Creatine and Guanidinoacetate (Plasma)

Evaluation of patients with a clinical suspicion of inborn errors of creatine metabolism including arginine:glycine amidinotransferase deficiency, guanidinoacetate methyltransferase deficiency, and creatine transporter (SLC6A8) defect. Plasma/serum creatine and guanidinoacetate testing may also be used for assessment of Variants of Uncertain Significance (VUS) identified during genetic testing (e.g. Next Generation Sequencing or Capillary Sequencing testing). Disorders of creatine synthesis (deficiency of arginine:glycine amidinotransferase [AGAT] and guanidinoacetate methyltransferase [GAMT]) and creatine transporter (SLC6A8) deficiency are collectively described creatine deficiency syndromes (CDS). AGAT and GAMT deficiencies are inherited in an autosomal recessive manner, while the creatine transporter defect is X-linked. Diagnosis is possible by measuring guanidinoacetate (GAA), creatine (Crn) in plasma and urine. The profiles are specific for each clinical entity. Patients with GAMT deficiency typically exhibit normal to low Cr, very elevated GAA, and low Crn. Patients with AGAT deficiency typically exhibit normal to low Cr, low GAA, and normal to low Crn. In comparison, elevated Cr, normal GAA, normal to low Crn, and an elevated Cr:Crn ratio characterize patients with creatine transporter defect. AGAT, GAMT and the creatine transporter defect result in a depletion of of cerebral creatine and typically present with global developmental delays, intellectual disability, and severe speech delay. Some patients with CDS develop seizures. Patients with GAMT and the creatine transporter deficiency exhibit behavioral problems and features of autism. Female carriers for the creatine transporter deficiency can have intellectual disability and behavioral problems, and some develop seizures. Treatment with oral supplementation of creatine monohydrate is available and effective for the AGAT and GAMT deficiencies. Creatine supplementation has not been shown to improve outcomes in males with the creatine transporter defect. Female carriers of creatine transporter deficiency who have symptoms, however, have been reported to benefit from creatine supplementation.