title: Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree.
abstract: Arginine:glycine amidinotransferase (AGAT, EC 2.1.4.1) deficiency is a recently recognized autosomal recessive inborn error of creatine biosynthesis, characterized by mental retardation and severe language impairment. We extensively investigated a third 5-year-old patient with AGAT deficiency, discovered in the pedigree of the same Italian family as the two index cases. At the age of 2 years he presented with psychomotor and language delay, and autistic-like behavior. Brain MRI was normal, but brain 1H-MRS disclosed brain creatine depletion, which almost completely normalized following creatine monohydrate supplementation. A remarkable clinical improvement paralleled the restoration of brain creatine concentration. AGAT and GAMT (guanidinoacetate:methyltransferase) genes were analyzed in the proband and in 26 relatives, including the two cousins with AGAT deficiency. Sequencing of the proband's AGAT gene disclosed the same homozygous mutation at nt position 9093 converting a tryptophan (TGG) to a stop codon (TAG) at residue 149 (W149X), as already described in the two previously reported cases. The proband's parents and 10 additional subjects of the pedigree were carriers for this mutation. AGAT deficiency was further confirmed by undetectable AGAT activity in the patient's lymphoblasts. Mutation analysis of the GAMT gene revealed a sequence variation in exon 6 (T209M), not in the proband, but in 15 additional subjects from the pedigree. The silent nature of this sequence variation is supported by its homozygosity in one AGAT deficient cousin and in one asymptomatic adult, both with normal GAMT activity.
authors.affiliation: Division of Child Neurology and Psychiatry, IRCCS Stella Maris and University of Pisa, Via dei Giacinti 2, Calambrone Pisa 56018, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Battini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leuzzi
authors.forename: Carla
authors.initials: C
authors.lastname: Carducci
authors.forename: Michela
authors.initials: M
authors.lastname: Tosetti
authors.forename: Maria C
authors.initials: MC
authors.lastname: Bianchi
authors.forename: Chike B
authors.initials: CB
authors.lastname: Item
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stöckler-Ipsiroglu
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cioni
mesh_terms: D000579:Amidinotransferases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002675:Child, Preschool; D003401:Creatine / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000652:urine; D050937:Guanidinoacetate N-Methyltransferase; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D011596:Psychomotor Disorders / Q000235:genetics* / Q000378:metabolism
chemical_list: D008780:Methyltransferases; C494506:GAMT protein, human; D050937:Guanidinoacetate N-Methyltransferase; D000579:Amidinotransferases; C020681:glycine amidinotransferase; C004946:glycocyamine; D003401:Creatine; D005998:Glycine