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Andreas Schulze - One of the best experts on this subject based on the ideXlab platform.
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Creatine deficiency syndromes.
Molecular and cellular biochemistry, 2020Co-Authors: Andreas SchulzeAbstract:Since the first description of a Creatine deficiency syndrome, the guanidinoacetate methyltransferase (GAMT) deficiency, in 1994, the two further suspected Creatine deficiency syndromes--the Creatine transporter (CrT1) defect and the arginine:glycine amidinotransferase (AGAT) deficiency were disclosed. GAMT and AGAT deficiency have autosomal-recessive traits, whereas the CrT1 defect is a X-linked disorder. All patients reveal developmental delay/regression, mental retardation, and severe disturbance of their expressive and cognitive speech. The common feature of all Creatine deficiency syndromes is the severe depletion of Creatine/phosphoCreatine in the brain. Only the GAMT deficiency is in addition characterized by accumulation of guanidinoacetic acid in brain and body fluids. Guanidinoacetic acid seems to be responsible for intractable seizures and the movement disorder, both exclusively found in GAMT deficiency. Treatment with oral Creatine supplementation is in part successful in GAMT and AGAT deficiency, whereas in CrT1 defect it is not able to replenish Creatine in the brain. Treatment of combined arginine restriction and ornithine substitution in GAMT deficiency is capable to decrease guanidinoacetic acid permanently and improves the clinical outcome. The lack of the Creatine/phosphoCreatine signal in the patient's brain by means of in vivo proton magnetic resonance spectroscopy is the common finding and the diagnostic clue in all three diseases. In AGAT deficiency guanidinoacetic acid is decreased, whereas Creatine in blood was found to be normal. On the other hand the CrT1 defect is characterized by an increased concentration of Creatine in blood and urine whereas guanidinoacetic acid concentration is normal. The increasing number of patients detected very recently suffering from a Creatine deficiency syndrome and the unfavorable outcome highlights the need of further attempts in early recognition of affected individuals and in optimizing its treatment. The study of Creatine deficiency syndromes and their comparative consideration contributes to the better understanding of the pathophysiological role of Creatine and other guanidino compounds in man.
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Creatine deficiency syndromes
Handbook of Clinical Neurology, 2013Co-Authors: Andreas SchulzeAbstract:The lack of Creatine in the central nervous system causes a severe but treatable neurological disease. Three inherited defects, AGAT, GAMT, and CrT deficiency, compromising synthesis and transport of Creatine have been discovered recently. Together these so-called Creatine deficiency syndromes (CDS) might represent the most frequent metabolic disorders with a primarily neurological phenotype. Patients with CDS present with global developmental delays, mental retardation, speech impairment especially affecting active language, seizures, extrapyramidal movement disorder, and autism spectrum disorder. The two defects in the Creatine synthesis, AGAT and GAMT, are autosomal recessive disorders. They can be diagnosed by analysis of the Creatine, guanidinoacetate, and creatinine in body fluids. Treatment is available and, especially when introduced in infancy, has a good outcome. The defect of Creatine transport, CrT, is an X-linked condition and perhaps the most frequent reasons for X-linked mental retardation. Diagnosis is made by an increased ratio of Creatine to creatinine in urine, but successful treatment still needs to be explored. CDS are under-diagnosed because easy to miss in standard diagnostic workup. Because CDS represent a frequent cause of cognitive and neurological impairment that is treatable they warrant consideration in the workup for genetic mental retardation syndromes, for intractable seizure disorders, and for neurological diseases with a predominant lack of active speech.
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Creatine deficiency syndromes
Molecular and Cellular Biochemistry, 2003Co-Authors: Andreas SchulzeAbstract:Since the first description of a Creatine deficiency syndrome, the guanidinoacetate methyltransferase (GAMT) deficiency, in 1994, the two further suspected Creatine deficiency syndromes – the Creatine transporter (CrT1) defect and the arginine:glycine amidinotransferase (AGAT) deficiency were disclosed.
Ton J Degrauw - One of the best experts on this subject based on the ideXlab platform.
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irreversible brain Creatine deficiency with elevated serum and urine Creatine a Creatine transporter defect
Annals of Neurology, 2001Co-Authors: Kim M Cecil, Gajja S Salomons, W S Ball, Brenda Wong, Gail Chuck, N M Verhoeven, Cornelis Jakobs, Ton J DegrauwAbstract:Recent reports highlight the utility of in vivo magnetic resonance spectroscopy (MRS) techniques to recognize Creatine deficiency syndromes affecting the central nervous system (CNS). Reported cases demonstrate partial reversibility of neurologic symptoms upon restoration of CNS Creatine levels with the administration of oral Creatine. We describe a patient with a brain Creatine deficiency syndrome detected by proton MRS that differs from published reports. Metabolic screening revealed elevated Creatine in the serum and urine, with normal levels of guanidino acetic acid. Unlike the case with other reported Creatine deficiency syndromes, treatment with oral Creatine monohydrate demonstrated no observable increase in brain Creatine with proton MRS and no improvement in clinical symptoms. In this study, we report a novel brain Creatine deficiency syndrome most likely representing a Creatine transporter defect. Ann Neurol 2001;49:401–404
Joseph F. Clark - One of the best experts on this subject based on the ideXlab platform.
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Creatine and Creatine Phosphate: Scientific and Clinical Perspectives
1996Co-Authors: M Conway, Joseph F. ClarkAbstract:List of Contributors. A Brief Review of the Sections. Preface. Acknowledgements. Basic Biochemistry of Creatine and Creatine Phosphate: Old and New Ideas on the Roles of Phoshagens and their Kinases, E.A. Newsholme and I. Beis. Creatine Phosphate Shuttle Pathway in Tissues with Dynamic Energy Demand, T.S. Ma, D.L. Friedman, and R. Roberts. Experimental Observations of Creatine and Creatine Phosphate Metabolism, J.F. Clark, J. Odoom, I. Tracey, J. Dunn, E.A. Boehm, G. Paternostro, and G.K. Radda. An Introduction to the Cellular Creatine Kinase System in Contractile Tissue, J.F. Clark, M.L. Field, and R.Ventura-Clapier. Cardiac Energetics: Compartmentation of Creatine Kinase and Regulation of Oxidative Phosphorylation, V.A. Saks. The Role of the Creatine Kinase/Creatine Phosphate System Studied by Molecular Biology, J.F. Clark. Biochemical Basis for a Therapeutic Role of Creatine and Creatine Phosphate. Molecular and Cellular Mechanisms of Action for the Cardioprotective and Therapeutic Role of Creatine Phosphate, V.A. Saks, Valery Stepanov, I.V. Jaliashvili, E.A. Konorev, S.A. Kryzkanovsky, and E. Strumia. Effects of Creatine Phosphate on Cultured Cardiac Cells, T.J. Lampidis, Y.-F. Shi, and L. Silvestro. Magnetic Resonance Spectroscopy of Creatine Phosphate in the Cardiovascular System: Creatine Phosphate: in vivo Human Cardiac Metabolism Studied by Magnetic Resonance Spectroscopy, M.A. Conway, R. Ouwerkerk, B. Rajagopalan, and G.K. Radda. Skeletal Muscle Metabolism in Heart Failure, M.A. Conway, B. Rajagopalan, and G.K. Radda. Therapeutic Aspects of Creatine and Creatine Phosphate Metabolism: Clinical Experience with Creatine Phosphate Therapy, P. Pauletto and E. Strumia. Creatine Phosphate Added to St. Thomas' Cardioplegia, D.J. Chambers. Uses of Creatine Phosphate and Creatine Supplementation for the Athlete, J.F. Clark. Creatine and Creatine Phosphate: Future Perspectives, M.A. Conway and J.F. Clark. Appendix: Assay for Creatine and Creatine Phosphate. Glossary. Index.
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Creatine and Creatine Phosphate: Future Perspectives
Creatine and Creatine Phosphate, 1996Co-Authors: M Conway, Joseph F. ClarkAbstract:This chapter discusses the future perspective of Creatine and Creatine phosphate. These two are the molecules that are widely distributed in muscle and other organs and their central role is the focus of the chapter. The relationship between arginine and Creatine metabolism, the distribution of the compound in skeletal muscle, the concentration differences in red compared with pale fish meat, in skeletal compared to heart and smooth muscle, were all studied by earlier investigators. Feeding moderate and large amounts of Creatine to rats was long ago shown to increase heart and skeletal muscle Creatine concentrations and the importance of the duodenum as the site of absorption identified. Low Creatine concentrations are found at autopsy studies of myositis and scurvy. The science of Creatine and Creatine phosphate metabolism is now moving rapidly and exciting observations have been reported to complement those summarized in the chapter. The therapeutic possibilities of agents that are natural and relatively inexpensive mean that much effort should be devoted to their detailed examination. The older literature and that outlined in the above chapters is a good starting point for the interested investigator.
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Uses of Creatine Phosphate and Creatine Supplementation for the Athlete
Creatine and Creatine Phosphate, 1996Co-Authors: Joseph F. ClarkAbstract:In this chapter the actions of Creatine (Cr) and Creatine phosphate (PCr), on muscle metabolism and performance are discussed. Creatine phosphate and Cr constitute an energetic shuttling mechanism which is essential for normal muscular function. Creatine can be supplemented in the diet and is able to enhance anaerobic capacity as well as being anabolic. Along with its energetic role, PCr has the ability to stabilize membranes and protect cells from damage. The membrane protection afforded by PCr appears to be a biophysical phenomenon at the membrane surface only, but when PCr is degraded, Cr is the product, and this has beneficial effects in the muscle also. The use and utility of any dietary supplement or other modality is highly variable, must be used cautiously, and must always be kept within limits. It is reported that three out of eight subjects studied showed no beneficial effects. There is, however, no evidence of performance impairment.
Angela T. S. Wyse - One of the best experts on this subject based on the ideXlab platform.
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cross talk between guanidinoacetate neurotoxicity memory and possible neuroprotective role of Creatine
Biochimica et Biophysica Acta, 2019Co-Authors: Eduardo Peil Marques, Fernanda Silva Ferreira, Tiago Marcon Dos Santos, Caroline A Prezzi, Leo Anderson Meira Martins, Larissa Daniele Bobermin, Andre Quincozessantos, Angela T. S. WyseAbstract:Abstract Guanidinoacetate Methyltransferase deficiency is an inborn error of metabolism that results in decreased Creatine and increased guanidinoacetate (GAA) levels. Patients present neurological symptoms whose mechanisms are unclear. We investigated the effects of an intrastriatal administration of 10 μM of GAA (0.02 nmol/striatum) on energy metabolism, redox state, inflammation, glutamate homeostasis, and activities/immunocontents of acetylcholinesterase and Na+,K+-ATPase, as well as on memory acquisition. The neuroprotective role of Creatine was also investigated. Male Wistar rats were pretreated with Creatine (50 mg/kg) or saline for 7 days underwenting stereotactic surgery. Forty-eight hours after surgery, the animals (then sixty-days-old) were divided into groups: Control, GAA, GAA + Creatine, and Creatine. Experiments were performed 30 min after intrastriatal infusion. GAA decreased SDH, complexes II and IV activities, and ATP levels, but had no effect on mitochondrial mass/membrane potential. Creatine totally prevented SDH and complex II, and partially prevented COX and ATP alterations. GAA increased dichlorofluorescein levels and decreased superoxide dismutase and catalase activities. Creatine only prevented catalase and dichlorofluorescein alterations. GAA increased cytokines, nitrites levels and acetylcholinesterase activity, but not its immunocontent. Creatine prevented such effects, except nitrite levels. GAA decreased glutamate uptake, but had no effect on the immunocontent of its transporters. GAA decreased Na+,K+-ATPase activity and increased the immunocontent of its α3 subunit. The performance on the novel object recognition task was also impaired. Creatine partially prevented the changes in glutamate uptake and Na+,K+-ATPase activity, and completely prevented the memory impairment. This study helps to elucidate the protective effects of Creatine against the damage caused by GAA.
Uwe Schlattner - One of the best experts on this subject based on the ideXlab platform.
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The Creatine kinase system and pleiotropic effects of Creatine
Amino Acids, 2011Co-Authors: Theo Wallimann, Malgorzata Tokarska-schlattner, Uwe SchlattnerAbstract:The pleiotropic effects of Creatine (Cr) are based mostly on the functions of the enzyme Creatine kinase (CK) and its high-energy product phosphoCreatine (PCr). Multidisciplinary studies have established molecular, cellular, organ and somatic functions of the CK/PCr system, in particular for cells and tissues with high and intermittent energy fluctuations. These studies include tissue-specific expression and subcellular localization of CK isoforms, high-resolution molecular structures and structure–function relationships, transgenic CK abrogation and reverse genetic approaches. Three energy-related physiological principles emerge, namely that the CK/PCr systems functions as (a) an immediately available temporal energy buffer, (b) a spatial energy buffer or intracellular energy transport system (the CK/PCr energy shuttle or circuit) and (c) a metabolic regulator. The CK/PCr energy shuttle connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases). Thus, diffusion limitations of ADP and ATP are overcome by PCr/Cr shuttling, as most clearly seen in polar cells such as spermatozoa, retina photoreceptor cells and sensory hair bundles of the inner ear. The CK/PCr system relies on the close exchange of substrates and products between CK isoforms and ATP-generating or -consuming processes. Mitochondrial CK in the mitochondrial outer compartment, for example, is tightly coupled to ATP export via adenine nucleotide transporter or carrier (ANT) and thus ATP-synthesis and respiratory chain activity, releasing PCr into the cytosol. This coupling also reduces formation of reactive oxygen species (ROS) and inhibits mitochondrial permeability transition, an early event in apoptosis. Cr itself may also act as a direct and/or indirect anti-oxidant, while PCr can interact with and protect cellular membranes. Collectively, these factors may well explain the beneficial effects of Cr supplementation. The stimulating effects of Cr for muscle and bone growth and maintenance, and especially in neuroprotection, are now recognized and the first clinical studies are underway. Novel socio-economically relevant applications of Cr supplementation are emerging, e.g. for senior people, intensive care units and dialysis patients, who are notoriously Cr-depleted. Also, Cr will likely be beneficial for the healthy development of premature infants, who after separation from the placenta depend on external Cr. Cr supplementation of pregnant and lactating women, as well as of babies and infants are likely to be of benefit for child development. Last but not least, Cr harbours a global ecological potential as an additive for animal feed, replacing meat- and fish meal for animal (poultry and swine) and fish aqua farming. This may help to alleviate human starvation and at the same time prevent over-fishing of oceans.
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Creatine transporter and mitochondrial Creatine kinase protein content in myopathies.
Muscle & Nerve, 2001Co-Authors: Mark A. Tarnopolsky, Uwe Schlattner, A. Parshad, Bernd Walzel, Theo WallimannAbstract:Total Creatine or phosphoCreatine, or both, are reduced in the skeletal muscle of patients with inflammatory myopathy, mitochondrial myopathy, and muscular dystrophy/congenital myopathy. We used Western blotting techniques to measure skeletal muscle Creatine transporter protein and sarcomeric mitochondrial Creatine kinase (mtCK) protein content in patients with inflammatory myopathy (N = 8), mitochondrial myopathy (N = 5), muscular dystrophy (N = 7), and congenital myopathy (N = 3), as compared to a control group without a neuromuscular diagnosis (N = 8). Creatine transporter protein content was lower for all groups compared to control subjects (P < 0.05; P < 0.01 for congenital myopathy). Mitochondrial CK (mtCK) was lower for inflammatory myopathy (P < 0.05), higher for mitochondrial myopathy (P < 0.05), not different for muscular dystrophy, and markedly lower for the congenital myopathy group (P < 0.01), compared to control subjects. Together, these data suggest that the reduction in total Creatine or phosphoCreatine in patients with certain myopathies is correlated with Creatine transporter and not mtCK protein content. This further supports the belief that Creatine monohydrate supplementation may benefit patients with low muscle Creatine stores, although the reduction in Creatine transporter protein may have implications for dosing. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 682–688, 2001
