{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:10:01Z","timestamp":1792195801566,"version":"4.4.0"},"reference-count":123,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"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>Guanidinoacetate Methyl Transferase (GAMT) deficiency is a rare disease characterized by neurodevelopmental derangements, epilepsy, and movement disorders. The condition arises from the combined effect of postnatal brain creatine (Cr) depletion and guanidinoacetate (GAA) toxicity. Consequently, current treatment relies on Cr supplementation and metabolic management to reduce GAA accumulation by limiting its synthesis through ornithine supplementation and precursor reduction. Although effective in preventing the severe GAMT phenotype, the therapy is limited in normalizing these metabolites\u2019 concentrations. Recently, interest has been growing in approaches aimed at restoring the mutant enzyme as the primary step toward a cure. Some of these approaches have been investigated at the preclinical level and are here summarized. Interestingly, a mouse model that replicates most of the patients\u2019 features is now available in various labs, and the strong commitment of the Association for Creatine Deficiency has fostered the coordination and support of many of these models\u2019 initiatives. This review introduces readers to the complexity of this ultrarare condition, describes current therapeutic approaches, provides information about the most accurate methods for an early diagnosis, and outlines the main features of the available animal models. Finally, some current preclinical investigations are described, along with some preliminary expectations of emerging data.<\/jats:p>","DOI":"10.3390\/ijms262311282","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T15:33:06Z","timestamp":1763739186000},"page":"11282","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["GAMT Deficiency: Clinical Presentation, Treatment, Diagnosis, Animal Models, Preclinical and Clinical Developments"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9554-7858","authenticated-orcid":false,"given":"Sara","family":"Biagiotti","sequence":"first","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8588-7276","authenticated-orcid":false,"given":"Elena","family":"Perla","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6120-2824","authenticated-orcid":false,"given":"Serafina Manila","family":"Guzzo","sequence":"additional","affiliation":[{"name":"Department of Psychology, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0263-4325","authenticated-orcid":false,"given":"Manuela","family":"Tolve","sequence":"additional","affiliation":[{"name":"Clinical Pathology Unit, AOU Policlinico Umberto I, 00161 Rome, 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":"Department of Human Neurosciences, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigia","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0515-9208","authenticated-orcid":false,"given":"Claudia","family":"Carducci","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome, 00185 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, Sapienza University of Rome, 00185 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":"Department of Human Neurosciences, Sapienza University of Rome, 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, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1086\/320595","article-title":"X-linked creatine-transporter gene (SLC6A8) defect: A new creatine-deficiency syndrome","volume":"68","author":"Salomons","year":"2001","journal-title":"Am. 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