Clinical Information

Disorders of creatine synthesis (guanidinoacetate methyltransferase [GAMT] deficiency, L-arginine:glycine amidinotransferases [AGAT] deficiency, and creatine transporter deficiency [CTD]) are collectively described as creatine deficiency syndromes (CDS). AGAT and GAMT deficiencies are inherited in an autosomal recessive manner, while the creatine transporter defect is X-linked. All 3 disorders result in a depletion of cerebral creatine and typically present with global developmental delays, intellectual disability, and severe speech delay. Commonly, patients with CDS develop seizures. Patients with GAMT and male patients with CTD exhibit behavioral problems and features of autism. Female carriers for CTD can be asymptomatic or exhibit features similar to affected male patients, such as intellectual disability, behavioral problems, and seizures.

Diagnosis is possible by measuring guanidinoacetate (GAA), creatine (Cr), and creatinine (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.

Treatment with oral supplementation of creatine monohydrate is available and effective for the AGAT and GAMT deficiencies. Early treatment has been reported to prevent disease manifestations in affected but presymptomatic newborn siblings of individuals with GAMT or AGAT deficiencies. Creatine supplementation has not been shown to improve outcomes in male patients with CTD. However, symptomatic female carriers of CTD have been reported to benefit from creatine supplementation.