title: A three-tier algorithm for guanidinoacetate methyltransferase (GAMT) deficiency newborn screening.
abstract: Guanidinoacetate methyltransferase (GAMT) deficiency is a rare disorder of creatine biosynthesis presenting with epilepsy and developmental delay in infancy. Excellent developmental outcomes have been reported for infants treated from birth due to a family history. The BC Newborn Screening Program initiated a 3year pilot screening study for GAMT deficiency to evaluate the performance of a novel three-tiered screening approach.
  
  
  
  Over 36months all bloodspots submitted for routine newborn screening were included in the pilot study (de-identified). Initial GAA measurement was integrated into the standard acylcarnitine/amino acid first-tier assay. All samples with elevated GAA were subjected to second-tier GAA analysis by LC-MS/MS integrated into an existing branched-chain amino acid (MSUD) method. GAMT gene sequencing was completed on the original bloodspot for all specimens with elevated GAA on the second-tier test. The protocol allowed for re-identification for treatment of any specimen with one or two likely pathogenic GAMT mutations.
  
  
  
  Over the study period 135,372 specimens were tested with 259 (0.19%) over the first-tier GAA cut-off. The second-tier assay removed an interference falsely elevating GAA levels, and only 3 samples required genotyping. No mutations were identified in any samples, all were deemed negative screens and no follow-up was initiated.
  
  
  
  A three-tier algorithm for GAMT newborn screening showed excellent test performance with zero false positives. No cases were detected, supporting a low incidence for this disorder. Given the low incremental costs and evidence of positive outcomes with early intervention, GAMT deficiency remains an excellent candidate for newborn screening.
authors.affiliation: Department of Pathology and Laboratory Medicine, Vancouver, BC, Canada; Treatable Intellectual Disability Endeavour, Vancouver, BC, Canada; British Columbia Children's Hospital, Vancouver, BC, Canada; University of British Columbia, Vancouver, BC, Canada. Electronic address: gsinclair@cw.bc.ca.
authors.forename: Graham B
authors.initials: GB
authors.lastname: Sinclair
authors.affiliation: Department of Pediatrics, Vancouver, BC, Canada; Treatable Intellectual Disability Endeavour, Vancouver, BC, Canada; British Columbia Children's Hospital, Vancouver, BC, Canada; University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics/Child and Family Research Institute, Vancouver, BC, Canada.
authors.forename: Clara D M
authors.initials: CDM
authors.lastname: van Karnebeek
authors.affiliation: Department of Pathology and Laboratory Medicine, Vancouver, BC, Canada; British Columbia Children's Hospital, Vancouver, BC, Canada.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ester
authors.affiliation: Department of Pathology and Laboratory Medicine, Vancouver, BC, Canada; British Columbia Children's Hospital, Vancouver, BC, Canada.
authors.forename: Frances
authors.initials: F
authors.lastname: Boyd
authors.affiliation: Department of Pathology and Laboratory Medicine, Vancouver, BC, Canada; British Columbia Children's Hospital, Vancouver, BC, Canada; University of British Columbia, Vancouver, BC, Canada.
authors.forename: Tanya
authors.initials: T
authors.lastname: Nelson
authors.affiliation: Department of Pediatrics, Vancouver, BC, Canada; Treatable Intellectual Disability Endeavour, Vancouver, BC, Canada; British Columbia Children's Hospital, Vancouver, BC, Canada; University of British Columbia, Vancouver, BC, Canada.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stockler-Ipsiroglu
authors.affiliation: Department of Pathology and Laboratory Medicine, Vancouver, BC, Canada; Treatable Intellectual Disability Endeavour, Vancouver, BC, Canada; British Columbia Children's Hospital, Vancouver, BC, Canada; University of British Columbia, Vancouver, BC, Canada.
authors.forename: Hilary
authors.initials: H
authors.lastname: Vallance
mesh_terms: D000465:Algorithms; D002853:Chromatography, Liquid; D050937:Guanidinoacetate N-Methyltransferase / Q000172:deficiency*; D006801:Humans; D007231:Infant, Newborn; D007805:Language Development Disorders / Q000175:diagnosis*; D009069:Movement Disorders / Q000151:congenital* / Q000175:diagnosis; D015997:Neonatal Screening / Q000379:methods*; D010865:Pilot Projects; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry
chemical_list: D050937:Guanidinoacetate N-Methyltransferase
keywords: Creatine; Guanidinoacetate; Guanidinoacetate methyltransferase; Mass spectrometry; Newborn screening; Second-tier