Characterization of seven novel mutations in seven patients with GAMT deficiency

Authors

  • C.B. Item,

    1. Department of Pediatrics, and National Newborn Screening Laboratory, University Hospital and General Hospital of Vienna, Austria
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  • S. Mercimek-Mahmutoglu,

    1. Department of Pediatrics, and National Newborn Screening Laboratory, University Hospital and General Hospital of Vienna, Austria
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  • R. Battini,

    1. Department of Pediatrics, and National Newborn Screening Laboratory, University Hospital and General Hospital of Vienna, Austria
    2. Division of Child Neurology & Psychiatry, IRCCS Stella Maris and University of Pisa, Calambrone, Italy
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  • C. Edlinger-Horvat,

    1. Department of Pediatrics, and National Newborn Screening Laboratory, University Hospital and General Hospital of Vienna, Austria
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  • C. Stromberger,

    1. Department of Pediatrics, and National Newborn Screening Laboratory, University Hospital and General Hospital of Vienna, Austria
    2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
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  • O. Bodamer,

    1. Department of Pediatrics, and National Newborn Screening Laboratory, University Hospital and General Hospital of Vienna, Austria
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  • A. Mühl,

    1. Department of Pediatrics, and National Newborn Screening Laboratory, University Hospital and General Hospital of Vienna, Austria
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  • M.A. Vilaseca,

    1. Hospital Sain Joan de Deu, Barcelona, Spain
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  • H. Korall,

    1. Laboratory Center for Biochemical Metabolic Disease, Reutlingen, Germany
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  • S. Stöckler-Ipsiroglu

    Corresponding author
    1. Department of Pediatrics, and National Newborn Screening Laboratory, University Hospital and General Hospital of Vienna, Austria
    2. Department of Clinical Chemistry University Hospital and General Hospital of Vienna, Austria
    • Departments of Pediatrics and Clinical Chemistry, University Hospital and General Hospital Vienna, hringer Gürtel 18-20, A-1090 Vienna, Austria
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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. © 2004 Wiley-Liss, Inc.

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