Amino Acids

, Volume 40, Issue 5, pp 1315–1324 | Cite as

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

  • Olivier BraissantEmail author
  • Hugues Henry
  • Elidie Béard
  • Joséphine Uldry
Review Article


Creatine deficiency syndromes, due to deficiencies in AGAT, GAMT (creatine synthesis pathway) or SLC6A8 (creatine transporter), lead to complete absence or very strong decrease of creatine in CNS as measured by magnetic resonance spectroscopy. Brain is the main organ affected in creatine-deficient patients, who show severe neurodevelopmental delay and present neurological symptoms in early infancy. AGAT- and GAMT-deficient patients can be treated by oral creatine supplementation which improves their neurological status, while this treatment is inefficient on SLC6A8-deficient patients. While it has long been thought that most, if not all, of brain creatine was of peripheral origin, the past years have brought evidence that creatine can cross blood–brain barrier, however, only with poor efficiency, and that CNS must ensure parts of its creatine needs by its own endogenous synthesis. Moreover, we showed very recently that in many brain structures, including cortex and basal ganglia, AGAT and GAMT, while found in every brain cell types, are not co-expressed but are rather expressed in a dissociated way. This suggests that to allow creatine synthesis in these structures, guanidinoacetate must be transported from AGAT- to GAMT-expressing cells, most probably through SLC6A8. This new understanding of creatine metabolism and transport in CNS will not only allow a better comprehension of brain consequences of creatine deficiency syndromes, but will also contribute to better decipher creatine roles in CNS, not only in energy as ATP regeneration and buffering, but also in its recently suggested functions as neurotransmitter or osmolyte.


Creatine deficiency syndromes Creatine Guanidinoacetate Brain AGAT GAMT SLC6A8 



This work was supported by the Swiss National Science Foundation, grants 3100A0-116859 and 31003A-130278.


  1. Acosta ML, Kalloniatis M, Christie DL (2005) Creatine transporter localization in developing and adult retina: importance of creatine to retinal function. Am J Physiol Cell Physiol 289:C1015–C1023PubMedCrossRefGoogle Scholar
  2. Almeida LS, Verhoeven NM, Roos B, Valongo C, Cardoso ML, Vilarinho L, Salomons GS, Jakobs C (2004) Creatine and guanidinoacetate: diagnostic markers for inborn errors in creatine biosynthesis and transport. Mol Genet Metab 82:214–219PubMedCrossRefGoogle Scholar
  3. Almeida LS, Salomons GS, Hogenboom F, Jakobs C, Schoffelmeer AN (2006) Exocytotic release of creatine in rat brain. Synapse 60:118–123PubMedCrossRefGoogle Scholar
  4. Andres RH, Ducray AD, Schlattner U, Wallimann T, Widmer HR (2008) Functions and effects of creatine in the central nervous system. Brain Res Bull 76:329–343PubMedCrossRefGoogle Scholar
  5. Arias A, Corbella M, Fons C, Sempere A, Garcia-Villoria J, Ormazabal A, Poo P, Pineda M, Vilaseca MA, Campistol J, Briones P, Pampols T, Salomons GS, Ribes A, Artuch R (2007) Creatine transporter deficiency: prevalence among patients with mental retardation and pitfalls in metabolite screening. Clin Biochem 40:1328–1331PubMedCrossRefGoogle Scholar
  6. Battini R, Leuzzi V, Carducci C, Tosetti M, Bianchi MC, Item CB, Stöckler-Ipsiroglu S, Cioni G (2002) Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree. Mol Genet Metab 77:326–331PubMedCrossRefGoogle Scholar
  7. Battini R, Alessandri MG, Leuzzi V, Moro F, Tosetti M, Bianchi MC, Cioni G (2006) Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: early treatment can prevent phenotypic expression of the disease. J Pediatr 148:828–830PubMedCrossRefGoogle Scholar
  8. Bizzi A, Bugiani M, Salomons GS, Hunneman DH, Moroni I, Estienne M, Danesi U, Jakobs C, Uziel G (2002) X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8. Ann Neurol 52:227–231PubMedCrossRefGoogle Scholar
  9. Bothwell JH, Styles P, Bhakoo KK (2002) Swelling-activated taurine and creatine effluxes from rat cortical astrocytes are pharmacologically distinct. J Membr Biol 185:157–164PubMedCrossRefGoogle Scholar
  10. Braissant O (2010a) Ammonia toxicity to the brain: effects on creatine metabolism and transport and protective roles of creatine. Mol Genet Metab 100(Suppl 1):S53–S58PubMedCrossRefGoogle Scholar
  11. Braissant O (2010b) Current concepts in the pathogenesis of urea cycle disorders. Mol Gen Metab 100(Suppl 1):S3–S12CrossRefGoogle Scholar
  12. Braissant O, Henry H (2008) AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: a review. J Inherit Metab Dis 31:230–239CrossRefGoogle Scholar
  13. Braissant O, Gotoh T, Loup M, Mori M, Bachmann C (1999) l-arginine uptake, the citrulline-NO cycle and arginase II in the rat brain: an in situ hybridization study. Mol Brain Res 70:231–241PubMedCrossRefGoogle Scholar
  14. Braissant O, Gotoh T, Loup M, Mori M, Bachmann C (2001a) Differential expression of the cationic amino acid transporter 2(B) in the adult rat brain. Mol Brain Res 91:189–195PubMedCrossRefGoogle Scholar
  15. Braissant O, Henry H, Loup M, Eilers B, Bachmann C (2001b) Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study. Mol Brain Res 86:193–201PubMedCrossRefGoogle Scholar
  16. Braissant O, Henry H, Villard AM, Zurich MG, Loup M, Eilers B, Parlascino G, Matter E, Boulat O, Honegger P, Bachmann C (2002) Ammonium-induced impairment of axonal growth is prevented through glial creatine. J Neurosci 22:9810–9820PubMedGoogle Scholar
  17. Braissant O, Henry H, Villard AM, Speer O, Wallimann T, Bachmann C (2005) Creatine synthesis and transport during rat embryogenesis: spatiotemporal expression of AGAT, GAMT and CT1. BMC Dev Biol 5:9PubMedCrossRefGoogle Scholar
  18. Braissant O, Bachmann C, Henry H (2007) Expression and function of AGAT, GAMT and CT1 in the mammalian brain. Subcell Biochem 46:67–81PubMedCrossRefGoogle Scholar
  19. Braissant O, Cagnon L, Monnet-Tschudi F, Speer O, Wallimann T, Honegger P, Henry H (2008) Ammonium alters creatine transport and synthesis in a 3D-culture of developing brain cells, resulting in secondary cerebral creatine deficiency. Eur J Neurosci 27:1673–1685PubMedCrossRefGoogle Scholar
  20. Braissant O, Béard E, Torrent C, Henry H (2010) Dissociation of AGAT, GAMT and SLC6A8 in CNS: relevance to creatine deficiency syndromes. Neurobiol Dis 37:423–433PubMedCrossRefGoogle Scholar
  21. Brosnan JT, Brosnan ME (2007) Creatine: endogenous metabolite, dietary, and therapeutic supplement. Annu Rev Nutr 27:241–261PubMedCrossRefGoogle Scholar
  22. Cagnon L, Braissant O (2007) Hyperammonemia-induced toxicity for the developing central nervous system. Brain Res Rev 56:183–197PubMedCrossRefGoogle Scholar
  23. Cagnon L, Braissant O (2008) Role of caspases, calpain and cdk5 in ammonia-induced cell death in developing brain cells. Neurobiol Dis 32:281–292PubMedCrossRefGoogle Scholar
  24. Cagnon L, Braissant O (2009) CNTF protects oligodendrocytes from ammonia toxicity: intracellular signaling pathways involved. Neurobiol Dis 33:133–142PubMedCrossRefGoogle Scholar
  25. Cecil KM, Salomons GS, Ball WS, Wong B, Chuck G, Verhoeven NM, Jakobs C, DeGrauw TJ (2001) Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect? Ann Neurol 49:401–404PubMedCrossRefGoogle Scholar
  26. Cecil KM, DeGrauw TJ, Salomons GS, Jakobs C, Egelhoff JC, Clark JF (2003) Magnetic resonance spectroscopy in a 9-day-old heterozygous female child with creatine transporter deficiency. J Comput Assist Tomogr 27:44–47PubMedCrossRefGoogle Scholar
  27. Choi CG, Yoo HW (2001) Localized proton MR spectroscopy in infants with urea cycle defect. AJNR Am J Neuroradiol 22:834–837PubMedGoogle Scholar
  28. Clark AJ, Rosenberg EH, Almeida LS, Wood TC, Jakobs C, Stevenson RE, Schwartz CE, Salomons GS (2006) X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology. Hum Genet 119:604–610PubMedCrossRefGoogle Scholar
  29. da Silva RP, Nissim I, Brosnan ME, Brosnan JT (2009) Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo. Am J Physiol Endocrinol Metab 296:E256–E261PubMedCrossRefGoogle Scholar
  30. Daly MM (1985) Guanidinoacetate methyltransferase activity in tissues and cultured cells. Arch Biochem Biophys 236:576–584PubMedCrossRefGoogle Scholar
  31. Davis BM, Miller RK, Brent RL, Koszalka TR (1978) Materno-fetal transport of creatine in the rat. Biol Neonate 33:43–54PubMedCrossRefGoogle Scholar
  32. DeGrauw TJ, Salomons GS, Cecil KM, Chuck G, Newmeyer A, Schapiro MB, Jakobs C (2002) Congenital creatine transporter deficiency. Neuropediatrics 33:232–238PubMedCrossRefGoogle Scholar
  33. Dringen R, Verleysdonk S, Hamprecht B, Willker W, Leibfritz D, Brand A (1998) Metabolism of glycine in primary astroglial cells: synthesis of creatine, serine, and glutathione. J Neurochem 70:835–840PubMedCrossRefGoogle Scholar
  34. Edison EE, Brosnan ME, Meyer C, Brosnan JT (2007) Creatine synthesis: production of guanidinoacetate by the rat and human kidney in vivo. Am J Physiol Renal Physiol 293:F1799–F1804PubMedCrossRefGoogle Scholar
  35. Ensenauer R, Thiel T, Schwab KO, Tacke U, Stöckler-Ipsiroglu S, Schulze A, Hennig J, Lehnert W (2004) Guanidinoacetate methyltransferase deficiency: differences of creatine uptake in human brain and muscle. Mol Genet Metab 82:208–213PubMedCrossRefGoogle Scholar
  36. Fons C, Sempere A, Arias A, Lopez-Sala A, Poo P, Pineda M, Mas A, Vilaseca MA, Salomons GS, Ribes A, Artuch R, Campistol J (2008) Arginine supplementation in four patients with X-linked creatine transporter defect. J Inherit Metab Dis 31:724–728PubMedCrossRefGoogle Scholar
  37. Fons C, Arias A, Sempere A, Poo P, Pineda M, Mas A, Lopez-Sala A, Garcia-Villoria J, Vilaseca MA, Ozaez L, Lluch M, Artuch R, Campistol J, Ribes A (2010) Response to creatine analogs in fibroblasts and patients with creatine transporter deficiency. Mol Genet Metab 99:296–299PubMedCrossRefGoogle Scholar
  38. Galbraith RA, Furukawa M, Li M (2006) Possible role of creatine concentrations in the brain in regulating appetite and weight. Brain Res 1101:85–91PubMedCrossRefGoogle Scholar
  39. Ganesan V, Johnson A, Connelly A, Eckhardt S, Surtees RA (1997) Guanidinoacetate methyltransferase deficiency: new clinical features. Pediatr Neurol 17:155–157PubMedCrossRefGoogle Scholar
  40. Gideon P, Henriksen O, Sperling B, Christiansen P, Olsen TS, Jorgensen HS, Arlien-Soborg P (1992) Early time course of N-acetylaspartate, creatine and phosphocreatine, and compounds containing choline in the brain after acute stroke. A proton magnetic resonance spectroscopy study. Stroke 23:1566–1572PubMedGoogle Scholar
  41. Happe HK, Murrin LC (1995) In situ hybridization analysis of CHOT1, a creatine transporter, in the rat central nervous system. J Comp Neurol 351:94–103PubMedCrossRefGoogle Scholar
  42. Hosokawa H, Ninomiya H, Sawamura T, Sugimoto Y, Ichikawa A, Fujiwara K, Masaki T (1999) Neuron-specific expression of cationic amino acid transporter 3 in the adult rat brain. Brain Res 838:158–165PubMedCrossRefGoogle Scholar
  43. Ireland Z, Dickinson H, Snow R, Walker DW (2008) Maternal creatine: does it reach the fetus and improve survival after an acute hypoxic episode in the spiny mouse (Acomys cahirinus)? Am J Obstet Gynecol 198:431–436PubMedCrossRefGoogle Scholar
  44. Ireland Z, Russell AP, Wallimann T, Walker DW, Snow R (2009) Developmental changes in the expression of creatine synthesizing enzymes and creatine transporter in a precocial rodent, the spiny mouse. BMC Dev Biol 9:39PubMedCrossRefGoogle Scholar
  45. Item CB, Stöckler-Ipsiroglu S, Stromberger C, Mühl A, Alessandri MG, Bianchi MC, Tosetti M, Fornai F, Cioni G (2001) Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet 69:1127–1133PubMedCrossRefGoogle Scholar
  46. Kan HE, Meeuwissen E, van Asten JJ, Veltien A, Isbrandt D, Heerschap A (2007) Creatine uptake in brain and skeletal muscle of mice lacking guanidinoacetate methyltransferase assessed by magnetic resonance spectroscopy. J Appl Physiol 102:2121–2127PubMedCrossRefGoogle Scholar
  47. Langan TJ, Slater MC (1992) Astrocytes derived from long-term primary cultures recapitulate features of astrogliosis as they re-enter the cell division cycle. Brain Res 577:200–209PubMedCrossRefGoogle Scholar
  48. Lei H, Berthet C, Hirt L, Gruetter R (2009) Evolution of the neurochemical profile after transient focal cerebral ischemia in the mouse brain. J Cereb Blood Flow Metab 29:811–819PubMedCrossRefGoogle Scholar
  49. Leonard JV, Morris AAM (2002) Urea cycle disorders. Semin Neonatol 7:27–35PubMedCrossRefGoogle Scholar
  50. Lion-François L, Cheillan D, Pitelet G, Acquaviva-Bourdain C, Bussy G, Cotton F, Guibaud L, Gerard D, Rivier C, Vianey-Saban C, Jakobs C, Salomons GS, des Portes V (2006) High frequency of creatine deficiency syndromes in patients with unexplained mental retardation. Neurology 67:1713–1714PubMedCrossRefGoogle Scholar
  51. Mak CS, Waldvogel HJ, Dodd JR, Gilbert RT, Lowe MT, Birch NP, Faull RL, Christie DL (2009) Immunohistochemical localisation of the creatine transporter in the rat brain. Neuroscience 163:571–585PubMedCrossRefGoogle Scholar
  52. Mancardi MM, Caruso U, Schiaffino MC, Baglietto MG, Rossi A, Battaglia FM, Salomons GS, Jakobs C, Zara F, Veneselli E, Gaggero R (2007) Severe epilepsy in X-linked creatine transporter defect (CRTR-D). Epilepsia 48:1211–1213PubMedCrossRefGoogle Scholar
  53. Mancini GM, Catsman-Berrevoets CE, de Coo IF, Aarsen FK, Kamphoven JH, Huijmans JG, Duran M, van der Knaap MS, Jakobs C, Salomons GS (2005) Two novel mutations in SLC6A8 cause creatine transporter defect and distinctive X-linked mental retardation in two unrelated Dutch families. Am J Med Genet A 132:288–295Google Scholar
  54. Mathews VP, Barker PB, Blackband SJ, Chatham JC, Bryan RN (1995) Cerebral metabolites in patients with acute and subacute strokes: concentrations determined by quantitative proton MR spectroscopy. AJR Am J Roentgenol 165:633–638PubMedGoogle Scholar
  55. Möller A, Hamprecht B (1989) Creatine transport in cultured cells of rat and mouse brain. J Neurochem 52:544–550PubMedCrossRefGoogle Scholar
  56. Nakashima T, Tomi M, Katayama K, Tachikawa M, Watanabe M, Terasaki T, Hosoya K (2004) Blood-to-retina transport of creatine via creatine transporter (CRT) at the rat inner blood-retinal barrier. J Neurochem 89:1454–1461PubMedCrossRefGoogle Scholar
  57. Nakashima T, Tomi M, Tachikawa M, Watanabe M, Terasaki T, Hosoya K (2005) Evidence for creatine biosynthesis in Müller glia. GLIA 52:47–52PubMedCrossRefGoogle Scholar
  58. Näntö-Salonen K, Komu M, Lundbom N, Heinänen K, Alanen A, Sipilä I, Simell O (1999) Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology 53:303–307PubMedGoogle Scholar
  59. Neu A, Neuhoff H, Trube G, Fehr S, Ullrich K, Roeper J, Isbrandt D (2002) Activation of GABA(A) receptors by guanidinoacetate: a novel pathophysiological mechanism. Neurobiol Dis 11:298–307PubMedCrossRefGoogle Scholar
  60. Obrenovitch TP, Garofalo O, Harris RJ, Bordi L, Ono M, Momma F, Bachelard HS, Symon L (1988) Brain tissue concentrations of ATP, phosphocreatine, lactate, and tissue pH in relation to reduced cerebral blood flow following experimental acute middle cerebral artery occlusion. J Cereb Blood Flow Metab 8:866–874PubMedCrossRefGoogle Scholar
  61. Ohtsuki S (2004) New aspects of the blood–brain barrier transporters; its physiological roles in the central nervous system. Biol Pharm Bull 27:1489–1496PubMedCrossRefGoogle Scholar
  62. Ohtsuki S, Tachikawa M, Takanaga H, Shimizu H, Watanabe M, Hosoya K, Terasaki T (2002) The blood-brain barrier creatine transporter is a major pathway for supplying creatine to the brain. J Cereb Blood Flow Metab 22:1327–1335PubMedCrossRefGoogle Scholar
  63. Perasso L, Cupello A, Lunardi GL, Principato C, Gandolfo C, Balestrino M (2003) Kinetics of creatine in blood and brain after intraperitoneal injection in the rat. Brain Res 974:37–42PubMedCrossRefGoogle Scholar
  64. Pisano JJ, Abraham D, Udenfriend S (1963) Biosynthesis and disposition of γ-guanidinobutyric acid in mammalian tissues. Arch Biochem Biophys 100:323–329CrossRefGoogle Scholar
  65. Póo-Argüelles P, Arias A, Vilaseca MA, Ribes A, Artuch R, Sans-Fito A, Moreno A, Jakobs C, Salomons G (2006) X-Linked creatine transporter deficiency in two patients with severe mental retardation and autism. J Inherit Metab Dis 29:220–223PubMedCrossRefGoogle Scholar
  66. Ratnakumari L, Qureshi IA, Butterworth RF, Marescau B, De Deyn PP (1996) Arginine-related guanidino compounds and nitric oxide synthase in the brain of ornithine transcarbamylase deficient spf mutant mouse: effect of metabolic arginine deficiency. Neurosci Lett 215:153–156PubMedCrossRefGoogle Scholar
  67. Rosenberg EH, Almeida LS, Kleefstra T, deGrauw RS, Yntema HG, Bahi N, Moraine C, Ropers HH, Fryns JP, DeGrauw TJ, Jakobs C, Salomons GS (2004) High prevalence of SLC6A8 deficiency in X-linked mental retardation. Am J Hum Genet 75:97–105PubMedCrossRefGoogle Scholar
  68. Salomons GS, van Dooren SJ, Verhoeven NM, Cecil KM, Ball WS, DeGrauw TJ, Jakobs C (2001) X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet 68:1497–1500PubMedCrossRefGoogle Scholar
  69. Sandell LL, Guan XJ, Ingram R, Tilghman SM (2003) Gatm, a creatine synthesis enzyme, is imprinted in mouse placenta. Proc Natl Acad Sci USA 100:4622–4627PubMedCrossRefGoogle Scholar
  70. Schloss P, Mayser W, Betz H (1994) The putative rat choline transporter CHOT1 transports creatine and is highly expressed in neural and muscle-rich tissues. Biochem Biophys Res Commun 198:637–645PubMedCrossRefGoogle Scholar
  71. Schmidt A, Marescau B, Boehm EA, Renema WK, Peco R, Das A, Steinfeld R, Chan S, Wallis J, Davidoff M, Ullrich K, Waldschütz R, Heerschap A, De Deyn PP, Neubauer S, Isbrandt D (2004) Severely altered guanidino compound levels, disturbed body weight homeostasis and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency. Hum Mol Genet 13:905–921PubMedCrossRefGoogle Scholar
  72. Schulze A, Battini R (2007) Pre-symptomatic treatment of creatine biosynthesis defects. Subcell Biochem 46:167–181PubMedCrossRefGoogle Scholar
  73. Schulze A, Hess T, Wevers R, Mayatepek E, Bachert P, Marescau B, Knopp MV, De Deyn PP, Bremer HJ, Rating D (1997) Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism. J Pediatr 131:626–631PubMedCrossRefGoogle Scholar
  74. Schulze A, Mayatepek E, Bachert P, Marescau B, De Deyn PP, Rating D (1998) Therapeutic trial of arginine restriction in creatine deficiency syndrome. Eur J Pediatr 157:606–607PubMedCrossRefGoogle Scholar
  75. Schulze A, Ebinger F, Rating D, Mayatepek E (2001) Improving treatment of guanidinoacetate methyltransferase deficiency: reduction of guanidinoacetic acid in body fluids by arginine restriction and ornithine supplementation. Mol Genet Metab 74:413–419PubMedCrossRefGoogle Scholar
  76. Schulze A, Bachert P, Schlemmer H, Harting I, Polster T, Salomons GS, Verhoeven NM, Jakobs C, Fowler B, Hoffmann GF, Mayatepek E (2003) Lack of creatine in muscle and brain in an adult with GAMT deficiency. Ann Neurol 53:248–251PubMedCrossRefGoogle Scholar
  77. Schulze A, Hoffmann GF, Bachert P, Kirsch S, Salomons GS, Verhoeven NM, Mayatepek E (2006) Presymptomatic treatment of neonatal guanidinoacetate methyltransferase deficiency. Neurology 67:719–721PubMedCrossRefGoogle Scholar
  78. Sijens PE, Verbruggen KT, Oudkerk M, van Spronsen FJ, Soorani-Lunsing RJ (2005) 1H MR spectroscopy of the brain in Cr transporter defect. Mol Genet Metab 86:421–422PubMedCrossRefGoogle Scholar
  79. Sipilä I (1980) Inhibition of arginine-glycine amidinotransferase by ornithine. A possible mechanism for the muscular and chorioretinal atrophies in gyrate atrophy of the choroid and retina with hyperornithinemia. Biochim Biophys Acta 613:79–84PubMedGoogle Scholar
  80. Stöckler S, Holzbach U, Hanefeld F, Marquardt I, Helms G, Requart M, Hänicke W, Frahm J (1994) Creatine deficiency in the brain: a new, treatable inborn error of metabolism. Pediatr Res 36:409–413PubMedGoogle Scholar
  81. Stöckler S, Hanefeld F, Frahm J (1996) Creatine replacement therapy in guanidinoacetate methyltransferase deficiency, a novel inborn error of metabolism. Lancet 348:789–790PubMedCrossRefGoogle Scholar
  82. Stöckler S, Schutz PW, Salomons GS (2007) Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology. Subcell Biochem 46:149–166PubMedCrossRefGoogle Scholar
  83. Tachikawa M, Fukaya M, Terasaki T, Ohtsuki S, Watanabe M (2004) Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK-Mi and CK-B suggest a novel neuron-glial relationship for brain energy homeostasis. Eur J Neurosci 20:144–160PubMedCrossRefGoogle Scholar
  84. Tachikawa M, Fujinawa J, Takahashi M, Kasai Y, Fukaya M, Sakai K, Yamazaki M, Tomi M, Watanabe M, Sakimura K, Terasaki T, Hosoya K (2008) Expression and possible role of creatine transporter in the brain and at the blood-cerebrospinal fluid barrier as a transporting protein of guanidinoacetate, an endogenous convulsant. J Neurochem 107:768–778PubMedCrossRefGoogle Scholar
  85. Tachikawa M, Kasai Y, Yokoyama R, Fujinawa J, Ganapathy V, Terasaki T, Hosoya KI (2009) The blood-brain barrier transport and cerebral distribution of guanidinoacetate in rats: involvement of creatine and taurine transporters. J Neurochem 111:499–509Google Scholar
  86. Valayannopoulos V, Boddaert N, Mention K, Touati G, Barbier V, Chabli A, Sedel F, Kaplan J, Dufier JL, Seidenwurm D, Rabier D, Saudubray JM, de Lonlay P (2009) Secondary creatine deficiency in ornithine delta-aminotransferase deficiency. Mol Genet Metab 97:109–113PubMedCrossRefGoogle Scholar
  87. Valle D, Walser M, Brusilow S, Kaiser-Kupfer MI, Takki K (1981) Gyrate atrophy of the choroid and retina. Biochemical considerations and experience with an arginine-restricted diet. Ophthalmology 88:325–330PubMedGoogle Scholar
  88. Van Pilsum JF, Stephens GC, Taylor D (1972) Distribution of creatine, guanidinoacetate and enzymes for their biosynthesis in the animal kingdom. Implications for phylogeny. Biochem J 126:325–345Google Scholar
  89. Virgintino D, Monaghan P, Robertson D, Errede M, Bertossi M, Ambrosi G, Roncali L (1997) An immunohistochemical and morphometric study on astrocytes and microvasculature in the human cerebral cortex. Histochem J 29:655–660PubMedCrossRefGoogle Scholar
  90. Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM (1992) Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem J 281(Pt 1):21–40PubMedGoogle Scholar
  91. Wallimann T, Tokarska-Schlattner M, Neumann D, Epand RM, Epand RF, Andres RH, Widmer HR, Hornemann T, Saks VA, Agarkova I, Schlattner U (2007) The phosphocreatine circuit: molecular and cellular physiology of creatine kinases, sensitivity to free radicals and enhancement of creatine supplementation. In: Saks VA (ed) Molecular systems bioenergetics: energy for life, basic principles, organization and dynamics of cellular energetics. Wiley VCH-Publisher Co., Weinheim, pp 195–264Google Scholar
  92. Wang L, Zhang Y, Shao M, Zhang H (2007) Spatiotemporal expression of the creatine metabolism related genes agat, gamt and ct1 during zebrafish embryogenesis. Int J Dev Biol 51:247–253PubMedCrossRefGoogle Scholar
  93. Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80:1107–1213PubMedGoogle Scholar
  94. Zugno AI, Scherer EB, Schuck PF, Oliveira DL, Wofchuk S, Wannmacher CM, Wajner M, Wyse AT (2006) Intrastriatal administration of guanidinoacetate inhibits Na+, K+-ATPase and creatine kinase activities in rat striatum. Metab Brain Dis 21:41–50PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Olivier Braissant
    • 1
    Email author
  • Hugues Henry
    • 1
  • Elidie Béard
    • 1
  • Joséphine Uldry
    • 1
  1. 1.Inborn Errors of Metabolism, Clinical Chemistry LaboratoryCentre Hospitalier Universitaire Vaudois and University of LausanneLausanneSwitzerland

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