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Creatine is both ingested in the diet and synthesized mainly in the liver and pancreas by the action of arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), with arginine, glycine, and S-adenosyl methionine as essential substrates (Fig. 138-1). AGAT catalyzes the first of the two reactions involved in the de novo synthesis of creatine. This reaction uses arginine and glycine as substrates and yields guanidinoacetate and ornithine as products. Guanidinoacetate is further converted to creatine by the action of GAMT, using S-adenosylmethionine as a methyl group donor, with this reaction consuming a significant fraction of all methyl groups. Creatine reaches muscle and brain via an active transmembrane creatine transport system (CRTR). Creatine is then used in the cellular pool of creatine/creatine-phosphate, which together with creatine kinase and adenosine triphosphate (ATP)/adenosine diphosphate (ADP) provides a high-energy phosphate buffering system. Intracellular creatine and creatine phosphate are nonenzymatically converted to creatinine, with a daily turnover rate of 1.5%. Creatinine is excreted in urine, and the daily urinary creatinine excretion is directly proportional to total body creatine.

Figure 138-1

Metabolic pathways of creatine and ornithine. 1 = AGAT (arginine:glycine aminotransferase); 2 = GAMT (guanidinoacetate methyltransferase); 3 = X-CRTR (X-linked creatine transporter deficiency, SLC6A8); 4 = CK (creatine kinase); 5 = OAT (ornithine aminotransferase); 6 = ORNT1 (ornithine transporter 1, SLC25A15); 7 = P5CS (pyrroline-5-carboxylate synthase); 8 = OTC (ornithine transcarbamylase); 9 = Arginase. ATP, adenosine triphosphate; CAP, carbamyl phosphate; P5C, pyrroline-5-carboxylate; GAA, guanidinoacetate.

Creatine deficiency syndromes represent a group of inborn errors of metabolism, including disorders of creatine synthesis (AGAT; Mendelian Inheritance in Man [MIM] no. 602360) and GAMT (MIM no. 601240) deficiency and disorders of creatine transport, including the X-linked transmembrane creatine transporter (X-CRTR; MIM no. 300036) deficiency. Inheritance of GAMT and AGAT deficiency is autosomal recessive, whereas the gene for X-CRTR deficiency (SLC6A8) is located on the X chromosome. GAMT and AGAT deficiency are rare disorders, whereas X-CRTR deficiency has been diagnosed in up to 2% of patients who have X-linked intellectual disability. This frequency is comparable to the frequency of fragile X syndrome, which constitutes a rather frequent cause of X-linked intellectual disability.


The main symptoms observed in all 3 creatine deficiency syndromes are intellectual disability with pronounced speech delay, autistic behavior, and seizures. To date, 16 patients have been described with AGAT deficiency. The presenting features included poor growth, delayed psychomotor and language development, and occasional seizures. Patients with GAMT deficiency may exhibit a more complex clinical phenotype, including intractable epilepsy, extrapyramidal movement disorder, and abnormal signal intensities of the basal ganglia. The clinical phenotype of X-CRTR deficiency varies from mild to severe intellectual disability associated with speech delay and seizures. Dysmorphic features, microcephaly, and moderate brain atrophy have been described in some patients. Heterozygote females may have learning ...

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