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Creatine is synthesized mainly in the liver and pancreas by the action of arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) with arginine, glycine, and S-adenosylmethionine as essential substrates (eFig. 142.1). AGAT catalyzes the first of the two reactions involved in the de novo synthesis of creatine. This reaction utilizes 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. Creatine reaches muscle and brain via an active transmembrane creatine transport system (CRTR). Creatine is then utilized in the cellular pool of creatine/creatine-phosphate, which together with creatine kinase and ATP/ADP provides a high energy phosphate buffering system. Intracellular creatine and creatine phosphate are nonenzymatically converted to creatinine, with a 1.5% constant daily turnover rate of body creatine. Creatinine is excreted in urine, and the daily urinary creatinine excretion is directly proportional to total body creatine.

eFigure 142.1.

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; P5C, pyrroline-5-carboxylate; CAP, carbamyl phosphate; GAA, guanidinoacetate; ATP, adenosine triphosphate.

Creatine deficiency syndromes represent a group of inborn errors of metabolism, including disorders of creatine synthesis (AGAT; OMIM 602360) and GAMT (OMOM 601240)[ deficiency, and disorders of creatine transport, including the X-linked transmembrane creatine transporter (X-CRTR; MIM 300036) deficiency.1 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 seem to be rare disorders, whereas X-CRTR deficiency has been diagnosed in up to 2% of patients who have X-linked mental retardation. This frequency is comparable to the frequency of fragile X syndrome, which constitutes a rather frequent cause of X-linked mental retardation.

Clinical Presentation

The main clinical symptoms observed in all three creatine deficiency syndromes are mental retardation with pronounced speech delay, autistic behavior, and seizures. Five patients from only two families have been described with AGAT deficiency so far. The presenting features included 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.2 The clinical phenotype of X-CRTR deficiency varies from mild to severe mental retardation associated with speech delay and epileptic seizures. Dysmorphic features, microcephaly, and moderate brain atrophy have been described in some of these patients. Heterozygote females may have learning difficulties. Skewed X-inactivation may cause pronounced clinical manifestations in these cases similar to the male phenotype. Interestingly, patients with disorders of creatine synthesis and creatine transport do not have signs of cardiomyopathy ...

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