Creatine deficiency syndromes: biochemical and molecular aspects

Introduction: Creatine deficiency syndromes (CDS) represent a group of inborn errors of creatine biosynthesis: L-arginine-glycine amidinotransferase - AGAT and guanidinoacetate methyltransferase - GAMT deficiencies and transport (creatine transporter - SLC6A8 deficiency). Patients with CDS may present with mental retardation (MR), expressive speech and language delay, and epilepsy. Patients with GAMT deficiency or SLC6A8 deficiency may also exhibit autistic-like behavior. The common denominator of these disorders is the depletion of the brain creatine pool, as demonstrated by in vivo 1H-MRS. Patients and Methods: The authors studied 6,600 urine samples from Portuguese autistic children and young adults for defects in creatine metabolism. We started with the determination of guanidinoacetate and creatine in urine by GC-MS-SIM. Based on these findings, enzyme assays or DNA mutation analysis may be performed. Molecular genetic analysis for GAMT deficiency and creatine transporter deficiency is also available in our laboratory. Results: A marked excretion of guanidinoacetate in urine compatible with GAMT deficiency was observed in seven cases. Furthermore, other 15 patients showed high urinary levels of creatine/creatinine ratio what suggests a defect of SLC6A8. All GAMT deficient patients show the same mutation (c.59G>C) which suggests a founder effect in our population. Molecular genetic analysis of the SLC6A8 deficiency patients revealed a large spectrum of mutations. Discussion: So far, 22 patients with CDS were identified in our laboratory (1:300). We believe these defects are still under diagnosed, so the possibility should be considered in all children affected by unexplained MR, seizures, and speech delay. SLC6A8 defect should also be considered in males with MR and negative fragile-X testing. GAMT deficiency is treatable with oral creatine monohydrate and ornithine supplementation with arginine dietary restriction.