Guanidinoacetate methyltransferase deficiency: First steps to newborn screening for a treatable neurometabolic disease

S. Mercimek-Mahmutoglu, G. Sinclair, S. J.M. van Dooren, W. Kanhai, P. Ashcraft, O. J. Michel, J. Nelson, O. T. Betsalel, L. Sweetman, C. Jakobs, G. S. Salomons

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Background: GAMT deficiency is an autosomal recessive disorder of creatine biosynthesis resulting in severe neurological complications in untreated patients. Currently available treatment is only successful to stop disease progression, but is not sufficient to reverse neurological complications occurring prior to diagnosis. Normal neurodevelopmental outcome in a patient, treated in the newborn period, highlights the importance of early diagnosis. Methods: Targeted mutation analysis (c.59G>C and c.327G>A) in the GAMT gene by the QIAxcel system and GAA measurement by a novel two-tier method were performed in 3000 anonymized newborn blood dot spot cards. Results: None of the targeted mutations were detected in any newborn. Two novel heterozygous variants (c.283_285dupGTC; p.Val95dup and c.278_283delinsCTCGATGCAC; p.Asp93AlafsX35) were identified by coincidence. Carrier frequency for these insertion/deletion types of GAMT mutations was 1/1475 in this small cohort of newborns. GAA levels were at or above the 99th percentile (3.12μmol/l) in 4 newborns. Second-tier testing showed normal results for 4 newborns revealing 0.1% false positive rate. No GAMT mutations were identified in 4 of the newborns with elevated GAA levels in the first tier testing. Conclusion: This is the first two-tier study to investigate carrier frequency of GAMT deficiency in the small cohort of newborn population to establish evidence base for the first steps toward newborn screening for this treatable neurometabolic disorder.

Original languageEnglish (US)
Pages (from-to)433-437
Number of pages5
JournalMolecular genetics and metabolism
Issue number3
StatePublished - Nov 2012
Externally publishedYes


  • GAA
  • GAMT deficiency
  • Newborn blood spots
  • Newborn screening
  • Treatment of GAMT deficiency

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology


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