Disorders of creatine metabolism

Primary disorders of creatine metabolism are a group of inborn errors of creatine synthesis (arginine:glycine amidinotransferase (AGAT, encoded by GATM), guanidinoacetate methyltransferase (GAMT, encoded by GAMT) deficiencies), and the X-linked creatine transporter (CRTR, encoded by SLC6A8) deficiency. They typically present with systemic and/or cerebral creatine deficiency and global developmental delay, cognitive dysfunction or intellectual disability along with epilepsy, movement disorders and behavioural problems. Diagnostic markers include high guanidinoacetate concentrations in body fluids in GAMT and low levels in AGAT deficiency in both sexes and increased urine creatine to creatinine ratio in CRTR deficiency in males and rarely in females. Oral creatine supplementation, leads to near complete restoration of cerebral creatine in creatine synthesis defects: In GAMT deficiency, reduction of guanidinoacetate is achieved by ornithine supplementation and / or dietary protein or arginine restriction. In CRTR deficiency, creatine, arginine and glycine supplementation does not significantly improve outcomes, although partial clinical improvement has been reported in few patients. Normal neurodevelopmental outcomes have been reported in early treated patients with creatine synthesis defects.