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AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: A review

  • SSIEM Symposium 2007
  • Published:
Journal of Inherited Metabolic Disease

Summary

Creatine deficiency syndromes, either due to AGAT, GAMT or SLC6A8 deficiencies, lead to a complete absence, or a very strong decrease, of creatine within the brain, as measured by magnetic resonance spectroscopy. While the mammalian central nervous system (CNS) expresses AGAT, GAMT and SLC6A8, the lack of SLC6A8 in astrocytes around the blood–brain barrier limits the brain capacity to import creatine from the periphery, and suggests that the CNS has to rely mainly on endogenous creatine synthesis through AGAT and GAMT expression. This seems contradictory with SLC6A8 deficiency, which, despite AGAT and GAMT expression, also leads to creatine deficiency in the CNS. We present novel data showing that in cortical grey matter, AGAT and GAMT are expressed in a dissociated way: e.g. only a few cells co-express both genes. This suggests that to allow synthesis of creatine within the CNS, at least for a significant part of it, guanidinoacetate must be transported from AGAT- to GAMT-expressing cells, possibly through SLC6A8. This would explain the creatine deficiency observed in SLC6A8-deficient patients. By bringing together creatine deficiency syndromes, AGAT, GAMT and SLC6A8 distribution in CNS, as well as a synthetic view on creatine and guanidinoacetate levels in the brain, this review presents a comprehensive framework, including new hypotheses, on brain creatine metabolism and transport, both in normal conditions and in case of creatine deficiency.

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Abbreviations

AGAT:

L-arginine:glycine amidinotransferase

BBB:

blood–brain barrier

CAT:

cationic amino acid transporter (system y+)

CK:

creatine kinase

CNS:

central nervous system

Cr:

creatine

CSF:

cerebrospinal fluid

GAA:

guanidinoacetate

GAMT:

guanidinoacetate methyltransferase

MCEC:

microcapillary endothelial cell

MRS:

magnetic resonance spectroscopy

SLC6A8:

creatine transporter

tCr:

total creatine (creatine + phosphocreatine)

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Acknowledgements

Our work is supported by the Swiss National Science Foundation, grants nos 3100A0-100778 and 3100A0-116859. Theo Wallimann is acknowledged for the anti-AGAT antibody, and Marc Loup for excellent technical work.

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Correspondence to O. Braissant.

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Communicating editor: Cornelis Jakobs

Competing interests: None declared

References to electronic databases:L-Arginine:glycine amidinotransferase (AGAT) deficiency: OMIM 602360. Guanidinoacetate N-methyltransferase (GAMT) deficiency: OMIM 601240. Creatine transporter (SLC6A8; Slc6a8) deficiency: OMIM 300352. AGAT: EC 2.1.4.1. GAMT: EC 2.1.1.2.

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Braissant, O., Henry, H. AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: A review. J Inherit Metab Dis 31, 230–239 (2008). https://doi.org/10.1007/s10545-008-0826-9

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