Creatine depletion in a new case with AGAT deficiency: Clinical and genetic study in a large pedigree

Roberta Battini, Vincenzo Leuzzi, Carla Carducci, Michela Tosetti, Maria C. Bianchi, Chike B. Item, Sylvia Stöckler-Ipsiroglu, Giovanni Cioni

Research output: Contribution to journalArticlepeer-review


Arginine:glycine amidinotransferase (AGAT, EC 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.

Original languageEnglish
Pages (from-to)326-331
Number of pages6
JournalMolecular Genetics and Metabolism
Issue number4
Publication statusPublished - 2002


  • Arginine:glycine amidinotransferase (AGAT)
  • Creatine deficiency
  • Genetical analysis
  • Guanidinoacetate methyltransferase (GAMT)
  • Proton spectroscopy

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Endocrinology, Diabetes and Metabolism


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