{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:22:10Z","timestamp":1790634130507,"version":"4.1.0"},"reference-count":78,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T00:00:00Z","timestamp":1627862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Guanidinoacetate methyltransferase deficiency (GAMT-D) is one of three cerebral creatine (Cr) deficiency syndromes due to pathogenic variants in the GAMT gene (19p13.3). GAMT-D is characterized by the accumulation of guanidinoacetic acid (GAA) and the depletion of Cr, which result in severe global developmental delay (and intellectual disability), movement disorder, and epilepsy. The GAMT knockout (KO) mouse model presents biochemical alterations in bodily fluids, the brain, and muscles, including increased GAA and decreased Cr and creatinine (Crn) levels, which are similar to those observed in humans. At the behavioral level, only limited and mild alterations have been reported, with a large part of analyzed behaviors being unaffected in GAMT KO as compared with wild-type mice. At the cerebral level, decreased Cr and Crn and increased GAA and other guanidine compound levels have been observed. Nevertheless, the effects of Cr deficiency and GAA accumulation on many neurochemical, morphological, and molecular processes have not yet been explored. In this review, we summarize data regarding behavioral and cerebral GAMT KO phenotypes, and focus on uncharted behavioral alterations that are comparable with the clinical symptoms reported in GAMT-D patients, including intellectual disability, poor speech, and autistic-like behaviors, as well as unexplored Cr-induced cerebral alterations.<\/jats:p>","DOI":"10.3390\/genes12081201","type":"journal-article","created":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T08:44:11Z","timestamp":1627893851000},"page":"1201","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Intellectual Disability and Brain Creatine Deficit: Phenotyping of the Genetic Mouse Model for GAMT Deficiency"],"prefix":"10.3390","volume":"12","author":[{"given":"Luigia","family":"Rossi","sequence":"first","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino \u201cCarlo Bo\u201d, 61029 Urbino, Italy"},{"name":"EryDel SpA, Via Sasso 36, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0808-2827","authenticated-orcid":false,"given":"Francesca","family":"Nardecchia","sequence":"additional","affiliation":[{"name":"Division of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Pierig\u00e8","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino \u201cCarlo Bo\u201d, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Ventura","sequence":"additional","affiliation":[{"name":"Department of Psychology and \u201cDaniel Bovet\u201d Center, Sapienza University, 00184 Rome, Italy"},{"name":"IRCCS Fondazione Santa Lucia, 00142 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Carducci","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2314-6139","authenticated-orcid":false,"given":"Vincenzo","family":"Leuzzi","sequence":"additional","affiliation":[{"name":"Division of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6456-6626","authenticated-orcid":false,"given":"Mauro","family":"Magnani","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino \u201cCarlo Bo\u201d, 61029 Urbino, Italy"},{"name":"EryDel SpA, Via Sasso 36, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8781-8603","authenticated-orcid":false,"given":"Simona","family":"Cabib","sequence":"additional","affiliation":[{"name":"Department of Psychology and \u201cDaniel Bovet\u201d Center, Sapienza University, 00184 Rome, Italy"},{"name":"IRCCS Fondazione Santa Lucia, 00142 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1520-7373","authenticated-orcid":false,"given":"Tiziana","family":"Pascucci","sequence":"additional","affiliation":[{"name":"Department of Psychology and \u201cDaniel Bovet\u201d Center, Sapienza University, 00184 Rome, Italy"},{"name":"IRCCS Fondazione Santa Lucia, 00142 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1007\/s00726-016-2189-0","article-title":"Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models?","volume":"48","author":"Braissant","year":"2016","journal-title":"Amino Acids"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1086\/323765","article-title":"Arginine: Glycine amidinotransferase deficiency: The third inborn error of creatine metabolism in humans","volume":"69","author":"Item","year":"2001","journal-title":"Am. 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