Abstract
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.
Similar content being viewed by others
References
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–C1023
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 82:214–219
Almeida LS, Salomons GS, Hogenboom F, Jakobs C, Schoffelmeer AN (2006) Exocytotic release of creatine in rat brain. Synapse 60:118–123
Andres RH, Ducray AD, Schlattner U, Wallimann T, Widmer HR (2008) Functions and effects of creatine in the central nervous system. Brain Res Bull 76:329–343
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 40:1328–1331
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 77:326–331
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 148:828–830
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 52:227–231
Bothwell JH, Styles P, Bhakoo KK (2002) Swelling-activated taurine and creatine effluxes from rat cortical astrocytes are pharmacologically distinct. J Membr Biol 185:157–164
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–S58
Braissant O (2010b) Current concepts in the pathogenesis of urea cycle disorders. Mol Gen Metab 100(Suppl 1):S3–S12
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 31:230–239
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 70:231–241
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 91:189–195
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 86:193–201
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 22:9810–9820
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 5:9
Braissant O, Bachmann C, Henry H (2007) Expression and function of AGAT, GAMT and CT1 in the mammalian brain. Subcell Biochem 46:67–81
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 27:1673–1685
Braissant O, Béard E, Torrent C, Henry H (2010) Dissociation of AGAT, GAMT and SLC6A8 in CNS: relevance to creatine deficiency syndromes. Neurobiol Dis 37:423–433
Brosnan JT, Brosnan ME (2007) Creatine: endogenous metabolite, dietary, and therapeutic supplement. Annu Rev Nutr 27:241–261
Cagnon L, Braissant O (2007) Hyperammonemia-induced toxicity for the developing central nervous system. Brain Res Rev 56:183–197
Cagnon L, Braissant O (2008) Role of caspases, calpain and cdk5 in ammonia-induced cell death in developing brain cells. Neurobiol Dis 32:281–292
Cagnon L, Braissant O (2009) CNTF protects oligodendrocytes from ammonia toxicity: intracellular signaling pathways involved. Neurobiol Dis 33:133–142
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 49:401–404
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 27:44–47
Choi CG, Yoo HW (2001) Localized proton MR spectroscopy in infants with urea cycle defect. AJNR Am J Neuroradiol 22:834–837
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 119:604–610
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–E261
Daly MM (1985) Guanidinoacetate methyltransferase activity in tissues and cultured cells. Arch Biochem Biophys 236:576–584
Davis BM, Miller RK, Brent RL, Koszalka TR (1978) Materno-fetal transport of creatine in the rat. Biol Neonate 33:43–54
DeGrauw TJ, Salomons GS, Cecil KM, Chuck G, Newmeyer A, Schapiro MB, Jakobs C (2002) Congenital creatine transporter deficiency. Neuropediatrics 33:232–238
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 70:835–840
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–F1804
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 82:208–213
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 31:724–728
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 99:296–299
Galbraith RA, Furukawa M, Li M (2006) Possible role of creatine concentrations in the brain in regulating appetite and weight. Brain Res 1101:85–91
Ganesan V, Johnson A, Connelly A, Eckhardt S, Surtees RA (1997) Guanidinoacetate methyltransferase deficiency: new clinical features. Pediatr Neurol 17:155–157
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 23:1566–1572
Happe HK, Murrin LC (1995) In situ hybridization analysis of CHOT1, a creatine transporter, in the rat central nervous system. J Comp Neurol 351:94–103
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 838:158–165
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 198:431–436
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 9:39
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 69:1127–1133
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 102:2121–2127
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 577:200–209
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 29:811–819
Leonard JV, Morris AAM (2002) Urea cycle disorders. Semin Neonatol 7:27–35
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 67:1713–1714
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 163:571–585
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 48:1211–1213
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 132:288–295
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 165:633–638
Möller A, Hamprecht B (1989) Creatine transport in cultured cells of rat and mouse brain. J Neurochem 52:544–550
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 89:1454–1461
Nakashima T, Tomi M, Tachikawa M, Watanabe M, Terasaki T, Hosoya K (2005) Evidence for creatine biosynthesis in Müller glia. GLIA 52:47–52
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 53:303–307
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 11:298–307
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 8:866–874
Ohtsuki S (2004) New aspects of the blood–brain barrier transporters; its physiological roles in the central nervous system. Biol Pharm Bull 27:1489–1496
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 22:1327–1335
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 974:37–42
Pisano JJ, Abraham D, Udenfriend S (1963) Biosynthesis and disposition of γ-guanidinobutyric acid in mammalian tissues. Arch Biochem Biophys 100:323–329
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 29:220–223
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 215:153–156
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 75:97–105
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 68:1497–1500
Sandell LL, Guan XJ, Ingram R, Tilghman SM (2003) Gatm, a creatine synthesis enzyme, is imprinted in mouse placenta. Proc Natl Acad Sci USA 100:4622–4627
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 198:637–645
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 13:905–921
Schulze A, Battini R (2007) Pre-symptomatic treatment of creatine biosynthesis defects. Subcell Biochem 46:167–181
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 131:626–631
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 157:606–607
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 74:413–419
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 53:248–251
Schulze A, Hoffmann GF, Bachert P, Kirsch S, Salomons GS, Verhoeven NM, Mayatepek E (2006) Presymptomatic treatment of neonatal guanidinoacetate methyltransferase deficiency. Neurology 67:719–721
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 86:421–422
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 613:79–84
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 36:409–413
Stöckler S, Hanefeld F, Frahm J (1996) Creatine replacement therapy in guanidinoacetate methyltransferase deficiency, a novel inborn error of metabolism. Lancet 348:789–790
Stöckler S, Schutz PW, Salomons GS (2007) Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology. Subcell Biochem 46:149–166
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 20:144–160
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 107:768–778
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 111:499–509
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 97:109–113
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 88:325–330
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 126:325–345
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 29:655–660
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):21–40
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 195–264
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 51:247–253
Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80:1107–1213
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 21:41–50
Acknowledgments
This work was supported by the Swiss National Science Foundation, grants 3100A0-116859 and 31003A-130278.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Braissant, O., Henry, H., Béard, E. et al. Creatine deficiency syndromes and the importance of creatine synthesis in the brain. Amino Acids 40, 1315–1324 (2011). https://doi.org/10.1007/s00726-011-0852-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-011-0852-z