In conclusion, Cr at high concentrations is able to penetrate cells probably through passive transport, and may act normalizing cell cycle progression and ROS levels, outstanding the contribution of energy depletion toward metabolic stress at least in selected CRTR cells. Background: Arginine:glycine amidinotransferase (OMIM 602360) deficiency (AGAT-d) is an autosomal recessive disease characterized by specific biochemical, brain spectroscopy and genetic findings. So far only six AGAT patients were described in the literature (Bianchi MC. et al.2000; Battini R. et al.2002; Edvardson S.2010 ) and supplementation of Cr has been shown to improve clinical symptoms in affected cases. Presymptomatic treatment has been reported in only one subject (Battini R. et al.2006) . Patients: We report the neuropsychological follow up of 4 AGAT-d cases, all members of the same family, two sisters (aged 20 and 18 yrs), one male cousin (15 yrs) and one presymptomatic child (7 yrs Guanidinoacetate methyltransferase (GAMT) deficiency is an inborn error of creatine biosynthesis. The enzyme catalyzes the conversion of guanidinoacetate to creatine. The clinical phenotype includes developmental delay/ intellectual disability, speech delay, seizures behavioral difficulties, and neurologic symptoms. Treatment with diet (arginine restriction/ ornithine supplementation) and creatine supplementation has been tried to decrease guanidinoacetate in the body. Treatment, both pre-symtpomatic and symptomatic, has shown significant improvement in clinical outcome. We evaluate a patient with GAMT deficiency. The patient is now 8.5 years old. He presented at 3.5 years with hypotonia, global developmental delay, and difficult to treat seizures. Testing revealed GAMT deficiency. After starting treatment, the patient no longer has clinical seizures, taking antiepileptic medication and has an improved EEG. Developmentally, he has made great strides. He has progressed from being unable to engage independently in classroom routines and activities, to reading at an approximately kindergarten to early first grade level, writing his name, counting objects and doing single digit addition. He has progressed form needing a PECS system for communication at the age of two and a half years to now consistently using 4-6 word phrases and descriptive speech. Our patient demonstrates the significant clinical improvement with treatment of GAMT deficiency. Creatine deficiency syndromes (due to AGAT, GAMT or SLC6A8 deficiencies) are inborn errors of metabolism characterized by an absence or a severe decrease of Cr in central nervous system, which is the main tissue affected. To investigate the effects of creatine deficiency on developing CNS, we developed a new experimental model of GAMT deficiency by gene knock-down, using RNA interference in 3D organotypic rat brain cell cultures in aggregates. A specific shRNA for the rat GAMT gene was transduced in brain cell aggregates by an adeno-associated virus (AAV2) under the control of the CMV promoter. The AAV2-transduced shRNA was able to efficiently knock down GAMT expression, as shown by the strong decrease of GAMT protein by western blotting. We show that GAMT knock-down strongly affected axonal growth (neurons, immunohistochemistry for pNF-M) and astrocytes (immunohistochemistry for GFAP), as well as increased cell death and apoptotic pathways in developing brain cells (TUNEL experiments and immunohistochemistry for activated caspase 3).