Congenital disorders of creatine metabolism
- Clara Van Karnebeek, MD, PhD, FCCMG
Clara Van Karnebeek, MD, PhD, FCCMG
- Emma Children's Hospital, Academic Medical Centre
- University of Amsterdam
- Sylvia Stockler-Ipsiroglu, MD, PhD, MBA, FRCPC
Sylvia Stockler-Ipsiroglu, MD, PhD, MBA, FRCPC
- Professor of Pediatrics
- University of British Columbia
- Head Division of Biochemical Diseases
- BC Canada
Creatine is a nitrogenous organic acid that is produced primarily in the kidney and liver and is stored in tissues with high energy demands, such as skeletal muscle and the brain. Its phosphorylated form (creatine-phosphate or phosphocreatine) is involved in the formation of adenosine triphosphate (ATP), which is used as an energy source for a number of intracellular metabolic processes.
There are three identified congenital metabolic disorders that lead to creatine deficiency [1-3]. Two are autosomal recessive disorders that affect the biosynthesis of creatine. They are arginine:glycine amidinotransferase (AGAT) deficiency and guanidinoacetate methyltransferase (GAMT) deficiency (figure 1). The third disorder, X-linked creatine transporter (CT) deficiency, is caused by a defect in the transport of creatine into the brain and muscle.
The pathogenesis, clinical features, diagnosis, and management of these disorders are reviewed here. Other inborn errors of metabolism are reviewed separately. (See "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Inborn errors of metabolism: Identifying the specific disorder".)
This section briefly reviews creatine metabolism and transport. It also reviews the common clinical features and the general diagnostic and treatment approaches for these disorders. The unique clinical features and management approaches are discussed in the separate sections on each disorder.
Creatine metabolism — Creatine synthesis involves two enzymatic steps and occurs primarily in the liver, kidney, and pancreas (figure 1). The first step involves L-arginine:glycine amidinotransferase (AGAT), which catalyzes the formation of guanidinoacetate (GAA) from arginine and glycine. The second involves guanidinoacetate methyltransferase (GAMT), which catalyzes the formation of creatinine from GAA and S-adenosylmethionine. Creatine is taken up by the tissues, mainly brain and muscle, by the creatine transporter (CT). It is nonenzymatically converted to creatinine and excreted into the urine.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Mercimek-Mahmutoglu S, Stöckler-Ipsiroglu S, Salomons GS. Creatine deficiency syndromes. In: GeneReviews [Internet] Creatine deficiency syndromes, Pagron RA, Adam MP, Ardinger HH, et al (Eds), University of Washington, Seattle 2009.
- Stockler-Ipsiroglu S, van Karnebeek CD. Cerebral creatine deficiencies: a group of treatable intellectual developmental disorders. Semin Neurol 2014; 34:350.
- Stockler S, Braissant O, Schulze A. Creatine disorders. In: Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, Blau N, Duran M, Gibson KM, Dionisi-Vici C. (Eds), Springer, New York 2014. p.529.
- van Karnebeek CD, Stockler S. Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Mol Genet Metab 2012; 105:368.
- Battini R, Leuzzi V, Carducci C, et al. Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree. Mol Genet Metab 2002; 77:326.
- Stöckler-Ipsiroglu S, Battini R, de Grauw T, Schulze A. Disorders of creatine metabolism. In: Physician´s guide to the treatment and follow up of metabolic diseases, Blau N, Hoffmann GF, Leonard J, Clarke JTR (Eds), Springer Verlag, Heidelberg 2005.
- 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.
- Cognat S, Cheillan D, Piraud M, et al. Determination of guanidinoacetate and creatine in urine and plasma by liquid chromatography-tandem mass spectrometry. Clin Chem 2004; 50:1459.
- 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.
- Item CB, Stöckler-Ipsiroglu S, Stromberger C, et al. Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet 2001; 69:1127.
- 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; 49:803.
- Johnston K, Plawner L, Cooper L, et al. The second family with AGAT deficiency (creatine biosynthesis defect): diagnosis, treatment and the first prenatal diagnosis. American Society of Human Genetics 55th Annual Meeting, Abstract 205, Salt Lake City, UT 2005.
- Pasquali M, Schwarz E, Jensen M, et al. Feasibility of newborn screening for guanidinoacetate methyltransferase (GAMT) deficiency. J Inherit Metab Dis 2014; 37:231.
- van Spronsen FJ, Reijngoud DJ, Verhoeven NM, et al. High cerebral guanidinoacetate and variable creatine concentrations in argininosuccinate synthetase and lyase deficiency: implications for treatment? Mol Genet Metab 2006; 89:274.
- Nänto-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.
- Stockler-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.
- Battini R, Alessandrì MG, Leuzzi V, et al. Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: early treatment can prevent phenotypic expression of the disease. J Pediatr 2006; 148:828.
- Ndika JD, Johnston K, Barkovich JA, et al. Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency. Mol Genet Metab 2012; 106:48.
- Dunbar M, Jaggumantri S, Sargent M, et al. Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases. Mol Genet Metab 2014; 112:259.
- Edvardson S, Korman SH, Livne A, et al. l-arginine:glycine amidinotransferase (AGAT) deficiency: clinical presentation and response to treatment in two patients with a novel mutation. Mol Genet Metab 2010; 101:228.
- Nouioua S, Cheillan D, Zaouidi S, et al. Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency. Neuromuscul Disord 2013; 23:670.
- Verma A. Arginine:glycine amidinotransferase deficiency: a treatable metabolic encephalomyopathy. Neurology 2010; 75:186.
- Bianchi MC, Tosetti M, Battini R, et al. Treatment monitoring of brain creatine deficiency syndromes: a 1H- and 31P-MR spectroscopy study. AJNR Am J Neuroradiol 2007; 28:548.
- Battini R, 2014, personal communication.
- Stöckler S, Isbrandt D, Hanefeld F, et al. Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. Am J Hum Genet 1996; 58:914.
- Dhar SU, Scaglia F, Li FY, et al. Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency. Mol Genet Metab 2009; 96:38.
- Mercimek-Mahmutoglu S, Stoeckler-Ipsiroglu S, Adami A, et al. GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis. Neurology 2006; 67:480.
- Mercimek-Mahmutoglu S, Ndika J, Kanhai W, et al. Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene. Hum Mutat 2014; 35:462.
- Morris AA, Appleton RE, Power B, et al. Guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy. J Inherit Metab Dis 2007; 30:100.
- Salomons GS, van Dooren SJ, Verhoeven NM, et al. X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet 2001; 68:1497.
- 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.
- 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.
- Newmeyer A, deGrauw T, Clark J, et al. Screening of male patients with autism spectrum disorder for creatine transporter deficiency. Neuropediatrics 2007; 38:310.
- Mercimek-Mahmutoglu S, Muehl A, Salomons GS, et al. Screening for X-linked creatine transporter (SLC6A8) deficiency via simultaneous determination of urinary creatine to creatinine ratio by tandem mass-spectrometry. Mol Genet Metab 2009; 96:273.
- 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.
- Rosenberg EH, Martínez Muñoz C, Betsalel OT, et al. Functional characterization of missense variants in the creatine transporter gene (SLC6A8): improved diagnostic application. Hum Mutat 2007; 28:890.
- 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.
- 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; 35:141.
- Chilosi A, Casarano M, Comparini A, et al. Neuropsychological profile and clinical effects of arginine treatment in children with creatine transport deficiency. Orphanet J Rare Dis 2012; 7:43.
- Braissant O, Henry H, Loup M, et al. Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study. Brain Res Mol Brain Res 2001; 86:193.
- Braissant O, Béard E, Torrent C, Henry H. Dissociation of AGAT, GAMT and SLC6A8 in CNS: relevance to creatine deficiency syndromes. Neurobiol Dis 2010; 37:423.
- van de Kamp JM, Jakobs C, Gibson KM, Salomons GS. New insights into creatine transporter deficiency: the importance of recycling creatine in the brain. J Inherit Metab Dis 2013; 36:155.
- Creatine metabolism
- Clinical manifestations
- Differential diagnosis
- ARGININE:GLYCINE AMIDINOTRANSFERASE (AGAT) DEFICIENCY
- Clinical features
- GUANIDINOACETATE METHYLTRANSFERASE (GAMT) DEFICIENCY
- Clinical features
- CREATINE TRANSPORTER (CT) DEFICIENCY
- Clinical manifestations