Abstract
Creatine (Cr) Transporter Deficiency (CTD) is an X-linked metabolic disorder, mostly caused by missense mutations in the SLC6A8 gene and presenting with intellectual disability, autistic behavior, and epilepsy. There is no effective treatment for CTD and patients need lifelong assistance. Thus, the research of novel intervention strategies is a major scientific challenge. Animal models are an excellent tool to dissect the disease pathogenetic mechanisms and drive the preclinical development of therapeutics. This review illustrates the current knowledge about Cr metabolism and CTD clinical aspects, with a focus on mainstay diagnostic and therapeutic options. Then, we discuss the rodent models of CTD characterized in the last decade, comparing the phenotypes expressed within clinically relevant domains and the timeline of symptom development. This analysis highlights that animals with the ubiquitous deletion/mutation of SLC6A8 genes well recapitulate the early onset and the complex pathological phenotype of the human condition. Thus, they should represent the preferred model for preclinical efficacy studies. On the other hand, brain- and cell-specific conditional mutants are ideal for understanding the basis of CTD at a cellular and molecular level. Finally, we explain how CTD models might provide novel insight about the pathogenesis of other disorders, including cancer.
Highlights
Using the Y maze, the object-recognition test (ORT), the Morris water maze (MWM), and the contextual and cued fear conditioning (FC), researchers demonstrated that human intellectual disability (ID) is well recapitulated by CRT deficiency (CTD) models, as they exhibited deficits in most of these tasks
This study identified dodecyl creatine ester (DCE) as the compound with the most interesting features in terms of brain penetrability and diffusion [147,148]
There is no cure for CTD and the mainstay of care includes pharmacological management of epilepsy and support for families
Summary
GAMT transfers a methyl group from S-adenosylmethionine (SAM) to GAA, generating Cr and S-adenosyl homocysteine [16] This apparently simple pathway is complicated by the fact that most cells do not express both AGAT and GAMT, requiring the transport of the synthesis intermediate GAA between tissues. CRT is expressed in oligodendrocytes and neurons, with remarkably high levels in fast-spiking parvalbumin inhibitory neurons [30,31] It is present in capillary endothelial cells composing the blood-brain barrier (BBB), whereas it has been detected only in a lesser amount in astrocytes [19]. Inborn errors of Cr metabolism refer to three different syndromes caused by mutations in the genes encoding for AGAT, GAMT and CRT, and mainly characterized by cerebral Cr deficiency [25,35,36] These genetic disorders share a common clinical picture with developmental delay/regression, intellectual disability (ID), severe disturbance of expressive and cognitive speech, autistic-like features, behavioral and motor abnormalities, and seizures [36,37]. We will depict how the study of CTD models might provide novel insight about the pathogenesis of other disorders, including cancer
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