The role of preclinical models in creatine transporter deficiency: Neurobiological mechanisms, biomarkers and therapeutic development

Elsa Ghirardini, Francesco Calugi, Giulia Sagona, Federica Di Vetta, Martina Palma, Roberta Battini, Giovanni Cioni, Tommaso Pizzorusso, Laura Baroncelli

Research output: Contribution to journalReview articlepeer-review

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.

Original languageEnglish
Article number1123
Number of pages22
JournalGenes
Volume12
Issue number8
DOIs
Publication statusPublished - Aug 2021

Keywords

  • Animal models
  • Autism
  • Creatine
  • Creatine transporter deficiency
  • Epilepsy
  • Intellectual disability
  • Metabolic disorders
  • Metabolism

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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