GAMT (guanidinoacetate N-methyltransferase) is a critical enzyme in creatine biosynthesis that converts guanidinoacetate to creatine using S-adenosylmethionine as the methyl donor 1. This enzyme is highly expressed in liver and kidney but is also distributed throughout the central nervous system, where it plays an essential role in maintaining cellular energy homeostasis through the creatine/phosphocreatine system 23. GAMT works in coordination with AGAT (arginine:glycine amidinotransferase) to complete the two-step creatine synthesis pathway, with evidence suggesting these enzymes are expressed in distinct cell populations requiring intercellular transport of intermediates 3. GAMT deficiency causes cerebral creatine deficiency syndrome 2, an autosomal recessive disorder characterized by severe global developmental delay, intellectual disability, speech impairment, epilepsy, movement disorders, and autism spectrum behaviors 456. The condition results from systemic creatine depletion and toxic accumulation of guanidinoacetate, which appears responsible for intractable seizures and movement disorders unique to GAMT deficiency 41. Treatment with oral creatine supplementation combined with arginine restriction and ornithine substitution can improve clinical outcomes, particularly when initiated early, though complete normalization is rarely achieved 61. Gene therapy approaches delivering both GATM and GAMT show promise for bypassing creatine transport defects 7.