Commentary Newborn screening for guanidinoacetate methyl transferase deficiency James J. Pitt a,b, ⁎, Nicholas Tzanakos a , Thanh Nguyen a a Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Melbourne, Australia b Department of Paediatrics, University of Melbourne, Melbourne, Australia ARTICLE INFO Article history: Received 30 December 2013 Received in revised form 6 January 2014 Accepted 6 January 2014 Available online 15 January 2014 Keywords: Newborn screening Guanidinoacetate methyltransferase deficiency Recent articles by Stockler-Ipsiroglu et al. [1] and other authors [2,3] have reported promising results for treatment of guanidinoacetate methyl transferase deficiency (GAMTD). This inborn error of creatine biosynthesis typically manifests in the first few years of life with devel- opmental delay and neurological features including epilepsy and move- ment disorders. These articles demonstrate that creatine treatment, usually in combination with ornithine, sodium benzoate or restriction of dietary arginine, is effective in improving symptoms and biochemis- try. Furthermore, preliminary data indicate that treatment is most effec- tive if started early in life [1,3,4,5], with some individuals and siblings having normal outcomes. These findings highlight the desirability of early detection and treatment of this disorder via newborn screening (NBS). Retro- spective studies have demonstrated the feasibility of NBS using guanidinoacetate measurement in neonatal dried blood spots [3,6,7]. However, there are few long-term, prospective NBS studies for GAMTD. NBS for GAMTD commenced in Victoria, Australia in 2002. A cut-off of 5 μmol/L guanidinoacetate was used to screen dried blood spots from 771,345 newborns between April 2002 and April 2013. 127 babies (0.02%) had increased levels, prompting a request for a repeat dried blood spot. Three of these babies had increased guanidinoacetate in their second sample. Urine testing of these three babies for guanidinoacetate, creatine and creatinine did not indicate GAMTD. Some premature babies had a significant guanidinoacetate interference in their second dried blood spot sample, collected as a hypothyroid- ism failsafe mechanism. This interference can be separated from guanidinoacetate with LC–MS/MS testing and we believe that it is due to treatment of premature babies. NBS, symptomatic metabolic screening and clinical management of inborn errors of metabolism for Victoria are performed by one organization and we believe any missed cases would be detected by this system. Our experience indicates that GAMTD is rare in the Victorian population, with no cases detected in a cohort of 771,345 babies. However, rarity of an individual disorder may not be an overriding factor when deciding whether to include an individual disorder in multiplex NBS using tandem mass spectrometry. For example, no cases of beta-ketothiolase deficiency, an accepted target for NBS [8], were detected in the Victorian population in the same period. Guanidinoacetate testing was easily implemented with an accept- ably low false positive rate. The false positive rate can be further improved with the use of creatine measurements and second-tier LC–MS/MS testing [6,7]. GAMTD was considered as part of the American College of Medical Genetics uniform panel for NBS in 2006 but failed to score sufficiently for inclusion in the panel [7]. At that time there was limited available information on the natural history and treatment of the disorder or the reliability of NBS. In the light of more recent information, GAMTD now satisfies many accepted criteria for NBS: there is a latent phase be- fore symptoms become apparent, reliable testing can be easily and cheaply implemented by modifying existing tandem mass spectrometry panels and treatment is available. As advocated by the above authors, there is now sufficient evidence to justify the wider scale consideration of NBS for GAMTD. References [1] S. Stockler-Ipsiroglu, C. van Karnebeek, N. Longo, G.C. Korenke, S. Mercimek- Mahmutoglu, I. Marquart, B. Barshop, C. Grolik, A. Schlune, B. Angle, H.C. Araujo, T. Coskun, L. Diogo, M. Geraghty, G. Haliloglu, V. Konstantopoulou, V. Leuzzi, A. Levtova, J. Mackenzie, B. Maranda, A.A. Mhanni, G. Mitchell, A. Morris, T. Newlove, D. Renaud, F. Scaglia, V. Valayannopoulos, F.J. van Spronsen, K.T. Verbruggen, N. Yuskiv, W. Nyhan, A. Schulze, Guanidinoacetate methyltransferase (GAMT) deficien- cy: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring, Mol. Genet. Metab. 111 (2014) 16–25. [2] S. Mercimek-Mahmutoglu, M. Dunbar, A. Friesen, S. Garret, C. Hartnett, L. Huh, G. Sinclair, S. Stockler, S. Wellington, P.J. Pouwels, G.S. Salomons, C. Jakobs, Evaluation of two year treatment outcome and limited impact of arginine restriction in a patient with GAMT deficiency, Mol. Genet. Metab. 105 (2012) 155–158. [3] A.H. El-Gharbawy, J.L. Goldstein, D.S. Millington, A.E. Vaisnins, A. Schlune, B.A. Barshop, A. Schulze, D.D. Koeberl, S.P. Young, Elevation of guanidinoacetate in new- born dried blood spots and impact of early treatment in GAMT deficiency, Mol. Genet. Metab. 109 (2013) 215–217. Molecular Genetics and Metabolism 111 (2014) 303–304 1096-7192/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ymgme.2014.01.005 ⁎ Corresponding author at: Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, 3052 Melbourne, Australia. Fax: +61 3 8341 6390. E-mail address: james.pitt@vcgs.org.au (J.J. Pitt). Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme