title: Feasibility of newborn screening for guanidinoacetate methyltransferase (GAMT) deficiency.
abstract: Guanidinoacetate methyltransferase (GAMT) deficiency causes brain creatine deficiency characterized by developmental delays, speech delay, seizures and autism-like behavior. Identification and therapy at birth because of a positive family history has prevented intellectual disability and seizures in all cases reported. The objective of this study was to develop a method to identify patients with GAMT deficiency from newborn screening blood spots. Creatine and guanidinoacetate were extracted from 10,000 deidentified blood spots using the same protocol routinely used for newborn screening and quantified by stable isotope dilution using deuterated creatine and guanidinoacetate as internal standards. Residual dried blood spots from three infants with GAMT deficiency were used to evaluate the sensitivity of the method. A second tier test using UPLC-MS/MS was performed to analyze samples with a concentration of guanidinoacetate >2.44 μmol/L (99.5th centile of the normal population). Fifty four blood spots required second tier testing in addition to seven blood spots from three patients with GAMT deficiency retrospectively analyzed. With second tier testing, only the samples from GAMT deficiency patients had elevated concentration of guanidinoacetate. Our results show that GAMT deficiency can be identified in newborns using routine extraction methods. The cost of this additional screening is minimal, as it does not require additional instrumentation, procedure, or sample collection. The use of a second tier test can reduce the false positive rate to a minimum. Summary Brain creatine deficiency syndromes cause mental retardation that can be prevented if therapy is initiated early in life. This manuscript reports that infants with GAMT deficiency (one of the brain creatine deficiency syndromes) can be identified from elevated guanidinoacetate in newborn blood spots with virtually absent false-positive results using a second tier test.
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT, 84108, USA, PASQUAM@aruplab.com.
authors.forename: Marzia
authors.initials: M
authors.lastname: Pasquali
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schwarz
authors.forename: Maren
authors.initials: M
authors.lastname: Jensen
authors.forename: Tatiana
authors.initials: T
authors.lastname: Yuzyuk
authors.forename: Irene
authors.initials: I
authors.lastname: DeBiase
authors.forename: Harper
authors.initials: H
authors.lastname: Randall
authors.forename: Nicola
authors.initials: N
authors.lastname: Longo
mesh_terms: D001921:Brain / Q000378:metabolism; D003401:Creatine / Q000097:blood; D059788:Dried Blood Spot Testing / Q000379:methods*; D005189:False Positive Reactions; D005240:Feasibility Studies; D005998:Glycine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D050937:Guanidinoacetate N-Methyltransferase / Q000097:blood / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007805:Language Development Disorders / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism; D009069:Movement Disorders / Q000097:blood / Q000151:congenital* / Q000175:diagnosis / Q000378:metabolism; D015997:Neonatal Screening / Q000379:methods*; D012189:Retrospective Studies
chemical_list: D050937:Guanidinoacetate N-Methyltransferase; C004946:glycocyamine; D003401:Creatine; D005998:Glycine