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X-linked creatine transporter deficiency: clinical aspects and pathophysiology

  • Metabolic Dissertation
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Creatine transporter deficiency was discovered in 2001 as an X-linked cause of intellectual disability characterized by cerebral creatine deficiency. This review describes the current knowledge regarding creatine metabolism, the creatine transporter and the clinical aspects of creatine transporter deficiency. The condition mainly affects the brain while other creatine requiring organs, such as the muscles, are relatively spared. Recent studies have provided strong evidence that creatine synthesis also occurs in the brain, leading to the intriguing question of why cerebral creatine is deficient in creatine transporter deficiency. The possible mechanisms explaining the cerebral creatine deficiency are discussed. The creatine transporter knockout mouse provides a good model to study the disease. Over the past years several treatment options have been explored but no treatment has been proven effective. Understanding the pathogenesis of creatine transporter deficiency is of paramount importance in the development of an effective treatment.

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Abbreviations

AGAT:

arginine:glycine amidinotransferase

AGAT-D:

AGAT deficiency

AMPK:

AMP-activated protein kinase

BBB:

blood–brain barrier

β-GPA:

β-guanidinopropionate

CDS:

creatine deficiency syndromes

CK:

creatine kinase

Cr:

creatine

Crn:

creatinine

Cr/Crn:

creatine/creatinine ratio

CRTR:

creatine transporter

CRTR-D:

creatine transporter deficiency

CSF:

cerebrospinal fluid

GAA:

guanidinoacetate

GAMT:

guanidinoacetate methyltransferase

GAMT-D:

GAMT deficiency

1H-MRS:

proton magnetic-resonance spectroscopy

ID:

intellectual disability

JAK2:

Janus-activated kinase-2

LeuT:

leucine transporter

MCT12:

monocarboxylate transporter 12

PKC:

protein kinase C

SAM:

S-adenosylmethionine

TM:

transmembrane

XL-ID:

X-linked intellectual disability

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Acknowledgments

We thank Ofir T Betsalel for providing Fig. 2.

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  1. Department of Clinical Genetics, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands

    Jiddeke M. van de Kamp

  2. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands

    Grazia M. Mancini

  3. Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands

    Gajja S. Salomons

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  1. Jiddeke M. van de Kamp
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van de Kamp, J.M., Mancini, G.M. & Salomons, G.S. X-linked creatine transporter deficiency: clinical aspects and pathophysiology. J Inherit Metab Dis 37, 715–733 (2014). https://doi.org/10.1007/s10545-014-9713-8

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