Genetic and neurobio­logical aspects of comorbid occurence of autism spectrum disorder and epilepsy

Authors: P. Danhofer 1;  O. Horák 1;  Š. Aulická 1;  K. Česká 1;  J. Pejčochová 1;  L. Fajkusová 2;  H. Ošlejšková 1
Authors‘ workplace: Klinika dětské neurologie LF MU a FN Brno, Centrum pro epilepsie Brno 1;  Centrum molekulární biologie a genové terapie Interní hematoonkologické kliniky LF MU a FN Brno 2
Published in: Cesk Slov Neurol N 2019; 82(2): 0
Category: Review Article
doi: 10.14735/amcsnn2019148


Autism spectrum disorder (ASD) is ranked among neurodevelopmental and neuropsychiatric disorders with clinical onset in childhood. In recent years, this disorder has come to the forefront of scientific interest, mainly due to increasing prevalence of up to 1/ 68 in 2014. The genetic causes of the disorder and the pathophysiological mechanisms that might be involved in the development of ASD are revealed. Comorbid occur­rence with epilepsy is quite com­mon, in up to 46% of cases. This article sum­marizes the cur­rent knowledge in this field with a focus on the hypothesis of excitatory-inhibitory imbalance. Some genetic causes of ASD and cur­rent dia­gnostic options are also discus­sed. The pathophysiology of the co-morbidity of ASD and epilepsy is discus­sed in terms of pos­sible therapeutic interventions.


autism – epilepsy – autism spectrum disorder – genetics – ASD


1. Arvids­son T, Daniels­son B, Forsberg P et al. Autism in 3-6-year-old children in a suburb of Goteborg, Sweden. Autism 1997; 1(2): 163– 173. doi: 10.1177/ 1362361397012004.

2. Baird G, Charman T, Baron-Cohen S et al. A screen­­ing instrument for autism in 18 months of age: a 6-year-fol­low-up study. J Am Acad Child and Adolesc Psychiatry 2000; 39(6): 694– 702. doi: 10.1097/ 00004583-200006000-00007.

3. Yin J, Schaaf CP. Autism genetics –  an overview. Prenatal Dia­gn 2017; 37(1): 14– 30. doi: 10.1002/ pd.4942.

4. Meltzer A, Van der Water J. The role of the im­mune system in autism spectrum disorder. Neuropsychopharmacology 2017; 42(1): 284– 298. doi: 10.1038/ npp.2016.158.

5. Brucato M, Ladd-Acosta C, Li M et al. Prenatal exposure to fever is as­sociated with autism spectrum disorder in the boston birth cohort. Autism Res 2017; 10(11): 1878– 1890. doi: 10.1002/ aur.1841.

6. Talbott EO, Marshall LP, Rager JR et al. Air toxics and the risk of autism spectrum disorder: the results of a population based case-control study in southwestern Pen­nsylvania. Environ Health 2015; 14: 80. doi: 10.1186/ s12940-015-0064-1.

7. Gold­­ing J, Rai D, Gregory S et al. Prenatal mercury exposure and features of autism: a prospective population study. Mol Autism 2018; 9: 30. doi: 10.1186/ s13229-018-0215-7.

8. Gump BB, Dykas MJ, MacKenzie JA et al. Background lead and mercutry exposures: psychological and behavioral problems in children. Environ Res 2017; 158: 576– 582. doi: 10.1016/ j.envres.2017.06.033.

9. American Psychiatric As­sociation. Dia­gnostic and statistical manual of mental disorders, 3rd ed. Washington, DC: American Psychiatric As­sociation 1980.

10. Kan­ner L. Early infantile autism. J Pediatr 1944; 25: 211– 217.

11. American Psychiatric As­sociation. Dia­gnostic and statistic manual of mental disorders, 4th ed. (DSM-IV). Washington, DC: American Psychiatric As­sociation 1994.

12. American Psychiatric As­sociation. Dia­gnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric As­sociation 2013.

13. Lord C, Rutter M, DiLavore PC et al. Autism dia­gnostic observation schedule. Los Angeles: Western Psychological Services 2001.

14. Ošlejšková H, Kontrová I, Foralová R et al. D. The course of dia­gnosis in autistic patients: the delay between recognition of the first symp­toms by parents and cor­rect dia­gnosis. Neuro Endocrinol Lett 2007; 28(6): 895– 900.

15. Juříková Z, Jambrikovičová M, Ošlejšková H. Vývoj socioekonomického statu u pa­cientů s poruchou autistického spektra v průběhu let. Neurol praxi 2016; 17(2): 108– 112.

16. Amiet C, Gourfinkel-An I, Laurent C et al. Epilepsy in simplex autism pedigrees is much lower than the rate in multiplex autism pedigrees. Biol Psychiatry 2013; 74(3): e3– e4. doi: 10.1016/­psych.2013.01.037.

17. Hughes JR, Melyn M. EEG and seizures in autistic children and adolescents: further findings with therapeutic implications. Clin EEG Neurosci 2005; 36(1): 15– 20.

18. Ošlejšková H. Dušek L, Makovská Z et al. The incidence of epileptic seizures and/ or epileptiform EEG abnormalities in children with childhood and atypical autism. Cesk Slov Neurol N 2008; 71/ 104(4): 435– 444.

19. Amiet C, Gourfinkel-An I, Bouzamondo A et al. Epilepsy in autismis as­sociated with intel­lectual disability and gender: evidence from a meta-analysis. Biol Psychiatry 2008; 64(7): 577– 582. doi: 10.1016/­psych.2008.04.030.

20. Woolfenden S, Sarkozy V, Ridley G et al. A systematic review of two outcomes in autism spectrum disorder –  epilepsy and mortality. Dev Med Child Neurol 2012; 54(4): 306– 312. doi: 10.1111/ j.1469-8749.2012.04223.x.

21. 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(6): 918– 923. doi: 10.1111/ j.1528-1167.2005.57504.x.

22. Parmeggiani A, Barcia G, Posar A et al. Epilepsy and EEG paroxysmal abnormalities in autism spectrum disorders. Brain Dev 2010; 32(9): 783– 789. doi: 10.1016/ j.braindev.2010.07.003.

23. Barger BD, Campbell JM, McDonough JD. Prevalence and onset of regres­sion within autism spectrum disorders: a meta-analytic review. J Autism Dev Disord 2013; 43(4): 817– 828. doi: 10.1007/ s10803-012-1621-x.

24. Hrdlicka M, Komarek V, Propper L et al. Not EEG abnormalities but epilepsy is as­sociated with autistic regres­sion and mental function­­ing in childhood autism. Eur Child Adolesc Psychiatry 2004; 13(4): 209– 213. doi: 10.1007/ s00787-004-0353-7.

25. Velíšková J, Silverman JL, Benson M et al. Autistic traits in epilepsy models: why, when and how? Epilepsy Res 2018; 144: 62– 70. doi: 10.1016/ j.eplepsyres.2018.05.009.

26. Deon­na T, Roulet-Perez E. Early-onset acquired epileptic aphasia (Landau-Klef­fner syndrome, LKS) and regres­sive autistic disorders with epileptic EEG abnormalities: the continu­­ing debate. Brain Dev 2010; 32(9): 746– 752. doi: 10.1016/ j.braindev.2010.06.011.

27. Besag FM. Epilepsy in patients with autism: links, risks and treatment chal­lenges. Neuropsychiatr Dis Treat 2017; 14: 1– 10. doi: 10.2147/ NDT.S120509.

28. Lenck-Santini PP, Scott RC, Mechanisms responsible for cognitive impairment in epilepsy. Cold Spr­­ing Harb Perpect Med 2015; 5(10): pii: a022772. doi: 10.1101/ cshperspect.a022772.

29. Stef­fenburg S, Gil­lberg C, Hel­lgren L et al. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry 1989; 30(3): 405– 416.

30. Folstein S, Rutter M. Infantile autism: a genetic study of 21 twin pairs. J Child Psychol Psychiatry 1977; 18(4): 297– 321.

31. Ozonoff S, Young GS, Carter A et al. Recur­rence risk for autism spectrum disorders: a baby siblings research consortium study. Pediatrics 2011; 128(3): e488– e495. doi: 10.1542/ peds.2010-2825.

32. Simons Foundation. Simons Foundation Autism Research Initiative Gene. [online]. Available from URL:http:/ / .

33. Amiet C, Gourfinkel-An I, Laurent C et al. Does epilepsy in multiplex autism pedigrees define a dif­ferent subgroup in terms of clinical characteristics and genetic risk? Mol Autism 2013; 4(1): 47. doi: 10.1186/ 2040-2392-4-47.

34. Ekinci O, Arman AR, Isik U et al. EEG abnormalities and epilepsy in autistic spectrum disorders: clinical and familial cor­relates. Epilepsy Behav 2010; 17(2): 178– 182. doi: 10.1016/ j.yebeh.2009.11.014.

35. Emanuele E, Boso M, Brondino N et al. Increased serum levels of high mobility group Box 1 protein in patients with autistic disorder. Prog Neuropharmacol Biol Psychiatry 2010; 34(4): 681– 683. doi: 10.1016/ j.pnpbp.2010.03.020.

36. Maroso M, Balos­so S, Ravizza T et al. Tol­l-like receptor 4 and high mobility group Box 1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med 2010; 16(4): 413– 419. doi: 10.1038/ nm.2127.

37. Choi J, Min HJ, Shin JS. Increased levels of HMGB1 and pro-inflam­matory cytokines in chldren with febrile seizures. J Neuroinflam­mation 2011; 8: 135. doi: 10.1186/ 1742-2094-8-135.

38. Jyonouchi H, Sun S, Le H. Proinflam­matory and regulatory cytokine production as­sociated with in­nate and adaptive im­mune responses in children with autism. J Neuroim­munol 2001; 120(1– 2): 170– 179.

39. Vezzani A, Granata T. Brain inflam­mation in epilepsy: experimental and clinical evidence. Epilepsia 2005; 46(11): 1724– 1743. doi: 10.1111/ j.1528-1167.2005.00298.x.

40. Theoharides TC, Zhang B. Neuroinflam­mation, blodd.brain bar­rier, seizures and autism. J Neuroinflam­mation 2011; 8: 168. doi: 10.1186/ 1742-2094-8-168.

41. Benson MJ, Manzanero S, Borges K. The ef­fects of C5aR1 on leukocyte infiltration fol­low­­ing pilokarpine-induced status epilepticus. Epilepsia 2017; 58(4): e54– e58. doi: 10.1111/ epi.13698.

42. Nelson TE, Olde Engberink A, Hernandez R et al. Altered synaptic transmis­sion in the hippocampus of transgenic mice with enhanced central nervous system expres­sion of interleukin-6. Brain Behav Im­mun 2012; 26(6): 959– 971. doi: 10.1016/ j.bbi.2012.05.005.

43. Bozzi Y, Provenzano G, Casarosa S. Neurobio­logical bases of autism-epilepsy comorbidity: a focus on excitation/ inhibition imbalance. Eur J Neurosci 2018; 47(6): 534– 548. doi: 10.1111/ ejn.13595.

44. Puts NA, Wodka EI, Har­ris AD et al. Reduced GABA and somatosensory function in children with autism spectrum disorder. Autism Res 2017; 10(4): 608– 619. doi: 10.1002/ aur.1691.

45. Zurcher NR, Bhanot A, McDougle CJ et al. A systematic review of molecular imag­­ing (PET and SPECT) in autism spectrum disorder: cur­rent state and future research opportunities. Neurosci Biobehav 2015; 52: 56– 73. doi: 10.1016/ j.neubio­rev.2015.02.002.

46. Ariza J, Rogers H, Hashemi E et al. The number of chandelier and basket cel­ls are dif­ferential­ly decreased in prefrontal cortex in autism. Cereb Cortex 2018; 28(2): 411– 420. doi: 10.1093/ cercor/ bhw349.

47. Han S, Tai C, Westenbroek RE et al. Autistic like behavior in Scn1a +- mice and rescue by enhanced GABA-mediated neurotransmis­sion. Nature 2012; 489(7416): 385– 390. doi: 10.1038/ nature11356.

48. Frye RE, Ros­signol D, Casanova MF et al. A review of traditional and novel treatments for seizures in autism spectrum disorder: findings from a systematic review and expert panel. Front Public Health 2013; 1: 31. doi: 10.3389/ fpubh.2013.00031.

49. Hel­lings JA, Nickel EJ, Weckbaugh M et al. The overt aggres­sion scale for ratin aggres­sion in outpatient youth with autistic disorder: preliminary findings. J Neuropsychiatry Clin Neurosci 2005; 17(1): 29– 35. doi: 10.1176/ jnp.17.1.29.

50. Buzsaki G. Neural syntax: cell as­semblies, synapsemblies and readers. Neuron 2012; 68(3): 362– 385. doi: 10.1016/ j.neuron.2010.09.023.

51. Vakorin VA, Doesburg SM, Leung RC et al. Develop­mental changes in neuromagnetic rhythms and network synchronyin autism. Ann Neurol 2017; 81(2): 199– 211. doi: 10.1002/ ana.24836.

52. Simon DM, Wal­lace MT. Dysfunction of sensory oscil­lations in autism spectrum disorder. Neurosci Biobehav Rev 2016; 68: 848– 861. doi: 10.1016/ j.neubio­rev.2016.07.016.

53. Mar­rosu F, Mar­rosu G, Rchel MG et al. Paradoxical reactions elicited by diazepam in children with clas­sic autism. Funct Neurol 1987; 2(3): 355– 361.

54. Silverman JL, Pride MC, Hayes JE et al. GABAb receptor agonist R-baclofen reverses social deficits and reduces repetitive behavior in two mouse models of autism. Neuropsychopharmacology 2015; 40(9): 2228– 2239. doi: 10.1038/ npp.2015.66.

55. Veenstra-VanderWeele J, Cook EH, K­­ing BH et al. Arbaclofen in children and adolescents with autism spectrum disorder: a randimizes control­led, phase II trial. Neuropsychopharmacology 2016; 42(7): 1390– 1398. doi: 10.1038/ npp.2016.237.

56. Brondino N, Fusar-Poli L, Panisi C et al. Pharmacological modulation of GABA function in autism spectrum disorders: a systematic review of human studies. J Autism Dev Disord 2016; 46(3): 825– 839. doi: 10.1007/ s10803-015-2619-y.

57. Yum MS, Lee M, Ko TS et al. A pottential ef­fect of ganaxolone in an animal model of infantile spasms. Epilepsy Res 2014; 108(9): 1492– 1500. doi: 10.1016/ j.eplepsyres.2014.08.015.

58. Kazdoba TM, Hagerman RJ, Zolkowska D et al. Evaluation of the neuriactive steroid ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism. Psychopharmacology (Berl) 2016; 233(2): 309– 323. doi: 10.1007/ s00213-015-4115-7.

59. Kim KC, Rhee J, Park JE et al. Overexpres­siono of telomerase reverse transcriptase induces autism-like excitatory phenotypes in mice. Mol Neurobio­l 2016; 53(10): 7312– 7328. doi: 10.1007/ s12035-015-9630-3.

60. Joshi G, Wozniak J, Faraone SV et al. A prospective open-label trial of memantine hydrochloride for the treatment of social deficits in intel­lectual­ly capable adults with autism spectrum disorder. J Clin Psychopharm 2016; 36(3): 262– 271. doi: 10.1097/ JCP.0000000000000499.

61. Huber KM, Klann E, Costa-Mattioli M et al. Dysregulation of mam­malian target of rapamycin signal­­ing in mouse models of autism. J Neurosci 2015; 35(41): 13836– 13842. doi: 10.1523/ JNEUROSCI.2656-15.2015.

62. French JA, Lawson JA, Yapici Z et al. Adjunctive everolimus ther­apy for treatment resistant focal-onset seizures as­sociated with tuberous sclerosis (EXIST-3): a pahes 3, randomised, double-blind, placebo conrol­led study. Lancet 2016; 388(10056): 2153– 2163. doi: 10.1016/ S0140-6736(16)31419-2

Paediatric neurology Neurosurgery Neurology

Article was published in

Czech and Slovak Neurology and Neurosurgery

Issue 2

2019 Issue 2

Most read in this issue

This topic is also in:

Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account