Abstract
Primary disorders of creatine metabolism are a group of inborn errors of creatine synthesis (arginine:glycine amidinotransferase (AGAT, encoded by GATM), guanidinoacetate methyltransferase (GAMT, encoded by GAMT) deficiencies), and the X-linked creatine transporter (CRTR, encoded by SLC6A8) deficiency. They typically present with systemic and/or cerebral creatine deficiency and global developmental delay, cognitive dysfunction or intellectual disability along with epilepsy, movement disorders and behavioural problems. Diagnostic markers include high guanidinoacetate concentrations in body fluids in GAMT and low levels in AGAT deficiency in both sexes and increased urine creatine to creatinine ratio in CRTR deficiency in males and rarely in females. Oral creatine supplementation, leads to near complete restoration of cerebral creatine in creatine synthesis defects: In GAMT deficiency, reduction of guanidinoacetate is achieved by ornithine supplementation and / or dietary protein or arginine restriction. In CRTR deficiency, creatine, arginine and glycine supplementation does not significantly improve outcomes, although partial clinical improvement has been reported in few patients. Normal neurodevelopmental outcomes have been reported in early treated patients with creatine synthesis defects.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Mercimek-Mahmutoglu S, Salomons GS (2015) Creatine deficiency syndromes. 2009 Jan 15 [updated 2015 Dec 10]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, LJH B, Stephens K, Amemiya A (eds) GeneReviews® [Internet]. University of Washington, Seattle, Seattle (WA), pp 1993–2020
Stockler-Ipsiroglu S, Apatean D, Battini R et al (2015) Arginine:glycine amidinotransferase (AGAT) deficiency: clinical features and long term outcomes in 16 patients diagnosed worldwide. Mol Genet Metab 116:252–259
Stockler-Ipsiroglu S, van Karnebeek C, Longo N et al (2014) Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab 111:16–25
Morris AA, Appleton RE, Power B et al (2007) Guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy. J Inherit Metab Dis 30:100
O’Rourke DJ, Ryan S, Salomons G et al (2009) Guanidinoacetate methyltransferase (GAMT) deficiency: late onset of movement disorder and preserved expressive language. Dev Med Child Neurol 51:404–407
van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S et al (2013a) Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet 50:463–472
Kleefstra T, Rosenberg EH, Salomons GS et al (2005) Progressive intestinal, neurological and psychiatric problems in two adult males with cerebral creatine deficiency caused by an SLC6A8 mutation. Clin Genet 68:379–381
van de Kamp JM, Mancini GM, Pouwels PJ et al (2011) Clinical features and X-inactivation in females heterozygous for creatine transporter defect. Clin Genet 79:264–272
Mercimek-Mahmutoglu S, Connolly MB, Poskitt KJ et al (2010) Treatment of intractable epilepsy in a female with SLC6A8 deficiency. Mol Genet Metab 101:409–412
Reichold M, Klootwijk ED, Reinders J et al (2018) Glycine amidinotransferase (GATM), renal Fanconi syndrome, and kidney failure. J Am Soc Nephrol 29:1849–1858
Edvardson S, Korman SH, Livne A, Shaag A, Saada A, Nalbandian R, Allouche-Arnon H et al (2010) L-arginine:glycine amidinotransferase (AGAT) deficiency: clinical presentation and response to treatment in two patients with a novel mutation. Mol Genet Metab 101:228–232
Ensenauer R, Thiel T, Schwab KO et al (2004) Guanidinoacetate methyltransferase deficiency: differences of creatine uptake in human brain and muscle. Mol Genet Metab 82:208–213
Schulze A, Bachert P, Schlemmer H et al (2003) Lack of creatine in muscle and brain in an adult with GAMT deficiency. Ann Neurol 53:248–251
Stockler S, Braissant O, Schulze A (2014) Creatine disorders. In: Blau N, Duran M, Gibson KM, Dionisi-Vici C (eds) Physician’s guide to diagnosis, treatment, and follow-up of inherited metabolic diseases. Springer, pp 529–540
Dhar SU, Scaglia F, Li FY, Smith L et al (2009) Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab 96:38–43
Mercimek-Mahmutoglu S, Ndika J, Kanhai W et al (2014b) Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene. Hum Mutat 35:462–469
Mercimek-Mahmutoglu S, Stöckler-Ipsiroglu S, Adami A et al (2006) Clinical, biochemical and molecular features of guanidinoacetate methyltransferase deficiency. Neurology 67:480–484
Mercimek-Mahmutoglu S, Pop A, Kanhai W, Fernandez Ojeda M, Holwerda U, Smith D, Loeber JG, Schielen PC, Salomons GS. A pilot study to estimate incidence of guanidinoacetate methyltransferase deficiency in newborns by direct sequencing of the GAMT gene. Gene. 2016;575(1):127–31. https://doi.org/10.1016/j.gene.2015.08.045. Epub 2015 Aug 28. PMID: 26319512
Desroches CL, Patel J, Wang P et al (2015) Carrier frequency of guanidinoacetate methyltransferase deficiency in the general population by functional characterization of missense variants in the GAMT gene. Mol Gen Genomics 290:2163–2171
Betsalel OT, Pop A, Rosenberg EH et al (2012) Detection of variants in SLC6A8 and functional analysis of unclassified missense variants. Mol Genet Metab 105:596–601
van de Kamp JM, Errami A, Howidi M et al (2015) Genotype-phenotype correlation of contiguous gene deletions of SLC6A8, BCAP31 and ABCD1. Clin Genet 87:141–147
van de Kamp JM, Mancini GM, Salomons GS (2014) X-linked creatine transporter deficiency: clinical aspects and pathophysiology. J Inherit Metab Dis 37:715–733
Arias A, Corbella M, Fons C et al (2007) Creatine transporter deficiency: prevalence among patients with mental retardation and pitfalls in metabolite screening. Clin Biochem 40:1328–1331
Mørkrid L, Rowe AD, Elgstoen KB et al (2015) Continuous age- and sex-adjusted reference intervals of urinary markers for cerebral creatine deficiency syndromes: a novel approach to the definition of reference intervals. Clin Chem 6:760–768
Berends LM, Struys EA, Roos B et al (2017) Guanidinoacetate methyltransferase activity in lymphocytes, for a fast diagnosis. JIMD Rep 37:13–17
Cheillan D, Salomons GS, Acquaviva C et al (2006) Prenatal diagnosis of guanidinoacetate methyltransferase deficiency: increased guanidinoacetate concentrations in amniotic fluid. Clin Chem 52:775–777
Schulze A, Hoffmann GF, Bachert P et al (2006) Presymptomatic treatment of neonatal guanidinoacetate methyltransferase deficiency. Neurology 67:719–721
Sinclair GB, van Karnebeek CD, Ester M et al (2016) A three-tier algorithm for guanidinoacetate methyltransferase (GAMT) deficiency newborn screening. Mol Genet Metab 118:173–177
Mercimek-Mahmutoglu S, Salomons GS, Chan A (2014) Case study for the evaluation of current treatment recommendations of guanidinoacetate methyltransferase deficiency: ineffectiveness of sodium benzoate. Pediatr Neurol 51:133–137
Khaikin Y, Sidky S, Abdenur J et al (2018) Treatment outcome of twenty-two patients with guanidinoacetate methyltransferase deficiency: an international retrospective cohort study. Eur J Paediatr Neurol 22:369–379
Dunbar M, Jaggumantri S, Sargent M, Stockler-Ipsiroglu S, van Karnebeek CD (2014) Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases. Mol Genet Metab 112:259–274
Valayannopoulos V, Boddaert N, Chabli A et al (2012) Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect. J Inherit Metab Dis 35:151–157
Jaggumantri S, Dunbar M, Edgar V et al (2015) Treatment of creatine transporter (SLC6A8) deficiency with oral S-adenosyl methionine as adjunct to L-arginine, glycine, and creatine supplements. Pediatr Neurol 53:360–363
Fons C, Arias A, Sempere A et al (2010) Response to creatine analogs in fibroblasts and patients with creatine transporter deficiency. Mol Genet Metab 99:296–299
Villar C, Campistol J, Fons C et al (2012) Glycine and L-arginine treatment causes hyperhomocysteinemia in cerebral creatine transporter deficiency patients. J Inherit Metab Dis:13–16
Bruun TUJ, Sidky S, Bandeira AO et al (2018) Treatment outcome of Creatine transporter deficiency: international retrospective cohort study. Metab Brain Dis 33:875–884
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 Springer-Verlag GmbH Germany, part of Springer Nature
About this chapter
Cite this chapter
Stöckler-Ipsiroglu, S., Mercimek-Andrews, S., Salomons, G.S. (2022). Disorders of Creatine Metabolism. In: Saudubray, JM., Baumgartner, M.R., García-Cazorla, Á., Walter, J. (eds) Inborn Metabolic Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-63123-2_9
Download citation
DOI: https://doi.org/10.1007/978-3-662-63123-2_9
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-63122-5
Online ISBN: 978-3-662-63123-2
eBook Packages: MedicineMedicine (R0)