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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.
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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.
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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 ...