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.
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Abbreviations
- GAA:
-
Guanidinoacetate
- GAMT:
-
Guanidinoacetate methyltransferase
References
Bodamer OA, Iqbal F, Muhl A, Hung C, Prayer D, Ratschmann R, Item BC (2009) Low creatinine: the diagnostic clue for a treatable neurologic disorder. Neurology 72:854–855
El-Gharbawy AH, Goldstein JL, Millington DS et al (2013) Elevation of guanidinoacetate in newborn dried blood spots and impact of early treatment in GAMT deficiency. Mol Genet Metab 109:215–217
Item CB, Stockler-Ipsiroglu S, Stromberger C et al (2001) Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet 69:1127–1133
Longo N, Ardon O, Vanzo R, Schwartz E, Pasquali M (2011) Disorders of creatine transport and metabolism. Am J Med Genet C: Semin Med Genet 157:72–78
McHugh DM, Cameron CA, Abdenur JE et al (2011) Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project. Genet Med 13:230–254
Mercimek-Mahmutoglu S, Stoeckler-Ipsiroglu S, Adami A et al (2006) GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis. Neurology 67:480–484
Mercimek-Mahmutoglu S, Sinclair G, van Dooren SJ et al (2012) Guanidinoacetate methyltransferase deficiency: first steps to newborn screening for a treatable neurometabolic disease. Mol Genet Metab 107:433–437
Salomons GS, van Dooren SJ, Verhoeven NM, Cecil KM, Ball WS, Degrauw TJ, Jakobs C (2001) X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet 68:1497–1500
Schulze A (2003) Creatine deficiency syndromes. Mol Cell Biochem 244:143–150
Schulze A, Battini R (2007) Pre-symptomatic treatment of creatine biosynthesis defects. Subcell Biochem 46:167–181
Schulze A, Ebinger F, Rating D, Mayatepek E (2001) Improving treatment of guanidinoacetate methyltransferase deficiency: reduction of guanidinoacetic acid in body fluids by arginine restriction and ornithine supplementation. Mol Genet Metab 74:413–419
Schulze A, Hoffmann GF, Bachert P et al (2006) Presymptomatic treatment of neonatal guanidinoacetate methyltransferase deficiency. Neurology 67:719–721
Stockler S, Hanefeld F, Frahm J (1996) Creatine replacement therapy in guanidinoacetate methyltransferase deficiency, a novel inborn error of metabolism. Lancet 348:789–790
Stockler S, Schutz PW, Salomons GS (2007) Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology. Subcell Biochem 46:149–166
Stromberger C, Bodamer OA, Stockler-Ipsiroglu S (2003) Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism. J Inherit Metab Dis 26:299–308
Viau KS, Ernst SL, Pasquali M, Botto LD, Hedlund G, Longo N (2013) Evidence-Based Treatment of Guanidinoacetate Methyltransferase (GAMT) Deficiency. Mol Genet Metab 110:255–262
Vodopiutz J, Item CB, Hausler M, Korall H, Bodamer OA (2007) Severe speech delay as the presenting symptom of guanidinoacetate methyltransferase deficiency. J Child Neurol 22:773–774
Watson MS, Mann MY, Lloyd-Puryear MA, Rinaldo P, Howell RR, Group ANSE (2006) Newborn screening: toward a uniform screening panel and system--executive summary. Pediatrics 117:S296–S307
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University of Utah Intramural Award VP_00000490.
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This study was approved by the Institutional Review Boards of the University of Utah and of the Utah Department of Health. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
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Communicated by: Georg Hoffmann
OMIM 612736 GUANIDINOACETATE METHYLTRANSFERASE DEFICIENCY
OMIM 601240 GUANIDINOACETATE METHYLTRANSFERASE; GAMT
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Pasquali, M., Schwarz, E., Jensen, M. et al. Feasibility of newborn screening for guanidinoacetate methyltransferase (GAMT) deficiency. J Inherit Metab Dis 37, 231–236 (2014). https://doi.org/10.1007/s10545-013-9662-7
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DOI: https://doi.org/10.1007/s10545-013-9662-7