Summary
Reduced creatine levels in the brain and in body fluids/tissues are the common denominator of primary creatine disorders (cerebral creatine deficiency syndromes types 1–3: X-linked creatine transporter (CrT/SLC6A8) deficiency, GAMT/GAMT deficiency, AGAT/GATM deficiency). Characteristic clinical features include developmental delay/intellectual disability; speech impairment and behavioral problems, combined with epilepsy; and movement disorders. Arginine:glycine amidinotransferase aggregation syndrome is a newly described genetic cause of renal Fanconi syndrome and kidney failure caused by aggregation of certain fully penetrant heterozygous GATM missense variants. OAT/OAT deficiency is a secondary creatine deficiency syndrome leading to chorioretinal degeneration. Diagnostic markers, besides brain creatine deficiency, include high or low levels of guanidinoacetate for GAMT and AGAT deficiency, a high urinary creatine excretion for CrT deficiency, and high plasma ornithine levels for OAT deficiency. Treatments comprise substitution of creatine (AGAT deficiency) combined with l-ornithine (GAMT deficiency) and arginine restricted diet (GAMT and OAT deficiency). Creatine and substrates for intracerebral creatine synthesis (l-arginine and l-glycine) have limited therapeutic effects in CrT deficiency. Improved outcomes after early recognition have prompted the implementation of GAMT newborn screening in various juridictions.
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
Almeida LS, Verhoeven NM, Roos B, et al. Creatine and guanidinoacetate: diagnostic markers for inborn errors in creatine biosynthesis and transport. Mol Genet Metab. 2004;82:214–9.
Berends LM, Struys EA, Roos B, et al. Guanidinoacetate methyltransferase activity in lymphocytes, for a fast diagnosis. JIMD Rep. 2017;37:13–7.
Bruun TUJ, Sidky S, Bandeira AO, et al. Treatment outcome of creatine transporter deficiency: international retrospective cohort study. Metab Brain Dis. 2018;33(3):875–84.
Cheillan D, Salomons GS, Acquaviva C, et al. Prenatal diagnosis of guanidinoacetate methyltransferase deficiency: increased guanidinoacetate concentrations in amniotic fluid. Clin Chem. 2006;52:775–7.
Desroches CL, Patel J, Wang P, et al. Carrier frequency of guanidinoacetate methyltransferase deficiency in the general population by functional characterization of missense variants in the GAMT gene. Mol Genet Genomics. 2015;290(6):2163–71.
Dewey KG, Beaton G, Fjeld C, Lönnerdal B, Reeds P. Protein requirements of infants and children. Eur J Clin Nut. 1996;50(Suppl 1):S119–47.
Dunbar M, Jaggumantri S, Sargent M, Stöckler-Ipsiroglu S, van Karnebeek CD. Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases. Mol Genet Metab. 2014;112:259–74.
Elpeleg N, Korman SH. Sustained oral lysine supplementation in ornithine delta-aminotransferase deficiency. J Inherit Metab Dis. 2001;24:423–4.
Hanna-El-Daher L, Braissant O. Creatine synthesis and exchanges between brain cells: what can be learned from human creatine deficiencies and various experimental models? Amino Acids. 2016;48:1877–95.
Hayasaka S, Saito T, Nakajima H, et al. Clinical trials of vitamin B6 and proline supplementation for gyrate atrophy of the choroid and retina. Br J Ophthalmol. 1985;69:283–90.
Heinänen K, Näntö-Salonen K, Komu M, et al. Creatine corrects muscle 31P spectrum in gyrate atrophy with hyperornithinaemia. Eur J Clin Invest. 1999;29:1060–5.
Jaggumantri S, Dunbar M, Edgar V, et al. Treatment of creatine transporter (SLC6A8) deficiency with oral s-adenosyl methionine as adjunct to l-arginine, glycine, and creatine supplements. Pediatr Neurol. 2015;53(4):360–3e2.
Joncquel M, Briand G, Valayannopoulos V, et al. Determination of new reference values for GAA and creatine from a large cohort of controls subjects and description of the French patients affected of creatine deficiency disorders (CDS). J Inherit Metab Dis. 2011;34(Suppl 3):S128.
Joncquel-Chevalier Curt M, Bout MA, Fontaine M, et al. Functional assessment of creatine transporter in control and X-linked SLC6A8-deficient fibroblasts. Mol Genet Metab. 2018;123(4):463–71.
Khaikin Y, Sidky S, Abdenur J, et al. Treatment outcome of twenty-two patients with guanidinoacetate methyltransferase deficiency: an international retrospective cohort study. Eur J Paediatr Neurol. 2018;22(3):369–79.
Mercimek-Mahmutoglu S, Salomons GS. Creatine deficiency syndromes. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle: University of Washington, Seattle; 1993-2019; 2009. [Updated 2015 Dec 10].
Mercimek-Mahmutoglu S, Connolly MB, Poskitt KJ, et al. Treatment of intractable epilepsy in a female with SLC6A8 deficiency. Mol Genet Metab. 2010;101:409–12.
Mercimek-Mahmutoglu S, Salomons GS, Chan A. Case Study for the evaluation of current treatment recommendations of guanidinoacetate methyltransferase deficiency: ineffectiveness of sodium benzoate. Pediatr Neurol. 2014;51:133–7.
Näntö-Salonen K, Komu M, Lundbom N, et al. Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology. 1999;53:303–7.
Pasquali M, Schwarz E, Jensen M, et al. Feasibility of newborn screening for guanidinoacetate methyltransferase (GAMT) deficiency. J Inherit Metab Dis. 2014;37(2):231–6.
Peltola K, Heinonen OJ, Näntö-Salonen K, Pulkki K, Simell O. Oral lysine feeding in gyrate atrophy with hyperornithinaemia—a pilot study. J Inherit Metab Dis. 2000;23:305–57.
Reichold M, Klootwijk ED, Reinders J, et al. Glycine amidinotransferase (GATM), renal Fanconi syndrome, and kidney failure. J Am Soc Nephrol. 2018;29(7):1849–58.
Rosenberg EH, Almeida LS, Kleefstra T, et al. High prevalence of SLC6A8 deficiency in X-linked mental retardation. Am J Hum Genet. 2004;75:97–105.
Schjelderup J, Hope S, Vatshelle C, van Karnebeek CDM. Treatment experience in two adults with creatinfe transporter deficiency. Mol Genet Metab Rep. 2021;27:100731.
Schulze A, Ebinger F, Rating D, Mayatepek E. Improving treatment of guanidinoacetate methyltransferase deficiency: reduction of guanidinoacetic acid in body fluids by arginine restriction and ornithine supplementation. Mol Genet Metab. 2001;74:413–9.
Sharer JD, Bodamer O, Longo N, et al. Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics. Genet Med. 2017;19(2):256–63.
Shih VE. Amino acid analysis. In: Blau N, Duran M, Blaskovics ME, Gibson KM, editors. Physician’s guide to the laboratory diagnosis of metabolic diseases. Berlin, Heidelberg, New York: Springer; 2003. p. 11–26.
Sinclair GB, van Karnebeek CD, Ester M, et al. A three-tier algorithm for guanidinoacetate methyltransferase (GAMT) deficiency newborn screening. Mol Genet Metab. 2016;118(3):173–7.
Stöckler-Ipsiroglu S, van Karnebeek CD. Cerebral creatine deficiencies: a group of treatable intellectual developmental disorders. Semin Neurol. 2014;35(3):350–6.
Stöckler-Ipsiroglu S, van Karnebeek C, Longo N, et al. Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Mol Genet Metab. 2014;111:16–25.
Stöckler-Ipsiroglu S, Apatean D, Battini R, et al. Arginine:Glycine Amidinotransferase (AGAT) deficiency: clinical features and long term outcomes in 16 patients diagnosed worldwide. Mol Genet Metab. 2015;116(4):252–9.
Struys EA, Verhoeven-Duif N, Jakobs C. Creatine and its metabolites. In: Blau N, Duran M, Gibson MK, editors. Laboratory guide to the methods in biochemical genetics. Berlin, Heidelberg: Springer; 2008. p. 739–49.
Valayannopoulos V, Boddaert N, Chabli A, et al. Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect. J Inherit Metab Dis. 2012;35:151–7.
Valle D, Simell O. The hyperornithinemias. In: Scriver CR, Beaudet A, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. New York: McGraw Hill; 1995. p. 1147–85.
Valle D, Walser M, Brusilow S, Kaiser-Kupfer MI, Takki K. Gyrate atrophy of the choroid and retina: biochemical considerations and experience with an arginine-restricted diet. Ophthalmology. 1981;88:325–30.
van de Kamp JM, Mancini GM, Pouwels PJ, et al. Clinical features and X-inactivation in females heterozygous for creatine transporter defect. Clin Genet. 2011;79:264–72.
van de Kamp JM, Pouwels PJ, Aarsen FK, et al. Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect. J Inherit Metab Dis. 2012;35(1):141–9.
van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, et al. Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet. 2013;50:463–72.
Verhoeven NM, Schor DS, Roos B, et al. Diagnostic enzyme assay that uses stable-isotope-labeled substrates to detect L-arginine:glycine amidinotransferase deficiency. Clin Chem. 2003;49(5):803–5.
Viau KS, Ernst SL, Pasquali M, et al. Evidence-based treatment of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab. 2013;110(3):255–62.
Weleber RG, Kennaway NG. Clinical trial of vitamin B6 for gyrate atrophy of the choroid and retina. Ophthalmology. 1981;88:316–24.
Young S, Struys E, Wood T (2007) Quantification of creatine and guanidinoacetate using GC-MS and LC-MS/MS for the detection of cerebral creatine deficiency syndromes. Curr Protoc Hum Genet 17.3.1–17.3.18
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Stöckler-Ipsiroglu, S., Braissant, O., Schulze, A. (2022). Disorders of Creatine Metabolism. In: Blau, N., Dionisi Vici, C., Ferreira, C.R., Vianey-Saban, C., van Karnebeek, C.D.M. (eds) Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Springer, Cham. https://doi.org/10.1007/978-3-030-67727-5_15
Download citation
DOI: https://doi.org/10.1007/978-3-030-67727-5_15
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-67726-8
Online ISBN: 978-3-030-67727-5
eBook Packages: MedicineMedicine (R0)