Creatine Deficiency Syndromes

Abstract

Creatine deficiency syndromes (CDS) are a novel group of inborn errors of creatine synthesis and transport including autosomal recessive arginine:glycine amidino transferase (AGAT) and guanidinoacetate methyltransferase (GAMT) deficiencies, and the X-linked creatine transporter (SLC6A8) deficiency. In all these disorders the common clinical hallmark is mental retardation, expressive speech delay and epilepsy; the common biochemical hallmark is cerebral creatine deficiency as detected by proton magnetic resonance spectroscopy (H-MRS). Increased levels of guanidinoacetic acid (GAA) in body fluids are pathognomonic for GAMT deficiency whereas these levels are reduced in AGAT deficiency. An increased urinary creatine/creatinine ratio is associated with SLC6A8 deficiency. Oral supplementation of creatine leads to partial restoration of the cerebral creatine pool and improvement of clinical symptoms in GAMT and AGAT deficiency. Reduction of GAA by additional dietary restriction of arginine (and supplemen tation of ornithine) appears to be of additional benefit for the long-term outcome of GAMT deficient patients. For SLC6A8 deficient patients no effective treatment is currently available. CDS may account for a considerable fraction of children and adults with mental retardation of unknown cause and, therefore, screening for these disorders (by urinary/plasma metabolites, brain H-MRS and/or DNA approach) should be included in the investigation of this population.