Intellectual Disability and Brain Creatine Deficit: Phenotyping of the Genetic Mouse Model for GAMT Deficiency.
Luigia RossiFrancesca NardecchiaFrancesca PierigèRossella VenturaClaudia CarducciVincenzo LeuzziMauro MagnaniSimona CabibTiziana PascucciPublished in: Genes (2021)
Guanidinoacetate methyltransferase deficiency (GAMT-D) is one of three cerebral creatine (Cr) deficiency syndromes due to pathogenic variants in the GAMT gene (19p13.3). GAMT-D is characterized by the accumulation of guanidinoacetic acid (GAA) and the depletion of Cr, which result in severe global developmental delay (and intellectual disability), movement disorder, and epilepsy. The GAMT knockout (KO) mouse model presents biochemical alterations in bodily fluids, the brain, and muscles, including increased GAA and decreased Cr and creatinine (Crn) levels, which are similar to those observed in humans. At the behavioral level, only limited and mild alterations have been reported, with a large part of analyzed behaviors being unaffected in GAMT KO as compared with wild-type mice. At the cerebral level, decreased Cr and Crn and increased GAA and other guanidine compound levels have been observed. Nevertheless, the effects of Cr deficiency and GAA accumulation on many neurochemical, morphological, and molecular processes have not yet been explored. In this review, we summarize data regarding behavioral and cerebral GAMT KO phenotypes, and focus on uncharted behavioral alterations that are comparable with the clinical symptoms reported in GAMT-D patients, including intellectual disability, poor speech, and autistic-like behaviors, as well as unexplored Cr-induced cerebral alterations.
Keyphrases
- intellectual disability
- autism spectrum disorder
- mouse model
- subarachnoid hemorrhage
- wild type
- cerebral ischemia
- copy number
- replacement therapy
- end stage renal disease
- white matter
- resting state
- ejection fraction
- dna methylation
- chronic kidney disease
- early onset
- prognostic factors
- functional connectivity
- gene expression
- skeletal muscle
- smoking cessation
- diabetic rats
- insulin resistance
- endothelial cells
- metabolic syndrome
- multiple sclerosis
- artificial intelligence
- drug induced
- high fat diet induced