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SLC6A8 deficiency

Marie Joncquel-Chevalier Curt, Marie-Adélaïde Bout, Monique Fontaine, Isabelle Kim, Guillemette Huet, Soumeya Bekri, Gilles Morin, Stéphanie Moortgat, Alexandre Moerman, Jean-Marie Cuisset, David Cheillan, Joseph Vamecq
Creatine transporter is currently the focus of renewed interest with emerging roles in brain neurotransmission and physiology, and the bioenergetics of cancer metastases. We here report on amendments of a standard creatine uptake assay which might help clinical chemistry laboratories to extend their current range of measurements of creatine and metabolites in body fluids to functional enzyme explorations. In this respect, short incubation times and the use of a stable-isotope-labeled substrate (D3 -creatine) preceded by a creatine wash-out step from cultured fibroblast cells by removal of fetal bovine serum (rich in creatine) from the incubation medium are recommended...
April 2018: Molecular Genetics and Metabolism
K C Udobi, A N Kokenge, E R Hautman, G Ullio, J Coene, M T Williams, C V Vorhees, A Mabondzo, M R Skelton
Creatine transporter (CrT; SLC6A8) deficiency (CTD) is an X-linked disorder characterized by severe cognitive deficits, impairments in language and an absence of brain creatine (Cr). In a previous study, we generated floxed Slc6a8 (Slc6a8 flox ) mice to create ubiquitous Slc6a8 knockout (Slc6a8-/y ) mice. Slc6a8-/y mice lacked whole body Cr and exhibited cognitive deficits. While Slc6a8-/y mice have a similar biochemical phenotype to CTD patients, they also showed a reduction in size and reductions in swim speed that may have contributed to the observed deficits...
January 31, 2018: Genes, Brain, and Behavior
Jessie M Cameron, Valeriy Levandovskiy, Wendy Roberts, Evdokia Anagnostou, Stephen Scherer, Alvin Loh, Andreas Schulze
Creatine deficiency syndrome (CDS) comprises three separate enzyme deficiencies with overlapping clinical presentations: arginine:glycine amidinotransferase (GATM gene, glycine amidinotransferase), guanidinoacetate methyltransferase (GAMT gene), and creatine transporter deficiency (SLC6A8 gene, solute carrier family 6 member 8). CDS presents with developmental delays/regression, intellectual disability, speech and language impairment, autistic behaviour, epileptic seizures, treatment-refractory epilepsy, and extrapyramidal movement disorders; symptoms that are also evident in children with autism...
July 31, 2017: International Journal of Molecular Sciences
Nicole Heussinger, Marc Saake, Angelika Mennecke, Helmuth-Günther Dörr, Regina Trollmann
BACKGROUND: The X-linked creatine transporter deficiency (CRTD) caused by an SLC6A8 mutation represents the second most common cause of X-linked intellectual disability. The clinical phenotype ranges from mild to severe intellectual disability, epilepsy, short stature, poor language skills, and autism spectrum disorders. The objective of this study was to investigate phenotypic variability in the context of genotype, cerebral creatine concentration, and volumetric analysis in a family with CRTD...
February 2017: Pediatric Neurology
Tatsuki Uemura, Shingo Ito, Yusuke Ohta, Masanori Tachikawa, Takahito Wada, Tetsuya Terasaki, Sumio Ohtsuki
Cerebral creatine deficiency syndromes (CCDSs) are caused by loss-of-function mutations in creatine transporter (CRT, SLC6A8), which transports creatine at the blood-brain barrier and into neurons of the central nervous system (CNS). This results in low cerebral creatine levels, and patients exhibit mental retardation, poor language skills and epilepsy. We identified a novel human CRT gene missense mutation (c.1681 G>C, G561R) in Japanese CCDSs patients. The purpose of the present study was to evaluate the reduction of creatine transport in G561R-mutant CRT-expressing 293 cells, and to clarify the mechanism of its functional attenuation...
2017: Biological & Pharmaceutical Bulletin
O Ardon, M Procter, R Mao, N Longo, Y E Landau, A Shilon-Hadass, L V Gabis, C Hoffmann, M Tzadok, G Heimer, S Sada, B Ben-Zeev, Y Anikster
X-linked cerebral creatine deficiency (MIM 300036) is caused by deficiency of the creatine transporter encoded by the SLC6A8 gene. Here we report three patients with this condition from Israel. These unrelated patients were evaluated for global developmental delays and language apraxia. Borderline microcephaly was noted in one of them. Diagnosis was prompted by brain magnetic resonance imaging and spectroscopy which revealed normal white matter distribution, but absence of the creatine peak in all three patients...
September 2016: Molecular Genetics and Metabolism Reports
Marla K Perna, Amanda N Kokenge, Keila N Miles, Kenea C Udobi, Joseph F Clark, Gail J Pyne-Geithman, Zaza Khuchua, Matthew R Skelton
Creatine (Cr) is a guanidino compound required for rapid replenishment of ATP in cells with a high-energy demand. In humans, mutations in the Cr transporter (CRT;SLC6A8) prevent Cr entry into tissue and result in a significant intellectual impairment, epilepsy, and aphasia. The lack of Cr on both the whole body and cellular metabolism was evaluated in Crt knockout (Crt (-/y) ) mice, a high-fidelity model of human CRT deficiency. Crt (-/y) mice have reduced body mass and, however, show a twofold increase in body fat...
August 2016: Amino Acids
Audrey Thurm, Daniel Himelstein, Precilla DʼSouza, Owen Rennert, Susanqi Jiang, Damilola Olatunji, Nicola Longo, Marzia Pasquali, Susan Swedo, Gajja S Salomons, Nuria Carrillo
OBJECTIVE: Creatine transporter deficiency (CTD) is an X-linked, neurometabolic disorder associated with intellectual disability that is characterized by brain creatine (Cr) deficiency and caused by mutations in SLC6A8, the Cr transporter 1 protein gene. CTD is identified by elevated urine creatine/creatinine (Cr/Crn) ratio or reduced Cr peak on brain magnetic resonance spectroscopy; the diagnosis is confirmed by decreased Cr uptake in cultured fibroblasts, and/or identification of a mutation in the SLC6A8 gene...
May 2016: Journal of Developmental and Behavioral Pediatrics: JDBP
Layane Hanna-El-Daher, Olivier Braissant
While it has long been thought that most of cerebral creatine is of peripheral origin, the last 20 years has provided evidence that the creatine synthetic pathway (AGAT and GAMT enzymes) is expressed in the brain together with the creatine transporter (SLC6A8). It has also been shown that SLC6A8 is expressed by microcapillary endothelial cells at the blood-brain barrier, but is absent from surrounding astrocytes, raising the concept that the blood-brain barrier has a limited permeability for peripheral creatine...
August 2016: Amino Acids
Andreas Schulze, Margaret Bauman, Anne Chun-Hui Tsai, Ann Reynolds, Wendy Roberts, Evdokia Anagnostou, Jessie Cameron, Alixandra A Nozzolillo, Shiyi Chen, Lianna Kyriakopoulou, Stephen W Scherer, Alvin Loh
BACKGROUND AND OBJECTIVE: Creatine deficiency may play a role in the neurobiology of autism and may represent a treatable cause of autism. The goal of the study was to ascertain the prevalence of creatine deficiency syndromes (CDSs) in children with autism spectrum disorder (ASD). METHODS: In a prospective multicenter study, 443 children were investigated after a confirmed diagnosis of ASD. Random spot urine screening for creatine metabolites (creatine, guanidinoacetate, creatinine, and arginine) with liquid chromatography-tandem mass spectrometry and second-tier testing with high-performance liquid chromatography methodology was followed by recall testing in 24-hour urines and confirmatory testing by Sanger-based DNA sequencing of GAMT, GATM, and SLC6A8 genes...
January 2016: Pediatrics
Marie Joncquel-Chevalier Curt, Pia-Manuela Voicu, Monique Fontaine, Anne-Frédérique Dessein, Nicole Porchet, Karine Mention-Mulliez, Dries Dobbelaere, Gustavo Soto-Ares, David Cheillan, Joseph Vamecq
Creatine is physiologically provided equally by diet and by endogenous synthesis from arginine and glycine with successive involvements of arginine glycine amidinotransferase [AGAT] and guanidinoacetate methyl transferase [GAMT]. A specific plasma membrane transporter, creatine transporter [CRTR] (SLC6A8), further enables cells to incorporate creatine and through uptake of its precursor, guanidinoacetate, also directly contributes to creatine biosynthesis. Breakthrough in the role of creatine has arisen from studies on creatine deficiency disorders...
December 2015: Biochimie
Sravan Jaggumantri, Mary Dunbar, Vanessa Edgar, Cristina Mignone, Theresa Newlove, Rajavel Elango, Jean Paul Collet, Michael Sargent, Sylvia Stockler-Ipsiroglu, Clara D M van Karnebeek
BACKGROUND: Creatine transporter (SLC6A8) deficiency is an X-linked inborn error of metabolism characterized by cerebral creatine deficiency, behavioral problems, seizures, hypotonia, and intellectual developmental disability. A third of patients are amenable to treatment with high-dose oral creatine, glycine, and L-arginine supplementation. METHODS: Given the limited treatment response, we initiated an open-label observational study to evaluate the effect of adjunct S-adenosyl methionine to further enhance intracerebral creatine synthesis...
October 2015: Pediatric Neurology
Caro-Lyne DesRoches, Jaina Patel, Peixiang Wang, Berge Minassian, Gajja S Salomons, Christian R Marshall, Saadet Mercimek-Mahmutoglu
Creatine transporter deficiency (CRTR-D) is an X-linked inherited disorder of creatine transport. All males and about 50% of females have intellectual disability or cognitive dysfunction. Creatine deficiency on brain proton magnetic resonance spectroscopy and elevated urinary creatine to creatinine ratio are important biomarkers. Mutations in the SLC6A8 gene occur de novo in 30% of males. Despite reports of high prevalence of CRTR-D in males with intellectual disability, there are no true prevalence studies in the general population...
July 10, 2015: Gene
Fumihito Nozaki, Tomohiro Kumada, Minoru Shibata, Tatsuya Fujii, Takahito Wada, Hitoshi Osaka
Creatine transporter deficiency (CRTR-D) is an X-linked disorder characterized by hypotonia, developmental delay, and seizures. We report the third Japanese family with CRTR-D. The proband was an 8-year-old boy who presented with hypotonia, severe intellectual disability and two episodes of seizures associated with/without fever. Among 7 siblings (4 males, 3 females), the eldest brother had severe intellectual disability, epilepsy, and sudden death at 17 years of age, while 18-year-old third elder brother had severe intellectual disability, autism, and drug-resistant epilepsy...
January 2015: No to Hattatsu. Brain and Development
Ahmad Almilaji, Mentor Sopjani, Bernat Elvira, José Borras, Miribane Dërmaku-Sopjani, Carlos Munoz, Jamshed Warsi, Undine E Lang, Florian Lang
BACKGROUND/AIMS: The transmembrane Klotho protein contributes to inhibition of 1,25(OH)2D3 formation. The extracellular domain of Klotho protein could function as an enzyme with e.g. β-glucuronidase activity, be cleaved off and be released into blood and cerebrospinal fluid. Klotho regulates several cellular transporters. Klotho protein deficiency accelerates the appearance of age related disorders including neurodegeneration and muscle wasting and eventually leads to premature death...
2014: Kidney & Blood Pressure Research
Laura Baroncelli, Maria Grazia Alessandrì, Jonida Tola, Elena Putignano, Martina Migliore, Elena Amendola, Cornelius Gross, Vincenzo Leuzzi, Giovanni Cioni, Tommaso Pizzorusso
Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement  and behavioral disturbances, language and speech impairment ( OMIM #300352). CCDS1 is still an untreatable pathology that can be very invalidating for patients and caregivers. Only two murine models of CCDS1, one of which is an ubiquitous knockout mouse, are currently available to study the possible mechanisms underlying the pathologic phenotype of CCDS1 and to develop therapeutic strategies...
2014: F1000Research
Sylvia Stockler-Ipsiroglu, Clara D M van Karnebeek
Currently there are 91 treatable inborn errors of metabolism that cause intellectual developmental disorders. Cerebral creatine deficiencies (CDD) comprise three of these: arginine: glycine amidinotransferase [AGAT], guanidinoacetate methyltransferase [GAMT], and X-linked creatine transporter deficiency [SLC6A8]. Intellectual developmental disorder and cerebral creatine deficiency are the hallmarks of CDD. Additional clinical features include prominent speech delay, autism, epilepsy, extrapyramidal movement disorders, and signal changes in the globus pallidus...
July 2014: Seminars in Neurology
Amy R U L Calhoun, Gerald V Raymond
The contiguous ABCD1/DXS1375E (BCAP31) deletion syndrome (CADDS) is a rare X-linked contiguous gene deletion syndrome with a severe clinical phenotype that includes marked delays, significant growth failure, liver dysfunction, and early death. The X-linked creatine transporter deficiency is a considerably more common and a cause of X-linked intellectual disability; however, multi-exon deletions of the creatine transporter are rare. We report the fifth case of CADDS, who also has a deletion of the X-linked creatine transporter...
October 2014: American Journal of Medical Genetics. Part A
Benjamin Nota, Joseph D T Ndika, Jiddeke M van de Kamp, Warsha A Kanhai, Silvy J M van Dooren, Mark A van de Wiel, Gerard Pals, Gajja S Salomons
Creatine transporter (SLC6A8) deficiency is the most common cause of cerebral creatine syndromes, and is characterized by depletion of creatine in the brain. Manifestations of this X-linked disorder include intellectual disability, speech/language impairment, behavior abnormalities, and seizures. At the moment, no effective treatment is available. In order to investigate the molecular pathophysiology of this disorder, we performed RNA sequencing on fibroblasts derived from patients. The transcriptomes of fibroblast cells from eight unrelated individuals with SLC6A8 deficiency and three wild-type controls were sequenced...
September 2014: Human Mutation
Mary Dunbar, Sravan Jaggumantri, Michael Sargent, Sylvia Stockler-Ipsiroglu, Clara D M van Karnebeek
BACKGROUND: Creatine transporter deficiency (CTD) is an X-linked inborn error of creatine metabolism characterized by reduced intra-cerebral creatine, developmental delay/intellectual disability, (ID), behavioral disturbance, seizures, and hypotonia in individuals harboring mutations in the SLC6A8 gene. Treatment for CTD includes supplementation with creatine, either alone or in combination with creatine precursors (arginine or glycine). Unlike other disorders of creatine metabolism, the efficacy of its treatment remains controversial...
August 2014: Molecular Genetics and Metabolism
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