Pediatric Neurology
Volume 42, Issue 3 , Pages 163-171 , March 2010

Creatine and Creatine Deficiency Syndromes: Biochemical and Clinical Aspects

Received 9 February 2009 ,Accepted 30 July 2009.

References 

  1. Chevreul ME. On the chemical composition of meat broth. [Sur la composition chimique du bouillon de viandes] [In French] J Pharm Sci Accessoires. 1835;21:231–242
  2. Wyss M, Schulze A. Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease?. Neuroscience. 2002;112:243–260
  3. Arias A, Ormazabal A, Moreno J, et al. Methods for the diagnosis of creatine deficiency syndromes: a comparative study. J Neurosci Methods. 2006;156:305–309
  4. Stöckler S, Holzbach U, Hanefeld F, et al. Creatine deficiency in the brain: a new, treatable inborn error of metabolism. Pediatr Res. 1994;36:409–413
  5. Salomons GS, Van Dooren SJ, Verhoeven NM, et al. X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet. 2001;68:1497–1500
  6. Item CB, Stromberger C, Mühl A, et al. Denaturing gradient gel electrophoresis for the molecular characterization of six patients with guanidinoacetate methyltransferase deficiency. Clin Chem. 2002;48:767–769
  7. Verhoeven NM, Schor DS, Roos B, et al. Diagnostic enzyme assay that uses stable-isotope-labeled substrates to detect l-arginine:glycine amidinotransferase deficiency. Clin Chem. 2003;49:803–805
  8. Almeida LS, Verhoeven NM, Roos B, et al. Creatine and guanidinoacetate: diagnostic markers for inborn errors in creatine biosynthesis and transport. Mol Genet Metab. 2004;82:214–219
  9. Rosenberg EH, Martínez Muñoz C, Betsalel OT, et al. Functional characterization of missense variants in the creatine transporter gene (SLC6A8): improved diagnostic application. Hum Mutat. 2007;28:890–896
  10. Schulze A, Ebinger F, Rating D, Mayatepek E. Improving treatment of guanidinoacetate methyltransferase deficiency: reduction of guanidinoacetic acid in body fluids by arginine restriction and ornithine supplementation. Mol Genet Metab. 2001;74:413–419
  11. Leuzzi V, Alessandri MG, Casarano M, Battini R, Cioni G. Arginine and glycine stimulate creatine synthesis in creatine transporter 1-deficient lymphoblasts. Anal Biochem. 2008;375:153–155
  12. Coman D, Yaplito-Lee J, Boneh A. New indications and controversies in arginine therapy. Clin Nutr. 2008;27:489–496
  13. Walker JB. Creatine: biosynthesis, regulation, and function. Adv Enzymol Relat Areas Mol Biol. 1979;50:177–242
  14. Braissant O, Henry H. GAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: a review. J Inherit Metab Dis. 2008;31:230–239
  15. Andres RH, Ducray AD, Schlattner U, Wallimann T, Widmer HR. Functions and effects of creatine in the central nervous system. Brain Res Bull. 2008;76:329–343
  16. Snow RJ, Murphy RM. Creatine and the creatine transporter: a review. Mol Cell Biochem. 2001;224:169–181
  17. Dinning JS, Day PL. Creatinuria during recovery from aminopterin-induced folic acid deficiency in the monkey. J Biol Chem. 1949;181:897–903
  18. Guthmiller P, Van Pilsum JF, Boen JR, McGuire DM. Cloning and sequencing of rat kidney L-arginine:glycine amidinotransferase: studies on the mechanism of regulation by growth hormone and creatine. J Biol Chem. 1994;269:17556–17560
  19. Van Pilsum JF, McGuire DM, Towle H. On the mechanism of the alterations of rat kidney transamidinase activities by diet and hormones. Adv Exp Med Biol. 1982;153:291–297
  20. Funahashi M, Kato H, Shiosaka S, Nakagawa H. Formation of arginine and guanidinoacetic acid in the kidney in vivo: their relations with the liver and their regulation. J Biochem. 1981;89:1347–1356
  21. Kim GS, Chevli KD, Fitch CD. Fasting modulates creatine entry into skeletal muscle in the mouse. Experientia. 1983;39:1360–1362
  22. Lee H, Ogawa H, Fujioka M, Gerton GL. Guanidinoacetate methyltransferase in the mouse: extensive expression in Sertoli cells of testis and in microvilli of caput epididymis. Biol Reprod. 1994;50:152–162
  23. Carlson M, Van Pilsum JF. S-adenosylmethionine: guanidinoacetate N-methyltransferase activities in livers from rats with hormonal deficiencies or excesses. Proc Soc Exp Biol Med. 1973;143:1256–1259
  24. Tsukuda K , Piontek GE, Lewin N, Jondal M, Klein E. Induction of K562 lysis in autologous LGL and dense T cell cocultures. Immunol Lett. 1985;9:291–295
  25. Kenyon GL, Reed GH. Creatine kinase: structure-activity relationships. Adv Enzymol Relat Areas Mol Biol. 1983;54:367–426
  26. Fujioka M, Takata Y, Konishi K, Gomi T, Ogawa H. Structure-function relationships of guanidinoacetate methyltransferase as revealed by chemical modification and site-directed mutagenesis of cysteine residues. In:  De Deyn PP,  Marescau B,  Stalon V,  Qureshi IA editor. Guanidino compounds in biology and medicine: Third International Symposium on Guanidino Compounds in Biology and Medicine. London: Libbey; 1992;p. 159–164
  27. Braissant O, Cagnon L, Monnet-Tschudi F, et al. Ammonium alters creatine transport and synthesis in a 3D culture of developing brain cells, resulting in secondary cerebral creatine deficiency. Eur J Neurosci. 2008;27:1673–1685
  28. Bessman SP, Carpenter CL. The creatine-creatine phosphate energy shuttle. Annu Rev Biochem. 1985;54:831–862
  29. O'Gorman E, Beutner G, Wallimann T, Brdiczka D. Differential effect of creatine depletion on the regulation of enzyme activities and on creatine stimulated mitochondrial respiration in the skeletal muscle, heart, and brain. Biochem Biophys Acta. 1996;1276:161–170
  30. Sipilä I, Rapola J, Simell O, Vannas A. Supplementary creatine as a treatment for gyrate atrophy of the choroid and retina. N Engl J Med. 1981;304:867–870
  31. Sharov VG, Saks VA, Kupriyanov VV, et al. Protection of ischemic myocardium by exogenous phosphocreatine: I. Morphologic and phosphorus 31-nuclear magnetic resonance studies. J Thorac Cardiovasc Surg. 1987;94:749–761
  32. Almeida LS, Salomons GS, Hogenboom F, Jakobs C, Schoffelmeer AN. Exocytotic release of creatine in rat brain. Synapse. 2006;60:118–123
  33. Galbraith RA, Furukawa M, Li M. Possible role of creatine concentrations in the brain in regulating appetite and weight. Brain Res. 2006;1101:85–91
  34. Humm A, Huber R, Mann K. The amino acid sequences of human and pig l-arginine:glycine amidinotransferase. FEBS Lett. 1994;339:101–107
  35. Gross MD, Eggen MA, Simon AM, Van Pilsum JF. The purification and characterization of human kidney l-arginine:glycine amidinotransferase. Arch Biochem Biophys. 1986;251:747–755
  36. Gross MD, Simon AM, Jenny RJ, Gray ED, McGuire DM, Van Pilsum JF. Multiple forms of rat kidney l-arginine:glycine amidinotransferase. J Nutr. 1988;118:1403–1409
  37. Chae YJ, Chung CE, Kim BJ, Lee MH, Lee H. The gene encoding guanidinoacetate methyltransferase (GAMT) maps to human chromosome 19 at band p13.3 and to mouse chromosome 10. Genomics. 1998;49:162–164
  38. Im YS, Chiang PK, Cantoni GL. Guanidoacetate methyltransferase: purification and molecular properties. J Biol Chem. 1979;254:11047–11050
  39. Nash SR, Giros B, Kingsmore SF, et al. Cloning, pharmacological characterization, and genomic localization of the human creatine transporter. Receptors Channels. 1994;2:165–174
  40. Sora I, Richman J, Santoro G, et al. The cloning and expression of a human creatine transporter. Biochem Biophys Res Commun. 1994;204:419–427
  41. Sandoval N, Bauer D, Brenner V, et al. The genomic organization of a human creatine transporter (CRTR) gene located in Xq28. Genomics. 1996;35:383–385
  42. Bayou N, M'rad R, Belhaj A, et al. The creatine transporter gene paralogous at 16p11.2 is expressed in human brain. Comp Funct Genomics. 2008;609684
  43. Martinez-Muñoz C, Rosenberg EH, Jakobs C, Salomons GS. Identification, characterization and cloning of SLC6A8C, a novel splice variant of the creatine transporter gene. Gene. 2008;418:53–59
  44. Item CB, Stöckler-Ipsiroglu S, Stromberger C, et al. Arginine: glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet. 2001;69:1127–1133
  45. Hiramatsu M, Ohba S, Edamatsu R, Kadowaki D, Mori A. Effect of guanidino compounds on membrane fluidity of rat synaptosomes. In:  De Deyn PP,  Marescau B,  Stalon V,  Qureshi IA editor. Guanidino compounds in biology and medicine: Third International Symposium on Guanidino Compounds in Biology and Medicine. London: Libbey; 1992;p. 387–393
  46. Neu A, Neuhoff H, Trube G, et al. Activation of GABAA receptors by guanidinoacetate: a novel pathophysiological mechanism. Neurobiol Dis. 2002;11:298–307
  47. Shulman RG, Rothman DL, Behar KL, Hyder F. Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci. 2004;27:489–495
  48. Ames A. CNS energy metabolism as related to function. Brain Res Brain Res Rev. 2000;34:42–68
  49. Hemmer W, Wallimann T. Functional aspects of creatine kinase in brain. Dev Neurosci. 1993;15:249–260
  50. Erecinska M, Silver IA. Ions and energy in mammalian brain. Prog Neurobiol. 1994;16:37–71
  51. da Silva CG, Parolo E, Streck EL, Wajner M, Wannmacher CMD, Wyse ATS. In vitro inhibition of Na+, K+-ATPase activity from rat cerebral cortex by guanidino compounds accumulating in hyperargininemia. Brain Res. 1999;838:78–84
  52. Dolder M, Walzel B, Speer O, Schlattner U, Wallimann T. Inhibition of the mitochondrial permeability transition by creatine kinase substrates requirement for microcompartmentation. J Biol Chem. 2003;278:17760–17766
  53. Sestili P, Martinelli C, Bravi G, et al. Creatine supplementation affords cytoprotection in oxidatively injured cultured mammalian cells via direct antioxidant activity. Free Radic Biol Med. 2006;40:837–849
  54. Rae C, Digney AL, McEwan SR, Bates TC. Oral creatine monohydrate supplementation improves brain performance: a double-blind placebo-controlled, cross-over trial. Proc Biol Sci [Proc R Soc Lond B]. 2003;270:2147–2150
  55. Watanabe A, Kato N, Kato T. Effects of creatine on mental fatigue and cerebral haemoglobin oxygenation. Neurosci Res. 2002;42:279–285
  56. Brewer GJ, Wallimann TW. Protective effects of the energy precursor creatine. J Neurochem. 2000;74:1968–1978
  57. Braissant O, Henry H, Villard AM, et al. Ammonium-induced impairment of axonal growth is prevented through glial creatine. J Neurosci. 2002;22:9810–9820
  58. in't Zandt HJ, Renema WK, Streijger F, et al. Cerebral creatine kinase deficiency influences metabolite levels and morphology in the mouse brain: a quantitative in vivo 1H and 31P magnetic resonance study. J Neurochem. 2004;90:1321–1330
  59. Wyss M, Wallimann T. Creatine metabolism and the consequences of creatine depletion in muscle. Mol Cell Biochem. 1994;133:51–66
  60. Almeida LS, Vilarinho L, Darmin PS, et al. A prevalent pathogenic GAMT mutation (c.59G>C) in Portugal. Mol Genet Metab. 2007;91:1–6
  61. Dhar SU, Scaglia F, Li FY, et al. Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab. 2009;96:38–43
  62. Battini R, Leuzzi V, Carducci C, et al. Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree. Mol Genet Metab. 2002;77:326–331
  63. Salomons GS, van Dooren SJ, Verhoeven NM, et al. X-linked creatine transporter defect: an overview. J Inherit Metab Dis. 2003;26:309–318
  64. Clark AJ, Rosenberg EH, Almeida LS, et al. X-Linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology. Hum Genet. 2006;119:604–610
  65. Rosenberg EH, Almeida LS, Kleefstra T, et al. High prevalence of SLC6A8 deficiency in X-linked mental retardation. Am J Hum Genet. 2004;75:97–105
  66. Sykut-Cegielska J, Gradowska W, Mercimek-Mahmutoglu S, Stöckler-Ipsiroglu S. Biochemical and clinical characteristics of creatine deficiency syndromes. Acta Biochim Pol. 2004;51:875–882
  67. Cheillan D, Cognat S, Vandenberghe N, Des Portes V, Vianey-Saban C. Creatine deficiency syndromes. [Les syndromes de deficit en créatine] [In French] Rev Neurol (Paris). 2005;161:285–289
  68. Stromberger C, Bodamer OA, Stöckler-Ipsiroglu S. Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism. J Inherit Metab Dis. 2003;26:299–308
  69. Mercimek-Mahmutoglu S, Stoeckler-Ipsiroglu S, Adami A, et al. GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis. Neurology. 2006;67:480–484
  70. Hahn KA, Salomons GS, Tackels-Horne D, et al. X-linked mental retardation with seizures and carrier manifestations is caused by a mutation in the creatine-transporter gene (SLC6A8) located in Xq28. Am J Hum Genet. 2002;70:1349–1356
  71. Anselm IA, Alkuraya FS, Salomons GS, et al. X-linked creatine transporter defect: a report on two unrelated boys with a severe clinical phenotype. J Inherit Metab Dis. 2006;29:214–219
  72. Schulze A, Bachert P, Schlemmer H, et al. Lack of creatine in muscle and brain in an adult with GAMT deficiency. Ann Neurol. 2003;53:248–251
  73. Verhoeven NM, Salomons GS, Jakobs C. Laboratory diagnosis of defects of creatine biosynthesis and transport. Clin Chim Acta. 2005;361:1–9
  74. Cognat S, Cheillan D, Piraud M, Roos B, Jakobs C, Vianey-Saban C. Determination of guanidinoacetate and creatine in urine and plasma by liquid chromatography-tandem mass spectrometry. Clin Chem. 2004;50:1459–1461
  75. Carducci C, Birarelli M, Leuzzi V, et al. Guanidinoacetate and creatine plus creatinine assessment in physiologic fluids: an effective diagnostic tool for the biochemical diagnosis of arginine:glycine amidinotransferase and guanidinoacetate methyltransferase deficiencies. Clin Chem. 2002;48:1772–1778
  76. Sipilä I. 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. 1980;613:79–84
  77. Valongo C, Cardoso ML, Domingues P, et al. Age related reference values for urine creatine and guanidinoacetic acid concentration in children and adolescents by gas chromatography-mass spectrometry. Clin Chim Acta. 2004;348:155–161
  78. Hunneman DH, Hanefeld F. GC-MS determination of guanidinoacetate in urine and plasma. J Inherit Metab Dis. 1997;20:450–452
  79. Arias A, Garcia-Villoria J, Ribes A. Guanidinoacetate and creatine/creatinine levels in controls and patients with urea cycle defects. Mol Genet Metab. 2004;82:220–223
  80. Bodamer OA, Bloesch SM, Gregg AR, Stöckler-Ipsiroglu S, O'Brien WE. Analysis of guanidinoacetate and creatine by isotope dilution electrospray tandem mass spectrometry. Clin Chim Acta. 2001;308:173–178
  81. Yasuda M, Sugahara K, Zhang J, et al. Simultaneous determination of creatinine, creatine and guanidinoacetic acid in human serum and urine using liquid chromatography-atmospheric pressure chemical ionization mass spectrometry. Anal Biochem. 1997;253:231–235
  82. Verhoeven NM, Guérand WS, Struys EA, Bouman AA, Van Der Knaap MS, Jakobs C. Plasma creatinine assessment in creatine deficiency: a diagnostic pitfall. J Inherit Metab Dis. 2000;23:835–840
  83. Verhoeven NM, Roos B, Struys EA, Salomons GS, Van Der Knaap MS, Jakobs C. Enzyme assay for diagnosis of guanidinoacetate methyltransferase deficiency. Clin Chem. 2004;50:441–443
  84. Caldeira Araújo H, Smit W, Verhoeven NM, et al. Guanidinoacetate methyltransferase deficiency identified in adults and child with mental retardation. Am J Med Genet A. 2005;133A:122–127
  85. Vilarinho L, Valongo C, Cardoso ML, et al. Five new Portuguese patients with guanidinoacetate methyltransferase deficiency: biochemical, enzymatic and molecular data. [Abstract] J Inherit Metab Dis. 2004;27(Suppl. 1):213S
  86. Item CB, Mercimek-Mahmutoglu S, Battini R, et al. Characterization of seven novel mutations in seven patients with GAMT deficiency. Hum Mutat. 2004;23:524–530
  87. Sijens PE, Verbruggen KT, Oudkerk M, Van Spronsen FJ, Soorani-Lunsing RJ. 1H MR spectroscopy of the brain in Cr transporter defect. Mol Genet Metab. 2005;86:421–422
  88. Michaelis T, Boretius S, Frahm J. Localized proton MRS of animal brain in vivo: models of human disorders. Prog Nucl Magn Reson Spectrosc. 2009;55:1–34
  89. Schulze A, Mayatepek P, Bachert B, Marescau B, De Deyn PP, Rating D. Therapeutic trial of arginine restriction in creatine deficiency syndrome. Eur J Pediatr. 1998;157:606–607
  90. Schulze A, Hoffmann GF, Bachert P, et al. Presymptomatic treatment of neonatal guanidinoacetate methyltransferase deficiency. Neurology. 2006;67:719–721
  91. Morris AA, Appleton RE, Power B, et al. Guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy. J Inherit Metab Dis. 2007;30:100
  92. Battini R, Alessandrì MG, Leuzzi V, et al. Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: early treatment can prevent phenotypic expression of the disease. J Pediatr. 2006;148:828–830
  93. Póo-Argüelles P, Arias A, Vilaseca MA, et al. X-linked creatine transporter deficiency in two patients with severe mental retardation and autism. J Inherit Metab Dis. 2006;29:220–223
  94. Chilosi A, Leuzzi V, Battini R, et al. Treatment with L-arginine improves neuropsychological disorders in a child with creatine transporter defect. Neurocase. 2008;14:151–161
  95. Fons C, Sempere A, Arias A, et al. Arginine supplementation in four patients with X-linked creatine transporter defect. J Inherit Metab Dis. 2008;31:724–728

PII: S0887-8994(09)00388-9

doi: 10.1016/j.pediatrneurol.2009.07.015

Pediatric Neurology
Volume 42, Issue 3 , Pages 163-171 , March 2010

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