H. Civils-de-lyon, Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal

. Département-de-biochimie-et-biologie-moléculaire, The Netherlands. 5 Centre de Référence des Maladies Héréditaires du Métabolisme

L. Bicêtre, ». Kremlin-bicêtre-cedex, . Cricm, G. Umr-s975, and . Hospitalier-pitié-salpêtrière, AP-HM Hôpital de la Timone, Marseille Cedex 5 13385, France. 18 Service de Génétique, CHU de Saint- Étienne Hôpital Nord, Saint-Etienne Cédex 2 42055, France, 14 Service de Neuropédiatrie. 16 Neuropédiatrie, CHRU Montpellier, & Inserm U1046, Université Montpellier 1 & 2, Montpellier Cedex 5 34295, France. 17 Service Neuropédiatrie Service de génétique Centre hospitalier Felix Guyon (Saint-Denis) Bellepierre, Saint-Denis cedex 97405, France. 20 Service de Neuropédiatrie, Hôpital de l'Archet

E. Chevreul, Sur la composition chimique du bouillon de viandes (On the chemical composition of meatbroth), J Pharm Sci Access, vol.1835, issue.21, pp.231-242

P. Balsom, K. Söderland, and B. Ekbolm, Creatine in Humans with Special Reference to Creatine Supplementation, Sports Medicine, vol.18, issue.4, pp.268-280, 1994.
DOI : 10.2165/00007256-199418040-00005

M. Wyss and R. Kaddurah-daouk, Creatine and creatinine metabolism, Physiol Rev, vol.80, issue.3, pp.1107-1213, 2000.

M. Wyss and A. Schulze, Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease?, Neuroscience, vol.112, issue.2, pp.243-260, 2002.
DOI : 10.1016/S0306-4522(02)00088-X

E. Lundsgaard, Untersuchungen über Muskel kontraktion en ohne Milchsäure bildung (Muscle contraction without formation of lactic acid

E. Lundsgaard, Weitere Untersuchungen fiber Muskel kontraktion en ohne Milchsäure bildung. (Further investigation on muscle contraction without lactate formation), Biochem Z, vol.227, pp.51-83, 1930.

K. Lohman, Über die enzymatische aufspaltung der kreatin phosphorsaure; zugleich ein beitrag zum chemismus der muskel kontraktion. (On the enzymic cleavage of creatinephosphate; also a contribution to the chemistry of the muscle contraction), Biochem Z, vol.271, pp.264-277, 1934.

W. Engelhardt and M. Lyubimova, Myosine and Adenosinetriphosphatase, Nature, vol.144, issue.3650, pp.668-669, 1939.
DOI : 10.1038/144668b0

R. Andres, A. Ducray, U. Schlattner, T. Wallimannb, and H. Widmer, Functions and effects of creatine in the central nervous system, Brain Research Bulletin, vol.76, issue.4, pp.329-343, 2008.
DOI : 10.1016/j.brainresbull.2008.02.035

URL : https://hal.archives-ouvertes.fr/inserm-00390933

O. Braissant and H. Henry, AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: A review, Journal of Inherited Metabolic Disease, vol.21, issue.Supplement 1, pp.31230-239, 2008.
DOI : 10.1007/s10545-008-0826-9

O. Braissant, E. Béard, C. Torrent, and H. Henry, Dissociation of AGAT, GAMT and SLC6A8 in CNS: Relevance to creatine deficiency syndromes, Neurobiology of Disease, vol.37, issue.2, pp.423-433, 2010.
DOI : 10.1016/j.nbd.2009.10.022

E. Béard and O. Braissant, Synthesis and transport of creatine in the CNS: importance for cerebral functions, Journal of Neurochemistry, vol.21, issue.Suppl 1, pp.297-313, 2010.
DOI : 10.1111/j.1471-4159.2010.06935.x

O. Braissant, H. Henry, M. Loup, B. Eilers, and C. Bachmann, Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study, Molecular Brain Research, vol.86, issue.1-2, pp.193-201, 2001.
DOI : 10.1016/S0169-328X(00)00269-2

O. Braissant, Creatine and guanidinoacetate transport at blood-brain and blood-cerebrospinal fluid barriers, Journal of Inherited Metabolic Disease, vol.20, issue.Suppl, pp.655-664
DOI : 10.1007/s10545-011-9433-2

A. Schulze and R. Battini, Pre-Symptomatic Treatment of Creatine Biosynthesis Defects, Subcell Biochem, vol.46, pp.167-181, 2007.
DOI : 10.1007/978-1-4020-6486-9_9

F. Nasrallah, M. Feki, and N. Kaabachi, Creatine and Creatine Deficiency Syndromes: Biochemical and Clinical Aspects, Pediatric Neurology, vol.42, issue.3, pp.163-171, 2010.
DOI : 10.1016/j.pediatrneurol.2009.07.015

A. Schulze, Creatine deficiency syndromes, Molecular and Cellular Biochemistry, vol.244, issue.1/2, pp.143-150, 2003.
DOI : 10.1023/A:1022443503883

S. Stockler, P. Schutz, and G. Salomons, Cerebral Creatine Deficiency Syndromes: Clinical Aspects, Treatment and Pathophysiology, Subcell Biochem, vol.46, pp.149-166, 2007.
DOI : 10.1007/978-1-4020-6486-9_8

C. Stromberger, O. Bodamer, and S. Stöckler-ipsiroglu, Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism, J Inherit Metab Dis, vol.26, pp.2-3299, 2003.

J. Sykut-cegielska, W. Gradowska, S. Mercimek-mahmutoglu, and S. Stöckler-ipsiroglu, Biochemical and clinical characteristics of creatine deficiency syndromes, Acta Biochim Pol, vol.51, issue.4, pp.875-882, 2004.

R. Battini, M. Alessandrì, V. Leuzzi, F. Moro, M. Tosetti et al., Arginine: glycine amidinotransferase (AGAT) deficiency in a newborn: early treatment can prevent phenotypic expression of the disease

C. Carducci, M. Birarelli, V. Leuzzi, C. Carducci, R. Battini et al., Antonozzi I: Guanidinoacetate and creatine plus creatinine assessment in physiologic fluids: an effective diagnostic tool for the biochemical diagnosis of arginine:glycine amidinotransferase and guanidinoacetate methyltransferase deficiencies, Clin Chem, issue.10, pp.481772-1778, 2002.

C. Item, S. Stöckler-ipsiroglu, C. Stromberger, A. Mühl, M. Alessandrì et al., Arginine:Glycine Amidinotransferase Deficiency: The Third Inborn Error of Creatine Metabolism in Humans, The American Journal of Human Genetics, vol.69, issue.5, pp.691127-1133, 2001.
DOI : 10.1086/323765

S. Mercimek-mahmutoglu, S. Stöckler-ipsiroglu, T. Bird, C. Dolan, and K. Stephens, Creatine deficiency syndromes.I nGeneReviews, 1993.

Q. Sun, O. Brien, and W. , Diagnosis of Creatine Metabolism Disorders by Determining Creatine and Guanidinoacetate in Plasma and Urine, Methods Mol Biol, vol.603, pp.175-185, 2010.
DOI : 10.1007/978-1-60761-459-3_17

O. Bodamer, S. Bloesch, A. Gregg, S. Stockler-ipsiroglu, O. Brien et al., Analysis of guanidinoacetate and creatine by isotope dilution electrospray tandem mass spectrometry, Clinica Chimica Acta, vol.308, issue.1-2, pp.173-178, 2001.
DOI : 10.1016/S0009-8981(01)00480-6

S. Dhar, F. Scaglia, F. Li, L. Smith, B. Barshop et al., Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency, Molecular Genetics and Metabolism, vol.96, issue.1, pp.38-43, 2009.
DOI : 10.1016/j.ymgme.2008.10.008

P. Alcaide, B. Merinero, P. Ruiz-sala, E. Richard, R. Navarrete et al., Defining the pathogenicity of creatine deficiency syndrome, Human Mutation, vol.33, issue.Pt 9, pp.282-291, 2011.
DOI : 10.1002/humu.21421

URL : https://hal.archives-ouvertes.fr/hal-00613911

L. Almeida, N. Verhoeven, B. Roos, C. Valongo, M. Cardoso et al., Creatine and guanidinoacetate: diagnostic markers for inborn errors in creatine biosynthesis and transport, Molecular Genetics and Metabolism, vol.82, issue.3
DOI : 10.1016/j.ymgme.2004.05.001

A. Bizzi, M. Bugiani, G. Salomons, D. Hunneman, I. Moroni et al., X-linked creatine deficiency syndrome: A novel mutation in creatine transporter geneSLC6A8, Annals of Neurology, vol.49, issue.2, pp.227-231, 2002.
DOI : 10.1002/ana.10246

S. Mercimek-mahmutoglu, A. Muehl, G. Salomons, B. Neophytou, D. Moeslinger et al., Screening for X-linked creatine transporter (SLC6A8) deficiency via simultaneous determination of urinary creatine to creatinine ratio by tandem mass-spectrometry, Molecular Genetics and Metabolism, vol.96, issue.4, pp.273-275, 2009.
DOI : 10.1016/j.ymgme.2008.12.020

G. Salomons, S. Van-dooren, N. Verhoeven, K. Cecil, W. Ball et al., Jakobs C: X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome, Am J Hum Genet, issue.6, pp.681497-1500, 2001.

A. Sempere, C. Fons, A. Arias, P. Rodríguez-pombo, R. Colomer et al., Creatine transporter deficiency in two adult patients with static encephalopathy, Journal of Inherited Metabolic Disease, vol.26, issue.S1, pp.10545-10554, 2009.
DOI : 10.1007/s10545-009-1083-2

A. Arias, M. Corbella, C. Fons, A. Sempere, J. García-villoria et al., Creatine transporter deficiency: Prevalence among patients with mental retardation and pitfalls in metabolite screening, Clinical Biochemistry, vol.40, issue.16-17, pp.4016-171328, 2007.
DOI : 10.1016/j.clinbiochem.2007.07.010

S. Cognat, D. Cheillan, M. Piraud, B. Roos, and C. Jakobs, Vianey-Saban C: Determination of guanidinoacetate and creatine in urine and plasma by liquid chromatography-tandem mass spectrometry, Clin Chem, issue.8, pp.501459-1461, 2004.

M. Jaffe, Uber den niederschlag, welchen pikrinsaure in normalen ham erzeugt und ubereineneue reaction des kreatinins, Z Physiol Chem, vol.1886, issue.10, pp.391-400

D. Tsikas, A. Wolf, A. Mitschke, F. Gutzki, W. Will et al., GC???MS determination of creatinine in human biological fluids as pentafluorobenzyl derivative in clinical studies and biomonitoring: Inter-laboratory comparison in urine with Jaff??, HPLC and enzymatic assays, Journal of Chromatography B, vol.878, issue.27, pp.2582-2592, 2010.
DOI : 10.1016/j.jchromb.2010.04.025

N. Verhoeven, G. Salomons, and C. Jakobs, Laboratory diagnosis of defects of creatine biosynthesis and transport, Clinica Chimica Acta, vol.361, issue.1-2, pp.1-9, 2005.
DOI : 10.1016/j.cccn.2005.04.022

N. Verhoeven, B. Roos, E. Struys, G. Salomons, M. Van-der-knaap et al., Enzyme Assay for Diagnosis of Guanidinoacetate Methyltransferase Deficiency, Clinical Chemistry, vol.50, issue.2, pp.441-443, 2004.
DOI : 10.1373/clinchem.2003.022764

I. Fokkema, P. Taschner, G. Schaafsma, J. Celli, and J. Laros, LOVD v.2.0: the next generation in gene variant databases, Human Mutation, vol.29, issue.5, pp.557-563, 2011.
DOI : 10.1002/humu.21438

A. Lung and C. Kao, Evaluation and management of the child with speech delay, Am Fam Physician, vol.59, issue.11, pp.3121-3128, 1999.

L. Wankoff, Warning Signs in the Development of Speech, Language, and Communication: When to Refer to a Speech-Language Pathologist, Journal of Child and Adolescent Psychiatric Nursing, vol.34, issue.3, pp.175-184, 2011.
DOI : 10.1111/j.1744-6171.2011.00292.x

M. Bianchi, M. Tosetti, R. Battini, V. Leuzzi, M. Alessandri et al., Treatment monitoring of brain creatine deficiency syndromes: a 1H-and 31P-MR spectroscopy study, Am J Neuroradiol, vol.28, issue.3, pp.548-554, 2007.

R. Ensenauer, T. Thiel, K. Schwab, U. Tacke, and S. Stöckler, Guanidinoacetate methyltransferase deficiency: differences of creatine uptake in human brain and muscle, Molecular Genetics and Metabolism, vol.82, issue.3, pp.208-213, 2004.
DOI : 10.1016/j.ymgme.2004.04.005

A. Schulze, G. Hoffmann, P. Bachert, S. Kirsch, G. Salomons et al., Presymptomatic treatment of neonatal guanidinoacetate methyltransferase deficiency, Neurology, vol.67, issue.4, pp.719-721, 2006.
DOI : 10.1212/01.wnl.0000230152.25203.01

E. Blanc, Approche thérapeutique d'une maladie génétique rare le déficit de synthèse en créatine par déficit en guanidinoacétate méthyltransferase, 2009.

V. Valayannopoulos, N. Boddaert, A. Chabli, V. Barbier, I. Desguerre et al., Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect, Journal of Inherited Metabolic Disease, vol.79, issue.3, pp.151-157
DOI : 10.1007/s10545-011-9358-9

O. Braissant, H. Henry, E. Béard, and J. Uldry, Creatine deficiency syndromes and the importance of creatine synthesis in the brain, Amino Acids, vol.21, issue.Pt 1, pp.1315-1324, 2011.
DOI : 10.1007/s00726-011-0852-z

A. Evangeliou, K. Vasilaki, P. Karagianni, and N. Nikolaidis, Clinical Applications of Creatine Supplementation on Paediatrics, Current Pharmaceutical Biotechnology, vol.10, issue.7, pp.683-690, 2009.
DOI : 10.2174/138920109789542075

C. Fons, A. Sempere, A. Arias, A. López-sala, P. Póo et al., Arginine supplementation in four patients with X-linked creatine transporter defect, Journal of Inherited Metabolic Disease, vol.80, issue.3, pp.31724-728, 2008.
DOI : 10.1007/s10545-008-0902-1

G. Salomons, S. Van-dooren, N. Verhoeven, D. Marsden, C. Schwartz et al., Jakobs C: X-linked creatine transporter defect: an overview, J Inherit Metab Dis, vol.26, pp.2-3309, 2003.

S. Mercimek-mahmutoglu, M. Connolly, K. Poskitt, G. Horvath, N. Lowry et al., Treatment of intractable epilepsy in a female with SLC6A8 deficiency, Molecular Genetics and Metabolism, vol.101, issue.4, pp.409-412, 2010.
DOI : 10.1016/j.ymgme.2010.08.016

A. Chilosi, V. Leuzzi, R. Battini, M. Tosetti, G. Ferretti et al., -Arginine improves neuropsychological disorders in a child with Creatine transporter defect, Neurocase, vol.336, issue.2, pp.151-161, 2008.
DOI : 10.1002/1531-8249(200004)47:4<540::AID-ANA23>3.0.CO;2-K

URL : https://hal.archives-ouvertes.fr/hal-00552327

A. Chilosi, M. Casarano, A. Comparini, F. Battaglia, M. Mancardi et al., Neuropsychological profile and clinical effects of arginine treatment in children with creatine transport deficiency, Orphanet Journal of Rare Diseases, vol.7, issue.1, p.43
DOI : 10.1146/annurev.pharmtox.41.1.79

A. Clark, E. Rosenberg, L. Almeida, T. Wood, C. Jakobs et al., X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology, Human Genetics, vol.26, issue.6, pp.604-610, 2006.
DOI : 10.1007/s00439-006-0162-9

L. Lion-françois, D. Cheillan, G. Pitelet, C. Acquaviva-bourdain, G. Bussy et al., High frequency of creatine deficiency syndromes in patients with unexplained mental retardation, Neurology, vol.67, issue.9, pp.1713-1714, 2006.
DOI : 10.1212/01.wnl.0000239153.39710.81

A. Newmeyer, K. Cecil, M. Schapiro, J. Clark, and T. Degrauw, Incidence of Brain Creatine Transporter Deficiency in Males with Developmental Delay Referred for Brain Magnetic Resonance Imaging, Journal of Developmental & Behavioral Pediatrics, vol.26, issue.4, pp.276-282, 2005.
DOI : 10.1097/00004703-200508000-00003

E. Rosenberg, L. Almeida, T. Kleefstra, D. Grauw, R. Yntema et al., High Prevalence of SLC6A8 Deficiency in X-Linked Mental Retardation, The American Journal of Human Genetics, vol.75, issue.1, pp.97-105, 2004.
DOI : 10.1086/422102

J. Mandel, Comparative Frequency of Fragile-X (FMR1) and Creatine Transporter (SLC6A8) Mutations in X-Linked Mental Retardation, The American Journal of Human Genetics, vol.75, issue.4, pp.730-731, 2004.
DOI : 10.1086/424821

O. Betsalel, E. Rosenberg, L. Almeida, T. Kleefstra, C. Schwartz et al., Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database, European Journal of Human Genetics, vol.132, issue.1, pp.56-63, 2011.
DOI : 10.1007/s10545-008-0843-8

J. Van-de-kamp, G. Mancini, P. Pouwels, O. Betsalel, S. Van-dooren et al., Clinical features and X-inactivation in females heterozygous for creatine transporter defect, Clinical Genetics, vol.3, issue.451, pp.79264-272, 2011.
DOI : 10.1111/j.1399-0004.2010.01460.x

C. Araújo, H. Smit, W. Verhoeven, N. Salomons, G. Silva et al., Guanidinoacetate methyltransferase deficiency identified in adults and a child with mental retardation, American Journal of Medical Genetics Part A, vol.112, issue.Suppl 1, pp.133-122, 2005.
DOI : 10.1002/ajmg.a.30226

D. Grauw, T. Salomons, G. Cecil, K. Chuck, G. Newmeyer et al., Congenital creatine transporter deficiency, Neuropediatrics, vol.33, issue.5, pp.232-238, 2002.

C. Fons, A. Sempere, F. Sanmartí, A. Arias, P. Póo et al., Epilepsy spectrum in cerebral creatine transporter deficiency, Epilepsia, vol.244, issue.9, pp.502168-2170, 2009.
DOI : 10.1111/j.1528-1167.2009.02142.x

I. Sipilä, Inhibition of arginine-glycine amidinotransferase by ornithine. A possible mechanism for the muscular and chorioretinal atrophies in gyrate atrophy of the choroid and retina with hyperornithinemia, Biochimica et Biophysica Acta (BBA) - Enzymology, vol.613, issue.1, pp.79-84, 1980.
DOI : 10.1016/0005-2744(80)90194-1

P. Lonlay, Secondary creatine deficiency in ornithine deltaaminotransferase deficiency, Mol Genet Metab, vol.97, issue.2, pp.109-113, 2009.

A. Arias, J. Garcia-villoria, and A. Ribes, Guanidinoacetate and creatine/creatinine levels in controls and patients with urea cycle defects, Molecular Genetics and Metabolism, vol.82, issue.3, pp.220-223, 2004.
DOI : 10.1016/j.ymgme.2004.04.009

O. Braissant, Ammonia toxicity to the brain: Effects on creatine metabolism and transport and protective roles of creatine, Molecular Genetics and Metabolism, vol.100, pp.53-58, 2010.
DOI : 10.1016/j.ymgme.2010.02.011

J. Brosnan and M. Brosnan, Creatine metabolism and the urea cycle, Molecular Genetics and Metabolism, vol.100, issue.1, pp.49-52, 2010.
DOI : 10.1016/j.ymgme.2010.02.020

E. Roze, C. Azuar, C. Menuel, J. Haberle, and R. Guillevin, Usefulness of Magnetic Resonance Spectroscopy in Urea Cycle Disorders, Pediatric Neurology, vol.37, issue.3, pp.222-225, 2007.
DOI : 10.1016/j.pediatrneurol.2007.05.003

I. Baric, K. Fumic, B. Glenn, M. Cuk, A. Schulze et al., S-adenosylhomocysteine hydrolase deficiency in a human: A genetic disorder of methionine metabolism, Proceedings of the National Academy of Sciences, vol.101, issue.12, pp.4234-4239, 2004.
DOI : 10.1073/pnas.0400658101

O. Bodamer, T. Sahoo, A. Beaudet, O. Brien, W. Bottiglieri et al., Creatine metabolism in combined methylmalonic aciduria and homocystinuria, Annals of Neurology, vol.269, issue.4, pp.557-560, 2005.
DOI : 10.1002/ana.20419

E. Jansen, N. Verhoeven, C. Jakobs, A. Schulze, H. Senephansiri et al., Increased guanidino species in murine and human succinate semialdehyde dehydrogenase (SSADH) deficiency, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol.1762, issue.4, pp.1762494-498, 2006.
DOI : 10.1016/j.bbadis.2006.01.006

J. Vamecq, J. Curt, M. Mention-mulliez, K. Dobbelaere, D. Briand et al., Rise in brain GABA to further stress the metabolic link between valproate and creatine, Molecular Genetics and Metabolism, vol.102, issue.2, pp.232-234, 2011.
DOI : 10.1016/j.ymgme.2010.10.006