Disorders of creatine transport and metabolism

Am J Med Genet C Semin Med Genet. 2011 Feb 15;157C(1):72-8. doi: 10.1002/ajmg.c.30292. Epub 2011 Feb 9.


Creatine is a nitrogen containing compound that serves as an energy shuttle between the mitochondrial sites of ATP production and the cytosol where ATP is utilized. There are two known disorders of creatine synthesis (both transmitted as autosomal recessive traits: arginine: glycine amidinotransferase (AGAT) deficiency; OMIM 602360; and guanidinoacetate methyltransferase (GAMT) deficiency (OMIM 601240)) and one disorder of creatine transport (X-linked recessive SLC6A8 creatine transporter deficiency (OMIM 300036)). All these disorders are characterized by brain creatine deficiency, detectable by magnetic resonance spectroscopy. Affected patients can have mental retardation, hypotonia, autism or behavioral problems and seizures. The diagnosis of these conditions relies on the measurement of plasma and urine creatine and guanidinoacetate. Creatine levels in plasma are reduced in both creatine synthesis defects and guanidinoacetate is increased in GAMT deficiency. The urine creatine/creatinine ratio is elevated in creatine transporter deficiency with normal plasma levels of creatine and guanidinoacetate. The diagnosis is confirmed in all cases by DNA testing or functional studies. Defects of creatine biosynthesis are treated with creatine supplements and, in GAMT deficiency, with ornithine and dietary restriction of arginine through limitation of protein intake. No causal therapy is yet available for creatine transporter deficiency and supplementation with the guanidinoacetate precursors arginine and glycine is being explored. The excellent response to therapy of early identified patients with GAMT or AGAT deficiency candidates these condition for inclusion in newborn screening programs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidinotransferases / genetics
  • Brain Diseases, Metabolic, Inborn* / diagnosis
  • Brain Diseases, Metabolic, Inborn* / genetics
  • Brain Diseases, Metabolic, Inborn* / therapy
  • Creatine / deficiency
  • Creatine / genetics
  • Creatinine / blood
  • Creatinine / urine
  • Glycine / analogs & derivatives
  • Glycine / blood
  • Glycine / urine
  • Guanidinoacetate N-Methyltransferase / genetics
  • Humans
  • Infant, Newborn
  • Magnetic Resonance Spectroscopy
  • Mental Retardation, X-Linked* / diagnosis
  • Mental Retardation, X-Linked* / genetics
  • Mental Retardation, X-Linked* / therapy
  • Neonatal Screening
  • Plasma Membrane Neurotransmitter Transport Proteins / deficiency
  • Plasma Membrane Neurotransmitter Transport Proteins / genetics


  • Plasma Membrane Neurotransmitter Transport Proteins
  • Creatinine
  • GAMT protein, human
  • Guanidinoacetate N-Methyltransferase
  • Amidinotransferases
  • glycine amidinotransferase
  • glycocyamine
  • Creatine
  • Glycine

Supplementary concepts

  • Creatine deficiency, X-linked