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English: Figure 1 Suggested mechanisms of neurochemical effects of GAA accumulation in the brain. Under GAMT deficiency, there is uptake of GAA from the periphery and GAA synthesis in the neuron occurring mainly in the mitochondria intermembrane space via AGAT. The GAA leaves the neuron through an unknown mechanism, and due to the lack of functional GAMT, it accumulates in the synaptic cliff and within the neuron itself. This accumulation leads to a series of imbalances in enzymes, receptors, and redox state. The GAA seems to act as a direct agonist of GABAA receptors, leading to their desensitization and internalization. It appears to cause a decrease in antioxidant defenses at the same time that inhibits the activity of crucial enzymes for energy generation: Na+, K+-ATPase, complex II in the mitochondrial respiratory chain, and creatine kinase. The GAA significantly increased AChE activity, leading to less AChE available in the synaptic cliff. Furthermore, GAA markedly inhibited glutamate uptake by astrocytes. AChE indicates acetylcholinesterase; AGAT, arginine glycine amidinotransferase; ATP, adenosine triphosphate; GAA, guanidinoacetate; GAMT, guanidinoacetate methyltransferase.