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Congenital disorders of creatine metabolism

Clara Van Karnebeek, MD, PhD, FCCMG
Sylvia Stockler-Ipsiroglu, MD, PhD, MBA, FRCPC
Section Editor
Sihoun Hahn, MD, PhD
Deputy Editor
Elizabeth TePas, MD, MS


Creatine is a nitrogenous organic acid that is produced primarily in the kidney and liver and is stored in tissues with high energy demands, such as skeletal muscle and the brain. Its phosphorylated form (creatine-phosphate or phosphocreatine) is involved in the formation of adenosine triphosphate (ATP), which is used as an energy source for a number of intracellular metabolic processes.

There are three identified congenital metabolic disorders that lead to creatine deficiency [1-3]. Two are autosomal recessive disorders that affect the biosynthesis of creatine. They are arginine:glycine amidinotransferase (AGAT) deficiency and guanidinoacetate methyltransferase (GAMT) deficiency (figure 1). The third disorder, X-linked creatine transporter (CT) deficiency, is caused by a defect in the transport of creatine into the brain and muscle.

The pathogenesis, clinical features, diagnosis, and management of these disorders are reviewed here. Other inborn errors of metabolism are reviewed separately. (See "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Inborn errors of metabolism: Identifying the specific disorder".)


This section briefly reviews creatine metabolism and transport. It also reviews the common clinical features and the general diagnostic and treatment approaches for these disorders. The unique clinical features and management approaches are discussed in the separate sections on each disorder.

Creatine metabolism — Creatine synthesis involves two enzymatic steps and occurs primarily in the liver, kidney, and pancreas (figure 1). The first step involves L-arginine:glycine amidinotransferase (AGAT), which catalyzes the formation of guanidinoacetate (GAA) from arginine and glycine. The second involves guanidinoacetate methyltransferase (GAMT), which catalyzes the formation of creatinine from GAA and S-adenosylmethionine. Creatine is taken up by the tissues, mainly brain and muscle, by the creatine transporter (CT). It is nonenzymatically converted to creatinine and excreted into the urine.

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Literature review current through: Sep 2017. | This topic last updated: Aug 15, 2016.
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