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Hereditary defects of creatine (Cr) synthesis or transport of Cr are described as Cr deficiency syndromes (CDSs).1 The group of CDSs consists of three different diseases: arginine:glycine amidinotransferase (AGAT), guanidinoacetate methyltransferase (GAMT), and Cr transporter (CrT) deficiency. They essentially affect the brain, where their common denominator is the virtually complete absence of Cr and phosphocreatine (PCr) when measured by magnetic resonance spectroscopy (MRS). Gyrate atrophy of choroid and retina represents an additional condition that may be added on to the CDSs because Cr deficiency is part of its clinical consequences.


The Cr/PCr system plays an important role in energy buffering and transmission. In addition to the mitochondrial and cytosolic Cr kinase system for shuttle of high-energy phosphates, synthesis and transport of Cr are integral parts of cellular energy metabolism. Recent data also suggest that Cr may act as neuromodulator or true neurotransmitter.2

Cr is taken up from the food by intestinal absorption or can be synthesized endogenously by two cytosolic enzyme reactions (Figure 12-1). In the first step, L-arginine:glycine amidinotransferase (AGAT) catalyzes the reversible transamidination of the guanidino group from arginine to glycine yielding guanidinoacetate and ornithine. The AGAT reaction is the rate-limiting step in Cr biosynthesis. Guanidinoacetate formation by AGAT is negatively controlled by high concentrations of guanidinoacetate, Cr, and ornithine. In the second step, the S-adenosylmethionine:guanidinoacetate N-methyltransferase (GAMT) catalyzes the S-adenosyl-L-methionine–dependent methylation of guanidinoacetate to yield Cr and S-adenosyl-L-homocysteine. While the main endogenous synthesis of Cr occurs in kidneys, pancreas, and liver, other tissues including CNS also express AGAT and GAMT and are capable of Cr synthesis. Cr is transported through the blood and is taken up into Cr-requiring tissues against a large concentration gradient (plasma [Cr] ~50 μM; intracellular [Cr + PCr] up to 40 mM). Uptake into the tissues is accomplished by a specific Na+/ Cl-dependent Cr transporter (CrT). Cr and PCr are non-enzymatically converted at an almost constant rate (~1.7%/d) into creatinine, which passively diffuses out of the cells and is excreted by the kidneys into the urine. The urinary creatinine excretion therefore represents a convenient indicator of the total Cr stores in the body. A 70-kg man contains approximately 120 g Cr, of which more than 90% is found in muscle tissue.1 For maintenance of the body Cr concentration, 1 to 2 g of Cr, which is equivalent to the amount of urinary excreted creatinine, must be provided every day through diet and endogenous synthesis.

FIGURE 12-1.

The metabolic pathway of creatine/phosphocreatine. AdoHcy, S-adenosylhomocysteine; AdoMet, S-adenosylmethionine; AGAT, arginine:glycine amidinotransferase; CrT, creatine transporter; GAMT, guanidinoacetate methyltransferase; GAP, guanidinoacetophosphate; OAT, Ornithine-Δ-aminotransferase; P5C, Δ1-pyrroline-5-carboxylate; PCr, phosphocreatine. (Adapted with permission from Schulze.1)



AGAT deficiency is a ...

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