The creatine transporter (CRTR) defect is a recently discovered cause of Xlinked intellectual disability which is associated with cerebral creatine deficiency. Treatment with creatine monohydrate has not proved effective. Supplementation with creatine precursors L-arginine and glycine might increase endogenous cerebral creatine synthesis. The effect of this treatment is still controversial. We followed nine boys aged between 8 months and 10 years with molecularly confirmed CRTR defect with repeated 1H-MRS and neuropsychological assessments during 4-6 years of combination treatment with creatine monohydrate, L-arginine and glycine. Treatment did not lead to a significant increase in cerebral creatine content as observed with H1-MRS. After an initial improvement of locomotor and personal-social IQ subscales, no lasting clinical improvement was recorded. Additionaly, we noticed an age-related decline of IQ subscales in boys affected with the CRTR defect. Background: It is not known whether mouse models of creatine synthesis disorders AGAT and GAMT deficiency express any anatomical phenotype in the brain. Methods: Applying high-resolution magnetic resonance imaging combined with advanced image analysis techniques and statistics, the study aimed to characterize anatomical changes between AGAT and GAMT mutant mouse and there corresponding heterozygote and wild type genotype. Results: When analyzing absolute volumes of brain structures for the AGAT group, we found that 15 different brain structures had significant size differences among genotypes, including the corpus callosum, fimbria and internal capsule. These structures also had significant size differences when normalized for total brain size. Significant peaks (local areas of difference in relative size) were found for a number of areas in the brain, including the corpus callosum, hypothalamus and cerebral cortex. For the GAMT group, we found that the corpus callosum and internal capsule are significantly different in size among genotypes. These differences were found for both absolute and normalized volumes. Significant peaks were found in several regions of the brain, including the cerebellar cortex and hippocampus.