A three-tier algorithm for guanidinoacetate methyltransferase (GAMT) deficiency newborn screening

作者：Sinclair Graham B^*; van Karnebeek Clara D M; Ester Manuel; Boyd Frances; Nelson Tanya; Stockler Ipsiroglu Sylvia; Vallance Hilary

来源：Molecular Genetics and Metabolism, 2016, 118(3): 173-177.

DOI：10.1016/j.ymgme.2016.05.002

• Guanidinoacetate methyltransferase
• Newborn screening
• Mass spectrometry
• Guanidinoacetate
• Creatine
• Second-tier

Background: 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 3 year pilot screening study for GAMT deficiency to evaluate the performance of a novel three-tiered screening approach.
Methods: Over 36 months 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.
Results: 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.
Conclusions: 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.

• 出版日期2016-7