X-linked Creatine Transporter Deficiency: Clinical Aspects and Pathophysiology

Overview

Journal J Inherit Metab Dis

Publisher Wiley

Date 2014 May 3

PMID 24789340

Citations 41

Authors

Jiddeke M van de Kamp

Grazia M Mancini

Gajja S Salomons

Affiliations

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Abstract

Creatine transporter deficiency was discovered in 2001 as an X-linked cause of intellectual disability characterized by cerebral creatine deficiency. This review describes the current knowledge regarding creatine metabolism, the creatine transporter and the clinical aspects of creatine transporter deficiency. The condition mainly affects the brain while other creatine requiring organs, such as the muscles, are relatively spared. Recent studies have provided strong evidence that creatine synthesis also occurs in the brain, leading to the intriguing question of why cerebral creatine is deficient in creatine transporter deficiency. The possible mechanisms explaining the cerebral creatine deficiency are discussed. The creatine transporter knockout mouse provides a good model to study the disease. Over the past years several treatment options have been explored but no treatment has been proven effective. Understanding the pathogenesis of creatine transporter deficiency is of paramount importance in the development of an effective treatment.

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References

Allen P . Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value?. Neurosci Biobehav Rev. 2012; 36(5):1442-62. PMC: 3340488. DOI: 10.1016/j.neubiorev.2012.03.005. View

van der Knaap M, Verhoeven N, Pouwels P, Onkenhout W, Peeters E, Stockler-Ipsiroglu S . Mental retardation and behavioral problems as presenting signs of a creatine synthesis defect. Ann Neurol. 2000; 47(4):540-3. DOI: 10.1002/1531-8249(200004)47:4<540::aid-ana23>3.3.co;2-b. View

Braissant O, Cagnon L, Monnet-Tschudi F, Speer O, Wallimann T, Honegger P . Ammonium alters creatine transport and synthesis in a 3D culture of developing brain cells, resulting in secondary cerebral creatine deficiency. Eur J Neurosci. 2008; 27(7):1673-85. DOI: 10.1111/j.1460-9568.2008.06126.x. View

Betsalel O, Pop A, Rosenberg E, Fernandez-Ojeda M, Jakobs C, Salomons G . Detection of variants in SLC6A8 and functional analysis of unclassified missense variants. Mol Genet Metab. 2012; 105(4):596-601. DOI: 10.1016/j.ymgme.2011.12.022. View

Sijens P, Verbruggen K, Oudkerk M, van Spronsen F, Soorani-Lunsing R . 1H MR spectroscopy of the brain in Cr transporter defect. Mol Genet Metab. 2005; 86(3):421-2. DOI: 10.1016/j.ymgme.2005.08.004. View

Newmeyer A, Cecil K, Schapiro M, Clark J, DeGrauw T . Incidence of brain creatine transporter deficiency in males with developmental delay referred for brain magnetic resonance imaging. J Dev Behav Pediatr. 2005; 26(4):276-82. DOI: 10.1097/00004703-200508000-00003. View

Moller A, Hamprecht B . Creatine transport in cultured cells of rat and mouse brain. J Neurochem. 1989; 52(2):544-50. DOI: 10.1111/j.1471-4159.1989.tb09154.x. View

Hathaway S, Friez M, Limbo K, Parker C, Salomons G, Vockley J . X-linked creatine transporter deficiency presenting as a mitochondrial disorder. J Child Neurol. 2010; 25(8):1009-12. DOI: 10.1177/0883073809352109. View

Carducci C, Carducci C, Santagata S, Adriano E, Artiola C, Thellung S . In vitro study of uptake and synthesis of creatine and its precursors by cerebellar granule cells and astrocytes suggests some hypotheses on the physiopathology of the inherited disorders of creatine metabolism. BMC Neurosci. 2012; 13:41. PMC: 3355046. DOI: 10.1186/1471-2202-13-41. View

10.

Snow R, Murphy R . Creatine and the creatine transporter: a review. Mol Cell Biochem. 2001; 224(1-2):169-81. DOI: 10.1023/a:1011908606819. View

11.

Garcia-Miranda P, Garcia-Delgado M, Peral M, Calonge M, Ilundain A . Ontogeny regulates creatine metabolism in rat small and large intestine. J Physiol Pharmacol. 2009; 60(3):127-33. View

12.

Taegtmeyer H, Ingwall J . Creatine--a dispensable metabolite?. Circ Res. 2013; 112(6):878-80. PMC: 3646410. DOI: 10.1161/CIRCRESAHA.113.300974. View

13.

Marescau B, Deshmukh D, Kockx M, Possemiers I, Qureshi I, WIECHERT P . Guanidino compounds in serum, urine, liver, kidney, and brain of man and some ureotelic animals. Metabolism. 1992; 41(5):526-32. DOI: 10.1016/0026-0495(92)90213-t. View

14.

Harris R, Soderlund K, Hultman E . Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond). 1992; 83(3):367-74. DOI: 10.1042/cs0830367. View

15.

Mancardi M, Caruso U, Schiaffino M, Baglietto M, Rossi A, Battaglia F . Severe epilepsy in X-linked creatine transporter defect (CRTR-D). Epilepsia. 2007; 48(6):1211-3. DOI: 10.1111/j.1528-1167.2007.01148.x. View

16.

Renema W, Schmidt A, van Asten J, Oerlemans F, Ullrich K, Wieringa B . MR spectroscopy of muscle and brain in guanidinoacetate methyltransferase (GAMT)-deficient mice: validation of an animal model to study creatine deficiency. Magn Reson Med. 2003; 50(5):936-43. DOI: 10.1002/mrm.10627. View

17.

Zuercher J, Neidhardt J, Magyar I, Labs S, Moore A, Tanner F . Alterations of the 5'untranslated region of SLC16A12 lead to age-related cataract. Invest Ophthalmol Vis Sci. 2010; 51(7):3354-61. PMC: 2904002. DOI: 10.1167/iovs.10-5193. View

18.

Bothwell J, Styles P, Bhakoo K . Swelling-activated taurine and creatine effluxes from rat cortical astrocytes are pharmacologically distinct. J Membr Biol. 2002; 185(2):157-64. DOI: 10.1007/s00232-001-0121-2. View

19.

Cecil K, Salomons G, Ball Jr W, Wong B, Chuck G, Verhoeven N . Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect?. Ann Neurol. 2001; 49(3):401-4. DOI: 10.1002/ana.79. View

20.

Valayannopoulos V, Bakouh N, Mazzuca M, Nonnenmacher L, Hubert L, Makaci F . Functional and electrophysiological characterization of four non-truncating mutations responsible for creatine transporter (SLC6A8) deficiency syndrome. J Inherit Metab Dis. 2012; 36(1):103-12. DOI: 10.1007/s10545-012-9495-9. View