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Presence of GAD65 autoantibodies in the serum of children with autism or ADHD

Abstract

Antibodies against glutamic acid decarboxylase 65 (GAD65) have been detected in the serum of patients with several neurological disorders. The presence of antibodies against GAD65 has not yet been examined in the serum of patients with neurodevelopmental disorders such as autism or attention-deficit/hyperactivity disorder (ADHD). In this study, GAD65 antibodies and total IgG were assayed in the serum of normal subjects and patients diagnosed with autism or ADHD. GAD65 antibodies were detected in the serum of 15% of children with autism (N = 20), 27% of children with ADHD (N = 15) and of none of the controls (N = 14). The serum of 60% of autistic and 53% of ADHD patients reacted with Purkinje neurons in mouse cerebellum. Serum from 20% of ADHD patients reacted also with the cells in the molecular and granule cell layers and cells in the vicinity of the Purkinje neurons. No association was found between the titer of GAD65 antibodies and total IgG levels, and presence of seizures or mental retardation. None of the ADHD patients were diagnosed with mental retardation. Serum anti-GAD65 antibodies may be a common marker of subgroups of patients with autism and ADHD. Reactions of serum antibodies with the cells in the cerebellum in these patients suggest direct effects on brain function. The subgroup of children with autism and ADHD that tests positive for GAD65 antibodies needs further characterization in a larger study.

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References

  1. Vianello M, Tavolato B, Giometto B (2002) Glutamic acid decarboxylase autoantibodies and neurological disorders. Neurol Sci 23(4):145–151

    PubMed  Article  CAS  Google Scholar 

  2. Blanc F, Ruppert E, Kleitz C, Valenti MP, Cretin B, Humbel RL, Honnorat J, Namer IJ, Hirsch E, Manning L et al (2009) Acute limbic encephalitis and glutamic acid decarboxylase antibodies: a reality? J Neurol Sci 287(1–2):69–71

    PubMed  Article  CAS  Google Scholar 

  3. Chattopadhyay S, Ito M, Cooper JD, Brooks AI, Curran TM, Powers JM, Pearce DA (2002) An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Hum Mol Genet 11(12):1421–1431

    PubMed  Article  CAS  Google Scholar 

  4. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington

    Google Scholar 

  5. Yip J, Soghomonian JJ, Blatt GJ (2009) Decreased GAD65 mRNA levels in select subpopulations of neurons in the cerebellar dentate nuclei in autism: an in situ hybridization study. Autism Res 2(1):50–59

    PubMed  Article  Google Scholar 

  6. Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, Realmuto GR (2002) Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry 52(8):805–810

    PubMed  Article  CAS  Google Scholar 

  7. Bauman M, Kemper TL (1985) Histoanatomic observations of the brain in early infantile autism. Neurology 35(6):866–874

    PubMed  CAS  Google Scholar 

  8. Rout UK, Dhossche DM (2008) A pathogenetic model of autism involving Purkinje cell loss through anti-GAD antibodies. Med Hypotheses 71(2):218–221

    PubMed  Article  CAS  Google Scholar 

  9. American-Psychiatric-Association: Diagnostic and statistical manual of mental disorders: DSM-IV-TR. Book: ISBN 0890420254 1994, Fourth Edition

  10. Rommelse NN, Franke B, Geurts HM, Hartman CA, Buitelaar JK (2010) Shared heritability of attention-deficit/hyperactivity disorder and autism spectrum disorder. Eur Child Adolesc Psychiatry

  11. Ronald A, Simonoff E, Kuntsi J, Asherson P, Plomin R (2008) Evidence for overlapping genetic influences on autistic and ADHD behaviours in a community twin sample. J Child Psychol Psychiatry 49(5):535–542

    PubMed  Article  Google Scholar 

  12. Lichtenstein P, Carlstrom E, Rastam M, Gillberg C, Anckarsater H (2010) The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am J Psychiatry 167(11):1357–1363

    PubMed  Article  Google Scholar 

  13. Pfutzner A, Forst T, Ambrosch A, Schmitz H, Lichtwald K, Beyer J (1995) Determination of anti GAD65 autoantibodies with an ELISA before and after standardization with the new international reference serum. Exp Clin Endocrinol Diabetes 103(2):123–125

    PubMed  Article  CAS  Google Scholar 

  14. Sokol DK, McIntyre JA, Wagenknecht DR, Dropcho EJ, Patel H, Salanova V, da Costa G (2004) Antiphospholipid and glutamic acid decarboxylase antibodies in patients with focal epilepsy. Neurology 62(3):517–518

    PubMed  CAS  Google Scholar 

  15. Kaplitt MG, Feigin A, Tang C, Fitzsimons HL, Mattis P, Lawlor PA, Bland RJ, Young D, Strybing K, Eidelberg D et al (2007) Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: an open label, phase I trial. Lancet 369(9579):2097–2105

    PubMed  Article  CAS  Google Scholar 

  16. Stoop JW, Zegers BJ, Sander PC, Ballieux RE (1969) Serum immunoglobulin levels in healthy children and adults. Clin Exp Immunol 4(1):101–112

    PubMed  CAS  Google Scholar 

  17. Perlov E (2010) Tebarzt van Elst L, Buechert M, Maier S, Matthies S, Ebert D, Hesslinger B, Philipsen A: H(1)-MR-spectroscopy of cerebellum in adult attention deficit/hyperactivity disorder. J Psychiatr Res 44(14):938–943

    PubMed  Article  CAS  Google Scholar 

  18. Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral DG, Van de Water J (2009) Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain Behav Immun 23(1):64–74

    PubMed  Article  CAS  Google Scholar 

  19. Alarcon-Segovia D, Ruiz-Arguelles A, Llorente L (1996) Broken dogma: penetration of autoantibodies into living cells. Immunol Today 17(4):163–164

    PubMed  Article  CAS  Google Scholar 

  20. Lees GJ, Horsburgh RJ (1984) Retrograde transport of dopamine beta-hydroxylase antibodies in sympathetic neurons: effects of drugs modifying noradrenergic transmission. Brain Res 301(2):281–286

    PubMed  Article  CAS  Google Scholar 

  21. Wenthold RJ, Skaggs KK, Reale RR (1984) Retrograde axonal transport of antibodies to synaptic membrane components. Brain Res 304(1):162–165

    PubMed  Article  CAS  Google Scholar 

  22. Friden PM, Olson TS, Obar R, Walus LR, Putney SD (1996) Characterization, receptor mapping and blood–brain barrier transcytosis of antibodies to the human transferrin receptor. J Pharmacol Exp Ther 278(3):1491–1498

    PubMed  CAS  Google Scholar 

  23. Banks WA, Terrell B, Farr SA, Robinson SM, Nonaka N, Morley JE (2002) Passage of amyloid beta protein antibody across the blood–brain barrier in a mouse model of Alzheimer’s disease. Peptides 23(12):2223–2226

    PubMed  Article  CAS  Google Scholar 

  24. Banks WA, Farr SA, Morley JE, Wolf KM, Geylis V, Steinitz M (2007) Anti-amyloid beta protein antibody passage across the blood–brain barrier in the SAMP8 mouse model of Alzheimer’s disease: an age-related selective uptake with reversal of learning impairment. Exp Neurol 206(2):248–256

    PubMed  Article  CAS  Google Scholar 

  25. Burton AR, Baquet Z, Eisenbarth GS, Tisch R, Smeyne R, Workman CJ, Vignali DA (2010) Central nervous system destruction mediated by glutamic acid decarboxylase-specific CD4+ T cells. J Immunol 184(9):4863–4870

    PubMed  Article  CAS  Google Scholar 

  26. Landas S, Fischer J, Wilkin LD, Mitchell LD, Johnson AK, Turner JW, Theriac M, Moore KC (1985) Demonstration of regional blood–brain barrier permeability in human brain. Neurosci Lett 57(3):251–256

    PubMed  Article  CAS  Google Scholar 

  27. Faust TW, Chang EH, Kowal C, Berlin R, Gazaryan IG, Bertini E, Zhang J, Sanchez-Guerrero J, Fragoso-Loyo HE, Volpe BT et al (2010) Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms. Proc Natl Acad Sci USA 107(43):18569–18574

    PubMed  Article  CAS  Google Scholar 

  28. Tanaka S, Matsunaga H, Kimura M, Tatsumi K, Hidaka Y, Takano T, Uema T, Takeda M, Amino N (2003) Autoantibodies against four kinds of neurotransmitter receptors in psychiatric disorders. J Neuroimmunol 141(1–2):155–164

    PubMed  Article  CAS  Google Scholar 

  29. Mitoma H, Song SY, Ishida K, Yamakuni T, Kobayashi T, Mizusawa H (2000) Presynaptic impairment of cerebellar inhibitory synapses by an autoantibody to glutamate decarboxylase. J Neurol Sci 175(1):40–44

    PubMed  Article  CAS  Google Scholar 

  30. Mitoma H, Ishida K, Shizuka-Ikeda M, Mizusawa H (2003) Dual impairment of GABAA- and GABAB-receptor-mediated synaptic responses by autoantibodies to glutamic acid decarboxylase. J Neurol Sci 208(1–2):51–56

    PubMed  Article  CAS  Google Scholar 

  31. Ishida K, Mitoma H, Mizusawa H (2008) Reversibility of cerebellar GABAergic synapse impairment induced by anti-glutamic acid decarboxylase autoantibodies. J Neurol Sci 271(1–2):186–190

    PubMed  Article  CAS  Google Scholar 

  32. Bauman ML, Kemper TL: The neuropathology of the autism spectrum disorders: what have we learned? Novartis Found Symp 2003, 251:112–122; discussion 122–118, 281–197

  33. Soliva JC, Moreno A, Fauquet J, Bielsa A, Carmona S, Gispert JD, Rovira M, Bulbena A, Vilarroya O (2010) Cerebellar neurometabolite abnormalities in pediatric attention/deficit hyperactivity disorder: a proton MR spectroscopic study. Neurosci Lett 470(1):60–64

    PubMed  Article  CAS  Google Scholar 

  34. Mackie S, Shaw P, Lenroot R, Pierson R, Greenstein DK, Nugent TF 3rd, Sharp WS, Giedd JN, Rapoport JL (2007) Cerebellar development and clinical outcome in attention deficit hyperactivity disorder. Am J Psychiatry 164(4):647–655

    PubMed  Article  Google Scholar 

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Acknowledgments

This study was supported by an intramural grant (PI: UK Rout) of the University of Mississippi Medical Center Jackson, MS. The help of the staff at Blair E. Batson Children’s Hospital, UMMC, in collecting blood samples is highly appreciated.

Conflict of interest

The authors have no conflicts of interests and have no financial interests of any kind in publishing the results of this study.

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Correspondence to Ujjwal K. Rout.

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Rout, U.K., Mungan, N.K. & Dhossche, D.M. Presence of GAD65 autoantibodies in the serum of children with autism or ADHD. Eur Child Adolesc Psychiatry 21, 141–147 (2012). https://doi.org/10.1007/s00787-012-0245-1

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  • DOI: https://doi.org/10.1007/s00787-012-0245-1

Keywords

  • Autoantibodies
  • Autism
  • ADHD
  • GAD
  • Serum
  • Brain and development