Journal of Molecular Neuroscience

, Volume 66, Issue 4, pp 492–511 | Cite as

Diagnostic and Severity-Tracking Biomarkers for Autism Spectrum Disorder

  • Geir BjørklundEmail author
  • Nagwa A. Meguid
  • Afaf El-Ansary
  • Mona A. El-Bana
  • Maryam Dadar
  • Jan Aaseth
  • Maha Hemimi
  • Joško Osredkar
  • Salvatore Chirumbolo


Autism spectrum disorder (ASD) is a neurodevelopmental disorder afflicting about one in every 68 children. It is behaviorally diagnosed based on a triad of symptoms, including impairment in communication, impairment in sociability and abnormal and stereotypic behavior. The subjectivity of behavioral diagnosis urges the need for clinical biomarker tests to improve and complement ASD diagnosis and treatment. Over the past two decades, researchers garnered a broad range of biomarkers associated with ASD and often correlating with the severity of ASD, which includes metabolic and genetic biomarkers or neuroimaging abnormalities. Metabolic biomarkers are either involved in key pathways such as a trans-sulfuration pathway or produced due to the derangement of these pathways in the case of oxidative stress. Recent studies reported several genetic abnormalities related to ASD, encompassing various mechanisms, from copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) to chromosomal anomalies. However, it is still premature to consider these genetic variants as true biomarkers for ASD, due to their low reproducibility and regional-specific nature. Herein, we comprehensively review state of the art about major biomarkers reported in ASD and the association of some biomarkers with ASD symptoms and severity. It is important to establish those biomarkers to be able to help in the diagnosis and to optimize the treatment of ASD.


Autism Biomarkers Diagnosis Severity 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. Adams J, Holloway C, George F, Quig D (2006) 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 110:193–209. CrossRefPubMedGoogle Scholar
  2. Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, Gehn E, Loresto M, Mitchell J, Atwood S (2011) Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity. Nutr Metab 8:34. CrossRefGoogle Scholar
  3. Adams J, Howsmon DP, Kruger U, Geis E, Gehn E, Fimbres V, Pollard E, Mitchell J, Ingram J, Hellmers R (2017) Significant association of urinary toxic metals and autism-related symptoms—a nonlinear statistical analysis with cross validation. PLoS One 12:e0169526. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Adamsen D, Ramaekers V, Ho HT, Britschgi C, Rüfenacht V, Meili D, Bobrowski E, Philippe P, Nava C, Van Maldergem L (2014) Autism spectrum disorder associated with low serotonin in CSF and mutations in the SLC29A4 plasma membrane monoamine transporter (PMAT) gene. Mol Autism. 5:43. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Alabdali A, Al-Ayadhi L, El-Ansary A (2014) Association of social and cognitive impairment and biomarkers in autism spectrum disorders. J Neuroinflammation 11:4. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Alary J, Debrauwer L, Fernandez Y, Paris A, Cravedi J-P, Dolo L, Rao D, Bories G (1998) Identification of novel urinary metabolites of the lipid peroxidation product 4-hydroxy-2-nonenal in rats. Chem Res Toxicol 11:1368–1376CrossRefGoogle Scholar
  7. Al-Gadani Y, El-Ansary A, Attas O, Al-Ayadhi L (2009) Metabolic biomarkers related to oxidative stress and antioxidant status in Saudi autistic children. Clin Biochem 42:1032–1040. CrossRefPubMedGoogle Scholar
  8. Al-Otaish H, Al-Ayadhi L, Bjørklund G, Chirumbolo S, Urbina MA, El-Ansary A (2018) Relationship between absolute and relative ratios of glutamate, glutamine and GABA and severity of autism spectrum disorder. Metab Brain Dis 33:843–854. CrossRefPubMedGoogle Scholar
  9. Al-Yafee YA, Al-Ayadhi LY, Haq SH, El-Ansary AK (2011) Novel metabolic biomarkers related to sulfur-dependent detoxification pathways in autistic patients of Saudi Arabia. BMC Neurol 11:139. CrossRefPubMedPubMedCentralGoogle Scholar
  10. An M, Gao Y (2015) Urinary biomarkers of brain diseases. Genomics, Proteomics & Bioinformatics 13:345–354. CrossRefGoogle Scholar
  11. Atladóttir HÓ, Thorsen P, Østergaard L, Schendel DE, Lemcke S, Abdallah M, Parner ET (2010) Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J Autism Dev Disord 40:1423–1430. CrossRefPubMedGoogle Scholar
  12. Baron-Cohen S, Auyeung B, Nørgaard-Pedersen B, Hougaard DM, Abdallah MW, Melgaard L, Cohen AS, Chakrabarti B, Ruta L, Lombardo MV (2015) Elevated fetal steroidogenic activity in autism. Mol Psychiatry 20:369 CrossRefGoogle Scholar
  13. Belalcázar AD, Ball JG, Frost LM, Valentovic MA, Wilkinson J (2013) Transsulfuration is a significant source of sulfur for glutathione production in human mammary epithelial cells. ISRN Biochemistry 2013. CrossRefGoogle Scholar
  14. Beri S, Tonna N, Menozzi G, Bonaglia MC, Sala C, Giorda R (2007) DNA methylation regulates tissue-specific expression of Shank3. J Neurochem 101:1380–1391. CrossRefPubMedGoogle Scholar
  15. Bjørklund G (2013) The role of zinc and copper in autism spectrum disorders. Acta Neurobiol Exp (Wars) 73:225–236Google Scholar
  16. Bjørklund G, Chirumbolo S (2017) Role of oxidative stress and antioxidants in daily nutrition and human health. Nutrition 33:311–321. CrossRefPubMedGoogle Scholar
  17. Bjørklund G, Saad K, Chirumbolo S, Kern JK, Geier DA, Geier MR, Urbina MA (2016) Immune dysfunction and neuroinflammation in autism spectrum disorder. Acta Neurobiol Exp (Wars) 76:257–268Google Scholar
  18. Bjørklund G, Chartrand MS, Aaseth J (2017) Manganese exposure and neurotoxic effects in children. Environ Res 155:380–384. CrossRefPubMedGoogle Scholar
  19. Bjørklund G, Kern JK, Urbina MA, Saad K, ElHoufey AA, Geier DA, Chirumbolo S, Geier MR, Mehta JA, Aaseth J (2018a) Cerebral hypoperfusion in autism spectrum disorder. Acta Neurobiol Exp 78:21–29. CrossRefGoogle Scholar
  20. Bjørklund G, Skalny AV, Rahman MM, Dadar M, Yassa HA, Aaseth J, Chirumbolo S, Skalnaya MG, Tinkov AA (2018b) Toxic metal (loid)-based pollutants and their possible role in autism spectrum disorder. Environ Res 166:234–250. CrossRefPubMedGoogle Scholar
  21. Blatt GJ, Fitzgerald CM, Guptill JT, Booker AB, Kemper TL, Bauman ML (2001) Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. J Autism Dev Disord 31:537–543. CrossRefPubMedGoogle Scholar
  22. Brack M, Brack O, Ménézo Y, Rousselot DB, Dreyfus G, Chapman MJC, Kontush A (2013) Distinct profiles of systemic biomarkers of oxidative stress in chronic human pathologies: cardiovascular, psychiatric, neurodegenerative, rheumatic, infectious, neoplasmic and endocrinological diseases. Adv Biosci Biotechnol 4:331. CrossRefGoogle Scholar
  23. Brack M, Brack O, Menezo Y (2016) Are there gender-related differences in oxidative stress markers? In: Menezo Y (ed) Oxidative stress and women’s health. ESKA, Paris, p 2016 9–21Google Scholar
  24. Broder-Fingert S, Brazauskas K, Lindgren K, Iannuzzi D, Van Cleave J (2014) Prevalence of overweight and obesity in a large clinical sample of children with autism. Acad Pediatr 14(4):408–414CrossRefGoogle Scholar
  25. Campbell DB, Datta D, Jones ST, Lee EB, Sutcliffe JS, Hammock EA, Levitt P (2011) Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder. J Neurodev Disord 3:101. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Careaga M, Ashwood P (2012) Autism spectrum disorders: from immunity to behavior. In: Psychoneuroimmunology. Springer, pp 219–240. Google Scholar
  27. Carson DS, Garner JP, Hyde SA, Libove RA, Berquist SW, Hornbeak KB, Jackson LP, Sumiyoshi RD, Howerton CL, Hannah SL (2015) Arginine vasopressin is a blood-based biomarker of social functioning in children with autism. PLoS One 10:e0132224. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Castejon A, Spaw J (2014) Autism and oxidative stress interventions: impact on autistic behavior. Austin J Pharmacol Ther 2:1015Google Scholar
  29. CDC - Centers for Disease Control and Prevention (2018) Autism spectrum disorder (ASD). Data & Statistics. Prevalence. Page last reviewed: April 26, 2018. Accessed 15 September 2018
  30. Chaste P, Leboyer M (2012) Autism risk factors: genes, environment, and gene-environment interactions. Dialogues Clin Neurosci 14:281PubMedPubMedCentralGoogle Scholar
  31. Chauhan A, Chauhan V (2006) Oxidative stress in autism. Pathophysiology 13:171–181. CrossRefPubMedGoogle Scholar
  32. Chauhan A, Chauhan V, Brown WT, Cohen I (2004) Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin-the antioxidant proteins. Life Sci 75:2539–2549. CrossRefPubMedGoogle Scholar
  33. Chauhan A, Gu F, Essa MM, Wegiel J, Kaur K, Brown WT, Chauhan V (2011) Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism. J Neurochem 117:209–220. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Chen S, Li Z, He Y, Zhang F, Li H, Liao Y, Wei Z, Wan G, Xiang X, Hu M (2015) Elevated mitochondrial DNA copy number in peripheral blood cells is associated with childhood autism. BMC Psychiatry 15:50. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Chen R, Davis LK, Guter S, Wei Q, Jacob S, Potter MH, Cox NJ, Cook EH, Sutcliffe JS, Li B (2017) Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism. Molecular Autism 8:14. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M (2007) Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol 36:361–365 CrossRefGoogle Scholar
  37. Chirumbolo S, Bjørklund G, Sboarina A, Vella A (2017) The role of vitamin D in the immune system as a pro-survival molecule. Clin Ther 39(5):894–916. CrossRefPubMedGoogle Scholar
  38. Ciancarelli I, Tozzi-Ciancarelli M, Massimo CD, Marini C, Carolei A (2003) Urinary nitric oxide metabolites and lipid peroxidation by-products in migraine. Cephalalgia 23:39–42. CrossRefPubMedGoogle Scholar
  39. Cohen I, Liu X, Schutz C, White B, Jenkins E, Brown W, Holden J (2003) Association of autism severity with a monoamine oxidase A functional polymorphism. Clin Genet 64:190–197. CrossRefPubMedGoogle Scholar
  40. Crăciun EC, Bjørklund G, Tinkov AA, Urbina MA, Skalny AV, Rad F, Dronca E (2016) Evaluation of whole blood zinc and copper levels in children with autism spectrum disorder. Metab Brain Dis 31:887–890. CrossRefPubMedGoogle Scholar
  41. Damodaran LPM, Arumugam G (2011) Urinary oxidative stress markers in children with autism. Redox Rep 16:216–222. CrossRefPubMedGoogle Scholar
  42. De Luca F (2016) Endocrinological abnormalities in autism. Semin Pediatr Neurol.
  43. Depino AM (2013) Peripheral and central inflammation in autism spectrum disorders. Mol Cell Neurosci 53:69–76. CrossRefPubMedGoogle Scholar
  44. Deth R, Muratore C, Benzecry J, Power-Charnitsky V-A, Waly M (2008) How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology 29:190–201. CrossRefPubMedGoogle Scholar
  45. Eapen V (2011) Genetic basis of autism: is there a way forward? Curr Opin Psychiatry 24:226–236. CrossRefPubMedGoogle Scholar
  46. El-Ansary A (2016) Data of multiple regressions analysis between selected biomarkers related to glutamate excitotoxicity and oxidative stress in Saudi autistic patients. Data Brief 7:111–116. CrossRefPubMedPubMedCentralGoogle Scholar
  47. El-Ansary A, Al-Ayadhi L (2012) Neuroinflammation in autism spectrum disorders. J Neuroinflammation 9:265. CrossRefPubMedPubMedCentralGoogle Scholar
  48. El-Ansary A, Al-Ayadhi L (2014) Relative abundance of short chain and polyunsaturated fatty acids in propionic acid-induced autistic features in rat pups as potential markers in autism. Lipids Health Dis 13:140. CrossRefPubMedPubMedCentralGoogle Scholar
  49. El-Ansary AK, Bacha AB, Al-Ayahdi LY (2011a) Relationship between chronic lead toxicity and plasma neurotransmitters in autistic patients from Saudi Arabia. Clin Biochem 44:1116–1120. CrossRefPubMedGoogle Scholar
  50. El-Ansary AK, Bacha AGB, Al-Ayadhi LY (2011b) Impaired plasma phospholipids and relative amounts of essential polyunsaturated fatty acids in autistic patients from Saudi. Arabia. Lipids Health Dis 10:63. CrossRefPubMedPubMedCentralGoogle Scholar
  51. El-Ansary AK, Bacha AGB, Al-Ayadhi LY (2011c) Proinflammatory and proapoptotic markers in relation to mono and di-cations in plasma of autistic patients from Saudi Arabia. J Neuroinflammation 8:142. CrossRefPubMedPubMedCentralGoogle Scholar
  52. El-Ansary A, Bjørklund G, Chirumbolo S, Alnakhli OM (2017a) Predictive value of selected biomarkers related to metabolism and oxidative stress in children with autism spectrum disorder. Metab Brain Dis 32:1209–1221. CrossRefPubMedGoogle Scholar
  53. El-Ansary A, Bjørklund G, Tinkov AA, Skalny AV, Al Dera H (2017b) Relationship between selenium, lead, and mercury in red blood cells of Saudi autistic children. Metab Brain Dis 32(4):1073–1080. CrossRefPubMedGoogle Scholar
  54. El-Ansary A, Cannell JJ, Bjørklund G, Bhat RS, Al Dbass AM, Alfawaz HA, Chirumbolo S, Al-Ayadhi L (2018) In the search for reliable biomarkers for the early diagnosis of autism spectrum disorder: the role of vitamin D. Metab Brain Dis 33:917–931. CrossRefPubMedGoogle Scholar
  55. El-Ansary A, Bjørklund G, Khemakhem AM, Al-Ayadhi L, Chirumbolo S, Bacha AB (2018a) Metabolism-associated markers and Childhood Autism Rating Scales (CARS) as a measure of autism severity. J Mol Neurosci 65:265–276. CrossRefPubMedGoogle Scholar
  56. El-Ansary A, Cannell JJ, Bjørklund G, Bhat RS, Al Dbass AM, Alfawaz HA, Chirumbolo S, Al-Ayadhi L (2018b) In the search for reliable biomarkers for the early diagnosis of autism spectrum disorder: the role of vitamin D. Metab Brain Dis 33:917–931. CrossRefPubMedGoogle Scholar
  57. ElBaz FM, Zaki MM, Youssef AM, ElDorry GF, Elalfy DY (2014) Study of plasma amino acid levels in children with autism: an Egyptian sample. Egypt J Med Human Genet 15:181–186. CrossRefGoogle Scholar
  58. Endreffy I, Bjørklund G, Dicső F, Urbina MA, Endreffy E (2016) Acid glycosaminoglycan (aGAG) excretion is increased in children with autism spectrum disorder, and it can be controlled by diet. Metab Brain Dis 31:273–278. CrossRefPubMedGoogle Scholar
  59. Faber S, Zinn GM, Kern Ii JC, Skip Kingston H (2009) The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders. Biomarkers 14:171–180. CrossRefPubMedGoogle Scholar
  60. Feuerstein G, Liu T, Barone F (1994) Cytokines, inflammation, and brain injury: role of tumor necrosis factor-alpha. Cerebrovasc Brain Metab Rev 6:341–360PubMedGoogle Scholar
  61. Frye R, Delatorre R, Taylor H, Slattery J, Melnyk S, Chowdhury N, James S (2013a) Redox metabolism abnormalities in autistic children associated with mitochondrial disease. Transl Psychiatry 3:e273. CrossRefPubMedPubMedCentralGoogle Scholar
  62. Frye RE, Melnyk S, MacFabe DF (2013b) Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Transl Psychiatry 3:e220. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Fujiwara T, Morisaki N, Honda Y, Sampei M, Tani Y (2016) Chemicals, nutrition, and autism spectrum disorder: a mini-review. Front Neurosci 10:174. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Fung TC, Olson CA, Hsiao EY (2017) Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci 20:145. CrossRefPubMedGoogle Scholar
  65. Geier DA, Geier MR (2007) A prospective assessment of androgen levels in patients with autistic spectrum disorders: biochemical underpinnings and suggested therapies. Neuroendocrinol Lett 28:565–574PubMedGoogle Scholar
  66. Geier DA, Kern JK, Garver CR, Adams JB, Audhya T, Geier MR (2009) A prospective study of transsulfuration biomarkers in autistic disorders. Neurochem Res 34:386. CrossRefPubMedGoogle Scholar
  67. Geier DA, Kern JK, King PG, Sykes LK, Geier MR (2012) An evaluation of the role and treatment of elevated male hormones in autism spectrum disorders. Acta Neurobiol Exp (Wars) 72:1–17Google Scholar
  68. Geier DA, Hooker BS, Kern JK, King PG, Sykes LK, Geier MR (2014) A dose-response relationship between organic mercury exposure from thimerosal-containing vaccines and neurodevelopmental disorders. Int J Environ Res Public Health 11:9156–9170. CrossRefPubMedPubMedCentralGoogle Scholar
  69. Ghaffari MA, Mousavinejad E, Riahi F, Mousavinejad M, Afsharmanesh MR (2016) Increased serum levels of tumor necrosis factor-alpha, resistin, and visfatin in the children with autism spectrum disorders: a case-control study. Neurol Res Int 2016. CrossRefGoogle Scholar
  70. Ghezzo A, Visconti P, Abruzzo PM, Bolotta A, Ferreri C, Gobbi G, Malisardi G, Manfredini S, Marini M, Nanetti L (2013) Oxidative stress and erythrocyte membrane alterations in children with autism: correlation with clinical features. PLoS One 8:e66418. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Gilbody S, Lewis S, Lightfoot T (2006) Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol 165:1–13. CrossRefPubMedGoogle Scholar
  72. Goddard MN, van Rijn S, Rombouts SA, Swaab H (2016) White matter microstructure in a genetically defined group at increased risk of autism symptoms, and a comparison with idiopathic autism: an exploratory study. Brain Imaging Behav 10:1280–1288. CrossRefPubMedGoogle Scholar
  73. Goh S, Dong Z, Zhang Y, DiMauro S, Peterson BS (2014) Mitochondrial dysfunction as a neurobiological subtype of autism spectrum disorder: evidence from brain imaging. JAMA Psychiat 71:665–671. CrossRefGoogle Scholar
  74. Goldani AA, Downs SR, Widjaja F, Lawton B, Hendren RL (2014) Biomarkers in autism. Front Psychiatry 5:100. CrossRefPubMedPubMedCentralGoogle Scholar
  75. Goldenthal MJ, Damle S, Sheth S, Shah N, Melvin J, Jethva R, Hardison H, Marks H, Legido A (2015) Mitochondrial enzyme dysfunction in autism spectrum disorders; a novel biomarker revealed from buccal swab analysis. Biomark Med 9:957–965. CrossRefPubMedGoogle Scholar
  76. Gorrindo P, Lane CJ, Lee EB, McLaughlin B, Levitt P (2013) Enrichment of elevated plasma F2t-isoprostane levels in individuals with autism who are stratified by presence of gastrointestinal dysfunction. PLoS One 8:e68444. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Grabrucker S, Jannetti L, Eckert M, Gaub S, Chhabra R, Pfaender S, Mangus K, Reddy PP, Rankovic V, Schmeisser MJ (2013) Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders. Brain 137:137–152. CrossRefPubMedGoogle Scholar
  78. Grandjean P, Landrigan PJ (2006) Developmental neurotoxicity of industrial chemicals. Lancet 368:2167–2178. CrossRefPubMedGoogle Scholar
  79. Gu F, Chauhan V, Kaur K, Brown W, LaFauci G, Wegiel J, Chauhan A (2013) Alterations in mitochondrial DNA copy number and the activities of electron transport chain complexes and pyruvate dehydrogenase in the frontal cortex from subjects with autism. Transl Psychiatry 3:e299. CrossRefPubMedPubMedCentralGoogle Scholar
  80. Gumusoglu SB, Fine RS, Murray SJ, Bittle JL, Stevens HE (2017) The role of IL-6 in neurodevelopment after prenatal stress. Brain Behav Immun 65:274–283. CrossRefPubMedPubMedCentralGoogle Scholar
  81. Han Y, Xi Q-q, Dai W, Yang S-h, Gao L, Y-y S, Zhang X (2015) Abnormal transsulfuration metabolism and reduced antioxidant capacity in Chinese children with autism spectrum disorders. Int J Dev Neurosci 46:27–32. CrossRefPubMedGoogle Scholar
  82. Hardan AY, Handen BL (2002) A retrospective open trial of adjunctive donepezil in children and adolescents with autistic disorder. J Child Adolesc Psychopharmacol 12:237–241. CrossRefPubMedGoogle Scholar
  83. Hartzell S, Seneff S (2012) Impaired sulfate metabolism and epigenetics: is there a link in autism? Entropy 14:1953–1977. CrossRefGoogle Scholar
  84. Hassan WM, Al-Ayadhi L, Bjørklund G, Alabdali A, Chirumbolo S, El-Ansary A (2018) The use of multi-parametric biomarker profiles may increase the accuracy of ASD prediction. J Mol Neurosci. CrossRefGoogle Scholar
  85. Hegazy HG, Ali EH, Elgoly AHM (2015) Interplay between pro-inflammatory cytokines and brain oxidative stress biomarkers: evidence of parallels between butyl paraben intoxication and the valproic acid brain physiopathology in autism rat model. Cytokine 71:173–180 CrossRefGoogle Scholar
  86. Hepel M, Stobiecka M (2011) Interactions of herbicide atrazine with DNA. Nova Science Publishers, Hauppauge, NYGoogle Scholar
  87. Hepel M, Stobiecka M, Peachey J, Miller J (2012) Intervention of glutathione in pre-mutagenic catechol-mediated DNA damage in the presence of copper (II) ions. Mutat Res Fundam Mol Mech Mutagen. 735:1–11. CrossRefGoogle Scholar
  88. Heyer NJ, Echeverria D, Woods JS (2012) Disordered porphyrin metabolism: a potential biological marker for autism risk assessment. Autism Res 5:84–92. CrossRefPubMedPubMedCentralGoogle Scholar
  89. Hibbs JB Jr, Taintor RR, Vavrin Z, Rachlin EM (1988) Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun 157:87–94. CrossRefPubMedGoogle Scholar
  90. Hill AP, Zuckerman KE, Fombonne E (2015) Obesity and autism. Pediatrics 136:1051–1061CrossRefGoogle Scholar
  91. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023. CrossRefPubMedGoogle Scholar
  92. Hölscher C, Rose SP (1992) An inhibitor of nitric oxide synthesis prevents memory formation in the chick. Neurosci Lett 145:165–167. CrossRefPubMedGoogle Scholar
  93. Hornig M, Bresnahan M, Che X, Schultz A, Ukaigwe J, Eddy M, Hirtz D, Gunnes N, Lie KK, Magnus P (2018) Prenatal fever and autism risk. Mol Psychiatry 23:759. CrossRefPubMedGoogle Scholar
  94. Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT (1999) Gastrointestinal abnormalities in children with autistic disorder. J Pediatr 135:559–563. CrossRefPubMedGoogle Scholar
  95. Hovatta I, Tennant RS, Helton R, Marr RA, Singer O, Redwine JM, Ellison JA, Schadt EE, Verma IM, Lockhart DJ (2005) Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice. Nature 438:662. CrossRefPubMedGoogle Scholar
  96. Hsu MJ, Hsueh HM (2013) The linear combinations of biomarkers which maximize the partial area under the ROC curves. Comput Stat 28:647–666. CrossRefGoogle Scholar
  97. Hu VW, Sarachana T, Sherrard RM, Kocher KM (2015) Investigation of sex differences in the expression of RORA and its transcriptional targets in the brain as a potential contributor to the sex bias in autism. Mol Autism 6:7. CrossRefPubMedPubMedCentralGoogle Scholar
  98. James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA (2004) Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 80:1611–1617. CrossRefPubMedGoogle Scholar
  99. Jamil K (2014) Clinical implications of MTHFR gene polymorphism in various diseases. Accessed 15 Sept 2018.
  100. Jikimoto T, Nishikubo Y, Koshiba M, Kanagawa S, Morinobu S, Morinobu A, Saura R, Mizuno K, Kondo S, Toyokuni S (2002) Thioredoxin as a biomarker for oxidative stress in patients with rheumatoid arthritis. Mol Immunol 38:765–772. CrossRefPubMedGoogle Scholar
  101. Kałużna-Czaplińska J, Żurawicz E, Michalska M (2013) Rynkowski J (2013) A focus on homocysteine in autism. Acta Biochim Pol 60(2):137–142 Accessed 15 Sept 2018PubMedGoogle Scholar
  102. Kałużna-Czaplińska J, Jóźwik-Pruska J, Chirumbolo S, Bjørklund G (2017a) Tryptophan status in autism spectrum disorder and the influence of supplementation on its level. Metab Brain Dis 32(5):1585–1593. CrossRefPubMedPubMedCentralGoogle Scholar
  103. Kałużna-Czaplińska J, Gątarek P, Chirumbolo S, Chartrand MS, Bjørklund G (2017b) How important is tryptophan in human health? Crit Rev Food Sci Nutr 2017:1–17. CrossRefGoogle Scholar
  104. Kane MJ, Angoa-Peréz M, Briggs DI, Sykes CE, Francescutti DM, Rosenberg DR, Kuhn DM (2012) Mice genetically depleted of brain serotonin display social impairments, communication deficits and repetitive behaviors: possible relevance to autism. PLoS One 7:e48975. CrossRefPubMedPubMedCentralGoogle Scholar
  105. Kang D-W, Adams JB, Gregory AC, Borody T, Chittick L, Fasano A, Khoruts A, Geis E, Maldonado J, McDonough-Means S (2017) Microbiota transfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome 5:10. CrossRefPubMedPubMedCentralGoogle Scholar
  106. Karri V, Schuhmacher M, Kumar V (2016) Heavy metals (Pb, Cd, As and MeHg) as risk factors for cognitive dysfunction: a general review of metal mixture mechanism in brain. Environ Toxicol Pharmacol 48:203–213. CrossRefPubMedGoogle Scholar
  107. Kern JK, Jones AM (2006) Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health Part B 9:485–499. CrossRefGoogle Scholar
  108. Kern JK, Geier DA, Adams JB, Garver CR, Audhya T, Geier MR (2011) A clinical trial of glutathione supplementation in autism spectrum disorders. Med Sci Monit 17:CR677. CrossRefPubMedPubMedCentralGoogle Scholar
  109. Kern JK, Geier DA, Sykes L, Geier M (2014) Urinary porphyrins in autism spectrum disorders. In: Comprehensive guide to autism. Springer, pp 1333–1348. CrossRefGoogle Scholar
  110. Kern JK, Geier DA, Sykes LK, Haley BE, Geier MR (2016) The relationship between mercury and autism: a comprehensive review and discussion. J Trace Elem Med Biol 37:8–24. CrossRefPubMedGoogle Scholar
  111. Khaled EM, Meguid NA, Bjørklund G, Gouda A, Bahary MH, Hashish A, Sallam NM, Chirumbolo S, El-Bana MA (2016) Altered urinary porphyrins and mercury exposure as biomarkers for autism severity in Egyptian children with autism spectrum disorder. Metab Brain Dis 31:1419–1426. CrossRefPubMedGoogle Scholar
  112. Kim H-C, Bing G, Jhoo W-K, Kim W-K, Shin E-J, Park E-S, Choi Y-S, Lee D-W, Shin CY, Ryu JR (2002) Oxidative damage causes formation of lipofuscin-like substances in the hippocampus of the senescence-accelerated mouse after kainate treatment. Behav Brain Res 131:211–220. CrossRefPubMedGoogle Scholar
  113. Kobal AB (2009) Possible influence of mercury on pathogenesis of autism. Slov Med J 78:37–44Google Scholar
  114. Kourtian S, Soueid J, Makhoul NJ, Guisso DR, Chahrour M, Boustany R-MN (2017) Candidate genes for inherited autism susceptibility in the Lebanese population. Sci Rep 7:45336. CrossRefPubMedPubMedCentralGoogle Scholar
  115. Kumsta R, Hummel E, Chen FS, Heinrichs M (2013) Epigenetic regulation of the oxytocin receptor gene: implications for behavioral neuroscience. Front Neurosci 7:83. CrossRefPubMedPubMedCentralGoogle Scholar
  116. Lacasaña-Navarro M, Galván-Portillo M, Chen J, Ma L-C, López-Carrillo L (2006) Methylenetetrahydrofolate reductase 677C> T polymorphism and gastric cancer susceptibility in Mexico. Eur J Cancer 42:528–533. CrossRefPubMedGoogle Scholar
  117. Leary SC, Winge DR, Cobine PA (2009) “Pulling the plug” on cellular copper: the role of mitochondria in copper export. Biochim Biophys Acta 1793:146–153. CrossRefPubMedGoogle Scholar
  118. Li Z, Dong T, Pröschel C, Noble M (2007) Chemically diverse toxicants converge on Fyn and c-Cbl to disrupt precursor cell function. PLoS Biol 5:e35. CrossRefPubMedPubMedCentralGoogle Scholar
  119. Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li X-M, Ji L, Brown T, Malik M (2009) Elevated immune response in the brain of autistic patients. J Neuroimmunol 207:111–116. CrossRefPubMedPubMedCentralGoogle Scholar
  120. Li SO, Wang JL, Bjørklund G, Zhao WN, Yin CH (2014) Serum copper and zinc levels in individuals with autism spectrum disorders. Neuroreport 25:1216–1220. CrossRefPubMedGoogle Scholar
  121. Lillig CH, Holmgren A (2007) Thioredoxin and related molecules—from biology to health and disease. Antioxid Redox Signal 9:25–47. CrossRefPubMedGoogle Scholar
  122. Liu X, Solehdin F, Cohen IL, Gonzalez MG, Jenkins EC, Lewis MS, Holden JJ (2011) Population-and family-based studies associate the MTHFR gene with idiopathic autism in simplex families. J Autism Dev Disord 41:938–944. CrossRefPubMedGoogle Scholar
  123. Lonart G, Wang J, Johnson KM (1992) Nitric oxide induces neurotransmitter release from hippocampal slices. Eur J Pharmacol 220:271–272. CrossRefPubMedGoogle Scholar
  124. Macedoni-Lukšič M, Gosar D, Bjørklund G, Oražem J, Kodrič J, Lešnik-Musek P, Zupančič M, France-Štiglic A, Sešek-Briški A, Neubauer D (2015) Levels of metals in the blood and specific porphyrins in the urine in children with autism spectrum disorders. Biol Trace Elem Res 163:2–10. CrossRefPubMedGoogle Scholar
  125. MacFabe DF (2015) Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders. Microb Ecol Health Dis 26:28177. CrossRefPubMedGoogle Scholar
  126. Main PA, Angley MT, Thomas P, O’Doherty CE, Fenech M (2010) Folate and methionine metabolism in autism: a systematic review. Am J Clin Nutr 91:1598–1620. CrossRefPubMedGoogle Scholar
  127. Main PA, Angley MT, O'Doherty CE, Thomas P, Fenech M (2012) The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis. Nutr Metab 9:35. CrossRefGoogle Scholar
  128. Manzi B, Loizzo AL, Giana G, Curatolo P (2008) Autism and metabolic diseases. J Child Neurol 23:307–314. CrossRefPubMedGoogle Scholar
  129. McDougle CJ, Erickson CA, Stigler KA, Posey DJ (2005) Neurochemistry in the pathophysiology of autism. J Clin Psychiatry 66:9–18PubMedGoogle Scholar
  130. McGinnis WR (2004) Oxidative stress in autism. Ann Arbor 1001:48105Google Scholar
  131. Meguid NA, Dardir AA, Abdel-Raouf ER, Hashish A (2011) Evaluation of oxidative stress in autism: defective antioxidant enzymes and increased lipid peroxidation. Biol Trace Elem Res 143:58–65. CrossRefPubMedGoogle Scholar
  132. Meguid NA, Ghozlan SA, Mohamed MF, Ibrahim MK, Dawood RM, Bader El Din NG, Abdelhafez TH, Hemimi M, El Awady MK (2017) Expression of reactive oxygen species-related transcripts in Egyptian children with autism. Biomark Insights 12:1177271917691035. CrossRefPubMedPubMedCentralGoogle Scholar
  133. Melnyk S, Fuchs GJ, Schulz E, Lopez M, Kahler SG, Fussell JJ, Bellando J, Pavliv O, Rose S, Seidel L (2012) Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism. J Autism Dev Disord 42:367–377. CrossRefPubMedPubMedCentralGoogle Scholar
  134. Ménézo Y, Mares P, Cohen M, Brack M, Viville S, Elder K (2011) Autism, imprinting and epigenetic disorders: a metabolic syndrome linked to anomalies in homocysteine recycling starting in early life?? J Assist Reprod Genet 28:1143–1145. CrossRefPubMedPubMedCentralGoogle Scholar
  135. Menezo YJ, Silvestris E, Dale B, Elder K (2016) Oxidative stress and alterations in DNA methylation: two sides of the same coin in reproduction. Reprod BioMed Online 33:668–683. CrossRefPubMedGoogle Scholar
  136. Metz CE (1986) ROC methodology in radiologic imaging. Investig Radiol 21:720–733. CrossRefGoogle Scholar
  137. Miller M, Bales KL, Taylor SL, Yoon J, Hostetler CM, Carter CS, Solomon M (2013) Oxytocin and vasopressin in children and adolescents with autism spectrum disorders: sex differences and associations with symptoms. Autism Res 6:91–102. CrossRefPubMedPubMedCentralGoogle Scholar
  138. Ming X, Stein T, Brimacombe M, Johnson W, Lambert G, Wagner G (2005) Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids 73:379–384. CrossRefPubMedGoogle Scholar
  139. Moretti P, Sahoo T, Hyland K, Bottiglieri T, Peters S, Del Gaudio D, Roa B, Curry S, Zhu H, Finnell R (2005) Cerebral folate deficiency with developmental delay, autism, and response to folinic acid. Neurology 64:1088–1090. CrossRefPubMedGoogle Scholar
  140. Moretti P, Peters SU, Del Gaudio D, Sahoo T, Hyland K, Bottiglieri T, Hopkin RJ, Peach E, Min SH, Goldman D (2008) Brief report: autistic symptoms, developmental regression, mental retardation, epilepsy, and dyskinesias in CNS folate deficiency. J Autism Dev Disord 38:1170–1177. CrossRefPubMedGoogle Scholar
  141. Mostafa GA, Bjørklund G, Urbina MA, Al-Ayadhi LY (2016a) The positive association between elevated blood lead levels and brain-specific autoantibodies in autistic children from low lead-polluted areas. Metab Brain Dis 31(5):1047–1054. CrossRefPubMedGoogle Scholar
  142. Mostafa GA, Bjørklund G, Urbina MA, Al-Ayadhi LY (2016b) The levels of blood mercury and inflammatory-related neuropeptides in the serum are correlated in children with autism spectrum disorder. Metab Brain Dis 31(3):593–599. CrossRefPubMedGoogle Scholar
  143. Muller CL, Anacker AM, Veenstra-VanderWeele J (2016) The serotonin system in autism spectrum disorder: from biomarker to animal models. Neuroscience 321:24–41. CrossRefPubMedGoogle Scholar
  144. Nakamura H, De Rosa S, Roederer M, Anderson MT, Dubs JG, Yodoi J, Holmgren A, Herzenberg LA, Herzenberg LA (1996) Elevation of plasma thioredoxin levels in HIV-infected individuals. Int Immunol 8:603–611. CrossRefPubMedGoogle Scholar
  145. Nasrat AM, Nasrat RM, Nasrat MM (2017) Autism; an approach for definite etiology and definitive etiologic management. Am J Med Sci 7:108–118. CrossRefGoogle Scholar
  146. Naveed S, Amray A, Waqas A, Chaudhary AM, Azeem MW (2017) Use of N-acetylcysteine in psychiatric conditions among children and adolescents: a scoping review. Cureus 9.
  147. Ogawa S, Lee Y-A, Yamaguchi Y, Shibata Y, Goto Y (2017) Associations of acute and chronic stress hormones with cognitive functions in autism spectrum disorder. Neuroscience 343:229–239. CrossRefPubMedGoogle Scholar
  148. Oliveira PVS, Laurindo FRM (2018) Implications of plasma thiol redox in disease. Clin Sci (Lond) 132(12):1257–1280CrossRefGoogle Scholar
  149. Oliveira G, Diogo L, Grazina M, Garcia P, Ataide A, Marques C, Miguel T, Borges L, Vicente A, Oliveira C (2005) Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Dev Med Child Neurol 47:185–189. CrossRefPubMedGoogle Scholar
  150. Palomba S, Marotta R, Di Cello A, Russo T, Falbo A, Orio F, Tolino A, Zullo F, Esposito R, Sala GBL (2012) Pervasive developmental disorders in children of hyperandrogenic women with polycystic ovary syndrome: a longitudinal case–control study. Clin Endocrinol 77:898–904. CrossRefGoogle Scholar
  151. Patowary A, Nesbitt R, Archer M, Bernier R, Brkanac Z (2017) Next generation sequencing mitochondrial DNA analysis in autism spectrum disorder. Autism Res 10:1338–1343. CrossRefPubMedPubMedCentralGoogle Scholar
  152. Pérez C, Sawmiller D, Tan J (2016) The role of heparan sulfate deficiency in autistic phenotype: potential involvement of Slit/Robo/srGAPs-mediated dendritic spine formation. Neural Dev 11:11. CrossRefPubMedPubMedCentralGoogle Scholar
  153. Perlis R (2011) Translating biomarkers to clinical practice. Mol Psychiatry 16:1076. CrossRefPubMedPubMedCentralGoogle Scholar
  154. Perry EK, Lee ML, Martin-Ruiz CM, Court JA, Volsen SG, Merrit J, Folly E, Iversen PE, Bauman ML, Perry RH (2001) Cholinergic activity in autism: abnormalities in the cerebral cortex and basal forebrain. Am J Psychiatry 158:1058–1066. CrossRefPubMedGoogle Scholar
  155. Pietropaolo S, Crusio WE, Feldon J (2017) Gene-environment interactions in neurodevelopmental disorders. Neural Plast 2017. CrossRefGoogle Scholar
  156. Prandota J (2010) Neuropathological changes and clinical features of autism spectrum disorder participants are similar to that reported in congenital and chronic cerebral toxoplasmosis in humans and mice. Res Autism Spectr Disord 4:103–118. CrossRefGoogle Scholar
  157. Puig-Alcaraz C, Fuentes-Albero M, Calderón J, Garrote D, Cauli O (2015) Increased homocysteine levels correlate with the communication deficit in children with autism spectrum disorder. Psychiatry Res 229:1031–1037. CrossRefPubMedGoogle Scholar
  158. Qasem H, Al-Ayadhi L, Bjørklund G, Chirumbolo S, El-Ansary A (2018) Impaired lipid metabolism markers to assess the risk of neuroinflammation in autism spectrum disorder. Metab Brain Dis 33(4):1141–1153. CrossRefPubMedGoogle Scholar
  159. Quattrocki E, Friston K (2014) Autism, oxytocin and interoception. Neurosci Biobehav Rev 47:410–430. CrossRefPubMedPubMedCentralGoogle Scholar
  160. Rahbar MH, Samms-Vaughan M, Pitcher MR, Bressler J, Hessabi M, Loveland KA, Christian MA, Grove ML, Shakespeare-Pellington S, Beecher C (2016) Role of metabolic genes in blood aluminum concentrations of Jamaican children with and without autism spectrum disorder. Int J Environ Res Public Health 13:1095. CrossRefPubMedCentralGoogle Scholar
  161. Ramaekers VT, Blau N (2004) Cerebral folate deficiency. Dev Med Child Neurol 46:843–851. CrossRefPubMedGoogle Scholar
  162. Ramaekers V, Häusler M, Opladen T, Heimann G, Blau N (2002) Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics 33:301–308. CrossRefPubMedGoogle Scholar
  163. Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J (2005) Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med 352:1985–1991. CrossRefPubMedGoogle Scholar
  164. Ramaekers V, Blau N, Sequeira J, Nassogne M-C, Quadros E (2007) Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits. Neuropediatrics 38:276–281. CrossRefPubMedGoogle Scholar
  165. Ramaekers VT, Sequeira JM, Blau N, Quadros EV (2008) A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Dev Med Child Neurol 50:346–352. CrossRefPubMedPubMedCentralGoogle Scholar
  166. Ratajczak HV, Sothern RB (2015) Measurement in saliva from neurotypical adults of biomarkers pertinent to autism spectrum disorders. Future Sci OA 1(4):FSO70. CrossRefPubMedPubMedCentralGoogle Scholar
  167. Reichelt KL, Tveiten Bioengineer D, Knivsberg A-M, Brønstad G (2012) Peptides’ role in autism with emphasis on exorphins. Microb Ecol Health Dis 23:18958. CrossRefGoogle Scholar
  168. Ren K, Dubner R (2010) Interactions between the immune and nervous systems in pain. Nat Med 16:1267. CrossRefPubMedPubMedCentralGoogle Scholar
  169. Roberts AL, Lyall K, Hart JE, Laden F, Just AC, Bobb JF, Koenen KC, Ascherio A, Weisskopf MG (2013) Perinatal air pollutant exposures and autism spectrum disorder in the children of Nurses’ Health Study II participants. Environ Health Perspect 121:978. CrossRefPubMedPubMedCentralGoogle Scholar
  170. Rogers EJ (2008) Has enhanced folate status during pregnancy altered natural selection and possibly autism prevalence? A closer look at a possible link. Med Hypotheses 71:406–410. CrossRefPubMedGoogle Scholar
  171. Romano E, Cosentino L, Laviola G, De Filippis B (2016) Genes and sex hormones interaction in neurodevelopmental disorders. Neurosci Biobehav Rev 67:9–24. CrossRefPubMedGoogle Scholar
  172. Rose S, Melnyk S, Pavliv O, Bai S, Nick TG, Frye RE, James SJ (2012) Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl Psychiatry 2:e134. CrossRefPubMedPubMedCentralGoogle Scholar
  173. Rose S, Frye R, Slattery J, Wynne R, Tippett M, Melnyk S, James S (2014) Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines. Transl Psychiatry 4:e377. CrossRefPubMedPubMedCentralGoogle Scholar
  174. Rose’Meyer R (2013) A review of the serotonin transporter and prenatal cortisol in the development of autism spectrum disorders. Molecular Autism 4:37 CrossRefGoogle Scholar
  175. Rossignol D, Frye R (2012) Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry 17:290. CrossRefPubMedGoogle Scholar
  176. Rossignol D, Genuis S, Frye R (2014) Environmental toxicants and autism spectrum disorders: a systematic review. Transl Psychiatry 4:e360. CrossRefPubMedPubMedCentralGoogle Scholar
  177. Rutigliano G, Rocchetti M, Paloyelis Y, Gilleen J, Sardella A, Cappucciati M, Palombini E, Dell’Osso L, Caverzasi E, Politi P (2016) Peripheral oxytocin and vasopressin: biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis. Psychiatry Res 241:207–220. CrossRefPubMedGoogle Scholar
  178. Saad K, Elserogy Y, Abdel Rahman AA, Al-Atram AA, Mohamad IL, ElMelegy TT, Bjørklund G, El-Houfy AA (2015a) ADHD, autism and neuroradiological complications among phenylketonuric children in Upper Egypt. Acta Neurol Belg 115(4):657–663. CrossRefPubMedGoogle Scholar
  179. Saad K, Eltayeb AA, Mohamad IL, Al-Atram AA, Elserogy Y, Bjørklund G, El-Houfey AA, Nicholson B (2015b) A randomized, placebo-controlled trial of digestive enzymes in children with autism spectrum disorders. Clin Psychopharmacol Neurosci 13(2):188–193CrossRefGoogle Scholar
  180. Saad K, Abdel-Rahman AA, Elserogy YM, Al-Atram AA, Cannell JJ, Bjørklund G, Abdel-Reheim MK, Othman HA, El-Houfey AA, Abd El-Aziz NH, Abd El-Baseer KA, Ahmed AE, Ali AM (2016) Vitamin D status in autism spectrum disorders and the efficacy of vitamin D supplementation in autistic children. Nutr Neurosci 19(8):346–351CrossRefGoogle Scholar
  181. Saad K, Abdel-Rahman AA, Elserogy YM, Al-Atram AA, El-Houfey AA, Othman HA, Bjørklund G, Jia F, Urbina MA, Abo-Elela MGM, Ahmad FA, Abd El-Baseer KA, Ahmed AE, Abdel-Salam AM (2018) Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder. J Child Psychol Psychiatry 59(1):20–29. CrossRefPubMedGoogle Scholar
  182. Saldanha Tschinkel PF, Bjørklund G, Conón LZZ, Chirumbolo S, Nascimento VA (2018) Plasma concentrations of the trace elements copper, zinc and selenium in Brazilian children with autism spectrum disorder. Biomed Pharmacother 106:605–609. CrossRefPubMedGoogle Scholar
  183. Schaefer GB, Mendelsohn NJ (2008) Clinical genetics evaluation in identifying the etiology of autism spectrum disorders. Genet Med 10:301. CrossRefPubMedPubMedCentralGoogle Scholar
  184. Schmidt N, Akaaboune M, Gajendran N, y Valenzuela IM-P, Wakefield S, Thurnheer R, Brenner HR (2011) Neuregulin/ErbB regulate neuromuscular junction development by phosphorylation of α-dystrobrevin. J Cell Biol 195:1171–1184. CrossRefPubMedPubMedCentralGoogle Scholar
  185. Schofield K (2016) Autism, chemicals, probable cause and mitigation: a new examination. Autism Open Access 6:2. CrossRefGoogle Scholar
  186. Sener EF, Oztop DB, Ozkul Y (2014) MTHFR gene C677T polymorphism in autism spectrum disorders. Genet Res Int 2014. CrossRefGoogle Scholar
  187. Shen Y, Dies KA, Holm IA, Bridgemohan C, Sobeih MM, Caronna EB, Miller KJ, Frazier JA, Silverstein I, Picker J (2010) Clinical genetic testing for patients with autism spectrum disorders. Pediatrics 125:e727–e735. CrossRefPubMedPubMedCentralGoogle Scholar
  188. Siddiqui MF, Elwell C, Johnson MH (2016) Mitochondrial dysfunction in autism spectrum disorders Autism-open access 6.
  189. Siniscalco D, Cirillo A, Bradstreet JJ, Antonucci N (2013) Epigenetic findings in autism: new perspectives for therapy. Int J Environ Res Public Health 10:4261–4273. CrossRefPubMedPubMedCentralGoogle Scholar
  190. Skalny AV, Skalnaya MG, Bjørklund G, Nikonorov AA, Tinkov AA (2016) Mercury as a possible link between maternal obesity and autism spectrum disorder. Med Hypotheses 91:90–94. CrossRefPubMedGoogle Scholar
  191. Skalny AV, Simashkova NV, Skalnaya AA, Klyushnik TP, Bjørklund G, Skalnaya MG, Tinkov AA (2017a) Assessment of gender and age effects on serum and hair trace element levels in children with autism spectrum disorder. Metab Brain Dis 32(5):1675–1684. CrossRefPubMedGoogle Scholar
  192. Skalny AV, Simashkova NV, Klyushnik TP, Grabeklis AR, Bjørklund G, Skalnaya MG, Nikonorov AA, Tinkov AA (2017b) Hair toxic and essential trace elements in children with autism spectrum disorder. Metab Brain Dis 32(1):195–202. CrossRefPubMedGoogle Scholar
  193. Söğüt S, Zoroğlu SS, Özyurt H, Yılmaz HR, Özuğurlu F, Sivaslı E, Yetkin Ö, Yanık M, Tutkun H, Savaş HA (2003) Changes in nitric oxide levels and antioxidant enzyme activities may have a role in the pathophysiological mechanisms involved in autism. Clin Chim Acta 331:111–117. CrossRefPubMedGoogle Scholar
  194. Søreide K (2008) Receiver-operating characteristic (ROC) curve analysis in diagnostic, prognostic and predictive biomarker research. J Clin Pathol. CrossRefGoogle Scholar
  195. Spratt EG, Nicholas JS, Brady KT, Carpenter LA, Hatcher CR, Meekins KA, Furlanetto RW, Charles JM (2012) Enhanced cortisol response to stress in children in autism. J Autism Dev Disord 42:75–81 CrossRefGoogle Scholar
  196. Stobiecka M, Prance A, Coopersmith K, Hepel M (2011) Antioxidant effectiveness in preventing paraquat-mediated oxidative DNA damage in the presence of H2O2 vol 1083. Oxford University Press, Inc., Washington, DC, USA. CrossRefGoogle Scholar
  197. Stoltenberg C, Schjølberg S, Bresnahan M, Hornig M, Hirtz D, Dahl C, Lie KK, Reichborn-Kjennerud T, Schreuder P, Alsaker E (2010) The Autism Birth Cohort: a paradigm for gene–environment–timing research. Mol Psychiatry 15:676. CrossRefPubMedPubMedCentralGoogle Scholar
  198. Streit WJ (2000) Microglial response to brain injury: a brief synopsis. Toxicol Pathol 28:28–30. CrossRefPubMedGoogle Scholar
  199. Surén P, Roth C, Bresnahan M, Haugen M, Hornig M, Hirtz D, Lie KK, Lipkin WI, Magnus P, Reichborn-Kjennerud T (2013) Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA 309:570–577. CrossRefPubMedPubMedCentralGoogle Scholar
  200. Surén P, Gunnes N, Roth C, Bresnahan M, Hornig M, Hirtz D, Lie KK, Lipkin WI, Magnus P, Reichborn-Kjennerud T (2014) Parental obesity and risk of autism spectrum disorder. Pediatrics 133:e1128–e1138. CrossRefPubMedPubMedCentralGoogle Scholar
  201. Sweeten TL, Posey DJ, Shankar S, McDougle CJ (2004) High nitric oxide production in autistic disorder: a possible role for interferon-γ. Biol Psychiatry 55:434–437 CrossRefGoogle Scholar
  202. Swets JA (1979) ROC analysis applied to the evaluation of medical imaging techniques. Investig Radiol 14:109–121CrossRefGoogle Scholar
  203. Swets JA (1986) Indices of discrimination or diagnostic accuracy: their ROCs and implied models. Psychol Bull 99:100. CrossRefPubMedGoogle Scholar
  204. Talkowski ME, Minikel EV, Gusella JF (2014) Autism spectrum disorder genetics: diverse genes with diverse clinical outcomes. Harv Rev Psychiatry 22:65–75. CrossRefPubMedGoogle Scholar
  205. Taniguchi Y, Taniguchi-Ueda Y, Mori K, Yodoi J (1996) A novel promoter sequence is involved in the oxidative stress-induced expression of the adult T-cell leukemia-derived factor (ADF)/human thioredoxin (Trx) gene. Nucleic Acids Res 24:2746–2752 CrossRefGoogle Scholar
  206. Tareen RS, Kamboj MK (2012) Role of endocrine factors in autistic spectrum disorders. Pediatr Clin 59:75–88 CrossRefGoogle Scholar
  207. Tinkov AA, Bjørklund G, Skalny AV, Holmgren A, Skalnaya MG, Chirumbolo S, Aaseth J (2018) The role of the thioredoxin/thioredoxin reductase system in the metabolic syndrome: towards a possible prognostic marker? Cell Mol Life Sci 75(9):1567–1586. CrossRefPubMedGoogle Scholar
  208. Tostes M, Teixeira H, Gattaz W, Brandao M, Raposo N (2012) Altered neurotrophin, neuropeptide, cytokines and nitric oxide levels in autism. Pharmacopsychiatry 45:241. CrossRefPubMedGoogle Scholar
  209. Truman JW, De Vente J, Ball EE (1996) Nitric oxide-sensitive guanylate cyclase activity is associated with the maturational phase of neuronal development in insects. Development 122:3949–3958PubMedGoogle Scholar
  210. Tschinkel PFS, Bjørklund G, Conón LZZ, Chirumbolo S, Nascimento VA (2018) Plasma concentrations of the trace elements copper, zinc and selenium in Brazilian children with autism spectrum disorder. Biomed Pharmacother 106:605–609. CrossRefGoogle Scholar
  211. Tu WJ, Chen H, He J (2012) Application of LC-MS/MS analysis of plasma amino acids profiles in children with autism. J Clin Biochem Nutr 51:248–249. CrossRefPubMedPubMedCentralGoogle Scholar
  212. Van Weyenbergh J, Santana G, D'Oliveira A, Santos AF, Costa CH, Carvalho EM, Barral A, Barral-Netto M (2004) Zinc/copper imbalance reflects immune dysfunction in human leishmaniasis: an ex vivo and in vitro study. BMC Infect Dis 4:50. CrossRefPubMedPubMedCentralGoogle Scholar
  213. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57:67–81. CrossRefPubMedGoogle Scholar
  214. Vargason T, Howsmon DP, Melnyk S, James SJ, Hahn J (2017) Mathematical modeling of the methionine cycle and transsulfuration pathway in individuals with autism spectrum disorder. J Theor Biol 416:28–37. CrossRefPubMedGoogle Scholar
  215. Vasquez A (2017) Biological plausibility of the gut–brain axis in autism. Ann N Y Acad Sci 1408:5–6. CrossRefPubMedGoogle Scholar
  216. Veenstra-VanderWeele J, Muller CL, Iwamoto H, Sauer JE, Owens WA, Shah CR, Cohen J, Mannangatti P, Jessen T, Thompson BJ (2012) Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior. Proc Natl Acad Sci U S A 201112345. CrossRefGoogle Scholar
  217. Vojdani A, Campbell A, Anyanwu E, Kashanian A, Bock K, Vojdani E (2002) Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group. A J Neuroimmunol 129:168–177. CrossRefPubMedGoogle Scholar
  218. Walker CF, Black RE (2004) Zinc and the risk for infectious disease. Annu Rev Nutr 24:255–275. CrossRefGoogle Scholar
  219. Wang L, Angley MT, Sorich MJ, Young RL, McKinnon RA, Gerber JP (2010) Is there a role for routinely screening children with autism spectrum disorder for creatine deficiency syndrome? Autism Res 3:268–272. CrossRefPubMedGoogle Scholar
  220. Wang L, Angley MT, Gerber JP, Sorich MJ (2011) A review of candidate urinary biomarkers for autism spectrum disorder. Biomarkers 16:537–552 CrossRefGoogle Scholar
  221. Wegiel J, Frackowiak J, Mazur-Kolecka B, Schanen NC, Cook EH Jr, Sigman M, Brown WT, Kuchna I, Wegiel J, Nowicki K (2012) Abnormal intracellular accumulation and extracellular Aβ deposition in idiopathic and Dup15q11. 2-q13 autism spectrum disorders. PLoS One 7:e35414. CrossRefPubMedPubMedCentralGoogle Scholar
  222. Wei H, Chadman KK, McCloskey DP, Sheikh AM, Malik M, Brown WT, Li X (2012) Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors. Biochim Biophys Acta 1822:831–842. CrossRefPubMedGoogle Scholar
  223. Weissman JR, Kelley RI, Bauman ML, Cohen BH, Murray KF, Mitchell RL, Kern RL, Natowicz MR (2008) Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. PLoS One 3:e3815. CrossRefPubMedPubMedCentralGoogle Scholar
  224. Whiteley P, Shattock P, Knivsberg A-M, Seim A, Reichelt KL, Todd L, Carr K, Hooper M (2013) Gluten-and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci 6:344. CrossRefPubMedPubMedCentralGoogle Scholar
  225. Wieand S, Gail MH, James BR, James KL (1989) A family of nonparametric statistics for comparing diagnostic markers with paired or unpaired data. Biometrika 76:585–592. CrossRefGoogle Scholar
  226. Wink LK, Adams R, Wang Z, Klaunig JE, Plawecki MH, Posey DJ, McDougle CJ, Erickson CA (2016) A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder. Mol Autism 7:26. CrossRefPubMedPubMedCentralGoogle Scholar
  227. Witters P, Debbold E, Crivelly K, Kerckhove KV, Corthouts K, Debbold B, Andersson H, Vannieuwenborg L, Geuens S, Baumgartner M (2016) Autism in patients with propionic acidemia. Mol Genet Metab 119:317–321. CrossRefPubMedGoogle Scholar
  228. Wong S, Giulivi C (2016) Autism, mitochondria and polybrominated diphenyl ether exposure. CNS Neurol Disord Drug Targets 15:614–623CrossRefGoogle Scholar
  229. Woodbury-Smith M, Scherer SW (2018) Progress in the genetics of autism spectrum disorder. Dev Med Child Neurol 60:445–451CrossRefGoogle Scholar
  230. Woods JS, Armel SE, Fulton DI, Allen J, Wessels K, Simmonds PL, Granpeesheh D, Mumper E, Bradstreet JJ, Echeverria D (2010) Urinary porphyrin excretion in neurotypical and autistic children. Environ Health Perspect 118:1450. CrossRefPubMedPubMedCentralGoogle Scholar
  231. Xu N, Li X, Zhong Y (2015) Inflammatory cytokines: potential biomarkers of immunologic dysfunction in autism spectrum disorders. Mediat Inflamm 2015:531518. CrossRefGoogle Scholar
  232. Yan C-L, Zhang J, Hou Y (2015) Decreased plasma levels of lipoxin A4 in children with autism spectrum disorders. Neuroreport 26:341–345. CrossRefPubMedGoogle Scholar
  233. Yang C-J, Liu C-L, Sang B, Zhu X-M, Du Y-J (2015) The combined role of serotonin and interleukin-6 as biomarker for autism. Neuroscience 284:290–296. CrossRefPubMedGoogle Scholar
  234. Yasuda H, Tsutsui T (2013) Assessment of infantile mineral imbalances in autism spectrum disorders (ASDs). Int J Environ Res Public Health 10:6027–6043. CrossRefPubMedPubMedCentralGoogle Scholar
  235. Yatawara C, Einfeld S, Hickie I, Davenport T, Guastella A (2016) The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Mol Psychiatry 21:1225. CrossRefPubMedGoogle Scholar
  236. Yoo HJ, Park M, Kim SA (2017) Difference in mitochondrial DNA copy number in peripheral blood cells between probands with autism spectrum disorders and their unaffected siblings. World J Biol Psychiatry 18:151–156. CrossRefPubMedGoogle Scholar
  237. Yorbik O, Sayal A, Akay C, Akbiyik D, Sohmen T (2002) Investigation of antioxidant enzymes in children with autistic disorder. Prostaglandins Leukot Essent Fatty Acids 67:341–343. CrossRefPubMedGoogle Scholar
  238. Yui K, Kawasaki Y, Yamada H, Ogawa S (2016) Oxidative stress and nitric oxide in autism spectrum disorder and other neuropsychiatric disorders. CNS Neurol Disord Drug Targets 15:587–596CrossRefGoogle Scholar
  239. Zafeiriou D, Ververi A, Vargiami E (2009) The serotonergic system: its role in pathogenesis and early developmental treatment of autism. Curr Neuropharmacol 7:150–157. CrossRefPubMedPubMedCentralGoogle Scholar
  240. Zerbo O, Qian Y, Yoshida C, Fireman BH, Klein NP, Croen LA (2017) Association between influenza infection and vaccination during pregnancy and risk of autism spectrum disorder. JAMA Pediatr 171:e163609–e163609. CrossRefPubMedGoogle Scholar
  241. Zhang Q-b, Gao S-j, Zhao H-x (2015) Thioredoxin: a novel, independent diagnosis marker in children with autism. Int J Dev Neurosci 40:92–96. CrossRefPubMedGoogle Scholar
  242. Zhao H-x, Yin S-s, Fan J-g (2015) High plasma neopterin levels in Chinese children with autism spectrum disorders. Int J Dev Neurosci 41:92–97. CrossRefPubMedGoogle Scholar
  243. Zilbovicius M, Meresse I, Chabane N, Brunelle F, Samson Y, Boddaert N (2006) Autism, the superior temporal sulcus and social perception. Trends Neurosci 29:359–366. CrossRefPubMedGoogle Scholar
  244. Zoroglu SS, Armutcu F, Ozen S, Gurel A, Sivasli E, Yetkin O, Meram I (2004) Increased oxidative stress and altered activities of erythrocyte free radical scavenging enzymes in autism. Eur Arch Psychiatry Clin Neurosci 254:143–147. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Geir Bjørklund
    • 1
    Email author
  • Nagwa A. Meguid
    • 2
    • 3
  • Afaf El-Ansary
    • 4
    • 5
  • Mona A. El-Bana
    • 3
    • 6
  • Maryam Dadar
    • 7
  • Jan Aaseth
    • 8
    • 9
  • Maha Hemimi
    • 2
    • 3
  • Joško Osredkar
    • 10
  • Salvatore Chirumbolo
    • 11
    • 12
  1. 1.Council for Nutritional and Environmental Medicine (CONEM)Mo i RanaNorway
  2. 2.Research on Children with Special Needs DepartmentNational Research CentreGizaEgypt
  3. 3.CONEM Egypt Child Brain Research GroupNational Research CenterGizaEgypt
  4. 4.Central LaboratoryKing Saud UniversityRiyadhSaudi Arabia
  5. 5.CONEM Saudi Autism Research GroupKing Saud UniversityRiyadhSaudi Arabia
  6. 6.Medical Biochemistry DepartmentNational Research CentreGizaEgypt
  7. 7.Agricultural Research, Education and Extension Organization (AREEO)Razi Vaccine and Serum Research InstituteKarajIran
  8. 8.Faculty of Public HealthInland Norway University of Applied SciencesElverumNorway
  9. 9.Department of ResearchInnlandet Hospital TrustBrumunddalNorway
  10. 10.Institute of Clinical Chemistry and Biochemistry (KIKKB)Ljubljana University Medical CentreLjubljanaSlovenia
  11. 11.Department of Neuroscience, Biomedicine and Movement SciencesUniversity of VeronaVeronaItaly
  12. 12.CONEM Scientific SecretaryVeronaItaly

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