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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Review

GAMT Deficiency: Clinical Presentation, Treatment, Diagnosis, Animal Models, Preclinical and Clinical Developments

by
Sara Biagiotti
1,
Elena Perla
1,
Serafina Manila Guzzo
2,
Manuela Tolve
3,
Francesca Nardecchia
4,
Luigia Rossi
1,
Claudia Carducci
5,
Tiziana Pascucci
2,
Vincenzo Leuzzi
4 and
Mauro Magnani
1,*
1
Department of Biomolecular Sciences, University of Urbino, 61029 Urbino, Italy
2
Department of Psychology, Sapienza University of Rome, 00185 Rome, Italy
3
Clinical Pathology Unit, AOU Policlinico Umberto I, 00161 Rome, Italy
4
Department of Human Neurosciences, Sapienza University of Rome, 00185 Rome, Italy
5
Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(23), 11282; https://doi.org/10.3390/ijms262311282
Submission received: 15 October 2025 / Revised: 18 November 2025 / Accepted: 18 November 2025 / Published: 21 November 2025
(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)
Versions Notes

Abstract

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’ 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’ 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’ 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.
Keywords: GAMT deficiency; creatine deficiency; GAMT gene; metabolic disorder; molecular pathology; diagnostics GAMT deficiency; creatine deficiency; GAMT gene; metabolic disorder; molecular pathology; diagnostics

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MDPI and ACS Style

Biagiotti, S.; Perla, E.; Guzzo, S.M.; Tolve, M.; Nardecchia, F.; Rossi, L.; Carducci, C.; Pascucci, T.; Leuzzi, V.; Magnani, M. GAMT Deficiency: Clinical Presentation, Treatment, Diagnosis, Animal Models, Preclinical and Clinical Developments. Int. J. Mol. Sci. 2025, 26, 11282. https://doi.org/10.3390/ijms262311282

AMA Style

Biagiotti S, Perla E, Guzzo SM, Tolve M, Nardecchia F, Rossi L, Carducci C, Pascucci T, Leuzzi V, Magnani M. GAMT Deficiency: Clinical Presentation, Treatment, Diagnosis, Animal Models, Preclinical and Clinical Developments. International Journal of Molecular Sciences. 2025; 26(23):11282. https://doi.org/10.3390/ijms262311282

Chicago/Turabian Style

Biagiotti, Sara, Elena Perla, Serafina Manila Guzzo, Manuela Tolve, Francesca Nardecchia, Luigia Rossi, Claudia Carducci, Tiziana Pascucci, Vincenzo Leuzzi, and Mauro Magnani. 2025. "GAMT Deficiency: Clinical Presentation, Treatment, Diagnosis, Animal Models, Preclinical and Clinical Developments" International Journal of Molecular Sciences 26, no. 23: 11282. https://doi.org/10.3390/ijms262311282

APA Style

Biagiotti, S., Perla, E., Guzzo, S. M., Tolve, M., Nardecchia, F., Rossi, L., Carducci, C., Pascucci, T., Leuzzi, V., & Magnani, M. (2025). GAMT Deficiency: Clinical Presentation, Treatment, Diagnosis, Animal Models, Preclinical and Clinical Developments. International Journal of Molecular Sciences, 26(23), 11282. https://doi.org/10.3390/ijms262311282

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