{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T15:23:29Z","timestamp":1789831409540,"version":"4.0.1"},"reference-count":36,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T00:00:00Z","timestamp":1676851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Biological bases of autism spectrum disorder (ASD) include both genetic and epigenetic causes. Patients with ASD show anomalies in the profile of certain plasma amino acids, including neuroactive amino acids. Monitoring plasma amino acids may be relevant for patient care and interventions. We evaluated the plasma amino acid profile in samples extracted from dry blood spots by electrospray ionization-tandem mass spectrometry. Fourteen amino acids and eleven amino acid ratios were examined in patients with ASD and intellectual disability (ID), and neurotypical control subjects (TD). The amino acid profile in the ASD group showed reduced levels of ornithine (p = 0.008), phenylalanine (p = 0.042) and tyrosine (p = 0.013). The statistically significant amino acid ratios were Leu+Val\/Phe+Tyr (p = 0.002), Tyr\/Leu (p = 0.007) and Val\/Phe (p = 0.028), such differences remaining significant only in the comparison between ASD and TD. Finally, a positive correlation emerged between the score of the restricted and repetitive behavior on ADOS-2 and the citrulline levels in the ASD group (p = 0.0047). To conclude, patients with ASD may show a distinguishable metabolic profile useful for studying their metabolic pathways in order to develop screening tests and targeted therapies.<\/jats:p>","DOI":"10.3390\/children10020412","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T02:07:44Z","timestamp":1676945264000},"page":"412","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Neuroactive Amino Acid Profile in Autism Spectrum Disorder: Results from a Clinical Sample"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3756-3934","authenticated-orcid":false,"given":"Martina","family":"Randazzo","sequence":"first","affiliation":[{"name":"Child Neurology and Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1083-7915","authenticated-orcid":false,"given":"Adriana","family":"Prato","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8652-4248","authenticated-orcid":false,"given":"MariaAnna","family":"Messina","sequence":"additional","affiliation":[{"name":"Referral Centre for Inherited Metabolic Disorders, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concetta","family":"Meli","sequence":"additional","affiliation":[{"name":"Referral Centre for Inherited Metabolic Disorders, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0180-4695","authenticated-orcid":false,"given":"Antonino","family":"Casabona","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3997-1328","authenticated-orcid":false,"given":"Renata","family":"Rizzo","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6302-2686","authenticated-orcid":false,"given":"Rita","family":"Barone","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"},{"name":"Referral Centre for Inherited Metabolic Disorders, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"},{"name":"Reseach Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2022). Diagnostic and Statistical Manual of Mental Disorders, Text Revision; American Psychiatric Association. [5th ed.].","DOI":"10.1176\/appi.books.9780890425787"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/S0140-6736(13)61539-1","article-title":"Autism","volume":"383","author":"Lai","year":"2014","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s00726-016-2332-y","article-title":"Body fluid levels of neuroactive amino acids in autism spectrum disorders: A review of the literature","volume":"49","author":"Zheng","year":"2017","journal-title":"Amino Acids."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"359","DOI":"10.12740\/PP\/65046","article-title":"The amino acid profile in blood plasma of young boys with autism","volume":"51","author":"Bugajska","year":"2017","journal-title":"Psychiatr. Pol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s10571-006-9062-8","article-title":"Glutamate and schizophrenia: Beyond the dopamine hypothesis","volume":"26","author":"Coyle","year":"2006","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1007\/BF02172145","article-title":"Autism diagnostic interview-revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders","volume":"24","author":"Lord","year":"1994","journal-title":"J. Autism Dev. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1023\/A:1005592401947","article-title":"The Autism Diagnostic Observation Schedule\u2014Generic: A Standard Measure of Social and Communication Deficits Associated with the Spectrum of Autism","volume":"30","author":"Lord","year":"2000","journal-title":"J. Autism Dev. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1177\/008124630603600111","article-title":"The Griffiths Scales of Mental Development: A Factorial Validity Study","volume":"36","author":"Luiz","year":"2006","journal-title":"South Afr. J. Psychol."},{"key":"ref_9","unstructured":"Naglieri, J.A., and Goldstein, S. (2009). Practitioner's Guide to Assessing Intelligence and Achievement, John Wiley & Sons Inc.. [4th ed.]."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"863","DOI":"10.3389\/fpsyg.2013.00863","article-title":"Calculating and reporting effect sizes to facilitate cumulative science: A practical primer for t-tests and ANOVAs","volume":"4","author":"Lakens","year":"2013","journal-title":"Front. Psychol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Barone, R., Bastin, J., Djouadi, F., Singh, I., Karim, M.A., Ammanamanchi, A., McCarty, P.J., Delhey, L., Shannon, R., and Casabona, A. (2021). Mitochondrial Fatty Acid \u03b2-Oxidation and Resveratrol Effect in Fibroblasts from Patients with Autism Spectrum Disorder. J. Pers. Med., 11.","DOI":"10.3390\/jpm11060510"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1023\/A:1025071014191","article-title":"Plasma amino acids profiles in children with autism: Potential risk of nutritional deficiencies","volume":"33","author":"Arnold","year":"2003","journal-title":"J. Autism Dev. Disord."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/1743-7075-8-34","article-title":"Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity","volume":"8","author":"Adams","year":"2011","journal-title":"Nutr. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1007\/s10803-011-1314-x","article-title":"Distinct plasma profile of polar neutral amino acids, leucine, and glutamate in children with Autism Spectrum Disorders","volume":"42","author":"TirouvanziamTetyana","year":"2012","journal-title":"J. Autism Dev. Disord."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ejmhg.2014.02.002","article-title":"Study of plasma amino acid levels in children with autism: An Egyptian sample","volume":"15","author":"ElBaz","year":"2014","journal-title":"Egypt. J. Med. Hum. Genet."},{"key":"ref_16","first-page":"248","article-title":"Application of LC-MS\/MS analysis of plasma amino acids profiles in children with autism","volume":"51","author":"Tu","year":"2012","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2147\/NDT.S233105","article-title":"Assessments of amino acids, ammonia and oxidative stress among cohort of Egyptian autistic children: Correlations with electroencephalogram and disease severity","volume":"16","author":"Saleem","year":"2020","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/2040-2392-4-16","article-title":"Decreased tryptophan metabolism in patients with autism spectrum disorders","volume":"4","author":"Boccuto","year":"2013","journal-title":"Mol. Autism"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s13229-016-0109-5","article-title":"Urinary Metabolomics of Young Italian Autistic Children Supports Abnormal Tryptophan and Purine Metabolism","volume":"7","author":"Gevi","year":"2016","journal-title":"Mol. Autism"},{"key":"ref_20","first-page":"474","article-title":"Autistic children exhibit distinct plasma amino acid profile","volume":"50","author":"Naushad","year":"2013","journal-title":"Indian J. Biochem. Biophys."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Brister, D., Rose, S., Delhey, L., Tippett, M., Jin, Y., Gu, H., and Frye, R.E. (2022). Metabolomic Signatures of Autism Spectrum Disorder. J. Pers. Med., 12.","DOI":"10.3390\/jpm12101727"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kelly, R.S., Boulin, A., Laranjo, N., Lee-Sarwar, K., Chu, S.H., Yadama, A.P., Carey, V., Litonjua, A.A., Lasky-Su, J., and Weiss, S.T. (2019). Metabolomics and Communication Skills Development in Children; Evidence from the Ages and Stages Questionnaire. Metabolites, 9.","DOI":"10.3390\/metabo9030042"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1016\/j.cell.2016.11.013","article-title":"Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder","volume":"167","author":"Deliu","year":"2016","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e1036","DOI":"10.1002\/mgg3.1036","article-title":"Abnormalities in the genes that encode Large Amino Acid Transporters increase the risk of Autism Spectrum Disorder","volume":"8","author":"Cascio","year":"2020","journal-title":"Mol. Genet. Genomic. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1038\/s41467-017-01191-2","article-title":"Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice","volume":"8","author":"Aloisi","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.neubiorev.2014.02.003","article-title":"Dysregulation of group-I metabotropic glutamate (mGlu) receptor mediated signalling in disorders associated with Intellectual Disability and Autism","volume":"46","author":"Spatuzza","year":"2014","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zheng, Z., Zhu, T., Qu, Y., and Mu, D. (2016). Blood Glutamate Levels in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158688"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41398-020-01135-3","article-title":"Oxidative stress marker aberrations in children with autism spectrum disorder: A systematic review and meta-analysis of 87 studies (N\u2009=\u20099109)","volume":"11","author":"Chen","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3389\/fnins.2018.00019","article-title":"Comparison of Treatment for Metabolic Disorders Associated with Autism:Reanalysis of Three Clinical Trials","volume":"12","author":"Delhey","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1023\/A:1022238706604","article-title":"Plasma amino acid levels in children with autism and their families","volume":"33","author":"Aldred","year":"2003","journal-title":"J. Autism Dev. Disord."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1002\/aur.2330","article-title":"A Metabolomics Approach to Screening for Autism Risk in the Children's Autism Metabolome Project","volume":"13","author":"Smith","year":"2020","journal-title":"Autism Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1126\/science.1224631","article-title":"Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy","volume":"338","author":"Novarino","year":"2012","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/humu.22513","article-title":"Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients","volume":"35","author":"Oyarzabal","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"932670","DOI":"10.3389\/fnut.2022.932670","article-title":"The Role of Branched-Chain Amino Acids and Branched-Chain \u03b1-Keto Acid Dehydrogenase Kinase in Metabolic Disorders","volume":"9","author":"Du","year":"2022","journal-title":"Front. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"636","DOI":"10.3389\/fpsyt.2018.00636","article-title":"A Subset of Patients With Autism Spectrum Disorders Show a Distinctive Metabolic Profile by Dried Blood Spot Analyses","volume":"9","author":"Barone","year":"2018","journal-title":"Front. Psychiatry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/s10545-017-0132-5","article-title":"Biochemical markers and neuropsychological functioning in distal urea cycle disorders","volume":"41","author":"Waisbren","year":"2018","journal-title":"J. Inherit. Metab. Dis."}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/10\/2\/412\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:37:31Z","timestamp":1760121451000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/10\/2\/412"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,20]]},"references-count":36,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["children10020412"],"URL":"https:\/\/doi.org\/10.3390\/children10020412","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,20]]}}}