{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:22:12Z","timestamp":1790634132584,"version":"4.1.0"},"reference-count":40,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2017,7,31]],"date-time":"2017-07-31T00:00:00Z","timestamp":1501459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Creatine deficiency syndrome (CDS) comprises three separate enzyme deficiencies with overlapping clinical presentations: arginine:glycine amidinotransferase (GATM gene, glycine amidinotransferase), guanidinoacetate methyltransferase (GAMT gene), and creatine transporter deficiency (SLC6A8 gene, solute carrier family 6 member 8). CDS presents with developmental delays\/regression, intellectual disability, speech and language impairment, autistic behaviour, epileptic seizures, treatment-refractory epilepsy, and extrapyramidal movement disorders; symptoms that are also evident in children with autism. The objective of the study was to test the hypothesis that genetic variability in creatine metabolism genes is associated with autism. We sequenced GATM, GAMT and SLC6A8 genes in 166 patients with autism (coding sequence, introns and adjacent untranslated regions). A total of 29, 16 and 25 variants were identified in each gene, respectively. Four variants were novel in GATM, and 5 in SLC6A8 (not present in the 1000 Genomes, Exome Sequencing Project (ESP) or Exome Aggregation Consortium (ExAC) databases). A single variant in each gene was identified as non-synonymous, and computationally predicted to be potentially damaging. Nine variants in GATM were shown to have a lower minor allele frequency (MAF) in the autism population than in the 1000 Genomes database, specifically in the East Asian population (Fisher\u2019s exact test). Two variants also had lower MAFs in the European population. In summary, there were no apparent associations of variants in GAMT and SLC6A8 genes with autism. The data implying there could be a lower association of some specific GATM gene variants with autism is an observation that would need to be corroborated in a larger group of autism patients, and with sub-populations of Asian ethnicities. Overall, our findings suggest that the genetic variability of creatine synthesis\/transport is unlikely to play a part in the pathogenesis of autism spectrum disorder (ASD) in children.<\/jats:p>","DOI":"10.3390\/ijms18081665","type":"journal-article","created":{"date-parts":[[2017,8,1]],"date-time":"2017-08-01T03:30:06Z","timestamp":1501558206000},"page":"1665","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Variability of Creatine Metabolism Genes in Children with Autism Spectrum Disorder"],"prefix":"10.3390","volume":"18","author":[{"given":"Jessie M.","family":"Cameron","sequence":"first","affiliation":[{"name":"Genetics and Genome Biology, Peter Gilgan Center for Research and Learning, Toronto, ON M5G 0A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeriy","family":"Levandovskiy","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Peter Gilgan Center for Research and Learning, Toronto, ON M5G 0A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, University of Toronto, Toronto, ON M5S 1A1, Canada"},{"name":"Holland Bloorview Kids Rehabilitation Hospital, 150 Kigour Rd, Toronto, ON M4G 1R8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evdokia","family":"Anagnostou","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, University of Toronto, Toronto, ON M5S 1A1, Canada"},{"name":"Holland Bloorview Kids Rehabilitation Hospital, 150 Kigour Rd, Toronto, ON M4G 1R8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Scherer","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Peter Gilgan Center for Research and Learning, Toronto, ON M5G 0A4, Canada"},{"name":"The Centre for Applied Genomics and Genetics and Genome Biology, the Hospital for Sick Children, Toronto, ON M5G 1X8, Canada"},{"name":"McLaughlin Centre and Department of Molecular Genetics, 686 Bay Street, 13th Floor, Peter Gilgan Center for Research and Learning, Toronto, ON M5G 0A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvin","family":"Loh","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, University of Toronto, Toronto, ON M5S 1A1, Canada"},{"name":"Surrey Place Center, 2 Surrey Place, Toronto, ON M5S 2C2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Schulze","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Peter Gilgan Center for Research and Learning, Toronto, ON M5G 0A4, Canada"},{"name":"Department of Paediatrics, University of Toronto, Toronto, ON M5S 1A1, Canada"},{"name":"Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/978-90-481-9485-8_23","article-title":"Inherited metabolic rare disease","volume":"686","author":"Pampols","year":"2010","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1007\/s10803-011-1414-7","article-title":"Clinical and laboratory data in a sample of Greek children with autism spectrum disorders","volume":"42","author":"Ververi","year":"2012","journal-title":"J. Autism Dev. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1177\/0883073807308698","article-title":"Autism and metabolic diseases","volume":"23","author":"Manzi","year":"2008","journal-title":"J. Child Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1023\/A:1022443503883","article-title":"Creatine deficiency syndromes","volume":"244","author":"Schulze","year":"2003","journal-title":"Mol. Cell. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1542\/peds.2015-2672","article-title":"Prevalence of Creatine Deficiency Syndromes in Children with Nonsyndromic Autism","volume":"137","author":"Schulze","year":"2016","journal-title":"Pediatrics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/ng.3039","article-title":"Most genetic risk for autism resides with common variation","volume":"46","author":"Gaugler","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Klei, L., Sanders, S.J., Murtha, M.T., Hus, V., Lowe, J.K., Willsey, A.J., Moreno-De-Luca, D., Yu, T.W., Fombonne, E., and Geschwind, D. (2012). Common genetic variants, acting additively, are a major source of risk for autism. Mol. Autism, 3.","DOI":"10.1186\/2040-2392-3-9"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1016\/B978-0-444-59565-2.00053-8","article-title":"Creatine deficiency syndromes","volume":"113","author":"Schulze","year":"2013","journal-title":"Handb. Clin. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1111\/epi.12020","article-title":"Inborn errors of creatine metabolism and epilepsy","volume":"54","author":"Leuzzi","year":"2013","journal-title":"Epilepsia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.ymgme.2013.10.018","article-title":"Guanidinoacetate methyltransferase (GAMT) deficiency: Outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring","volume":"111","author":"Longo","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1136\/jmedgenet-2013-101658","article-title":"Phenotype and genotype in 101 males with X-linked creatine transporter deficiency","volume":"50","author":"Betsalel","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1042\/bj2810021","article-title":"Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: The \u2018phosphocreatine circuit\u2019 for cellular energy homeostasis","volume":"281","author":"Wallimann","year":"1992","journal-title":"Biochem. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1002\/syn.20280","article-title":"Exocytotic release of creatine in rat brain","volume":"60","author":"Almeida","year":"2006","journal-title":"Synapse"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1046\/j.1471-4159.2000.0741968.x","article-title":"Protective effect of the energy precursor creatine against toxicity of glutamate and beta-amyloid in rat hippocampal neurons","volume":"74","author":"Brewer","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1471-4159.2005.03337.x","article-title":"Effects of creatine treatment on survival and differentiation of GABA-ergic neurons in cultured striatal tissue","volume":"95","author":"Andres","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.neuroscience.2005.03.004","article-title":"Effects of creatine treatment on the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue","volume":"133","author":"Andres","year":"2005","journal-title":"Neuroscience"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/S0168-0102(02)00007-X","article-title":"Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation","volume":"42","author":"Watanabe","year":"2002","journal-title":"Neurosci. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1098\/rspb.2003.2492","article-title":"Oral creatine monohydrate supplementation improves brain performance: A double-blind, placebo-controlled, cross-over trial","volume":"270","author":"Rae","year":"2003","journal-title":"Proc. Biol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1023\/A:1024453704800","article-title":"Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism","volume":"26","author":"Stromberger","year":"2003","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.ymgme.2013.04.006","article-title":"Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes","volume":"109","author":"Comeaux","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1203\/00006450-199409000-00023","article-title":"Creatine deficiency in the brain: A new, treatable inborn error of metabolism","volume":"36","author":"Holzbach","year":"1994","journal-title":"Pediatr. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/S0022-3476(97)70075-1","article-title":"Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: Diagnostic tools for a new inborn error of metabolism","volume":"131","author":"Schulze","year":"1997","journal-title":"J. Pediatr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1212\/01.wnl.0000234852.43688.bf","article-title":"GAMT deficiency: Features, treatment, and outcome in an inborn error of creatine synthesis","volume":"67","author":"Adami","year":"2006","journal-title":"Neurology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.braindev.2009.01.008","article-title":"Guanidinoacetate methyltransferase deficiency (GAMT)","volume":"32","author":"Gordon","year":"2009","journal-title":"Brain Dev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/S1096-7192(02)00175-0","article-title":"Creatine depletion in a new case with AGAT deficiency: Clinical and genetic study in a large pedigree","volume":"77","author":"Battini","year":"2002","journal-title":"Mol. Genet. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.nmd.2013.04.011","article-title":"Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency","volume":"23","author":"Nouioua","year":"2013","journal-title":"Neuromuscul. Disord."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1101\/gr.176601","article-title":"Predicting deleterious amino acid substitutions","volume":"11","author":"Ng","year":"2001","journal-title":"Genome Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1002\/humu.21438","article-title":"LOVD v.2.0: The next generation in gene variant databases","volume":"32","author":"Fokkema","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/ejhg.2010.134","article-title":"Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database","volume":"19","author":"Betsalel","year":"2011","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1007\/s00439-006-0162-9","article-title":"X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology","volume":"119","author":"Clark","year":"2006","journal-title":"Hum. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1086\/422102","article-title":"High prevalence of SLC6A8 deficiency in X-linked mental retardation","volume":"75","author":"Rosenberg","year":"2004","journal-title":"Am. J. Hum. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Schiff, M., Benoist, J.F., Aissaoui, S., Boepsflug-Tanguy, O., Mouren, M.C., de Baulny, H.O., and Delorme, R. (2011). Should metabolic diseases be systematically screened in nonsyndromic autism spectrum disorders?. PLoS ONE, 6.","DOI":"10.1371\/annotation\/456e2365-a067-4063-b11b-6a2abeba3f20"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1055\/s-2008-1065353","article-title":"Screening of male patients with autism spectrum disorder for creatine transporter deficiency","volume":"38","author":"Newmeyer","year":"2007","journal-title":"Neuropediatrics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1023\/A:1005592401947","article-title":"The autism diagnostic observation schedule-generic: 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_37","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/BF02408436","article-title":"Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS)","volume":"10","author":"Schopler","year":"1980","journal-title":"J. Autism Dev. Disord."},{"key":"ref_38","unstructured":"The International Genome Sample Resource (IGSR) (2015, May 20). 1000 Genomes Phase 3 Dataset. Available online: http:\/\/www.1000genomes.org."},{"key":"ref_39","unstructured":"National Heart Lung and Blood Institute (NHLBI) (2015, May 20). Exome Sequencing Project (ESP). Available online: http:\/\/evs.gs.washington.edu\/EVS\/."},{"key":"ref_40","unstructured":"Exome Aggregation Consortium (ExAC) (2015, May 20). ExAC Browser (Beta). Available online: http:\/\/exac.broadinstitute.org\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/8\/1665\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:44:36Z","timestamp":1760208276000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/8\/1665"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,31]]},"references-count":40,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2017,8]]}},"alternative-id":["ijms18081665"],"URL":"https:\/\/doi.org\/10.3390\/ijms18081665","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,31]]}}}