Arginine:Glycine Amidinotransferase Deficiency: The Third Inborn Error of Creatine Metabolism in Humans

• Published in: American journal of human genetics 2001-11, Vol.69 (5), p.1127-1133
• Main Authors: Item, Chike Bellarmine, Stöckler-Ipsiroglu, Sylvia, Stromberger, Carmen, Mühl, Adolf, Alessandrì, Maria Grazia, Bianchi, Maria Cristina, Tosetti, Michela, Fornai, Francesco, Cioni, Giovanni
• Format: Article
• Language: English
• Subjects: Amidinotransferases - deficiency; Amidinotransferases - genetics; Amidinotransferases - metabolism; Amino Acid Metabolism, Inborn Errors - drug therapy; Amino Acid Metabolism, Inborn Errors - enzymology; Amino Acid Metabolism, Inborn Errors - genetics; Amino Acid Metabolism, Inborn Errors - metabolism; Amino Acid Sequence; Aminoacid disorders; Arginine:glycine amidinotransferase; Base Sequence; Biological and medical sciences; Brain - metabolism; Child; Child, Preschool; Codon, Nonsense - genetics; creatine; Creatine - administration & dosage; Creatine - metabolism; Creatine - therapeutic use; Errors of metabolism; Female; Fibroblasts; Genotype; Glycine - analogs & derivatives; Glycine - urine; Humans; Intellectual Disability - complications; Intellectual Disability - enzymology; Intellectual Disability - genetics; Intellectual Disability - metabolism; Lymphocytes; Medical sciences; Metabolic diseases; Molecular Sequence Data; Nuclear Family; RNA, Messenger - analysis; RNA, Messenger - genetics
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/323765

Arginine:glycine amidinotransferase (AGAT) catalyzes the first step of creatine synthesis, resulting in the formation of guanidinoacetate, which is a substrate for creatine formation. In two female siblings with mental retardation who had brain creatine deficiency that was reversible by means of oral creatine supplementation and had low urinary guanidinoacetate concentrations, AGAT deficiency was identified as a new genetic defect in creatine metabolism. A homozygous G-A transition at nucleotide position 9297, converting a tryptophan codon (TGG) to a stop codon (TAG) at residue 149 (T149X), resulted in undetectable cDNA, as investigated by reverse-transcription PCR, as well as in undetectable AGAT activity, as investigated radiochemically in cultivated skin fibroblasts and in virus-transformed lymphoblasts of the patients. The parents were heterozygous for the mutant allele, with intermediate residual AGAT activities. Recognition and treatment with oral creatine supplements may prevent neurological sequelae in affected patients.