European Child & Adolescent Psychiatry

, Volume 21, Issue 3, pp 141–147 | Cite as

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

  • Ujjwal K. Rout
  • Nils K. Mungan
  • Dirk M. Dhossche
Original Contribution

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.

Keywords

Autoantibodies Autism ADHD GAD Serum Brain and development 

References

  1. 1.
    Vianello M, Tavolato B, Giometto B (2002) Glutamic acid decarboxylase autoantibodies and neurological disorders. Neurol Sci 23(4):145–151PubMedCrossRefGoogle Scholar
  2. 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):69–71PubMedCrossRefGoogle Scholar
  3. 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):1421–1431PubMedCrossRefGoogle Scholar
  4. 4.
    American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, WashingtonGoogle Scholar
  5. 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):50–59PubMedCrossRefGoogle Scholar
  6. 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):805–810PubMedCrossRefGoogle Scholar
  7. 7.
    Bauman M, Kemper TL (1985) Histoanatomic observations of the brain in early infantile autism. Neurology 35(6):866–874PubMedGoogle Scholar
  8. 8.
    Rout UK, Dhossche DM (2008) A pathogenetic model of autism involving Purkinje cell loss through anti-GAD antibodies. Med Hypotheses 71(2):218–221PubMedCrossRefGoogle Scholar
  9. 9.
    American-Psychiatric-Association: Diagnostic and statistical manual of mental disorders: DSM-IV-TR. Book: ISBN 0890420254 1994, Fourth EditionGoogle Scholar
  10. 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 PsychiatryGoogle Scholar
  11. 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):535–542PubMedCrossRefGoogle Scholar
  12. 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):1357–1363PubMedCrossRefGoogle Scholar
  13. 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):123–125PubMedCrossRefGoogle Scholar
  14. 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):517–518PubMedGoogle Scholar
  15. 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):2097–2105PubMedCrossRefGoogle Scholar
  16. 16.
    Stoop JW, Zegers BJ, Sander PC, Ballieux RE (1969) Serum immunoglobulin levels in healthy children and adults. Clin Exp Immunol 4(1):101–112PubMedGoogle Scholar
  17. 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):938–943PubMedCrossRefGoogle Scholar
  18. 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):64–74PubMedCrossRefGoogle Scholar
  19. 19.
    Alarcon-Segovia D, Ruiz-Arguelles A, Llorente L (1996) Broken dogma: penetration of autoantibodies into living cells. Immunol Today 17(4):163–164PubMedCrossRefGoogle Scholar
  20. 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):281–286PubMedCrossRefGoogle Scholar
  21. 21.
    Wenthold RJ, Skaggs KK, Reale RR (1984) Retrograde axonal transport of antibodies to synaptic membrane components. Brain Res 304(1):162–165PubMedCrossRefGoogle Scholar
  22. 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):1491–1498PubMedGoogle Scholar
  23. 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):2223–2226PubMedCrossRefGoogle Scholar
  24. 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):248–256PubMedCrossRefGoogle Scholar
  25. 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):4863–4870PubMedCrossRefGoogle Scholar
  26. 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):251–256PubMedCrossRefGoogle Scholar
  27. 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):18569–18574PubMedCrossRefGoogle Scholar
  28. 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):155–164PubMedCrossRefGoogle Scholar
  29. 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):40–44PubMedCrossRefGoogle Scholar
  30. 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):51–56PubMedCrossRefGoogle Scholar
  31. 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):186–190PubMedCrossRefGoogle Scholar
  32. 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, 281–197Google Scholar
  33. 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):60–64PubMedCrossRefGoogle Scholar
  34. 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):647–655PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Ujjwal K. Rout
    • 1
  • Nils K. Mungan
    • 2
  • Dirk M. Dhossche
    • 3
  1. 1.Department of SurgeryUniversity of Mississippi Medical Center, Clinical Sciences BuildingJacksonUSA
  2. 2.Department of OphthalmologyUniversity of Mississippi Medical CenterJacksonUSA
  3. 3.Department of Psychiatry and Human BehaviorUniversity of Mississippi Medical CenterJacksonUSA

Personalised recommendations