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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...
October 17, 2016: 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
Saghar Ghasemi Firouzabadi, Roxana Kariminejad, Roshanak Vameghi, Hossein Darvish, Hamid Ghaedi, Susan Banihashemi, Mahboubeh Firouzkouhi Moghaddam, Peyman Jamali, Hassan Farbod Mofidi Tehrani, Hossein Dehghani, Mehrnaz Narooie-Nejad, Javad Jamshidi, Abbas Tafakhori, Saeid Sadabadi, Hossein Najmabadi, Farkhondeh Behjati
Autism is a common neurodevelopmental disorder estimated to affect 1 in 68 children. Many studies have shown the role of copy number variants (CNVs) as a major contributor in the etiology of autism with the overall detection rate of about 10-15 % and over 20 % when syndromic forms of autism exist. In this study, we used array CGH to identify CNVs in 15 Iranian patients with autism. To elevate our diagnostic yield, we selected the sporadic patients who had additional clinical features including intellectual disability (ID), craniofacial anomaly, and seizure...
October 28, 2016: Molecular Neurobiology
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
Yasuhiro Hijikata, Masahisa Katsuno, Keisuke Suzuki, Atsushi Hashizume, Amane Araki, Shinichiro Yamada, Tomonori Inagaki, Madoka Iida, Seiya Noda, Hirotaka Nakanishi, Haruhiko Banno, Tomoo Mano, Akihiro Hirakawa, Hiroaki Adachi, Hirohisa Watanabe, Masahiko Yamamoto, Gen Sobue
OBJECTIVE: The aim of this study was to explore the pathomechanism underlying the reduction of serum creatinine (Cr) concentrations in spinal and bulbar muscular atrophy (SBMA). METHODS: We evaluated blood chemistries, motor function, and muscle mass measured by dual-energy X-ray absorptiometry in male subjects with SBMA (n = 65), amyotrophic lateral sclerosis (ALS; n = 27), and healthy controls (n = 25). We also examined the intramuscular concentrations of creatine, a precursor of Cr, as well as the protein and mRNA expression levels of the creatine transporter (SLC6A8) in autopsy specimens derived from subjects who had SBMA and ALS and disease controls...
July 2016: Annals of Clinical and Translational Neurology
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
Lucia Santacruz, Danny O Jacobs
Creatine (Cr) and phosphocreatine constitute an energy shuttle that links ATP production in mitochondria to subcellular locations of ATP consumption. Cells in tissues that are reliant on this energy shuttle, such as myocytes and neurons, appear to have very limited ability to synthesize creatine. Therefore, these cells depend on Cr uptake across the cell membrane by a specialized creatine transporter (CrT solute carrier SLC6A8) in order to maintain intracellular creatine levels. Cr supplementation has been shown to have a beneficial effect in numerous in vitro and in vivo models, particularly in cases of oxidative stress, and is also widely used by athletes as a performance enhancement nutraceutical...
August 2016: Amino Acids
Lan Qin, Jing Wang, Xia Tian, Hui Yu, Cavatina Truong, John J Mitchell, Klaas J Wierenga, William J Craigen, Victor Wei Zhang, Lee-Jun C Wong
The identification of mosaicism is important in establishing a disease diagnosis, assessing recurrence risk, and genetic counseling. Next-generation sequencing (NGS) with deep sequence coverage enhances sensitivity and allows for accurate quantification of the level of mosaicism. NGS identifies low-level mosaicism that would be undetectable by conventional Sanger sequencing. A customized DNA probe library was used for capturing targeted genes, followed by deep NGS analysis. The mean coverage depth per base was approximately 800×...
May 2016: Journal of Molecular Diagnostics: JMD
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
Kristyen A Tomcik, William J Smiles, Donny M Camera, Helmut M Hügel, John A Hawley, Rani Watts
PURPOSE: Creatine uptake by muscle cells is increased in the presence of insulin. Accordingly, compounds with insulin-like actions may also augment creatine uptake. The aim of this study was to investigate whether Trigonella foenum-graecum (fenugreek), an insulin mimetic, increases total intracellular creatine levels in vitro. METHODS: Total cellular creatine content was measured fluorometrically in L6C11 muscle myotubes treated for 1, 4, and 24 h with 0.5 mM creatine (CR), CR and 20 μg/mL fenugreek seed extract (CR + FEN), CR and 100 nM insulin (CR + INS), and CR + INS + FEN (n = 6 per treatment group)...
January 5, 2016: European Journal of Nutrition
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
Carla Rosenberg, Érika L Freitas, Daniela T Uehara, Maria Teresa B M Auricchio, Silvia S Costa, Jeanne Oiticica, Amanda G Silva, Ana C Krepischi, Regina C Mingroni-Netto
Genetic heterogeneity has made the identification of genes related to hearing impairment a challenge. In the absence of a clear phenotypic aetiology, recurrence risk estimates are often based on family segregation and may be imprecise. We profiled by oligonucleotide array-CGH patients presenting non-syndromic hearing loss with presumptive autosomal recessive (n = 50) or autosomal dominant (n = 50) patterns of inheritance. Rare copy number variants (CNVs) were detected in 12 probands; four of the detected CNVs comprised genes previously associated with hearing loss (POU4F3, EYA4, USH2A, BCAP31) and were considered causative, stressing the contribution of genomic imbalance to non-syndromic deafness...
October 12, 2015: Clinical Genetics
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
Jia Min Loo, Alexis Scherl, Alexander Nguyen, Fung Ying Man, Ethan Weinberg, Zhaoshi Zeng, Leonard Saltz, Philip B Paty, Sohail F Tavazoie
Colorectal cancer primarily metastasizes to the liver and globally kills over 600,000 people annually. By functionally screening 661 microRNAs (miRNAs) in parallel during liver colonization, we have identified miR-551a and miR-483 as robust endogenous suppressors of liver colonization and metastasis. These miRNAs convergently target creatine kinase, brain-type (CKB), which phosphorylates the metabolite creatine, to generate phosphocreatine. CKB is released into the extracellular space by metastatic cells encountering hepatic hypoxia and catalyzes production of phosphocreatine, which is imported through the SLC6A8 transporter and used to generate ATP—fueling metastatic survival...
January 29, 2015: Cell
Myriam Fezai, Bernat Elvira, Jose Borras, Mossadok Ben-Attia, Zohreh Hoseinzadeh, Florian Lang
BACKGROUND/AIMS: Transport regulation involves several kinases including SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1), which are under control of WNK (with-no-K[Lys]) kinases. The present study explored whether SPAK and/or OSR1 participate in the regulation of the creatine transporter CreaT (SLC6A8), which accomplishes Na+ coupled cellular uptake of creatine in several tissues including kidney, intestine, heart, skeletal muscle and brain...
2014: Kidney & Blood Pressure Research
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
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