Early Indicators of Creatine Transporter Deficiency

Miller, Judith S.; Thomas, Rebecca P.; Bennett, Amanda; Bianconi, Simona; Bruchey, Aleksandra K.; Davis, Robert J.; Fıçıcıoğlu, Can; Guthrie, W. Spencer; Porter, Forbes D.; Thurm, Audrey

doi:10.1016/j.jpeds.2018.11.008

Cited by 12 publications

(16 citation statements)

References 11 publications

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“…We observed this difference already after weaning, but taking into account the degree of significance, it is likely that it extends from previous time points. This body weight gain issue is in agreement with reported early signs of CTD 39 .…”

Section: Discussionsupporting

confidence: 92%

“…These negative results in learning and memory performance contrast with the data from the ubiquitous CrT KO mice with exons 2–4 and 5–7 deleted, where deficits were present although with milder phenotype in NOR test around the same age in the last one 13 , 16 . Interestingly, these results showing normal recognition of an object or a location in KI males are aligned with data from CTD patients, as they are able to remember people, objects or locations but fail in the performance of more complex daily tasks and learning new abilities 17 , 39 . Performance of tasks with little or high level of complexity/difficulty can also be influenced by emotional learning and memory, and by other cognitive processes such as language or attention.…”

Section: Discussionsupporting

confidence: 64%

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A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

Durán-Trío

Fernandes-Pires

Simicic

et al. 2021

Sci Rep

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Creatine is an organic compound used as fast phosphate energy buffer to recycle ATP, important in tissues with high energy demand such as muscle or brain. Creatine is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Deficit in the endogenous synthesis or in the transport leads to Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain creatine deficiency, intellectual disability with severe speech delay, behavioral troubles such as attention deficits and/or autistic features, and epilepsy. Among CCDS, the X-linked creatine transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different mouse models of CTD were generated by doing long deletions in the Slc6a8 gene showing reduced brain creatine and cognitive deficiencies or impaired motor function. We present a new knock-in (KI) rat model of CTD holding an identical point mutation found in patients with reported lack of transporter activity. KI males showed brain creatine deficiency, increased urinary creatine/creatinine ratio, cognitive deficits and autistic-like traits. The Slc6a8Y389C KI rat fairly enriches the spectrum of CTD models and provides new data about the pathology, being the first animal model of CTD carrying a point mutation.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 64%

A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

Durán-Trío

Fernandes-Pires

Simicic

et al. 2021

Sci Rep

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show abstract

Section: Discusionsupporting

confidence: 92%

“…These negative results in learning and memory performance contrast with the data from the ubiquitous CrT KO mice with exons 2-4 and 5-7 deleted, where deficits were present although with milder phenotype in NOR test around the same age in the last one 13,16 . Interestingly, these negative results are consistent with data from CTD patients, as they are able to remember people, objects or locations but fail in the performance of more complex daily tasks and learning new abilities 17,38 .…”

Section: Discusionsupporting

confidence: 84%

A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

Durán-Trío

Fernandes-Pires

Simicic

et al. 2020

Preprint

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Creatine is an organic compound used as fast phosphate energy buffer to recycle ATP, important in tissues with high energy demand such as muscle or brain. Creatine is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Deficit in the endogenous synthesis or in the transport leads to Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain creatine deficiency, intellectual disability with severe speech delay, behavioral troubles such as attention deficits and/or autistic features, and epilepsy. Among CCDS, the X-linked creatine transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different mouse models of CTD were generated by doing long deletions in the Slc6a8 gene showing reduced brain creatine and cognitive deficiencies or impaired motor function. We present a new knock-in (KI) rat model of CTD holding an identical point mutation found in patients with reported lack of transporter activity. KI males showed brain creatine deficiency, increased urinary creatine/creatinine ratio, cognitive deficiency and autistic features. Slc6a8xY389C KI rat fairly enriches the spectrum of CTD models and provides new data about the pathology, being the first animal model of CTD carrying a point mutation.

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“…Despite a precocious onset of symptoms, the average age of diagnosis of CTD ranges from 2 to 20 years [72]. The identification of early clinical indicators, alerting pediatricians to seek a specialty referral and/or conduct a urine screen, might accelerate the diagnosis.…”

Section: Diagnostic Methods and Prevalencementioning

confidence: 99%

The Role of Preclinical Models in Creatine Transporter Deficiency: Neurobiological Mechanisms, Biomarkers and Therapeutic Development

Ghirardini

Calugi

Sagona

et al. 2021

Genes

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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.

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Early Indicators of Creatine Transporter Deficiency

Cited by 12 publications

References 11 publications

A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

A new rat model of creatine transporter deficiency reveals behavioral disorder and altered brain metabolism

The Role of Preclinical Models in Creatine Transporter Deficiency: Neurobiological Mechanisms, Biomarkers and Therapeutic Development

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