Abstract:
Creatine deficiency syndromes, due to deficiencies in AGAT and GAMT, the two enzymes of the creatine synthesis pathway, or in the creatine transporter SLC6A8, are inborn errors of metabolism which lead to a complete absence, or a very strong decrease, of creatine within the brain. Patients suffering from these syndromes show severe neurodevelopmental delay and present neurological symptoms in early infancy such as mental retardation, disturbance of active and comprehensible speech, autism, auto-mutilating behavior and hypotonia. The creatine/phosphocreatine/creatine kinase system plays essential roles to maintain the high energy levels necessary for the brain, through regeneration and buffering of ATP levels. Recent works also suggest new roles for creatine in CNS, where it may act as neurotransmitter and appears as one of the main CNS osmolytes.
While it has long been thought that most, if not all, of brain creatine was of peripheral origin, the recent years have brought evidence that AGAT and GAMT are expressed in the brain, which can synthesize creatine. Moreover, the absence of the creatine transporter SLC6A8 in the astrocytic feet lining microcapillaries made us suggest that blood brain barrier has a limited permeability for creatine. In vivo data confirmed this hypothesis, as the long term treatment of AGAT- and GAMT-deficient patients with high doses of creatine only allows a very slow and in most cases partial replenishment of their CNS creatine. Consequently, the brain most probably depends for an important proportion on its own creatine synthesis rather than on an exclusive supply from the blood. The “brain endogenous creatine synthesis” hypothesis contradicts the in vivo characteristics of SLC6A8 deficiency, which, despite normal expression of AGAT and GAMT in CNS, causes brain creatine deficiency. This apparent contradiction is probably explained by our very recent data showing that in many brain structures, AGAT and GAMT are in most cases not co-expressed but are rather expressed in a dissociated way. This suggests that to allow creatine synthesis, the intermediate guanidinoacetate must be transported from AGAT- to GAMT-expressing cells, most probably through SLC6A8. These observations may explain the absence of creatine in the brain of SLC6A8-deficient patient, despite their normal CNS expression of AGAT and GAMT.

Brief Biography of the Speaker:
Olivier Braissant, biologist, obtained his PhD thesis at the University of Lausanne, Switzerland, in 1994. After a post-doc on nuclear receptors and their expression in central nervous system, he moved to the University Hospital of Lausanne (CHUV) in 1997, in the Clinical Chemistry Laboratory of the Department of Pathology and Molecular Medicine. There, he started working on inborn errors of metabolism and in particular on their effect on brain development. He is "Privat Docent" and "Maitre d'Enseignement et de Recherche" of the University of Lausanne since 2004, and now head of the research section of the Clinical Chemistry Laboratory of the CHUV. His research interests focus on brain development and metabolism, and how various inborn errors of metabolism, in particular creatine deficiencies, organic acidemias and diseases causing hypermamonemia, can affect them. He is author of about 50 papers published in international journals and conference proceedings, as well as invited book chapters.