title: Characterization of seven novel mutations in seven patients with GAMT deficiency.
abstract: Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive error of creatine synthesis characterized by cerebral creatine deficiency, accumulation of guanidinoacetate, mental retardation, epilepsy and extrapyramidal signs. So far, six mutations have been identified in seven patients. We investigated seven new patients by screening the promoter, 3'UTR, and six exons and exon/intron boundaries using direct sequencing and denaturing gradient gel electrophoresis. The clinical and biochemical phenotype was characterized by scoring the degree of main clinical manifestations and by determination of urinary guanidinoacetate concentrations and of GAMT activity in fibroblasts / lymphoblasts, respectively. We identified 7 novel mutations, including c.64dupG (exon 1; 4/14 alleles); c.59G>C (exon 1; 3/14 alleles); c.491delG (exon 5; 2/14 alleles); c.160G>C (exon 1; 2/14 alleles); and c.152A>C (exon 1; 1/14 alleles); c.526dupG (exon 5; 1/14 alleles); c.521G>A (exon 5; 1/14 alleles), and two polymorphisms c.626C>T (exon 6) and c.459+71G>A (intron 4). Frameshift and missense mutations in exon 1 were prevalent in the 4 patients with the severe phenotype, however a clear genotype-phenotype correlation has not been established in the limited number of patients characterized so far.
authors.affiliation: Department of Pediatrics, and National Newborn Screening Laboratory, University Hospital and General Hospital of Vienna, Austria.
authors.forename: C B
authors.initials: CB
authors.lastname: Item
authors.forename: S
authors.initials: S
authors.lastname: Mercimek-Mahmutoglu
authors.forename: R
authors.initials: R
authors.lastname: Battini
authors.forename: C
authors.initials: C
authors.lastname: Edlinger-Horvat
authors.forename: C
authors.initials: C
authors.lastname: Stromberger
authors.forename: O
authors.initials: O
authors.lastname: Bodamer
authors.forename: A
authors.initials: A
authors.lastname: Mühl
authors.forename: M A
authors.initials: MA
authors.lastname: Vilaseca
authors.forename: H
authors.initials: H
authors.lastname: Korall
authors.forename: S
authors.initials: S
authors.lastname: Stöckler-Ipsiroglu
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D003677:Deficiency Diseases / Q000175:diagnosis / Q000235:genetics; D005091:Exons; D005260:Female; D050937:Guanidinoacetate N-Methyltransferase; D006801:Humans; D007438:Introns; D008297:Male; D008780:Methyltransferases / Q000172:deficiency* / Q000235:genetics*; D009154:Mutation
chemical_list: D008780:Methyltransferases; C494506:GAMT protein, human; D050937:Guanidinoacetate N-Methyltransferase