The Experts below are selected from a list of 1443 Experts worldwide ranked by ideXlab platform
Cornelis Jakobs - One of the best experts on this subject based on the ideXlab platform.
-
Guanidinoacetate methyltransferase gamt deficiency late onset of movement disorder and preserved expressive language
Developmental Medicine & Child Neurology, 2009Co-Authors: Declan Orourke, Cornelis Jakobs, Gajja S. Salomons, Stephanie Ryan, Ahmad Monavari, Mary D KingAbstract:Guanidinoacetate methyltransferase (GAMT) deficiency is a disorder of creatine biosynthesis, characterized by early-onset learning disability and epilepsy in most affected children. Severe expressive language delay is a constant feature even in the mildest clinical phenotypes. We report the clinical, biochemical, imaging, and treatment data of two female siblings (18y and 13y) with an unusual phenotype of GAMT deficiency. The oldest sibling had subacute onset of a movement disorder at age 17 years, later than has been previously reported. The younger sibling had better language skills than previously described in this disorder. After treatment with creatine, arginine restriction and ornithine-supplemented diet, seizure severity and movement disorder were reduced but cognition did not improve. This report confirms that GAMT deficiency, a heterogeneous, potentially treatable disorder, detected by increased levels of Guanidinoacetate in body fluids (e.g. plasma or urine) or by an abnormal creatine peak on magnetic resonance spectroscopy, should be considered in patients of any age with unexplained, apparently static learning disability and epilepsy.
-
successful treatment of a Guanidinoacetate methyltransferase deficient patient findings with relevance to treatment strategy and pathophysiology
Molecular Genetics and Metabolism, 2007Co-Authors: K T Verbruggen, Cornelis Jakobs, Gajja S. Salomons, Paul E Sijens, Andreas Schulze, R J Lunsing, Francjan J Van SpronsenAbstract:Biochemical and developmental results of treatment of a Guanidinoacetate methyltransferase (GAMT) deficient patient with a mild clinical presentation and remarkable developmental improvement after treatment are presented. Treatment with creatine (Cr) supplementation resulted in partial normalization of cerebral (measured with magnetic resonance proton spectroscopy) and plasma levels of Cr and Guanidinoacetate (GAA). Addition of high dose ornithine to the treatment led to further normalization of plasma GAA, while cerebral Cr and GAA did not improve further.
-
high cerebral Guanidinoacetate and variable creatine concentrations in argininosuccinate synthetase and lyase deficiency implications for treatment
Molecular Genetics and Metabolism, 2006Co-Authors: F J Van Spronsen, Cornelis Jakobs, N M Verhoeven, Dirkjan Reijngoud, R J Sooranilunsing, Paul E SijensAbstract:Cerebral creatine and Guanidinoacetate and blood and urine metabolites were studied in four patients with argininosuccinate synthetase (ASS) or argininosuccinate lyase (ASL) deficiency receiving large doses of arginine. Urine and blood metabolites varied largely. Cerebral Guanidinoacetate was increased in all patients, while cerebral creatine was low in ASS and high in ASL deficiency. Because high cerebral Guanidinoacetate might be toxic, lowering the arginine supplementation with additional creatine supplementation might be important.
-
prenatal diagnosis of Guanidinoacetate methyltransferase deficiency increased Guanidinoacetate concentrations in amniotic fluid
Clinical Chemistry, 2006Co-Authors: David Cheillan, Cornelis Jakobs, Gajja S. Salomons, Cecile Acquaviva, Catherine Boisson, Philippe Roth, Mariepierre Cordier, Laurence Francois, Christine VianeysabanAbstract:Guanidinoacetate methyltransferase (GAMT; EC 2.1.1.2) deficiency (OMIM 601240) is an autosomal recessive disorder of creatine biosynthesis, characterized clinically by mental retardation, language delay, extrapyramidal movements, epilepsy, and autistic behavior (1). Biochemically, GAMT deficiency is characterized by depletion of creatine and accumulation of Guanidinoacetate (GAA) in the brain and body fluids (2). Treatment by creatine supplementation (combined with arginine restriction and ornithine supplementation) partially restores (∼70%) cerebral creatine, reduces seizures, and improves behavior, but it does not reverse the mental retardation (3). We have described a method to measure GAA and creatine in plasma and urine by liquid chromatography–tandem mass spectrometry (LC-MS/MS) (4). In the present study, we validated this method for measurement of GAA and creatine in amniotic fluid, and we report the first GAMT prenatal diagnosis based on a combination of molecular and biochemical investigations. We …
-
Guanidinoacetate methyltransferase deficiency identified in adults and a child with mental retardation.
American journal of medical genetics. Part A, 2005Co-Authors: H Caldeira Araújo, Cornelis Jakobs, Gajja S. Salomons, N M Verhoeven, W Smit, S Silva, R Vasconcelos, H Tomás, I Tavares De Almeida, M DuranAbstract:Our study describes the adult clinical and biochemical spectrum of Guanidinoacetate methyltransferase (GAMT) deficiency, a recently discovered inborn error of metabolism. The majority of the previous reports dealt with pediatric patients, in contrast to the present study. A total of 180 institutionalized patients with a severe mental handicap were investigated for urine and plasma uric acid and creatinine. Patients with an increased urinary uric acid/creatinine ratio and/or decreased creatinine were subjected to the analysis of Guanidinoacetate (GAA). Four patients (three related and one from an unrelated family) were identified with GAMT-deficiency. A fifth patient had died before a biochemical diagnosis could be made. They all had shown a normal psychomotor development for the first year of life, after which they developed a profound mental retardation. Three out of four had convulsions and all four totally lacked the development of speech. Their GAMT activity in lymphoblasts was impaired and two novel mutations were identified: the 59 G > C and 506 G > A missense mutations. Urinary GAA was increased, but highly variable 347-1,624 mmol/mol creat (Controls
Dirk Isbrandt - One of the best experts on this subject based on the ideXlab platform.
-
Phosphorylated Guanidinoacetate is present and metabolic active in muscle of Guanidinoacetate methyltransferase deficient mice
2020Co-Authors: Andreas Schmidt, J. Van Asten, C. Soede, Dirk Isbrandt, K. Ulrich, Bé Wieringa, Arend HeerschapAbstract:Skeletal muscle of Guanidinoacetate (Gua) methyltransferasc deficient (GAMT-/-) mice was studied in vivo by 'H and "P MRS and in vitro by HRMAS. Striking differences in residual phosphocreatine (PCr) levels were found in individual hind leg muscle. As was shown by ischemia experiments, the newly formed compound phosphorylated Guanidinoacetate (PGua) appeared to be metabolic active. HRMAS experiments confirmed the presence of Gna in the hind leg of mutant mice; its broad signal in the in vivo 'H MR spectrum indicates a molecular interaction.
-
creatine uptake in brain and skeletal muscle of mice lacking Guanidinoacetate methyltransferase assessed by magnetic resonance spectroscopy
Journal of Applied Physiology, 2007Co-Authors: Esther Meeuwissen, Dirk Isbrandt, Jack J A Van Asten, Andor Veltien, Arend HeerschapAbstract:Creatine (Cr) levels in skeletal muscle and brain of a mouse model of Cr deficiency caused by Guanidinoacetate methyltransferase absence (GAMT−/−) were studied after Cr supplementation with 2 g·kg ...
-
in vivo magnetic resonance spectroscopy of transgenic mice with altered expression of Guanidinoacetate methyltransferase and creatine kinase isoenzymes
Sub-cellular biochemistry, 2007Co-Authors: Arend Heerschap, Dirk Isbrandt, Klaas Jan W Renema, Christine Nabuurs, Bé WieringaAbstract:Mice with an under- or over-expression of enzymes catalyzing phosphoryl transfer in high-energy supplying reactions are particulary attractive for in vivo magnetic resonance spectroscopy (MRS) studies as substrates of these enzymes are visible in MR spectra. This chapter reviews results of in vivo MRS studies on transgenic mice with alterations in the expression of the enzymes creatine kinase and Guanidinoacetate methyltransferase. The particular metabolic consequences of these enzyme deficiencies in skeletal muscle, brain, heart and liver are addressed. An overview is given of metabolite levels determined by in vivo MRS in skeletal muscle and brain of wild-type and transgenic mice.
-
reduced inotropic reserve and increased susceptibility to cardiac ischemia reperfusion injury in phosphocreatine deficient Guanidinoacetate n methyltransferase knockout mice
Circulation, 2005Co-Authors: Michiel Ten Hove, Craig A Lygate, Alexandra Fischer, Jurgen E Schneider, Elisabeth A Sang, Karen Hulbert, Liam Sebagmontefiore, Hugh Watkins, Kieran Clarke, Dirk IsbrandtAbstract:Background— The role of the creatine kinase (CK)/phosphocreatine (PCr) energy buffer and transport system in heart remains unclear. Guanidinoacetate-N-methyltransferase–knockout (GAMT−/−) mice represent a new model of profoundly altered cardiac energetics, showing undetectable levels of PCr and creatine and accumulation of the precursor (phospho-)Guanidinoacetate (P-GA). To characterize the role of a substantially impaired CK/PCr system in heart, we studied the cardiac phenotype of wild-type (WT) and GAMT−/− mice. Methods and Results— GAMT−/− mice did not show cardiac hypertrophy (myocyte cross-sectional areas, hypertrophy markers atrial natriuretic factor and β-myosin heavy chain). Systolic and diastolic function, measured invasively (left ventricular conductance catheter) and noninvasively (MRI), were similar for WT and GAMT−/− mice. However, during inotropic stimulation with dobutamine, preload-recruitable stroke work failed to reach maximal levels of performance in GAMT−/− hearts (101±8 mm Hg in WT ve...
-
phosphorylated Guanidinoacetate partly compensates for the lack of phosphocreatine in skeletal muscle of mice lacking Guanidinoacetate methyltransferase
The Journal of Physiology, 2004Co-Authors: Klaas Jan W Renema, Dirk Isbrandt, Arend HeerschapAbstract:To maintain homeostasis and carry out mechanical work, skeletal muscle cells require a constant input of free energy derived from high energy phosphoryl transfer. Hydrolysis of ATP serves as an instantaneous donor of free energy but its concentration in the muscle cell is limited. The phosphorylated form of creatine (Cr), phosphocreatine (PCr), however, is available in much higher concentrations and can regenerate ATP through the transfer of its high energy phosphoryl group to ADP in an equilibrium reaction catalysed by one of the three isoforms of creatine kinase (CK) found in muscle (Wallimann et al. 1992; Wyss & Kaddurah-Daouk, 2000): One of the main functions attributed to the PCr–CK system is that of a temporal energy buffer for high energy phosphates by keeping ATP/ADP ratios balanced (Wallimann et al. 1992). Another function that has been ascribed to the PCr–CK system is that of a spatial energy buffer, or energy shuttle, linking sites of high energy phosphate production (mitochondria) to utilization sites (e.g. myofibrils, sarcoplasmatic reticulum) (Bessman & Geiger, 1981). However, the mechanism and importance of this transport in muscle are topics of ongoing debate (e.g. Meyer et al. 1986; Wallimann et al. 1992; Wyss & Kaddurah-Daouk, 2000; Dzeja & Terzic, 2003). The importance of intact Cr metabolism in humans was recently highlighted by the identification of a Cr deficiency syndrome caused by a deficiency of Guanidinoacetate methyltransferase (GAMT, EC 2.1.1.2) due to mutations in the human GAMT gene, which leads to severe symptoms including mental retardation and muscle hypotonia (Stockler et al. 1994). GAMT is an essential enzyme in the biosynthesis of Cr where it catalyses the final step. The first step in this biosynthesis, catalysed by l-arginine: glycine amidinotransferase, consists of the transfer of the amidino group from arginine to glycine to yield l-ornithine and guanidinoacetic acid (Gua). Subsequently, the amidino group of Gua is methylated by GAMT to give Cr and, since it is assumed that in vertebrates this process mainly occurs in the pancreas and liver, Cr is exported to the blood and taken up by tissues such as muscle and brain (Wyss & Kaddurah-Daouk, 2000). Since a constant fraction of Cr is converted non-enzymatically to creatinine and excreted daily, biosynthesis and/or dietary Cr sources are needed to maintain a constant body pool of Cr (Walker, 1979). In mice, studies of the physiological significance of the PCr–CK system have mainly focused on knockout mice lacking one or more of the CK isoforms (e.g. van Deursen et al. 1993; Steeghs et al. 1997; In 't Zandt et al. 1999, 2003) or mice fed creatine analogues (van Deursen et al. 1994; Boehm et al. 1996; among others). Recently, GAMT-deficient knockout mice (GAMT–/–) have become available (Schmidt et al. 2004) that completely lack the essential enzyme GAMT and thus cannot form Cr. This new mouse model provides an excellent opportunity to study the function of the PCr–CK system in energy metabolism from a different perspective. Magnetic resonance spectroscopy (MRS) allows non-invasive assessment of various compounds central in the study of energy metabolism related to the PCr–CK system (Meyer et al. 1982) and is instrumental in the diagnosis of Cr deficiency syndromes in human patients. Our 31P and 1H MRS measurements with GAMT–/– mice validated their use as an animal model for creatine deficiency as they were in agreement with observations in patients (Renema et al. 2003). So far, in one patient only, 31P MRS of the calf muscle has been performed (Schulze et al. 2003) which showed a strongly reduced PCr signal along with a new signal that, in brain, had previously been assigned to phosphorylated Gua (PGua) (Frahm & Hanefeld, 1997). In addition to the measurement of steady-state compound levels using MRS, the method of saturation transfer (ST) (Forsen & Hoffman, 1963) provides a window on enzyme kinetics in vivo. During steady-state conditions, ST can be used to measure unidirectional rate constants of chemically exchanging compounds like PCr and ATP (Meyer et al. 1982). In ST measurements of the brain of a GAMT-deficient patient, flux between ATP and PGua was decreased below detection level (Frahm & Hanefeld, 1997). Despite the absence of Cr biosynthesis, GAMT–/– mice are viable and show only minor overt abnormalities (Schmidt et al. 2004). Since possible adaptations and subtle deviations that result from this deficiency could elucidate the function of the Cr circuit in vivo, the aim of the present study was to investigate the consequences of GAMT deficiency on muscle energy metabolism. We examined muscle energy metabolism of GAMT–/– mice non-invasively during rest and ischaemia using 31P MRS and ST. To study the effects of Cr supplementation on enzyme kinetics, a separate group of GAMT–/– animals was supplemented with Cr and their muscles subjected to ischaemia. By comparing the results of the present investigation to the results from studies on CK-deficient mice, a distinct metabolic phenotype was uncovered for GAMT–/– mice.
Gajja S. Salomons - One of the best experts on this subject based on the ideXlab platform.
-
Guanidinoacetate methyltransferase activity in lymphocytes for a fast diagnosis
JIMD reports, 2017Co-Authors: Lisette M Berends, Gajja S. Salomons, Erwin E W Jansen, Eduard A Struys, Birthe Roos, Ulbe Holwerda, Mirjam M C WamelinkAbstract:Introduction. Guanidinoacetate methyltransferase (GAMT) deficiency is an inborn error of metabolism (IEM), clinically characterized by intellectual disability, developmental delay, seizures, and movement disorders. Biochemical diagnosis of GAMT deficiency is based on the measurement of creatine and Guanidinoacetate in urine, plasma, or CSF and is confirmed genetically by DNA analysis or by enzyme assay in lymphoblasts or fibroblasts. To obtain enough cells, these cells need to be cultured for at least 1 month. A less time-consuming diagnostic functional test is needed, since GAMT deficiency is a candidate for newborn screening (NBS) programs, to be able to confirm or rule out this IEM after an initial positive result in the NBS.
-
case study for the evaluation of current treatment recommendations of Guanidinoacetate methyltransferase deficiency ineffectiveness of sodium benzoate
Pediatric Neurology, 2014Co-Authors: Saadet Mercimekmahmutoglu, Gajja S. Salomons, Alicia ChanAbstract:Abstract Background Guanidinoacetate methyltransferase deficiency is an autosomal recessively inherited disorder of creatine biosynthesis. We report a new patient with Guanidinoacetate methyltransferase deficiency and her >3-year treatment outcome. Patient This is a 6-year-old girl who was diagnosed with Guanidinoacetate methyltransferase deficiency at the age of 28 months. She presented with moderate global developmental delay, one afebrile seizure, and hypotonia between 6 and 18 months of life. She was treated with creatine and ornithine supplementation and a strict arginine-restricted diet for 42 months. Results Mutation analysis (compound heterozygous mutations, a known c.327G>A and a novel c.58dupT [p.Trp20LeufsX65]) and enzyme studies in primary fibroblasts confirmed the diagnosis. After 33 months of therapy, her cerebrospinal fluid Guanidinoacetate level decreased from 47 to 5.3 times the normal level. Brain creatine by proton magnetic resonance spectroscopy increased by >75% but did not normalize in the basal ganglia and white matter after 3 years of therapy. Additional treatment with sodium benzoate for 17 months did not further improve plasma Guanidinoacetate levels, which questions the relevance of this therapy. Conclusion Treatment did not improve moderate intellectual disability or normalize Guanidinoacetate accumulation in the central nervous system.
-
1 h magnetic resonance spectroscopy of urine diagnosis of a Guanidinoacetate methyl transferase deficiency case
Journal of Child Neurology, 2010Co-Authors: Maria Tassini, Gajja S. Salomons, Raffaella Zannolli, Sabrina Buoni, Udo F H Engelke, Antonio Vivi, Gianni Valensin, A De Nicola, Mirella Strambi, L MontiAbstract:For the first time, the use of urine [(1)H] magnetic resonance spectroscopy has allowed the detection of 1 case of Guanidinoacetate methyl transferase in a database sample of 1500 pediatric patients with a diagnosis of central nervous system impairment of unknown origin. The urine [(1)H] magnetic resonance spectroscopy of a 9-year-old child, having severe epilepsy and nonprogressive mental and motor retardation with no apparent cause, revealed a possible guanidinoacetic acid increase. The definitive assignment of guanidinoacetic acid was checked by addition of pure substance to the urine sample and by measuring [(1)H]-[(1)H] correlation spectroscopy. Diagnosis of Guanidinoacetate methyl transferase deficiency was further confirmed by liquid chromatography-mass spectrometry, brain [(1)H] magnetic resonance spectroscopy, and mutational analysis of the Guanidinoacetate methyl transferase gene. The replacement therapy was promptly started and, after 1 year, the child was seizure free. We conclude that for this case, urine [(1)H] magnetic resonance spectroscopy screening was able to diagnose Guanidinoacetate methyl transferase deficiency.
-
Guanidinoacetate methyltransferase gamt deficiency late onset of movement disorder and preserved expressive language
Developmental Medicine & Child Neurology, 2009Co-Authors: Declan Orourke, Cornelis Jakobs, Gajja S. Salomons, Stephanie Ryan, Ahmad Monavari, Mary D KingAbstract:Guanidinoacetate methyltransferase (GAMT) deficiency is a disorder of creatine biosynthesis, characterized by early-onset learning disability and epilepsy in most affected children. Severe expressive language delay is a constant feature even in the mildest clinical phenotypes. We report the clinical, biochemical, imaging, and treatment data of two female siblings (18y and 13y) with an unusual phenotype of GAMT deficiency. The oldest sibling had subacute onset of a movement disorder at age 17 years, later than has been previously reported. The younger sibling had better language skills than previously described in this disorder. After treatment with creatine, arginine restriction and ornithine-supplemented diet, seizure severity and movement disorder were reduced but cognition did not improve. This report confirms that GAMT deficiency, a heterogeneous, potentially treatable disorder, detected by increased levels of Guanidinoacetate in body fluids (e.g. plasma or urine) or by an abnormal creatine peak on magnetic resonance spectroscopy, should be considered in patients of any age with unexplained, apparently static learning disability and epilepsy.
-
successful treatment of a Guanidinoacetate methyltransferase deficient patient findings with relevance to treatment strategy and pathophysiology
Molecular Genetics and Metabolism, 2007Co-Authors: K T Verbruggen, Cornelis Jakobs, Gajja S. Salomons, Paul E Sijens, Andreas Schulze, R J Lunsing, Francjan J Van SpronsenAbstract:Biochemical and developmental results of treatment of a Guanidinoacetate methyltransferase (GAMT) deficient patient with a mild clinical presentation and remarkable developmental improvement after treatment are presented. Treatment with creatine (Cr) supplementation resulted in partial normalization of cerebral (measured with magnetic resonance proton spectroscopy) and plasma levels of Cr and Guanidinoacetate (GAA). Addition of high dose ornithine to the treatment led to further normalization of plasma GAA, while cerebral Cr and GAA did not improve further.
Angela T S Wyse - One of the best experts on this subject based on the ideXlab platform.
-
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.
-
Guanidinoacetate methyltransferase deficiency a review of Guanidinoacetate neurotoxicity
Journal of Inborn Errors of Metabolism and Screening, 2016Co-Authors: Eduardo Peil Marques, Angela T S WyseAbstract:Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessively inherited disorder of the metabolism of creatine that leads to depleted levels of creatine and excessive concentrati...
-
Guanidinoacetate alters antioxidant defenses and butyrylcholinesterase activity in the blood of rats
Clinical & Biomedical Research, 2015Co-Authors: Guilherme Andre Eger, Angela T S Wyse, Vinicius Vialle Ferreira, Camila Ribeiro Batista, Daniela Delwing De Lima, Julia Niehues Da Cruz, Debora Delwing Dal Magro, Jose Geraldo Pereira Da CruzAbstract:Deficiency of Guanidinoacetate methyltransferase, the first described creatine biosynthesis defect, leads to depletion of creatine and phosphocreatine, and accumulation of Guanidinoacetate (GAA) in brain and body fluids. The present study aimed to investigate the influence of GAA on the activities of antioxidant enzymes, as well as on thiobarbituric acid-reactive substances (TBARS) and butyrylcholinesterase (BuChE) activity in the blood of rats. Results showed that GAA enhanced the activities of catalase (CAT) and glutathione peroxidase (GSH-Px) in the erythrocytes and BuChE activity. In addition, GAA enhanced TBARS levels in the plasma. Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), GSH (glutathione) and L-NAME (NG-nitro-L-arginine methyl ester) addition prevented the majority of alterations in oxidative stress parameters and the increase of BuChE activity that were caused by GAA. Data suggest that GAA alters antioxidant defenses and induces lipid peroxidation in the blood, as well altering BuChE activity. However, in the presence of trolox, GSH and L-NAME some of these alterations in oxidative stress and BuChE activity were prevented. Our findings lend support to a potential therapeutic strategy for this condition, which may include the use of appropriate antioxidants for ameliorating the damage caused by GAA.
-
Guanidinoacetate administration increases acetylcholinesterase activity in striatum of rats and impairs retention of an inhibitory avoidance task
Metabolic Brain Disease, 2008Co-Authors: Alexandra I Zugno, Lenir Orlandi Pereira, Cristiane Bastos De Mattos, Emilene B S Scherer, Carlos Alexandre Netto, Angela T S WyseAbstract:Guanidinoacetate methyltransferase deficiency (GAMT-deficiency) is an inborn error of metabolism biochemically characterized by accumulation of Guanidinoacetate (GAA) and depletion of creatine; the pathogenesis of brain dysfunction in this disorder is not yet established. In the present study we investigated the effect of intrastriatal administration of GAA on acetylcholinesterase (AChE) activity and on memory acquisition, consolidation and retrieval of step-down inhibitory avoidance task in rat. Results showed that GAA significantly increased AChE activity in rat striatum 30 min (50%) and 3 h (25%), but not 6 h after drug administration. GAA impaired test session performance when applied 30 min before training or after training, and before testing sessions, i.e., impaired memory acquisition, consolidation and retrieval. When injected with a 6 hour interval, GAA affected only memory retrieval. Although the mechanisms of action of GAA on AChE activity and on memory are unclear, these findings suggest that the accumulation of GAA found in patients with GAMT-deficiency may be one of the mechanisms involved in neural dysfunction. Further studies are necessary to evaluate these mechanisms.
-
Guanidinoacetate decreases antioxidant defenses and total protein sulfhydryl content in striatum of rats
Neurochemical Research, 2008Co-Authors: Alexandra I Zugno, Francieli M Stefanello, Clovis Milton Duval Wannmacher, Moacir Wajner, Cristiane Bastos De Mattos, Emilene B S Scherer, Carolina Didonet Pederzolli, Vanessa Moraes De Andrade, Carlos Severo Dutrafilho, Angela T S WyseAbstract:Guanidinoacetate methyltransferase (GAMT) deficiency is an inherited neurometabolic disorder biochemically characterized by tissue accumulation of Guanidinoacetate (GAA) and depletion of creatine. Affected patients present epilepsy and mental retardation whose pathogeny is unclear. In the present study we investigated the in vitro and in vivo (intrastriatal administration) effects of GAA on some oxidative stress parameters in rat striatum. Sixty-day-old rats were used for intrastriatal infusion of GAA. For the in vitro studies, 60-day-old Wistar rats were killed by decapitation and the striatum was pre-incubated for 1 h at 37°C in the presence of GAA at final concentrations ranging from 10 to 100 μM. Parameters of oxidative stress such as total radical-trapping antioxidant potential (TRAP), antioxidant enzymes (SOD, GPx, and CAT), protein carbonyl and thiol contents were measured. DNA damage was also evaluated. Results showed that GAA administration (in vivo studies) or the addition of 100 μM GAA to assays (in vitro studies) significantly decreased TRAP, SOD activity, and total thiol levels in rat striatum. In contrast, this guanidino compound did not alter protein carbonyl content and the activities of CAT and GPx. DNA damage was not found after intrastriatal administration of GAA. The data indicate that the metabolite accumulating in GAMT deficiency decreases antioxidant capacity and total thiol content in the striatum. It is therefore presumed that this pathomechanism may contribute at least in part to the pathophysiology of the brain injury observed in patients affected by GAMT deficiency.
Arend Heerschap - One of the best experts on this subject based on the ideXlab platform.
-
Phosphorylated Guanidinoacetate is present and metabolic active in muscle of Guanidinoacetate methyltransferase deficient mice
2020Co-Authors: Andreas Schmidt, J. Van Asten, C. Soede, Dirk Isbrandt, K. Ulrich, Bé Wieringa, Arend HeerschapAbstract:Skeletal muscle of Guanidinoacetate (Gua) methyltransferasc deficient (GAMT-/-) mice was studied in vivo by 'H and "P MRS and in vitro by HRMAS. Striking differences in residual phosphocreatine (PCr) levels were found in individual hind leg muscle. As was shown by ischemia experiments, the newly formed compound phosphorylated Guanidinoacetate (PGua) appeared to be metabolic active. HRMAS experiments confirmed the presence of Gna in the hind leg of mutant mice; its broad signal in the in vivo 'H MR spectrum indicates a molecular interaction.
-
creatine uptake in brain and skeletal muscle of mice lacking Guanidinoacetate methyltransferase assessed by magnetic resonance spectroscopy
Journal of Applied Physiology, 2007Co-Authors: Esther Meeuwissen, Dirk Isbrandt, Jack J A Van Asten, Andor Veltien, Arend HeerschapAbstract:Creatine (Cr) levels in skeletal muscle and brain of a mouse model of Cr deficiency caused by Guanidinoacetate methyltransferase absence (GAMT−/−) were studied after Cr supplementation with 2 g·kg ...
-
in vivo magnetic resonance spectroscopy of transgenic mice with altered expression of Guanidinoacetate methyltransferase and creatine kinase isoenzymes
Sub-cellular biochemistry, 2007Co-Authors: Arend Heerschap, Dirk Isbrandt, Klaas Jan W Renema, Christine Nabuurs, Bé WieringaAbstract:Mice with an under- or over-expression of enzymes catalyzing phosphoryl transfer in high-energy supplying reactions are particulary attractive for in vivo magnetic resonance spectroscopy (MRS) studies as substrates of these enzymes are visible in MR spectra. This chapter reviews results of in vivo MRS studies on transgenic mice with alterations in the expression of the enzymes creatine kinase and Guanidinoacetate methyltransferase. The particular metabolic consequences of these enzyme deficiencies in skeletal muscle, brain, heart and liver are addressed. An overview is given of metabolite levels determined by in vivo MRS in skeletal muscle and brain of wild-type and transgenic mice.
-
phosphorylated Guanidinoacetate partly compensates for the lack of phosphocreatine in skeletal muscle of mice lacking Guanidinoacetate methyltransferase
The Journal of Physiology, 2004Co-Authors: Klaas Jan W Renema, Dirk Isbrandt, Arend HeerschapAbstract:To maintain homeostasis and carry out mechanical work, skeletal muscle cells require a constant input of free energy derived from high energy phosphoryl transfer. Hydrolysis of ATP serves as an instantaneous donor of free energy but its concentration in the muscle cell is limited. The phosphorylated form of creatine (Cr), phosphocreatine (PCr), however, is available in much higher concentrations and can regenerate ATP through the transfer of its high energy phosphoryl group to ADP in an equilibrium reaction catalysed by one of the three isoforms of creatine kinase (CK) found in muscle (Wallimann et al. 1992; Wyss & Kaddurah-Daouk, 2000): One of the main functions attributed to the PCr–CK system is that of a temporal energy buffer for high energy phosphates by keeping ATP/ADP ratios balanced (Wallimann et al. 1992). Another function that has been ascribed to the PCr–CK system is that of a spatial energy buffer, or energy shuttle, linking sites of high energy phosphate production (mitochondria) to utilization sites (e.g. myofibrils, sarcoplasmatic reticulum) (Bessman & Geiger, 1981). However, the mechanism and importance of this transport in muscle are topics of ongoing debate (e.g. Meyer et al. 1986; Wallimann et al. 1992; Wyss & Kaddurah-Daouk, 2000; Dzeja & Terzic, 2003). The importance of intact Cr metabolism in humans was recently highlighted by the identification of a Cr deficiency syndrome caused by a deficiency of Guanidinoacetate methyltransferase (GAMT, EC 2.1.1.2) due to mutations in the human GAMT gene, which leads to severe symptoms including mental retardation and muscle hypotonia (Stockler et al. 1994). GAMT is an essential enzyme in the biosynthesis of Cr where it catalyses the final step. The first step in this biosynthesis, catalysed by l-arginine: glycine amidinotransferase, consists of the transfer of the amidino group from arginine to glycine to yield l-ornithine and guanidinoacetic acid (Gua). Subsequently, the amidino group of Gua is methylated by GAMT to give Cr and, since it is assumed that in vertebrates this process mainly occurs in the pancreas and liver, Cr is exported to the blood and taken up by tissues such as muscle and brain (Wyss & Kaddurah-Daouk, 2000). Since a constant fraction of Cr is converted non-enzymatically to creatinine and excreted daily, biosynthesis and/or dietary Cr sources are needed to maintain a constant body pool of Cr (Walker, 1979). In mice, studies of the physiological significance of the PCr–CK system have mainly focused on knockout mice lacking one or more of the CK isoforms (e.g. van Deursen et al. 1993; Steeghs et al. 1997; In 't Zandt et al. 1999, 2003) or mice fed creatine analogues (van Deursen et al. 1994; Boehm et al. 1996; among others). Recently, GAMT-deficient knockout mice (GAMT–/–) have become available (Schmidt et al. 2004) that completely lack the essential enzyme GAMT and thus cannot form Cr. This new mouse model provides an excellent opportunity to study the function of the PCr–CK system in energy metabolism from a different perspective. Magnetic resonance spectroscopy (MRS) allows non-invasive assessment of various compounds central in the study of energy metabolism related to the PCr–CK system (Meyer et al. 1982) and is instrumental in the diagnosis of Cr deficiency syndromes in human patients. Our 31P and 1H MRS measurements with GAMT–/– mice validated their use as an animal model for creatine deficiency as they were in agreement with observations in patients (Renema et al. 2003). So far, in one patient only, 31P MRS of the calf muscle has been performed (Schulze et al. 2003) which showed a strongly reduced PCr signal along with a new signal that, in brain, had previously been assigned to phosphorylated Gua (PGua) (Frahm & Hanefeld, 1997). In addition to the measurement of steady-state compound levels using MRS, the method of saturation transfer (ST) (Forsen & Hoffman, 1963) provides a window on enzyme kinetics in vivo. During steady-state conditions, ST can be used to measure unidirectional rate constants of chemically exchanging compounds like PCr and ATP (Meyer et al. 1982). In ST measurements of the brain of a GAMT-deficient patient, flux between ATP and PGua was decreased below detection level (Frahm & Hanefeld, 1997). Despite the absence of Cr biosynthesis, GAMT–/– mice are viable and show only minor overt abnormalities (Schmidt et al. 2004). Since possible adaptations and subtle deviations that result from this deficiency could elucidate the function of the Cr circuit in vivo, the aim of the present study was to investigate the consequences of GAMT deficiency on muscle energy metabolism. We examined muscle energy metabolism of GAMT–/– mice non-invasively during rest and ischaemia using 31P MRS and ST. To study the effects of Cr supplementation on enzyme kinetics, a separate group of GAMT–/– animals was supplemented with Cr and their muscles subjected to ischaemia. By comparing the results of the present investigation to the results from studies on CK-deficient mice, a distinct metabolic phenotype was uncovered for GAMT–/– mice.
-
Phosphorylated Guanidinoacetate partly compensates for the lack of phosphocreatine in skeletal muscle of mice lacking Guanidinoacetate methyltransferase.
The Journal of physiology, 2004Co-Authors: W Klaas Jan Renema, Dirk Isbrandt, Arend HeerschapAbstract:The effects of creatine (Cr) absence in skeletal muscle caused by a deletion of Guanidinoacetate methyltransferase (GAMT) were studied in a knockout mouse model by in vivo (31)P magnetic resonance (MR) spectroscopy. (31)P MR spectra of hindleg muscle of GAMT-deficient (GAMT-/-) mice showed no phosphocreatine (PCr) signal and instead showed the signal for phosphorylated Guanidinoacetate (PGua), the immediate precursor of Cr, which is not normally present. Tissue pH did not differ between wild-type (WT) and GAMT-/- mice, while relative inorganic phosphate (P(i)) levels were increased in the latter. During ischaemia, PGua was metabolically active in GAMT-/- mice and decreased at a rate comparable to the decrease of PCr in WT mice. However, the recovery rate of PGua in GAMT-/- mice after ischaemia was reduced compared to PCr in WT mice. Saturation transfer measurements revealed no detectable flux from PGua to gamma-ATP, indicating severely reduced enzyme kinetics. Supplementation of Cr resulted in a rapid increase in PCr signal intensity until only this resonance was visible, along with a reduction in relative P(i) values. However, the PGua recovery rate after ischaemia did not change. Our results show that despite the absence of Cr, GAMT-/- mice can cope with mild ischaemic stress by using PGua for high energy phosphoryl transfer. The reduced affinity of creatine kinase (CK) for (P)Gua only becomes apparent during recovery from ischaemia. It is argued that absence of Cr causes the higher relative P(i) concentration also observed in animals lacking muscle CK, indicating an important role of the CK system in P(i) homeostasis.
