Potential Biomarkers for Diagnosis and Screening of Autism Spectrum Disorders

Anna Meiliana, Andi Wijaya


BACKGROUND: Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental condition, which is typically characterized by a triad of symptoms: impaired social communication, social reciprocity and repetitive stereotypic behavior. While the behavioral phenotype of ASD is well described, the search for reliable ‘autism biomarkers’ continues.

CONTENT: Insulin growth factor (IGF) is essential for the myelination of developing fetal neurons; this is in addition to the well-known links between IGF, maternal inflammation, infection and autism supporting IGF as a potential marker. Combining IGF data with data regarding levels of the known markers, serotonin and anti-myelin basic protein, in order to calculate an autism index, could provide a new diagnostic method for at-risk neonates. Disruptions to multiple pathophysiological systems, including redox, folate, methylation, tryptophan metabolism, and mitochondrial metabolism, have been well documented in autistic patients. Maternal infection and inflammation have known links with autism. Autoimmunity has therefore been a well-studied area of autism research. The potential of using autoantibodies as novel biomarkers for autism, in addition to providing insights into the neurodevelopmental processes that lead to autism.

SUMMARY: The six proposed causes of autism involve both metabolic and immunologic dysfunctions and include: increased oxidative stress; decreased methionine metabolism and trans-sulfuration: aberrant free and bound metal burden; gastrointestinal (GI) disturbances; immune/inflammation dysregulation; and autoimmune targeting. A newborn screening program for early-onset ASD should be capable of utilizing a combination of ASD-associated biomarkers representative of the six proposed causes of autism in order to identify newborns at risk. The biomarkers discussed in this article are useful to guide the selection, efficacy and sufficiency of biomedical interventions, which would likely include nutritional supplementation, dietary changes and specific medications for treating GI pathogens and reducing inflammation.

KEYWORDS: ASD, autism, biomarkers, newborn screening, diagnosis

Full Text:



Kidd PM. Autism, an extreme challenge to integrative medicine. Part: 1: The knowledge base. Altern Med Rev. 2002; 7: 292-316, PMID.

Jepson B. Changing the Course of Autism. Boulder: Sentient Publications; 2007, link.

Posey DJ, Stigler KA, Erickson CA, McDougle CJ. Antipsychotics in the treatment of autism. J Clin Invest. 2008; 118: 6-14, CrossRef.

Bryson SE, Smith IM. Epidemiology of autism: Prevalence, associated characteristics, and implications for research and service delivery. Mental Retard Dev Disab Res Rev. 1998; 4: 97-103, CrossRef.

Cohen DJ, Donnellan AM, Paul R. Handbook of Autism and Pervasive Developmental Disorders. New York: John Wiley & Sons, Inc.; 1987, NLMID.

Schonauer K, Klar M, Kehrer HE, Arolt V. [The course of infantile autism through adulthood. An overview of long-term follow-up data]. Fortschr Neurol Psychiatr. 2001; 69: 221-35, CrossRef.

Volkmar FR, Klin A. Issues in the classification of autism and related conditions. In: Volkmar FR, Paul R, Klin A, Cohen D, editors. Handbook of Autism and Pervasive Developmental Disorders. 3rd Ed. Hoboken: NJ: John Wiley & Sons, Inc.; 2005. p.5-41, CrossRef.

Barbaresi WJ, Katusic SK, Voigt RG. Autism: a review of the state of the science for pediatric primary health care clinicians. Arch Pediatr Adolesc Med. 2006; 160: 1167-75, CrossRef.

Ecker C, Marquand A, Mourão-Miranda J, Johnston P, Daly EM, Brammer MJ, et al. Describing the brain in autism in five dimensions–magnetic resonance imaging-assisted diagnosis of autism spectrum disorder using a multiparameter classification approach. J Neurosci. 2010; 30: 10612-23, CrossRef.

Weintraub K. Autism Count. Nature. 2011; 479: 22-4, PMID.

Ecker C. Autism biomarker for more efficacious diagnosis. Biomarkers Med. 2011; 5: 193-5, CrossRef.

Ratajczak HV. Theoretical aspects of autism: causes A review. J Immunotoxicol. 2011; 8: 68-79, CrossRef.

Mottron L. Changing perceptions: The power of autism. Nature. 2011; 479: 33-5, CrossRef.

Geschwind DH, Levitt P. Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol. 2007; 17: 103-11, CrossRef.

Amaral DG. Neuroanatomy of auism. Trends in Neurosci. 2008; 31: 137-45, CrossRef.

Kanner L. Autistic disturbances of affective contact. Nervous Child. 1943; 2: 217-50, article.

DiCicco-Bloom E, Lord C, Zwaigenbaum L, Courchesne E, Dager SR, Schmitz C, et al. The developmental neurobiology of autism spectrum disorder. J Neurosci. 2006; 26: 6897-906, CrossRef.

Fombonne E. Past and future perspectives on autism epidemiology. In: Moldin SO, Rubenstein JLR, editors. Understanding Autism from Basic Neuroscience to Treatment. London: CRC Press; 2006. p.25-48, CrossRef.

Tuchman R, Rapin I. Epilepsy in autism. Lancet Neurol. 2002; 1: 352-8, CrossRef.

Lecavalier L. Behavioral and emotional problems in young people with pervasive developmental disorders: relative prevalence, effects of subject characteristics, and empirical classification. J Autism Dev Disord. 2006; 36: 1101-14, CrossRef.

Werner E, Dawson G. Validation of the phenomenon of autistic regression using home videotapes. Arch Gen Psychiatry. 2005; 62: 889-95, CrossRef.

Casanova MF. The neuropathology of autism. Brain Pathol. 2007; 17: 422-33, CrossRef.

Persico AM, Bourgeron T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci. 2006; 29: 349-58, CrossRef.

Watts TJ. The pathogenesis of autism. Clin Med Pathol. 2008; 1: 99-103, PMID.

Pardo CA, Eberhart CG. The neurobiology of autism. Brain Pathol. 2007; 17: 434-47, CrossRef.

Herbert MR, Russo JP, Yang S, Roohi J, Blaxill M, Kahler SG, et al. Autism and environmental genomics. Neurotoxicology. 2006; 27: 671-84, CrossRef.

Minshew NJ, Williams DL. The new neurobiology of autism: cortex, connectivity, and neuronal organization. Arch Neurol. 2007; 64: 945-50, CrossRef.

Courchesne E. Brain development in autism: early overgrowth followed by premature arrest of growth. Ment Retard Dev Disabil Res Rev. 2004; 10: 106-11, CrossRef.

Courchesne E, Redcay E, Kennedy DP. The autistic brain: birth through adulthood. Curr Opin Neurol. 2004; 17: 489-96, CrossRef.

Courchesne E, Pierce K. Brain overgrowth in autism during a critical time in development: Implications for frontal pyramidal neuron and interneuron development and connectivity. Int J Dev Neurosci. 2005; 23: 153-70, CrossRef.

Schumann CM, Hamstra J, Goodlin-Jones BL, Lotspeich LJ, Kwon H, Buonocore MH, et al. The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. J Neurosci. 2004; 24: 6392-401, CrossRef.

Polleux F, Lauder JM. Toward a developmental neurobiology of autism. Ment Retard Dev Disabil Res Rev. 2004; 10: 303-17, CrossRef.

Bauman ML, Kemper TL. Neuro-anatomic observations of the brain in autism. In: Bauman ML, Kemper TL, editors. The Neurobiology of Autism. Baltimore: Johns Hopkins University Press; 1994. p.119-45, NLMID.

Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism: A review and future directions. Int J Dev Neurosci. 2005; 23: 183-7, CrossRef.

Courchesne E, Karns CM, Davis HR, Ziccardi R, Carper RA, Tigue ZD, et al. Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study. Neurology. 2001; 57: 245-54, CrossRef.

Haas RH. Autism and mitochondrial disease. Dev Disabil Res Rev. 2010; 16: 144-53, CrossRef.

[n.a]. Child Health Safety [cited 2010 Jun 30]. Available from: https://childhealthsafety.wordpress.com.

Steinman G, Mankuta D. Umbilical cord biomarkers in autism determination. Biomarkers Med. 2014; 8: 317-9, CrossRef.

Rossignol DA, Frye RE. A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol Physichiatry. 2012; 17: 389-401, CrossRef.

Li Z, Dong T, Proschel C, Noble M. Chemically diverse toxicants converge on Fyn and c-Cbl to disrupt precursor cell function. PLoS Biol. 2007; 5: e35, CrossRef.

Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet. 2006; 368: 2167-78, CrossRef.

Braun JM, Kahn RS, Froehlich T, Auinger P, Lanphear BP. Exposures to environmental toxicants and attention deficit hyperactivity disorder in US children. Environ Health Perspect. 2006; 114: 1904-9, CrossRef.

Nigg JT, Knottnerus GM, Martel MM, Nikolas M, Cavanagh K, Karmaus W, et al. Low blood lead levels associated with clinically diagnosed attention-deficit/hyperactivity disorder and mediated by weak cognitive control. Biol Psychiatry. 2008; 63: 325-31, CrossRef.

Bouchard MF, Bellinger DC, Wright RO, Weisskopf MG. Attention-deficit/hyperactivity disorder and urinary metabolites of organophosphate pesticides. Pediatrics. 2010; 125: e1270-7, CrossRef.

Amr MM, Halim ZS, Moussa SS. Psychiatric disorders among Egyptian pesticide applicators and formulators. Environ Res. 1997; 73: 193-9, CrossRef.

Opler MG, Brown AS, Graziano J, Desai M, Zheng W, Schaefer C, et al. Prenatal lead exposure, delta-aminolevulinic acid, and schizophrenia. Environ Health Perspect. 2004; 112: 548-52, CrossRef.

Palmer RF, Blanchard S, Wood R. Proximity to point sources of environmental mercury release as a predictor of autism prevalence. Health Place. 2009; 15: 18-24, CrossRef.

Windham GC, Zhang L, Gunier R, Croen LA, Grether JK. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco bay area. Environ Health Perspect. 2006; 114: 1438-44, CrossRef.

Roberts EM, English PB, Grether JK, Windham GC, Somberg L, Wolff C. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Environ Health Perspect. 2007; 115: 1482-9, CrossRef.

Mutter J, Naumann J, Guethlin C. Comments on the article “The toxicology of mercury and its chemical compounds” by Clarkson and Magos (2006). Crit Rev Toxicol. 2007; 37: 537-49, CrossRef.

Kern JK, Jones AM. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health B Crit Rev. 2006; 9: 485-99, CrossRef.

Mutter J, Naumann J, Schneider R, Walach H, Haley B. Mercury and autism: accelerating evidence? Neuro Endocrinol Lett. 2005; 26: 439-46, CrossRef.

Geier DA, Kern JK, Garver CR, Adams JB, Audhya T, Nataf R, et al. Biomarkers of environmental toxicity and susceptibility in autism. J Neurol Sci. 2009; 280: 101-8, CrossRef.

Nath R. Health and disease: Role of micronutrients and trace elements. New Delhi: APH Publishing Corporation; 2000, link.

Bornhorst JA, Gwendolyn A, Millin M. Trace and toxic elemental testing in the clinical laboratory. Lab Med. 2006; 37: 690-5, CrossRef.

Adams JB, Baral M, Geis E, Mitchell J, Ingram J, Hensley A, et al. The severity of autism is associated with toxic metal body burden and red blood cell glutathione levels. J Toxicol. 2009; 2009: 1-7, CrossRef.

Madsen E, Gitlin JD. Copper and iron disorders of the brain. Annu Rev Neurosci. 2007; 30: 317-3, CrossRef.

Werbach MR. Nutritional influences on mental illness: A sourcebook of clinical research. Tarzana, California: Third Line Press; 1991, NLMID.

Hoffer A. Children with learning and behavioral disorders. J Orthomol Psychiatry. 1976; 5: 228-30, article.

Haas EM. Staying healthy with nutrition, celestial arts; 1992. Available from: https://www.healthy.net/.

Adams J, Holloway C, George F, Quig D. Analyses of toxic metals and essential minerals in the hair of Arizona children with autism and associated conditions, and their mothers. Biol Trace Elem Res. 2006; 110: 193-209, CrossRef.

Martineau J, Laffont F, Bruneau N, Roux S, Le Lord G. Event related potentials evoked by sensory stimulation in normal, mentally retarded and autistic children. Electroencephalogr Clin Neurophysiol. 1980; 48: 140-53, CrossRef.

Watts DL. The nutritional relationships of magnesium. J Orthomol Med. 1988; 3: 197-201, article.

Werbach M. Nutritional influences on aggressive behavior. J Orthomol Med. 1992; 7: 45-51, article.

Passwater RA, Cranton EM. Trace elements: hair analysis and nutrition. New Caanan, CT: Keats Pub; 1983, NLMID.

Marlowe M, Cossairt A, Stellern J, Errera J. Decreased magnesium in the hair of autistic children. J orthomol psychiatry. 1984; 3: 117-22, article.

Environmental working group [homepage on the Internet]. Environmental Triggers & New Clues, 2004 [cited 2014 Jan 31]. Available from: http://www.ewg.org/.

Windham B. Annotated bibliography: health effects related to mercury from amalgam fillings and documented clinical results of replacement of amalgam fillings; 1999. Available from: http://www.fda.gov/.

Bernard S, Enayati A, Redwood L, Roger H, Binstock T. Autism: a unique form of mercury poisoning. Med Hypotheses. 2001; 56: 462-71, CrossRef.

Brockel BJ, Cory-Slechta DA. Lead, attention and impulsive behavior. Pharmacol Biochem Behav. 1998; 60: 545-52, CrossRef.

Priya MDL, Geetha A. Level of trace elements (copper, zinc, magnesium and selenium) and toxic elements (lead and mercury) in the hair and nail of children with autism. Biol Trace Elem Res. 2011; 142: 148-58, CrossRef.

Kazi TG, Jalbani N, Kazi N, Jamali MK, Arain MS, Afridi HI, et al. Evaluation of toxic metals in blood and urine samples of chronic renal failure patients, before and after dialysis. Ren Fail. 2008; 30: 737-45, CrossRef.

Ayodele JT, Bayero AS. Lead and zinc concentrations in hair and nail of some kano inhabitants. African J Env Sci Tech. 2009; 3: 164-70, article.

Beard JL. Iron biology in immune function, muscle metabolism and neuronal functioning. J Nutr. 2001; 131: 568S-79, PMID.

McCann JC, Ames BN. An overview of evidence for a causal relation between iron deficiency during development and deficits in cognitive or behavioral function. Am J Clin Nutr. 2007; 85: 931-45, PMID.

Erikson KM, Jones BC, Hess EJ, Zhang Q, Beard JL. Iron deficiency decreases dopamine D1 and D2 receptors in rat brain. Pharmacol Biochem Behav. 2001; 69: 409-18, CrossRef.

King CR. A novel embryological theory of autism causation involving endogenous biochemicals capable of initiating cellular gene transcription: A possible link between twelve autism risk factors and the autism ‘epidemic’. Med Hypotheses. 2011; 76: 653-60, CrossRef.

Libbey JE, Sweeten TL, Mcmahon WM, Fujinami RS. Autistic disorder and viral infections. J Neurovirol. 2005; 11: 1-10, CrossRef.

Fatemi SH, Earle J, Kanodia R, Kist D, Emamian ES, Patterson PH, et al. Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol Neurobiol. 2002; 22: 25-33, CrossRef.

Steinman G. Predicting autism at birth. Med Hypotheses. 2012; 81: 21-5, CrossRef.

Zikopoulos B, Barbas H. Changes in prefrontal axons may disrupt the network in autism. J Neurosci. 2010; 30: 14595-608, CrossRef.

Bondy CA, Lee WH, Cheng CM. . Insulin-like growth factor I (IGFI) and brain development. In: LeRoith D, Zumkeller W, Baxter RC, editors. Insulin-like growth factors. New York: Kluwer Academic/Plenum Publishers; 2003. p.37-157, NLMID.

Koul O. Myelin and autism. In: Bauman M, Kemper TL, editors. The neurobiology of autism. Johns Hopkins University Press; 2005. p.150-63, NLMID.

Ye P, Li L, Richards RG, DiAugustine RP, D’Ercole AJ. Myelination is altered in insulin-like growth factor-I null mutant mice. J Neurosci. 2002; 22: 6041-51, PMID.

Granero-Molto F. Autocrine effects of mesenchymal stem cells expressing IGF-1 rescue the fracture-healing defects of Irs1 knockout mice. Endocr Rev. 2011; 32: OR12-5.

Herbert MR. Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr Opin Neurol. 2010; 23:103-10, CrossRef.

Valicenti-McDermott MD, McVicar K, Cohen HJ, Wershil BK, Shinnar S. Gastrointestinal symptoms in children with an autism spectrum disorder and language regression. Pediatr Neurol. 2008; 39: 392-8, CrossRef.

Wiest MM, German JB, Harvey DJ, Watkins SM, Hertz-Picciotto I. Plasma fatty acid profiles in autism: a case-control study. Prostaglandins Leukot Essent Fatty Acids. 2009; 80: 221-7, CrossRef.

Morris C, Agin MC. Syndrome of allergy, apraxia, and malabsorption: characterization of a neurodevelopmental phenotype that responds to omega 3 and vitamin E supplementation. Altern Ther Health Med. 2009; 15: 34-43, PMID.

Bent S, Bertoglio K, Hendren RL. Omega-3 fatty acids for autistic spectrum disorder: a systematic review. J Autism Dev Disord. 2009; 39: 1145-54, CrossRef.

Dufault R, Schnoll R, Lukiw WJ, et al. Mercury exposure, nutritional deficiencies and metabolic disruptions may affect learning in children. Behav Brain Funct. 2009; 5: 44, CrossRef.

Herndon AC, DiGuiseppi C, Johnson SL, Leiferman J, Reynolds A. Does nutritional intake differ between children with autism spectrum disorders and children with typical development? J Autism Dev Disord. 2009; 39: 212-22, CrossRef.

Persico AM, Napolioni V. Urinary p-cresol in autism spectrum disorder. Neurotoxicol Teratol. 2012; 36: 82-90, CrossRef.

Nunomura A, Moreira PI, Lee HG, Zhu X, Castellani RJ, Smith MA, et al. Neuronal death and survival under oxidative stress in Alzheimer and Parkinson diseases. CNS Neurol Disord Drug Targets. 2007; 6: 411-23, CrossRef.

Gerhardsson L, Blennow K, Lundh T, Londos E, Minthon L. Concentrations of metals, b-amyloid and tau-markers in cerebrospinal fluid in patients with Alzheimer’s disease. Dement Geriatr Cognit Disord. 2009; 28: 88-94, CrossRef.

Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress. Curr Med Chem. 2005; 12: 1161-208, CrossRef.

Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M. How environmental and genetic factors combine to cause autism: a redox/ methylation hypothesis. Neurotoxicology. 2008; 29: 190-201, CrossRef.

Campagnoni AT. Molecular biology of myelin proteins from the central nervous system. J Neurochem. 1988; 51: 1-14, CrossRef.

Rawal N, Lee YJ, Paik WK, Kim S. Studies on NG-methylarginine derivatives in myelin basic protein from developing and mutant mouse brain. Biochem J. 1992; 287: 929-35, CrossRef.

Ballatori N, Clarkson TW. Biliary secretion of glutathione and of glutathione-metal complexes. Fundam Appl Toxicol. 1985; 5: 816-31, CrossRef.

Ahearn GA, Mandal PK, Mandal A. Mechanisms of heavy metal sequestration and detoxification in crustaceans: A review. J Comp Physiol. 2004; 174: 439-52, CrossRef.

Woods JS. Altered porphyrin metabolism as a biomarker of mercury exposure and toxicity. Can J Physiol Pharmacol. 1996; 74: 210-5, CrossRef.

Frustaci A, Neri M, Cesario A, Adams JB, Domenici E, Bernardina BD, et al. Oxidative stress-related biomarker in autism: Systemic review and meta-analysis. Free Rad Biol Med. 2012; 52: 2128-41, CrossRef.

Winyard PG, Moody CJ, Jacob C. Oxidative activation of antioxidant defence. Trends Biochem Sci. 2005; 30: 453-61, CrossRef.

James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr. 2004; 80: 1611-7, PMID.

Waly M, Olteanu H, Banerjee R, Choi SW, Mason JB, Parker BS, et al. Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal. Mol Psychiatry. 2004; 9: 358-70, CrossRef.

Demiralp T, Herrmann CS, Erdal ME, Ergenoglu T, Keskin YH, Ergen M, et al. DRD4 and DAT1 polymorphisms modulate human gamma band responses. Cereb Cortex. 2007; 17: 1007-19, CrossRef.

Deth RC. Molecular origins of attention: the dopamine-folate connection. Amsterdam: Kluwer Academic Publishers; 2003, NLMID.

Faraone SV, Khan SA. Candidate gene studies of attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2006; 67(Suppl 8): 13-20, PMID.

LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, et al. Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry. 1996; 1: 121-4, PMID.

Anderson GM, Lombroso PJ. Genetics of childhood disorders: XLV. Autism, part 4: serotonin in autism. J Am Acad Child Adolesc Psychiatry. 2001; 41: 1513-6, CrossRef.

Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, et al. Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity. Nutr Metabol. 2011; 8: 34, CrossRef.

D’eufemia P, Finocchiaro R, Celli M, Viozzi L, Monteleone D, Giardini O. Low serum tryptophan to large neutral amino acids ratio in idiopathic infantile autism. Biomed Pharmacother. 1995; 49: 288-92, CrossRef.

Boccuto L, Chen CF, Pittman AR, Skinner CD, McCartney HJ, Jones K, et al. Decreased tryptophan metabolism in patients with autism spectrum disorders. Mol Autism. 2013; 4: 16, CrossRef.

Stone TW, Darlington LG. Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov. 2002; 1: 609-20, CrossRef.

Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999; 38: 1083-152, CrossRef.

Bonnin A, Goeden N, Chen K, Wilson ML, King J, Shih JC, et al. A transient placental source of serotonin for the fetal forebrain. Nature. 2011; 472: 347-50, CrossRef.

Schwartz CE. Aberrant tryptophan metabolism: the unifying biochemical basis for autism spectrum disorders? Biomarkers Med. 2014; 8: 313-5, CrossRef.

Rimland B. DAN! (Defeat Autism Now!) Spring 2002 Conference Practitioner Training. San Diego, CA: Autism Research Intitute; 2002.

Gupta S. Immunological treatments for autism. J Autism Dev Disord. 2000; 30: 475-9, CrossRef.

Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 1998; 35: 637-41, CrossRef.

Cohly HHP, Panja A. Immunological findings in autism. Int Rev Neurobiol. 2005; 71: 317-41, CrossRef.

Ciaranello AL, Ciaranello RD. The neurobiology of infantile autism. Annu Rev Neurosci. 1995; 18: 101-28, CrossRef.

Patterson PH. Maternal infection: Window on neuroimmune interactions in fetal brain development and mental illness. Curr Opin Neurobiol. 2002; 12: 115-8, CrossRef.

Pletnikov MV, Moran TH, Carbone KM. Borna disease virus infection of the neonatal rat: developmental brain injury model of autism spectrum disorders. Fro Biosci. 2002; 7: d593-607, CrossRef.

Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN. Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol. 1999; 14: 388-94, CrossRef.

Giralt M, Penkowa M, Hernández J, Molinero A, Carrasco J, Lago N, et al. Metallothionein-1+2 deficiency increases brain pathology in transgenic mice with astrocyte-targeted expression of interleukin 6. Neurobiology Dis. 2002; 9: 319-38, CrossRef.

Urakubo A, Jarskog LF, Lieberman JA, Gilmore JH. Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid and fetal brain. Schizophrenia Res. 2001; 47: 27-36, CrossRef.

Hornig M, Mervis R, HoVman K, Lipkin WI. Infectious and immune factors in neurodevelopmental damage. Mol Psychiatry. 2002; 7 (Suppl 2): S34-5, CrossRef.

Goines P, Van de Water J. The immune system’s role in the biology of autism. Curr Opin Neurol. 2010; 23: 111-7, CrossRef.

Buehler MR. A proposed mechanism for autism: an aberrant neuroimmune response manifested as a psychiatric disorder. Med Hypotheses. 2011; 863-70, CrossRef.

Pollak Y, Yirmiya R. Cytokine-induced changes in mood and behaviour: implications for ‘depression due to a general medical condition’, immunotherapy and antidepressive treatment. Int J Neuropscyhopharmacol. 2002; 5: 389-99, CrossRef.

Ashwood P, Van de Water. Is autism an autoimmune disease? Autoimmun Rev. 2004; 3: 557-62, CrossRef.

Cook EH, Leventhal BL. The serotonin system in autism. Curr Opin Pediatr. 1996; 8: 348-54, CrossRef.

Cook EH. Autism: review of neurochemical investigation. Synapse 1990; 6: 292-308, CrossRef.

Betancur C, Corbex M, Spielewoy C, Philippe A, Laplanche JL, Launay JM, et al. Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder. Mol Psychiatry. 2002; 7: 67-71, CrossRef.

Delneste Y, Herbault N, Galea B, Magistrelli G, Bazin I, Bonnefoy JY, et al. Vasoactive intestinal peptide synergizes with TNF-alpha in inducing human dendritic cell maturation. J Immunol. 1999; 163: 3071-5, PMID.

Trottier G, Srivastava L, Walker CD. Etiology of infantile autism: a review of recent advances in genetic and neuro- biological research. J Psychiatry Neurosci. 1999; 24: 103-15, PMID.

van Gent T, Heijnen CJ, Treffers PD. Autism and the immune system. J Child Psychol Psychiatry Allied Discip. 1997; 38: 337-49, CrossRef.

Cook Jr EH, Perry BD, Dawson G, Wainwright MS, Leventhal BL. Receptor inhibition by immunoglobulins: specific inhibition by autistic children, their relatives, and control subjects. J Autism Dev Disord. 1993; 23: 67-78, CrossRef.

Singh VK, Warren R, Averett R, Ghaziuddin M. Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr Neurol. 1997; 17: 88-90, CrossRef.

Kozlovskaia GV, Kliushnik TP, Goriunova AV, Turkova IL, Kalinina MA, Sergienko NS. Nerve growth factor autoantibodies in children with various forms of mental dysontogenesis and in schizophrenia high risk group. Zh Nevropatol Psihiatr SS Korsakova. 2000; 100: 50-2, PMID.

Todd RD, Hickok JM, Anderson GM, Cohen DJ. Antibrain antibodies in infantile autism. Biol Psychiatry. 1988; 23: 644-7, CrossRef.

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: 607-13, CrossRef.

Singh VK, Rivas WH. Prevalence of serum antibodies to caudate nucleus in autistic children. Neurosci Lett. 2004; 355: 53-6, CrossRef.

Plioplys AV, Greaves A, Yoshida W. Anti-CNS antibodies in childhood neurologic diseases. Neuropediatrics. 1989; 20: 93-102, CrossRef.

Todd RD, Ciaranello RD. Demonstration of inter- and intra-species differences in serotonin binding sites by antibodies from an autistic child. Proc Natl Acad Sci USA. 1985; 82: 612-6, CrossRef.

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, CrossRef.

Silva SC, Correia C, Fesel C, Barreto M, Coutinho AM, Marques C, et al. Autoantibody repertoires to brain tissue in autism nuclear families. J Neuroimmunol. 2004; 152: 176-82, CrossRef.

Careaga M, Van de Water J, Ashwood P. Immune dysfunction in autism: a pathway to treatment. Neurotherapeutics. 2010; 7: 283-92, CrossRef.

Onore C, Careaga M, Ashwood P. The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun. 2012; 26: 383-92, CrossRef.

Money J, Bobrow NA, Clarke FC. Autism and autoimmune disease: a family study. J Autism Child Schizophr. 1971; 1: 146-60, CrossRef.

Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ. Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics. 2003; 112: e420, CrossRef.

Atladóttir HO, Pedersen MG, Thorsen P, Mortensen PB, DeleuranB, Eaton WW, et al. Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics. 2009; 124: 687-94, CrossRef.

Molloy CA, Morrow AL, Meinzen-Derr J, Dawson G, Bernier R, Dunn M, et al. Familial autoimmune thyroid disease as a risk factor for regression in children with autism spectrum disorder: a CPEA study. J Autism Dev Disord. 2006; 36: 317-24, CrossRef.

Keil A, Daniels JL, Forssen U, Hultman C, Cnattingius S, Söderberg KC, et al. Parental autoimmune diseases associated with autism spectrum disorders in offspring. Epidemiology. 2010; 21: 805-8, CrossRef.

Croen LA, Grether JK, Yoshida CK, Odouli R, Van de Water J. Maternal autoimmune diseases, asthma and allergies, and childhood autism spec- trum disorders: a case-control study. Arch Pediatr Adolesc Med. 2005; 159: 151-7, CrossRef.

Gesundheit B, Rosensweig JP, Naor D, Lerer B, Zachor DA, et al. Immunological and autoimmune considerations of autism spectrum disorders. J Autoimmun. 2013; 44: 1-7, CrossRef.

Williams BL, Hornig M, Buie T, Bauman ML, Paik MC, et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. Plos One. 2011; 6: e24585, CrossRef.

D'Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, et al. Abnormal intestinal permeability in children with autism. Acta Paediatr. 1996; 85: 1076-9,CrossRef.

Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr. 1999; 135: 559-563, CrossRef.

Finegold SM, Molitoris D, Song Y, Liu C, Vaisanen ML, et al. Gastrointestinal microflora studies in late-onset autism. Clin Infect Dis. 2002; 35: S6-16, CrossRef.

Song Y, Liu C, Finegold SM. Real-time PCR quantitation of clostridia in feces of autistic children. Appl Environ Microbiol. 2004; 70: 6459-65, CrossRef.

Parracho HM, Bingham MO, Gibson GR, McCartney AL. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol. 2005; 54: 987-91, CrossRef.

Knivsberg AM, Reichelt KL, Hoien T, Nodland M. A randomised, controlled study of dietary intervention in autistic syndromes. Nutr Neurosci. 2002; 5: 251-61, CrossRef.

Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol. 2000; 15: 429-35, CrossRef.

Adams JB, Johansen LJ, Powell LD, Quig D, Rubin RA. Gastrointestinal flora and gastrointestinal status in children with autism-comparisons to typical children and correlation with autism severity. BMC Gastroenterol. 2011; 11: 22, CrossRef.

Cryan JF, O’Mahony SM. The mocrobiome-gut-brain axis: from bowel to behavior. Neurogastroenterol Motil. 2011; 23: 187-92, CrossRef.

Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011; 68: 1095-102, CrossRef.

Lucarelli S, Frediani T, Zingoni AM, Ferruzzi F, Giardini O, Quintieri F, et al. Food allergy and infantile autism. Panminerva Med. 1995; 37: 137-41, PMID.

Van Oudenhove L, Demyttenaere K, Tack J, Aziz Q. Central nervous system involvement in functional gastrointestinal disorders. Best Pract Res Clin Gastroenterol. 2004; 18: 663-80, CrossRef.

Altaf MA, Sood MR. The nervous system and gastrointestinal function. Dev Disabil Res Rev. 2008; 14: 87-95, CrossRef.

Sullivan PB. Gastrointestinal disorders in children with neurodevelopmental disabilities. Dev Disabil Res Rev. 2008; 14: 128-36, CrossRef.

Drossman DA, Creed FH, Olden KW, Svedlund J, Toner BB, Whitehead WE. Psychosocial aspects of the functional gastrointestinal disorders. Gut. 1999; 45 (Suppl 2): II25-30, CrossRef.

Larsen N, Vogensen FK, van den Berg FW, Nielsen DS, Andreasen AS, Pedersen BK, et al. Gut microbiota in human adults with Type 2 diabetes differs from non­diabetic adults. PLoS ONE 2010; 5: e9085, CrossRef.

Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, et al. Enterotypes of the human gut microbiome. Nature. 2011; 473: 174-80, CrossRef.

Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA,et al. Linking long­term dietary patterns with gut microbial enterotypes. Science. 2011; 334: 105-8, CrossRef.

Huse SM, Ye Y, Zhou Y, Fodor AA. A core human microbiome as viewed through 16S rRNA sequence clusters. PLoS ONE. 2012; 7: e34242, CrossRef.

McKay DM. Intestinal inflammation and the gut microflora. Can J Gastroenterol. 1999; 13: 509-16, PMID.

Bjarnason I, Macpherson A, Hollander D. Intestinal permeability: an overview. Gastroenterology. 1995; 108: 1566-81, CrossRef.

Garvey J. Diet in autism and associated disorders. J Fam Health Care. 2002; 12: 34-8, PMID.

Wang L, Conlon MA, Christophersen CT, Sorich MJ, Angley MT. Gastrointestinal microbiota and metabolite biomarkers in children with autism spectrum disorders. Biomarkers Med. 2014; 8: 331-44, CrossRef.

Cummings JH, MacFarlane GT. The control and consequences of bacterial fermentation in the human colon. J Appl Bacteriol. 1991; 70: 443-59, CrossRef.

Wang L, Angley MT, Gerber JP, Sorich MJ. A review of candidate urinary biomarkers for autism spectrum disorder. Biomarkers. 2011; 16: 537-52, CrossRef.

El­Ansary AK, Ben Bacha A, Kotb M. Etiology of autistic features: the persisting neurotoxic effects of propionic acid. J Neuroinflammation. 2012; 9: 74, CrossRef.

MacFabe DF. Short­chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microb Ecol Health Dis. 2012; 23: 19260:, CrossRef.

Al­Lahham SH, Peppelenbosch MP, Roelofsen H, Vonk RJ, Venema K. Biological effects of propionic acid in humans; metabolism, potential applications and underlying mechanisms. Biochim Biophys Acta. 2010; 1801: 1175-83, CrossRef.

Shultz SR, MacFabe DF, Martin S, Jackson J, Taylor R, Boon F, et al. Intracerebroventricular injections of the enteric bacterial metabolic product propionic acid impair cognition and sensorimotor ability in the Long–Evans rat: further development of a rodent model of autism. Behav Brain Res. 2009; 200: 33-4, CrossRef.

MacFabe DF, Rodraguez­Capote K, Hoffman JE, Jennifer E. Franklin, Martin Kavaliers, et al. A novel rodent model of autism: Intraventricular infusions of propionic acid increase locomotor activity and induce neuroinflammation and oxidative stress in discrete regions of adult rat brain. Am J Biochem Biotechnol. 2008; 4: 146-66, CrossRef.

Tjellström B, Stenhammar L, Högberg L, Fälth-Magnusson K, Magnusson KE, Midtvedt T, et al. Gut microflora associated characteristics in children with celiac disease. Am J Gastroenterol. 2005; 100: 2784-8, CrossRef.

Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature. 2011; 474: 327-36, CrossRef.

Maslowski KM, Vieira AT, Ng A, Kranich J, Kranich J, Sierro F, Yu D, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009; 461: 1282-6, CrossRef.

de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastr Nutr. 2010; 51: 418-24, CrossRef.

Wang L, Conlon MA, Christophersen CT, Sorich MJ, gerber JP, Angley MT, et al. Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. Dig Dis Sci. 2012; 57: 2096-102, CrossRef.

Ramakrishna BS, Gee D, Weiss A, Pannall P, Roberts­Thomson IC, Roediger WE. Estimation of phenolic conjugation by colonic mucosa. J Clin Pathol. 1989; 42: 620-3, CrossRef.

Altieri L, Neri C, Sacco R, Curatolo P, Benvenuto A, Muratori F, et al. Urinary p­cresol is elevated in small children with severe autism spectrum disorder. Biomarkers. 2011; 16: 252-60, CrossRef.

Hsiao EY, MxBride SW, Hsien S, Hyde ER, Sharon J, McGue T, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013; 155: 1451-63, CrossRef.

Mizejewsky G. Biomarker testing for suspected autism spectrum disorder in early childhood: is such testing now feasible? Biomarkers Med. 2012; 6: 503-6, CrossRef.

Steinman G, Mankuta D. Insulin-like growth factor and the etiology of autism. Med Hypotheses. 2013; 80: 475-80, CrossRef.

Arends N, Johnston L, Hokken-Koelega A, van Duijn C, de Ridder M, Savage M, Clark A, et al. Polymorphism in the IGF-I gene: clinical relevance for short children born small for gestational age (SGA). J Clin Endocrinol Metab. 2002; 87: 2720-4, CrossRef.

Blanco CL, Ferry RJ. Jr. The insulin-like growth factor axis in the fetus and neonate. In: Houston MS, Holly NMP, Feldman EL, editors. IGF and Nutrition in Health and Disease. Totowa, NJ: Humana Press; 2005. p.133-43, CrossRef.

Durkin MS, Maenner MJ, Newschaffer CJ, Lee LC, Cunniff CM, Daniels JL, et al. Advanced parental age and the risk of autism spectrum disorder. Am J Epidemiol. 2008; 168: 1268-76, CrossRef.

Patterson PH. Maternal infection and immune involvement in autism. Trends Mol Med. 2011; 17: 389-94, CrossRef.

Geschwind DH. Genetics of autism spectrum disorder. Trends Cogn Sci. 2011; 15: 409-16, CrossRef.

Hsiao EY, Patterson PH. Activation of the maternal immune system induces endocrine changes in the placenta via IL-6. Brain, Behavior, and Immunity. 2010; 25: 604-15, CrossRef.

Benirschke K, Kaufmann P. Infectious Diseases. In: Benirschke K, Kaufmann P, editors. Pathology of the human placenta. 4th ed. New York: Springer-Verlag; 2000. pp. 591-608, CrossRef.

Meyer U, Yee BK, Feldon J. The neurodevelopmental impact of prenatal infections at different times of pregnancy: the earlier the worse? Neuroscientist. 2007; 13: 241-56, CrossRef.

Wei H, Zou H, Sheikh AM, Malik M, Dobkin C, Brown WT, et al. IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion migration and synaptic formation. J Neuroinflam. 2011; 18: 52, CrossRef.

Dammann O, Leviton A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res. 1997; 42: 1-8, CrossRef.

Morell P, Quarles RH. Myelin formation, structure, and biochemistry. In: Siegel G, Agranoff BW, Albers RW, Fisher SK, Uhler MD, editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th ed. Philadelphia: Lippincott-Raven; 1999. p.81-92, NLMID.

Mattson MP, Maudsley S, Martin B. A neural signaling triumvirate that influences ageing and age-related disease: insulin/IGF-1. BDNF and serotonin. Ageing Res Rev. 2004; 3: 445-64, CrossRef.

Mostafa GA, Al-Ayadhi LY. A lack of association between hyperserotonemia and the increased frequency of serum anti-myelin basic protein auto- antibodies in autistic children. J Neuroinflammation. 2011; 8: 71, CrossRef.

Leboyer M, Philippe A, Bouvard M, Guilloud-Bataille M, Bondoux D, Tabuteau F, et al. Whole blood serotonin and plasma beta-endorphin in autistic probands and their first-degree relatives. Biol Psychiatry. 1999; 45: 158-63, CrossRef.

Whitaker-Azmitia PM. Serotonin and brain development: role in human developmental diseases. Brain Res Bull. 2001; 56: 479-85, CrossRef.

Mansour M, Mohamed A, Azam H, Henedy M. Brain derived neurotrophic factor in autism. Curr Psychiatry. 2010; 17: 23-9, article.

Yirmiya N, Pilowsky T, Nemanov L, Arbelle S, Feinsilver T, Fried I, et al. Evidence for an association with the serotonin transporter promoter region polymorphism and autism. A J Med Genet. 2001; 105: 381-6, CrossRef.

Schain RJ, Freeman BJ. Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children. J Pediatr 1961; 58: 315-20, CrossRef.

Veenstra-VanderWeele J, Muller CL, Iwamoto H, Sauer JE, Owens WA, Shah CR, et al. Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior. Proc Natl Acad Sci USA. 2012; 109: 5469-74, CrossRef.

Angelidou A, Francis K, Vasiadi M, Alysandratos KD, Zhang B, Theoharides A, et al. Neurotensin is increased in serum of young children with autistic disorders. J Neuroinflammation. 2010; 7: 48, CrossRef.

Persico AM. Autisms. In: Rubenstein J, Rakic P, editors. Neural Circuit Development and Function in the Brain: Comprehensive Developmental Neuroscience. San Diego: Elsevier; 2013. p.651-94, CrossRef.

Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in Feces of Children with Autism. Appl Environ Microbiol. 2011; 77: 6718-21, CrossRef.

Veenstra-VanderWeele J, Blakely RD. Networking in autism: leveraging genetic, biomarker and model system findings in the search for new treatments. Neuropsychopharmacology. 2012; 37: 196-212, CrossRef.

Walsh P, Elsabbagh M, Bolton P, Singh I. In search of biomarkers for autism: scientific, social and ethical challenges. Nat Rev Neurosci. 2011; 12: 603-12, CrossRef.

Frye RE, James SJ. Metabolic pathology of autism in relation to redox metabolism. Biomarkers Med. 2014; 8: 321-30, CrossRef.

Mizejewsky GJ, Lindau-shepard B, Pass KA. Newborn screening for autism: in search of candidate biomarkers. Biomarkers Med. 2013; 7: 247-60, CrossRef.

DOI: https://doi.org/10.18585/inabj.v6i3.27

Indexed by:






The Prodia Education and Research Institute