Inborn errors of creatine metabolism and epilepsy


Address correspondence to Vincenzo Leuzzi, Department of Paediatrics and Child Neurology and Psychiatry, Via dei Sabelli 108, 00185 Roma, Italy. E-mail:


Creatine metabolism disorders include guanidinoacetate methyltransferase (GAMT) deficiency, arginine:glycine amidinotransferase (AGAT) deficiency, and the creatine transporter (CT1-encoded by SLC6A8 gene) deficiency. Epilepsy is one of the main symptoms in GAMT and CT1 deficiency, whereas the occurrence of febrile convulsions in infancy is a relatively common presenting symptom in all the three above-mentioned diseases. GAMT deficiency results in a severe early onset epileptic encephalopathy with development arrest, neurologic deterioration, drug-resistant seizures, movement disorders, mental disability, and autistic-like behavior. In this disorder, epilepsy and associated abnormalities on electroencephalography (EEG) are more responsive to substitutive treatment with creatine monohydrate than to conventional antiepileptic drugs. AGAT deficiency is mainly characterized by mental retardation and severe language disorder without epilepsy. In CT1 deficiency epilepsy is generally less severe than in GAMT deficiency. All creatine disorders can be investigated through measurement of creatine metabolites in body fluids, brain proton magnetic resonance spectroscopy (1H-MRS), and molecular genetic techniques. Blood guanidinoacetic acid (GAA) assessment and brain H-MRS examination should be part of diagnostic workup for all patients presenting with epileptic encephalopathy of unknown origin. In girls with learning and/or intellectual disabilities with or without epilepsy, SLC6A8 gene assessment should be part of the diagnostic procedures. The aims of this review are the following: (1) to describe the electroclinical features of epilepsy occurring in inborn errors of creatine metabolism; and (2) to delineate the metabolic alterations associated with GAMT, AGAT, and CT1 deficiency and the role of a substitutive therapeutic approach on their clinical and electroencephalographic epileptic patterns.