with autism: a prospective population-based follow-up study of 120 individuals diagnosed in childhood. Epilepsia. 2005;46:918–23.PubMedCrossRefGoogle Scholar
  8. 8.
    Mouridsen SE, Rich B, Isager T. A longitudinal study of epilepsy and other central nervous system diseases in individuals with and without a history of infantile autism. Brain Dev. 2010.Google Scholar
  9. 9.
    Gillberg C, Billstedt E, Sundh V, et al. Mortality in autism: a prospective longitudinal community-based study. J Autism Dev Disord. 2010;40:352–7.PubMedCrossRefGoogle Scholar
  10. 10.
    van Blarikom W, Tan IY, Aldenkamp AP, et al. Epilepsy, intellectual disability, and living environment: a critical review. Epilepsy Behav. 2006;9:14–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Berg AT, Langfitt JT, Testa FM, et al. Global cognitive function in children with epilepsy: a community-based study. Epilepsia. 2008;49:608–14.PubMedCrossRefGoogle Scholar
  12. 12.
    Plioplys S, Dunn DW, Caplan R. 10-year research update review: psychiatric problems in children with epilepsy. J Am Acad Child Adolesc Psychiatry. 2007;46:1389–402.PubMedCrossRefGoogle Scholar
  13. 13.
    Hamiwka LD, Wirrell EC. Comorbidities in pediatric epilepsy: beyond “just” treating the seizures. J Child Neurol. 2009;24:734–42.PubMedCrossRefGoogle Scholar
  14. 14.
    Sillanpaa M, Shinnar S. Long-term mortality in childhood-onset epilepsy. N Engl J Med. 2010;363:2522.PubMedCrossRefGoogle Scholar
  15. 15.
    Steffenburg U, Hagberg G, Kyllerman M. Characteristics of seizures in a population-based series of mentally retarded children with active epilepsy. Epilepsia. 1996;37:850–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Clarke DF, Roberts W, Daraksan M, et al. The prevalence of autistic spectrum disorder in children surveyed in a tertiary care epilepsy clinic. Epilepsia. 2005;46:1970–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Matsuo M, Maeda T, Sasaki K, et al. Frequent association of autism spectrum disorder in patients with childhood onset epilepsy. Brain Dev. 2010;32:759–63.PubMedCrossRefGoogle Scholar
  18. 18.
    • Berg AT, Plioplys S, Tuchman R. Risk and correlates of autism spectrum disorder in children with epilepsy: a community-based study. J Child Neurol. In Press. This is the first study assessing the risk of developing autism in a community-based population of children with epilepsy.Google Scholar
  19. 19.
    Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010;51:676–85.PubMedCrossRefGoogle Scholar
  20. 20.
    Tuchman R, Moshe SL, Rapin I. Convulsing toward the pathophysiology of autism. Brain Dev. 2009;31:95–103.PubMedCrossRefGoogle Scholar
  21. 21.
    Holland KD, Hallinan BE. What causes epileptic encephalopathy in infancy?: the answer may lie in our genes. Neurology. 2010;75:1132–3.PubMedCrossRefGoogle Scholar
  22. 22.
    •• Saemundsen E, Ludvigsson P, Rafnsson V. Risk of autism spectrum disorders after infantile spasms: a population-based study nested in a cohort with seizures in the first year of life. Epilepsia. 2008;49:1865–70. The findings of this study clearly documents risk factors and specific subgroups of infants with seizures in the first year of life who are at very high risk for developing autism.PubMedCrossRefGoogle Scholar
  23. 23.
    Saemundsen E, Ludvigsson P, Rafnsson V. Autism spectrum disorders in children with a history of infantile spasms: a population-based study. J Child Neurol. 2007;22:1102–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Saemundsen E, Ludvigsson P, Hilmarsdottir I, et al. Autism spectrum disorders in children with seizures in the first year of life—a population-based study. Epilepsia. 2007;48:1724–30.PubMedCrossRefGoogle Scholar
  25. 25.
    • Brooks-Kayal A. Epilepsy and autism spectrum disorders: are there common developmental mechanisms? Brain Dev. 2010;32:731–8. This is a comprehensive review of the developmental mechanisms that may drive both the development of epilepsy and autism.PubMedCrossRefGoogle Scholar
  26. 26.
    Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol. 2009;5:380–91.PubMedCrossRefGoogle Scholar
  27. 27.
    Brooks-Kayal A. Molecular mechanisms of cognitive and behavioral comorbidities of epilepsy in children. Epilepsia. 2011;52 Suppl 1:13–20.PubMedCrossRefGoogle Scholar
  28. 28.
    Gutierrez RC, Hung J, Zhang Y, et al. Altered synchrony and connectivity in neuronal networks expressing an autism-related mutation of neuroligin 3. Neuroscience. 2009;162:208–21.PubMedCrossRefGoogle Scholar
  29. 29.
    Wong M. Mechanisms of epileptogenesis in tuberous sclerosis complex and related malformations of cortical development with abnormal glioneuronal proliferation. Epilepsia. 2008;49:8–21.PubMedCrossRefGoogle Scholar
  30. 30.
    •• Wegiel J, Kuchna I, Nowicki K, et al. The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathol. 2010;119:755–70. This comprehensive neuropathological report is the first to document that children with autism may have the same type of neuropathology as found in children with epilepsy.PubMedCrossRefGoogle Scholar
  31. 31.
    Poduri A, Lowenstein D. Epilepsy genetics-past, present, and future. Curr Opin Genet Dev. 2011.Google Scholar
  32. 32.
    •• Mefford HC, Muhle H, Ostertag P, et al. Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet. 2010;6:e1000962. This study presents an excellent overview of the role of CNVs in epilepsy and clearly articulates the importance of the three major variants identified to date.PubMedCrossRefGoogle Scholar
  33. 33.
    Mitchell KJ. The genetics of neurodevelopmental disease. Curr Opin Neurobiol. 2010.Google Scholar
  34. 34.
    Mefford HC, Mulley JC. Genetically complex epilepsies, copy number variants and syndrome constellations. Genome Med. 2010;2:71.PubMedCrossRefGoogle Scholar
  35. 35.
    • Betancur C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 2010. This article provides an exhaustive review of the varied genetic and genomic disorders that have been linked to ASD over the past several years. The author offers an exceptionally strong argument that ASD is the end product of multiple genes and that careful examination of disorders in which an ASD phenotype is present are necessary.Google Scholar
  36. 36.
    Strauss KA, Puffenberger EG, Huentelman MJ, et al. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med. 2006;354:1370–7.PubMedCrossRefGoogle Scholar
  37. 37.
    •• Zweier C, de Jong EK, Zweier M, et al. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am J Hum Genet. 2009;85:655–66. This article foreshadows the value of advancing genomic technologies (ie, massive parallel sequencing) in identifying causal genetic underpinnings for clinically defined disorders that are negative for standard genetic tests.PubMedCrossRefGoogle Scholar
  38. 38.
    Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008;9:341–55.PubMedCrossRefGoogle Scholar
  39. 39.
    Mefford HC, Cooper GM, Zerr T, et al. A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Res. 2009;19:1579–85.PubMedCrossRefGoogle Scholar
  40. 40.
    •• Mulley JC, Mefford HC. Epilepsy and the new cytogenetics. Epilepsia 2011. This article describes the new and exciting ways that available technologies can help pinpoint potentially causal genetic variants for complex disorders such as epilepsy and a host of other phenotypes.Google Scholar
  41. 41.
    Heinzen EL, Radtke RA, Urban TJ, et al. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet. 2010;86:707–18.PubMedCrossRefGoogle Scholar
  42. 42.
    Ullmann R, Turner G, Kirchhoff M, et al. Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation. Hum Mutat. 2007;28:674–82.PubMedCrossRefGoogle Scholar
  43. 43.
    Corbett MA, Bahlo M, Jolly L, et al. A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24. Am J Hum Genet. 2010;87:371–5.PubMedCrossRefGoogle Scholar
  44. 44.
    de Kovel CG, Trucks H, Helbig I, et al. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain. 2010;133:23–32.PubMedCrossRefGoogle Scholar
  45. 45.
    •• Girirajan S, Eichler EE. Phenotypic variability and genetic susceptibility to genomic disorders. Hum Mol Genet. 2010;19:R176–87. This article provides an excellent overview of genomic disorders and potential reasons for the high phenotypic or clinical variability that is observed with similar mutations.PubMedCrossRefGoogle Scholar
  46. 46.
    Buxbaum JD. Multiple rare variants in the etiology of autism spectrum disorders. Dialogues Clin Neurosci. 2009;11:35–43.PubMedGoogle Scholar
  47. 47.
    • Pinto D, Pagnamenta AT, Klei L, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466:368–72. This article summarizes the most recent and largest study of CNVs in an ASD dataset.PubMedCrossRefGoogle Scholar
  48. 48.
    Bucan M, Abrahams BS, Wang K, et al. Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet. 2009;5:e1000536.PubMedCrossRefGoogle Scholar
  49. 49.
    Scott-Van Zeeland AA, Abrahams BS, Alvarez-Retuerto AI, et al. Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2. Sci Transl Med. 2010;2:56ra80.PubMedGoogle Scholar
  50. 50.
    • Tuchman R, Alessandri M, Cuccaro M. Autism spectrum disorders and epilepsy: moving towards a comprehensive approach to treatment. Brain Dev. 2010;32:719–30. This article is a comprehensive review of available pharmacologic and behavioral interventions for children with epilepsy and autism. A review of converging molecular pathways in epilepsy and autism provides insight into potential future targets for pharmacologic intervention. The article also highlights the importance of early behavioral interventions for children with epilepsy and autism.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Neurology Miami Children’s HospitalDan Marino CenterWestonUSA
  2. 2.Department of Neurology, Herbert Wertheim College of MedicineFlorida International UniversityMiamiUSA
  3. 3.Department of Human Genetics, John P. Hussman Institute for Human GenomicsUniversity of Miami Miller School of MedicineMiamiUSA

Personalised recommendations