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Molecular and Cellular Biochemistry

, Volume 244, Issue 1–2, pp 143–150 | Cite as

Creatine deficiency syndromes

  • Andreas Schulze
Article

Abstract

Since the first description of a creatine deficiency syndrome, the guanidinoacetate methyltransferase (GAMT) deficiency, in 1994, the two further suspected creatine deficiency syndromes – the creatine transporter (CrT1) defect and the arginine:glycine amidinotransferase (AGAT) deficiency were disclosed.

GAMT and AGAT deficiency have autosomal-recessive traits, whereas the CrT1 defect is a X-linked disorder. All patients reveal developmental delay/regression, mental retardation, and severe disturbance of their expressive and cognitive speech. The common feature of all creatine deficiency syndromes is the severe depletion of creatine/phosphocreatine in the brain. Only the GAMT deficiency is in addition characterized by accumulation of guanidinoacetic acid in brain and body fluids. Guanidinoacetic acid seems to be responsible for intractable seizures and the movement disorder, both exclusively found in GAMT deficiency. Treatment with oral creatine supplementation is in part successful in GAMT and AGAT deficiency, whereas in CrT1 defect it is not able to replenish creatine in the brain. Treatment of combined arginine restriction and ornithine substitution in GAMT deficiency is capable to decrease guanidinoacetic acid permanently and improves the clinical outcome. The lack of the creatine/phosphocreatine signal in the patient's brain by means of in vivo proton magnetic resonance spectroscopy is the common finding and the diagnostic clue in all three diseases. In AGAT deficiency guanidinoacetic acid is decreased, whereas creatine in blood was found to be normal. On the other hand the CrT1 defect is characterized by an increased concentration of creatine in blood and urine whereas guanidinoacetic acid concentration is normal.

The increasing number of patients detected very recently suffering from a creatine deficiency syndrome and the unfavorable outcome highlights the need of further attempts in early recognition of affected individuals and in optimizing its treatment. The study of creatine deficiency syndromes and their comparative consideration contributes to the better understanding of the pathophysiological role of creatine and other guanidino compounds in man.

creatine deficiency inborn errors of metabolism GAMT deficiency AGAT deficiency creatine transporter deficiency guanidonoacetic acid 

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References

  1. 1.
    Bianchi MC, Tosetti M, Fornai F, Alessandri' MG, Cipriani P, De Vito G, Canapicchi R: Reversible brain creatine deficiency in two sisters with normal blood creatine level. Ann Neurol 47: 511-513, 2000Google Scholar
  2. 2.
    Item CB, Stockler-Ipsiroglu S, Stromberger C, Muhl A, Alessandri MG, Bianchi MC, Tosetti M, Fornai F, Cioni G: Arginine:glycine amidinotransferase deficiency: The third inborn error of creatine metabolism in humans. Am J Hum Genet 69: 1127-1133, 2001Google Scholar
  3. 3.
    Stöckler S, Holzbach U, Hanefeld F, Marquardt I, Helms G, Requart M, Hanicke W, Frahm J: Creatine deficiency in the brain: A new, treatable inborn error of metabolism. Pediatr Res 36: 409-413, 1994Google Scholar
  4. 4.
    Cecil KM, Salomons GS, Ball WS Jr, Wong B, Chuck G, Verhoeven NM, Jakobs C, Degrauw TJ: Irreversible brain creatine deficiency with elevated serum and urine creatine: A creatine transporter defect? Ann Neurol 49: 401-404, 2001Google Scholar
  5. 5.
    Salomons GS, van Dooren SJ, Verhoeven NM, Cecil KM, Ball WS, Degrauw TJ, Jakobs C: X-Linked creatine-transporter gene (SLC6A8) defect: A new creatine-deficiency syndrome. Am J Hum Genet 68: 1497-1500, 2001Google Scholar
  6. 6.
    Wyss M, Kaddurah-Daouk R: Creatine and creatinine metabolism. Physiol Rev 80: 1107-1213, 2000Google Scholar
  7. 7.
    Walker JB: Creatine: Biosynthesis, regulation, and function. Adv Enzymol 50: 177-242, 1979Google Scholar
  8. 8.
    Guimbal C, Kilimann MW: A Na(+)-dependent creatine transporter in rabbit brain, muscle, heart, and kidney. cDNA cloning and functional expression. J Biol Chem 268: 8418-8421, 1993Google Scholar
  9. 9.
    von Figura K, Hanefeld F, Isbrandt D, Stöckler-Ipsirogly S: Guanidinoacetate methyltransferase deficiency. In: C.R. Scriver, A. Beaudet, W.S. Sly, D. Valle (eds). The Metabolic and Molecular Basis of Inherited Disease. McGraw Hill, New York, 2001, pp 1897-1908Google Scholar
  10. 10.
    McGuire DM, Gross MD, Elde RP, van Pilsum JF: Localization of L-arginine-glycine amidinotransferase protein in rat tissues by immunofluorescence microscopy. J Histochem Cytochem 34: 429-435, 1986.Google Scholar
  11. 11.
    Braissant O, Henry H, Loup M, Eilers B, Bachmann C: Endogenous synthesis and transport of creatine in the rat brain: An in situ hybridization study. Mol Brain Res 86: 193-201, 2001Google Scholar
  12. 12.
    Stöckler S, Isbrandt D, Hanefeld F, Schmidt B, von Figura K: Guanidino-acetate methyltransferase deficiency: The first inborn error of creatine metabolism in man. Am J Hum Genet 58: 914-922, 1996Google Scholar
  13. 13.
    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 49: 162-164, 1998Google Scholar
  14. 14.
    Carducci C, Leuzzi V, Carducci C, Prudente S, Mercuri L, Antonozzi I: Two new severe mutations causing guanidinoacetate methyltransferase deficiency. Mol Genet Metab 71: 633-638, 2000Google Scholar
  15. 15.
    Ensenauer R, Thiel T, Schwab KO, Lehnert W: Presence of muscle creatine in a patient with guanidinacetate methyltransferase (GAMT) deficiency. J Inherit Metab Dis 23: 212, 2001Google Scholar
  16. 16.
    Ganesan V, Johnson A, Connelly A, Eckhardt S, Surtees RAH: Guanidinoacetate methyltransferase deficiency: New clinical features. Pediatr Neurol 17: 155-157, 1997Google Scholar
  17. 17.
    Leuzzi V, Bianchi MC, Tosetti M, Carducci C, Cerquiglini CA, Cioni G, Antonozzi I: Brain creatine depletion: Guanidinoacetate methyltransferase deficiency (improving with creatine supplementation). Neurology 55: 1407-1409, 2000Google Scholar
  18. 18.
    Schulze A, Hess T, Wevers R, Mayatepek E, Bachert P, Marescau B, Knopp MV, De Deyn PP, Bremer HJ, Rating D: Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: Diagnostic tools for a new inborn error of metabolism see comments. J Pediatr 131: 626-631, 1997Google Scholar
  19. 19.
    van der Knaap MS, Verhoeven NM, Maaswinkel-Mooij P, Pouwels PJ, Onkenhout W, Peeters EA, Stockler-Ipsiroglu S, Jakobs C: Mental retardation and behavioral problems as presenting signs of a creatine synthesis defect. Ann Neurol 47: 540-543, 2000Google Scholar
  20. 20.
    Schulze A, Bachert P, Schlemmer H, Harting I, Polster T, Salomons GS, Verhoeven NM, Jakobs C, Fowler B, Hoffmann GF, Mayatepek E: Lack of creatine in muscle and brain in an adult with guanidinoacetate methyltransferase deficiency. Ann Neurol (in press)Google Scholar
  21. 21.
    Wilichowski E (personal communication)Google Scholar
  22. 22.
    Zinn A (personal communication)Google Scholar
  23. 23.
    Verhoeven NM, Guerand WS, Struys EA, Bouman AA, van der Knaap MS, Jakobs C: Plasma creatinine assessment in creatine deficiency: A diagnostic pitfall. J Inherit Metab Dis 23: 835-840, 2000Google Scholar
  24. 24.
    Schulze A, Mayatepek E, Rating D, Bremer HJ: Sakaguchi reaction: A useful method for screening guanidinoacetate-methyltransferase deficiency. J Inherit Metab Dis 19: 706, 1996Google Scholar
  25. 25.
    Marescau B, Deshmukh DR, Kockx M, Possemiers I, Qureshi IA, Wiechert P, De Deyn PP: Guanidino compounds in serum, urine, liver, kidney, and brain of man and some ureotelic animals. Metabolism 41: 526-532, 1992Google Scholar
  26. 26.
    Struys EA, Jansen EE, ten Brink HJ, Verhoeven NM, van der Knaap MS, Jakobs C: An accurate stable isotope dilution gas chromatographicmass spectrometric approach to the diagnosis of guanidinoacetate methyltransferase deficiency. J Pharm Biomed Anal 18: 659-665, 1998Google Scholar
  27. 27.
    Has J, Muhl A, Stockler-Ipsiroglu S: Guanidinoacetate methyltransferase (GAMT) deficiency: Non-invasive enzymatic diagnosis of a newly recognized inborn error of metabolism. Clin Chim Acta 290: 179-188, 2000Google Scholar
  28. 28.
    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 74: 413-419, 2001Google Scholar
  29. 29.
    Nash SR, Giros B, Kingsmore SF, Rochelle JM, Suter ST, Gregor P, Seldin MF, Caron MG: Cloning, pharmacological characterization, and genomic localization of the human creatine transporter. Receptors Channels 2: 165-174, 1994Google Scholar
  30. 30.
    Sora I, Richman J, Santoro G, Wei H, Wang Y, Vanderah T, Horvath R, Nguyen M, Waite S, Roeske WR, 1. a: The cloning and expression of a human creatine transporter. Biochem Biophys Res Commun 204: 419-427, 1994Google Scholar
  31. 31.
    Gregor P, Nash SR, Caron MG, Seldin MF, Warren ST: Assignment of the creatine transporter gene (SLC6A8) to human chromosome Xq28 telomeric to G6PD. Genomics 25: 332-333, 1995Google Scholar
  32. 32.
    Degrauw TJ, Cecil KM, Salomons GS, van Dooren SJ, Verhoeven NM, Ball WS, Jakobs C: The clinical syndrome of creatine transporter deficiency. Oral presentation on 6th International Meeting on Guanidino Compounds in Biology and Medicine, Cincinatti, Ohio, USA, 31.08–03.09, 2001Google Scholar
  33. 33.
    Salomons GS, van Dooren SJ, Bunea D, Verhoeven NM, Cecil KM, Ball WS, Degrauw TJ, Jakobs C: X-linked creatine transporter defect: The first two families. Oral presentation on 6th International Meeting on Guanidino Compounds in Biology and Medicine, Cincinatti, Ohio, USA, 31.08.–03.09, 2001Google Scholar
  34. 34.
    Carducci C, Birarelli M, Santagata P, Leuzzi V, Carducci C, Antonozzi I: Automated high-performance liquid chromatographic method for the determination of guanidinoacetic acid in dried blood spots: A tool for early diagnosis of guanidinoacetate methyltransferase deficiency. J Chromatogr B Biomed Sci Appl 755: 343-348, 2001Google Scholar
  35. 35.
    Ensenauer R. (personal communication)Google Scholar
  36. 36.
    Degrauw TJ, Cecil KM, Ball WS, Wong B, Jakobs C, Verhoeven NM: A new disorder of creatine metabolism; a patient with possible creatine transport defect. J Inherit Metab Dis 23: 211, 2001Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Andreas Schulze
    • 1
  1. 1.Division of Metabolic and Endocrine DiseasesUniversity Children's HospitalHeidelbergGermany

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