Hostname: page-component-cd9895bd7-gxg78 Total loading time: 0 Render date: 2024-12-27T14:25:11.613Z Has data issue: false hasContentIssue false
  • English
  • Français

Pathophysiology of autism: current opinions

Published online by Cambridge University Press:  24 June 2014

J Croonenberghs ,
D Deboutte  and
M Maes
J Croonenberghs*
Affiliation:
University of Antwerp, the University Center of Child and Adolescent Psychiatry, A.Z.M., Antwerp
D Deboutte
Affiliation:
University of Antwerp, the University Center of Child and Adolescent Psychiatry, A.Z.M., Antwerp
M Maes
Affiliation:
The Clinical Research Center for Mental Health (CRC-MH), Antwerp
*
University Center of Child and Adolescent Psychiatry, AZ Middelheim Lindendreef 1, 2020, Antwerp, Belgium. Fax: 32 3 2304051; E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Research on the neurochemical aspects of the pathophysiology of autism is still increasing and publications are abundant. In this paper we reviewed significant data from the last decade and recent research results from our center. We focused on molecules influencing the central nervous system (CNS) and consecutively responsible for typical autistic behavior. We highlighted the mutual relationship between the serotonergic, immunological and endocrinological system and the interaction of these three pivotal systems with predisposing (genetic)and external (pre-, peri- and postnatal) conditions and xenobiotics. We stressed the influence of age, pubertal stage, sex, race and IQ on biological data. There is growing evidence that the complexity and variability of those interactions might be responsible for the heterogeneity of behavioral phenotypes and biological findings in Autism. Genetic, neuroanatomical and neurophysiological data were mentioned according their relevance to neurochemical opinions.

Keywords

autismpathophysiologyneurochemical aspectsserotoninimmunologyendocrinology
Type
Research Article
Information
Acta Neuropsychiatrica , Volume 14 , Issue 2 , April 2002 , pp. 93 - 102
Copyright
Copyright © Acta Neuropsychiatrica 2002

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th edn. Washington, DC: APA, 1994.Google Scholar
Gillberg, C, Coleman, M.The biology of the autistic syndromes, 3rd edn. New York: Cambridge University Press, 2000. Google ScholarPubMed
Cook, E, Leventhal, BL.The serotonin system in autism. Curr Opin Pediatr 1996;8: 348–354.CrossRefGoogle ScholarPubMed
McBride, PA, Anderson, GM, Hertzig, MEet al. Effects of diagnosis, race, and puberty on platelet serotonin levels in autism and mental retardation. J Am Acad Child Adolesc Psychiatry 1998;37: 767–776.CrossRefGoogle ScholarPubMed
Hanley, HG, Stahl, SM, Freeman, DX.Hyperserotonemia and amine metabolites in autistic and retarded children. Arch Gen Psychiatry 1977;34: 521–531.CrossRefGoogle Scholar
McDougle, CJ, Naylor, ST, Cohen, DJ, Aghajanian, GK, Heninger, GR, Price, LH.Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry 1996;53: 993–1000.CrossRefGoogle ScholarPubMed
McDougle, CJ, Naylor, ST, Cohen, DJ, Volkmar, FR, Heninger, GR, Price, LH.A double-blind, placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry 1996;53: 1001–1008.CrossRefGoogle ScholarPubMed
Chugani, DC, Behen, M, Muzik, O, Chugani, HT.Focal abnormalities in serotonin synthesis in autistic children. Ann Neurol 1998;44: 555. Google Scholar
Chugani, DC, Muzik, O, Behen, Met al. Developmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol 1999;45: 287–295.3.0.CO;2-9>CrossRefGoogle ScholarPubMed
Cook, EH, Chourchesne, R, Lord, Cet al. Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry 1997;2: 247–250.Google ScholarPubMed
Klauck, SM, Poustka, F, Benner, A, Lesch, KP, Poustka, A.Serotonin transporter (5-HTT) gene variants associated with autism? Hum Mol Genet 1997;6: 2233–2238.CrossRefGoogle ScholarPubMed
Weizman, A, Gonen, N, Tyano, S, Szekely, GA, Rehavi, M.Platelet [3H]imipramine binding in autism and schizophrenia. Psychopharmacology 1987;91: 101–103.CrossRefGoogle Scholar
Croonenberghs, J, Delmeire, L, Verkerk, R.et al. Serotonergic and noradrenergic markers of the autistic disorder. Neuropsychopharmacology 2000;22: 275–283.CrossRefGoogle ScholarPubMed
Minderaa, R, Anderson, GM, Volkmar, FR, Akkerhuis, GW, Cohen, DI.Noradrenergic and adrenergic functioning in autism. Biol Psychiatry 1994;36: 237–241.CrossRefGoogle ScholarPubMed
Maes, M, Wauters, A, Verkerk, Ret al. Lower l-tryptophan availability in depression: a marker of a more generalized disorder in protein metabolism. Neuropsychopharmacology 1996;15: 243–251.CrossRefGoogle Scholar
Pardridge, WM.Tryptophan transport through the blood–brain barrier: in vivo measurement of free and albumin-bound amino acid. Life Sci 1979;25: 1519–1528.CrossRefGoogle ScholarPubMed
McBride, PA, Tierney, H, Demeo, M, Chen, JS, Mann, JJ.Effects of age and gender on CNS serotonergic responsivity in normal adults. Biol Psychiatry 1990;27: 1143–1155.CrossRefGoogle ScholarPubMed
Cook, EH, Leventhal, BL, Heller, W, Metz, J, Wainwright, M, Freedman, DX.Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine levels and intelligence. J Neuropsych Clin Neurosci 1990;2: 268–274. Google ScholarPubMed
Gillberg, C, Svennerholm, L.CSF monoamines in autistic syndromes and other pervasive developmental disorders of early childhood. Br J Psychiatry 1987;151: 89–94.CrossRefGoogle ScholarPubMed
Visconti, P, Piazzi, S, Posar, A, Santi, A, Pipitone, E, Rossi, PG.Amino acids and infantile autism. Dev Brain Dysfunct 1994;7: 86–92. Google Scholar
Voog, L, Eriksson, T.Relationship between plasma and brain large neutral amino acids in rats fed diets with different compositions at different times of the day. J Neurochem 1992;59: 1868–1874.CrossRefGoogle Scholar
Ernst, M, Zametkin, AJ, Matochik, JA, Pascualvaca, D, Cohen, RM.Low medial prefrontal dopaminergic activity in autistic children. Lancet 1997;30: 638. CrossRefGoogle Scholar
Rolf, LH, Haarmann, FY, Grotemeyer, KH, Kehrer, H.Serotonin and amino acid content in platelets of autistic children. Acta Psychiatr Scand 1993;87: 312–316.CrossRefGoogle ScholarPubMed
Moreno-Fuenmayor, H, Borjas, L, Arrieta, A, Valera, V, Socorro-Candanoza, L.Plasma excitatory amino acids in autism. Invest Clin 1996;37: 113–128.Google ScholarPubMed
Messahel, S, Pheasant, AE, Pall, H, Ahmed-Choudhury, J, Sungum-Paliwal, RS, Vostanis, P.Urinary levels of neopterin and biopterin in autism. Neurosci Lett 1998;241: 17–20.CrossRefGoogle ScholarPubMed
Harrison, KL, Pheasant, AE.Analysis of urinary pterins in autism. Biochem Soc Trans 1995;23: 603S.CrossRefGoogle ScholarPubMed
Eto, I, Bandy, MD, Butterworth, CE Jr.Plasma and urinary levels of biopterin, neopterin, and related pterins and plasma levels of folate in infantile autism. J Autism Dev Disord 1992;22: 295–308.CrossRefGoogle ScholarPubMed
Takesada, M, Nakane, A, Yamazaki, K, Noguchi, T, Watanabe, Y, Hayaishi, O.Therapeutic effect of tetrahydrobiopterin in infantile autism. Proc Jap Acad Series B 1987;63: 231–239. Google Scholar
Nordin, V, Lekman, A, Johansson, M, Fredman, P, Gillberg, C.Gangliosides in cerebrospinal fluid in children with autism spectrum disorders. Dev Med Child Neurol 1998;40: 587–594.CrossRefGoogle ScholarPubMed
Ahlsen, G, Rosengren, L, Belfrage, Met al. Glial fibrillary acidic protein in the cerebrospinal fluid of children with autism and other neuropsychiatric disorders. Biol Psychiatry 1993;33: 734–743.CrossRefGoogle ScholarPubMed
Hendren, RL, De Backer, I, Pandina, GJ.Review of neuroimaging studies of child and adolescent psychiatric disorders from the past 10 years. J Am Acad Child Adolesc Psychiatry 2000;39: 815–828.CrossRefGoogle ScholarPubMed
Kemper, TL, Bauman, M.Neuropathology of infantile autism. J Neuropathol Exp Neurol 1998;57: 645–652.CrossRefGoogle ScholarPubMed
Skjeldal, OH, Sponheim, E, Ganes, T, Jellum, E, Bakke, S.Childhood autism: the need for physical investigations. Brain Dev 1998;20: 227–233.CrossRefGoogle ScholarPubMed
Courchesne, E, Muller, RA, Saitoh, O.Brain weight in autism: normal in the majority of cases, megalencephalic in rare cases. Neurology 1999;52: 1057–1059.CrossRefGoogle ScholarPubMed
Wybran, J.Enkephalins and endorphins: activation molecules for the immune system and natural killer activity? Neuropeptides 1985;5: 371–374.Google Scholar
Willemsen-Swinkels, SH, Buitelaar, JK, Weijnen, FG, Thijssen, JH, Van Engeland, H.Plasma beta-endorphin concentrations in people with learning disability and self-injurious and/or autistic behaviour. Br J Psychiatry 1996;168: 105–109.CrossRefGoogle ScholarPubMed
Tordjman, S, Anderson, GM, McBride, PAet al. Plasma beta-endorphin, adrenocorticotropin hormone, and cortisol in autism. J Child Psychol Psychiatry 1997;38: 705–715.CrossRefGoogle Scholar
Leboyer, M, Bouvard, MP, Recasens, Cet al. Difference between plasma N- and C-terminally directed beta-endorphin immunoreactivity in infantile autism. Am J Psychiatry 1994;151: 1797–1801.Google ScholarPubMed
Leboyer, M, Philippe, A, Bouvard, Met al. Whole blood serotonin and plasma beta-endorphin in autistic probands and their first-degree relatives. Biol Psychiatry 1999;45: 158–163.CrossRefGoogle ScholarPubMed
Ross, DL, Klykylo, WM, Hitzemann, R.Reduction of elevated CSF beta-endorphin by fenfluramine in infantile autism. Pediatr Neurol 1987;3: 83–86.CrossRefGoogle ScholarPubMed
Gillberg, C, Terenius, L, Hagberg, B, Witt-Engerstrom, I, Eriksson, I.CSF beta-endorphins in childhood neuropsychiatric disorders. Brain Dev 1990;12: 88–92.CrossRefGoogle ScholarPubMed
Nagamitsu, S, Matsuishi, T, Kisa, Tet al. CSF beta-endorphin levels in patients with infantile autism. J Autism Dev Disord 1997;27: 155–163.CrossRefGoogle ScholarPubMed
Marchetti, B, Morale, MC, Guarcello, Vet al. Cross-talk communication in the neuroendocrine-reproductive-immune axis. Age-dependent alterations in the common communication networks. Ann NY Acad Sci 1990;594: 309–325.CrossRefGoogle ScholarPubMed
Herman, BH, Hammock, MK, Arthur-Smith, Aet al. Naltrexone decreases self-injurious behavior. Ann Neurol 1987;22: 550–552.CrossRefGoogle Scholar
Campbell, M, Anderson, LT, Small, AMet al. Naltrexone in autistic children. behavioral symptoms and attentional learning. J Am Acad Child Adolesc Psychiatry 1993;32: 1283–1291.CrossRefGoogle Scholar
Buitelaar, JK, Van Engeland, H, De Kogel, Ket al. The adrenocorticotrophic hormone (4–9) analog ORG 2766 benefits autistic children. report on a second controlled clinical trial. J Am Acad Child Adolesc Psychiatry 1992;31: 1149–1156.CrossRefGoogle ScholarPubMed
Modahl, C, Green, L, Fein, Det al. Plasma oxytocin levels in autistic children. Biol Psychiatry 1998;43: 270–277.CrossRefGoogle ScholarPubMed
Page, T, Coleman, M.De novo purine synthesis is increased in the fibroblasts of purine autism patients. Adv Exp Med Biol 1998;431: 793–796.CrossRefGoogle ScholarPubMed
Stone, RL, Aimi, J, Barshop, BAet al. A mutation in adenylosuccinate lyase associated with mental retardation and autistic features. Nat Genet 1992;1: 59–63.CrossRefGoogle ScholarPubMed
Fon, EA, Sarrazin, J, Meunier, Cet al. Adenylsuccinate lyase (ADSL) and infantile autism: absence of previously reported point mutation. Am J Med Genet 1995;60: 554–557.CrossRefGoogle Scholar
De Luca, D, Bottini, N, Porfirio, Cet al. Adenosine deaminase polymorphism in autistic children. Ann Neurol 1999;46: 529. Google Scholar
Stubbs, EG, Litt, M, Lis, Eet al. Adenosine deaminase activity decreased in autism. J Am Acad Pediatr 1982;21: 71–74. Google ScholarPubMed
Page, T, Yu, A, Fontanesi, J, Nyhan, WL.Developmental disorder associated with increased cellular nucleotidase activity. Proc Natl Acad Sci USA 1997;94: 11601–11606.CrossRefGoogle ScholarPubMed
Stubbs, G.Interferonemia and autism. J Autism Dev Disord 1995;25: 71–73.CrossRefGoogle ScholarPubMed
Singh, VK, Warren, RP, Odell, JD, Cole, P.Changes of soluble interleukin-2, interleukin-2 receptor, T8 antigen, and interleukin-1 in the serum of autistic children. Clin Immunol Immunopathol 1991;61: 448–455.CrossRefGoogle ScholarPubMed
Singh, VK, Cheng, JF.Plasma increase of IL-12 and interferon-gamma. Pathological significance in autism. J Neuroimmunol 1996;64: 135–139.CrossRefGoogle Scholar
Denney, DR, Frei, BW, Gaffney, GR.Lymphocyte subsets and interleukin-2 receptors in autistic children. J Autism Dev Disord 1996;26: 87–97.CrossRefGoogle ScholarPubMed
Hill, NO, Pardue, A, Khan, A, Aleman, C, Dorn, G, Hill, JM.Phase 1 human leucocyte interferon trials in cancer and leukemia. J Clin Hematol Oncol 1981;11: 23–25. Google Scholar
Stubbs, EG.Autistic children exhibit undetectable hemagglutination-inhibition antibody titers despite previous rubella vaccination. J Autism Child Schizophr 1976 1987;6: 269–274.CrossRefGoogle Scholar
Stubbs, G.Does intrauterine cytomegalovirus plus autoantibodies contribute to autism? In: Wing, L, ed. Aspects of autism: biological research. London: Gaskell Psychiatry Series; 1987; 91–101. Google Scholar
Weizman, A, Weizman, R, Szekely, GA, Wijsenbeek, H, Livni, E.Abnormal immune response to brain tissue antigen in the syndrome of autism. Am J Psychiatry 1982;139: 1462–1465.Google ScholarPubMed
Singh, VK, Warren, RP, Odell, JD, Warren, WL, Cole, P.Antibodies to myelin basic protein in children with autistic behavior. Brain Behav Immun 1993;7: 97–103.CrossRefGoogle ScholarPubMed
Singh, VK, Warren, R, Averett, R, Ghaziuddin, M.Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr Neurol 1997;17: 88–90.CrossRefGoogle ScholarPubMed
Singh, VK, Fudenburg, HH, Emerson, D, Coleman, M.Immunodiagnosis and immunotherapy in autistic children. Ann NY Acad Sci 1988;540: 602–604.CrossRefGoogle ScholarPubMed
Plioplys, AV, Greaves, A, Yoshida, W.Anti-CNS antibodies in childhood neurologic diseases. Neuropediatrics 1989;20: 93–102.CrossRefGoogle ScholarPubMed
Zimmerman, AW, Brashear, HR, Frye, VH, Potter, NT. Anticerebellar antibodies in autism [abstract]. International Conference on Autism. Toronto, Canada, 1993. Google Scholar
Todd, RD, Hickok, JM, Anderson, GM, Cohen, DJ.Antibrain antibodies in infantile autism. Biol Psychiatry 1988;15: 644–647. CrossRefGoogle Scholar
Connolly, AM, Chez, MG, Pestronk, A, Arnold, ST, Mehta, S, Deuel, RK.Serum autoantibodies to brain in Landau–Kleffner variant, autism, and other neurologic disorders. J Pediatr 1999;134: 607–613.CrossRefGoogle ScholarPubMed
Bashina, VM, Kozlova, IA, Kliushnik, TPet al. An elevation in the level of autoantibodies to nerve-growth factor in the blood serum of schizophrenic children. Zh Nevropatol Psikhiatr Im S S Korsakova 1997;97: 47–51.Google Scholar
Singh, VK, Lin, SX, Yang, VC.Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Clin Immunol Immunopathol 1998;89: 105–108.CrossRefGoogle Scholar
Cook, EH Jr,Perry, BD, Dawson, G, Wainwright, MS, Leventhal, BS.Receptor inhibition by immunoglobulins. specific inhibition by autistic children, their relatives, and control subjects. J Autism Dev Disord 1993;23: 67–78.CrossRefGoogle ScholarPubMed
Warren, RP, Singh, VK.Elevated serotonin levels in autism: association with the major histocompatibility complex. Neuropsychobiol 1996;34: 72–75. CrossRefGoogle ScholarPubMed
Hollander, EI, Giudice-Asch, G, Simon, Let al. B lymphocyte antigen D8/17 and repetitive behaviors in autism. Am J Psychiatry 1999;156: 317–320.Google ScholarPubMed
Lucarelli, S, Frediani, T, Zingoni, AMet al. Food allergy and infantile autism. Panminerva Med 1995;37: 137–141.Google ScholarPubMed
Warren, RP, Odell, JD, Warren, WLet al. Strong association of the third hypervariable region of HLA-DR beta 1 with autism. J Neuroimmunol 1996;67: 97–102.CrossRefGoogle ScholarPubMed
Warren, RP, Yonk, J, Burger, RW, Warren, WL.DR-positive cells in autism. association with decreased plasma levels of the complement C4b protein. Neuropsychobiology 1995;31: 53–57.CrossRefGoogle Scholar
Clement, HW, Buschmann, J, Rex, Set al. Effects of interferon-gamma, interleukin-1beta, and tumour necrosis factor-alfa on the serotonin metabolism in the nucleus raphe dorsalis of the rat. J Neur Transm 1997;104: 981–991. CrossRefGoogle Scholar
Ramamoorthy, S, Ramamoorthy, JD, Prasad, PDet al. Regulation of the human serotonin transporter by interleukin-1 beta. Biochem Biophys Res Comm 1995;216: 560–567.CrossRefGoogle ScholarPubMed
Maes, M, Song, C, Lin, AHet al. Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion. Neuropsychopharmacology 1999;20: 370–379.CrossRefGoogle ScholarPubMed
Faraj, BA, Olkowski, ZL, Jackson, RT.Expression of a high-affinity serotonin transporter in human lymphocytes. Int J Immunopharmacol 1994;16: 561–566.CrossRefGoogle ScholarPubMed
Young, MR, Matthews, JP.Serotonin regulation of T cell subpopulations and of macrophage accessory function. Immunology 1995;84: 148–152.Google ScholarPubMed
Maes, M, Scharpe, S, Meltzer, HY, Okayli, G, D'Hondt, P, Cosyns, P.Increased neopterin and interferon gamma secretion and lower l-tryptophan levels in major depression: further evidence for immune activation in severe depression. Psychiatr Res 1994;54: 143–160. CrossRefGoogle Scholar
Cook, EH.Autism: review of neurochemical investigation. Synapse 1990;6: 292–308.CrossRefGoogle ScholarPubMed
Nir, I, Meir, D, Zilber, N, Knobler, H, Hadjez, J, Lerner, Y.Brief report. circadian melatonin, thyroid-stimulating hormone, prolactin and cortisol levels in serum of young adults with autism. J Autism Dev Disord 1995;25: 641–654.CrossRefGoogle ScholarPubMed
Deutsch, SI, Campbell, M, Sachar, EJ, Green, WH, David, R.Plasma growth hormone response to L-DOPA in infantile autism. J Autism Dev Disord 1985;15: 205–212.CrossRefGoogle ScholarPubMed
McBride, PA, Anderson, GM, Hertzig, MEet al. Serotonergic responsivity in male young adults with autistic disorder. Arch General Psychiatry 1989;46: 205–212. CrossRefGoogle ScholarPubMed
Jensen, JB, Realmuto, GM, Garfinkel, BD.The dexamethasone suppression test in infantile autism. J Am Acad Child Psychiatry 1985;24: 263–265.CrossRefGoogle ScholarPubMed
Tordjman, S, Ferrari, P, Sulmont, V, Duyme, M, Roubertoux, P.Androgenic activity in autism. Am J Psychiatry 1997;154: 1626–1627.CrossRefGoogle ScholarPubMed
McBride, PA, Anderson, GM, Mann, JJ.Serotonin-mediated responses in autism. Biol Psychiatry 1989;25: 183A. CrossRefGoogle Scholar
Navarra, P, Tsagarakis, S, Faria, MS, Rees, LH, Besser, GM, Grossman, AB.Interleukins-1 and -6 stimulate the release of corticotropin-releasing hormone 41 from rat hypothalamus in vitro via the eicosanoid cyclooxygenase pathway. Endocrinology 1991;128: 37–44.CrossRefGoogle ScholarPubMed
Szatmari, P.Heterogeneity and the genetics of autism. J Psychiatry Neurosci 1999;24: 159–165.Google ScholarPubMed
Piven, J, Arndt, S, Bailey, J, Andreasen, N.Regional brain enlargement in autism – a magnetic resonance imaging study. J Am Acad Child Adolesc Psychiatry 1996;35: 530–536.CrossRefGoogle ScholarPubMed
Minshew, NJ.Brief report: brain mechanisms in autism. functional and structural abnormalities. J Autism Dev Disord 1996;26: 205–209.CrossRefGoogle ScholarPubMed
Horvath, K, Papadimitriou, JC, Rabsztyn, A, Drachenberg, C, Tildon, JT.Gastrointestinal abnormalities in children with autistic disorder. J Pediatr 1999 1988;135: 559–563.CrossRefGoogle ScholarPubMed
Shattock, P.Autism: possible clues to the underlying etiology. A parent's view. In: Wing, R, ed. Aspects of autism. London: Gaskell Psychiatry Series; 1988;1–18. Google ScholarPubMed
Pavone, L, Fiumara, A, Bottaro, G, Mazzone, D, Coleman, M.Autism and celiac disease: failure to validate the hypothesis that a link might exist. Biol Psychiatry 1997;42: 72–75.CrossRefGoogle Scholar
Sandler, AD, Sutton, KA, De Weese, J, Girardi, MA, Sheppard, V, Bodfish, JW.Lack of benefit of a single dose of synthetic human secretin in the treatment of autism and pervasive developmental disorder. N Engl J Med 1999;341: 1801–1806.CrossRefGoogle ScholarPubMed
Stejskal, J, Stejskal, V.The role of metals in autoimmunity and the link to neuroendocrinology. Neuroendocrinol Lett 1999;20: 351–364.Google ScholarPubMed