title: Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency.
abstract: BACKGROUND
  Arginine:glycineamidinotransferase (AGAT/GATM) deficiency has been described in 9 patients across 4 families. Here we describe the clinical outcome and response to creatine supplementation in a patient of the second family affected with AGAT deficiency-a 9-year-old girl.
  
  
  METHODS
  Delayed motor milestones were noticed from 4 months of age and at 14 months moderate hypotonia, developmental delay and failure to thrive. Laboratory studies revealed low plasma creatine as well as extremely low levels of guanidinoacetic acid in urine and plasma. Proton magnetic resonance spectroscopy (MRS) of the brain showed absence of creatine. DNA sequence analysis revealed a homozygous mutation (c.484+1G>T) in the AGAT/GATM gene. AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay. At 16 months, Bayley's Infant Development Scale (BIDS) showed functioning at 43% of chronologic age. Oral creatine supplementation (up to 800 mg/kg/day) was begun.
  
  
  RESULTS
  At age 9 years she demonstrated advanced academic performance. Partial recovery of cerebral creatine levels was demonstrated on MRS at 25 months of age. Brain MRS at 40 months of age revealed a creatine/NAA ratio of about 80% of that in age-matched controls.
  
  
  CONCLUSIONS
  8 years post initiation of oral creatine supplementation, patient demonstrates superior nonverbal and academic abilities, with average verbal skills. We emphasize that early diagnosis combined with early treatment onset of AGAT deficiency may lead to improvement of developmental outcome.
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Joseph D T
authors.initials: JD
authors.lastname: Ndika
authors.forename: Kathreen
authors.initials: K
authors.lastname: Johnston
authors.forename: James A
authors.initials: JA
authors.lastname: Barkovich
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wirt
authors.forename: Patricia
authors.initials: P
authors.lastname: O'Neill
authors.forename: Ofir T
authors.initials: OT
authors.lastname: Betsalel
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
mesh_terms: D000579:Amidinotransferases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002648:Child; D003401:Creatine / Q000008:administration & dosage* / Q000097:blood*; D002658:Developmental Disabilities / Q000097:blood / Q000178:diet therapy; D019587:Dietary Supplements; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D006801:Humans; D009154:Mutation
chemical_list: D000579:Amidinotransferases; C020681:glycine amidinotransferase; C004946:glycocyamine; D003401:Creatine; D005998:Glycine