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Soumen Bera, Sanjay Lamba, Mubasher Rashid, Anuj K Sharma, Alexander B Medvinsky, Claudia Acquisti, Amit Chakraborty, Bai-Lian Li
Impaired glutamate dehydrogenase (GDH) sensitivity to its inhibitors causes excessive insulin secretion by pancreatic beta-cells and defective ammonia metabolism in the liver. These symptoms are commonly associated with hyperinsulinism/hyperammonemia syndrome (HI/HA), which causes recurrent hypoglycaemia in early infancy. Hepatic localization of GDH amination and deamination activities linked with the urea cycle is known to be involved in ammonia metabolism and detoxification. Although deamination activities of hepatic GDH in the periportal zones of liver lobules and its connection to the urea cycle have been exhaustively investigated, physiological roles of GDH amination activity observed at pericentral zones have often been overlooked...
October 17, 2016: Integrative Biology: Quantitative Biosciences From Nano to Macro
Ruby Upadhyay, Thomas P Bleck, Katharina M Busl
Purpose. A 66-year-old man who presented with coma was found to have isolated severe hyperammonemia and diagnosed with a late-onset urea-cycle disorder. He was treated successfully and had full recovery. Methods. We report a novel case of noncirrhotic hyperammonemia and review the literature on this topic. Selected literature for review included English-language articles concerning hyperammonemia using the search terms "hyperammonemic encephalopathy", "non-cirrhotic encephalopathy", "hepatic encephalopathy", "urea-cycle disorders", "ornithine transcarbamylase (OTC) deficiency", and "fulminant hepatic failure"...
2016: Case Reports in Medicine
Jung Ju Choi, Hong Soon Kim, Kyung Cheon Lee, Youseok Shin, Youn Yi Jo
BACKGROUND: Citrullinemia type II is an autosomal recessive urea cycle disorder and a subtype of citrin deficiency. However, the management of recurrent hyperammonemia with neurologic symptoms in patients with citrullinemia type II is quite different from the management of other types of urea cycle disorders. In pats with citrullinemia type II, regional anesthesia might be a good choice for the early detection of hyperammonemic symptoms and addressing psychic stress. CASE PRESENTATION: A 48-year-old male with adult onset citrullinemia type II was scheduled for urethral scrotal fistula repair...
October 11, 2016: BMC Anesthesiology
Paula J Waters, Fanny Thuriot, Joe T R Clarke, Serge Gravel, David Watkins, David S Rosenblatt, Sébastien Lévesque
Methylmalonyl-coA epimerase (MCE) follows propionyl-coA carboxylase and precedes methylmalonyl-coA mutase in the pathway converting propionyl-coA to succinyl-coA. MCE deficiency has previously been described in six patients, one presenting with metabolic acidosis, the others with nonspecific neurological symptoms or asymptomatic. The clinical significance and biochemical characteristics of this rare condition have been incompletely defined. We now describe a patient who presented acutely at 5 years of age with vomiting, dehydration, confusion, severe metabolic acidosis and mild hyperammonemia...
December 2016: Molecular Genetics and Metabolism Reports
David J Gagnon, Gabriel V Fontaine, Kathryn E Smith, Richard R Riker, Russell R Miller, Patricia A Lerwick, F L Lucas, John T Dziodzio, Kristen C Sihler, Gilles L Fraser
PURPOSE: The purpose was to describe the use of valproate therapy for agitation in critically ill patients, examine its safety, and describe its relationship with agitation and delirium. MATERIALS AND METHODS: This retrospective cohort study evaluated critically ill adults treated with valproate for agitation from December 2012 through February 2015. Information on valproate prescribing practices and safety was collected. Incidence of agitation, delirium, and concomitant psychoactive medication use was compared between valproate day 1 and valproate day 3...
September 11, 2016: Journal of Critical Care
Andrea Cabrera-Pastor, Marta Llansola, Vicente Felipo
Extracellular protein kinases, including cAMP-dependent protein kinase (PKA), modulate neuronal functions including N-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation. NMDA receptor activation increases calcium, which binds to calmodulin and activates nitric oxide synthase (NOS), increasing nitric oxide (NO), which activates guanylate cyclase, increasing cGMP, which is released to the extracellular fluid, allowing analysis of this glutamate-NO-cGMP pathway in vivo by microdialysis. The function of this pathway is impaired in hyperammonemic rats...
October 5, 2016: ACS Chemical Neuroscience
Marie-Caroline Husson, Manuel Schiff, Alain Fouilhoux, Aline Cano, Dries Dobbelaere, Anais Brassier, Karine Mention, Jean-Baptiste Arnoux, François Feillet, Brigitte Chabrol, Nathalie Guffon, Caroline Elie, Pascale de Lonlay
BACKGROUND: The efficacy and safety of intra-venous (i.v.) sodium benzoate for treating acute episodes of hyperammonemia in urea cycle enzyme disorders (UCD) is well known. However, published data do not provide a clear picture of the benefits and risks of this drug. We report a retrospective multicentre study on the use of i.v. sodium benzoate in patients treated for UCD between 2000 and 2010 in the 6 French reference centres for metabolic diseases. RESULTS: Sixty-one patients with UCDs - 22 ornithine transcarbamylase (20 confirmed, 2 suspected), 18 arginino-succinate synthetase, 15 carbamoyl phosphate synthetase, 3 arginosuccinate lyase, 1 arginase deficiency, 1 N-acetylglutamate synthetase, 1 HHH syndrome - required i...
2016: Orphanet Journal of Rare Diseases
Rune Gangsoy Kristiansen
Alterations in interorgan metabolism of ammonia play an important role in the onset of hyperammonemia in liver failure. Glutamine synthetase (GS) in muscle is an important target for ammonia removal strategies in hyperammonemia. Ornithine Phenylacetate (OP) is hypothesized to remove ammonia by providing glutamate as a substrate for increased GS activity and hence glutamine production. The newly generated glutamine conjugates with phenylacetate forming phenylacetylglutamine which can be excreted in the urine, providing an excretion pathway for ammonia...
September 21, 2016: Metabolic Brain Disease
Theodorus B M Hakvoort, Youji He, Wim Kulik, Jacqueline L M Vermeulen, Suzanne Duijst, Jan M Ruijter, Jurgen H Runge, Nicolaas E P Deutz, S Eleonore Koehler, Wouter H Lamers
: Glutamine synthetase (GS) catalyzes condensation of ammonia with glutamate to glutamine. Glutamine serves, with alanine, as major nontoxic interorgan ammonia carrier. Elimination of hepatic GS expression in mice causes only mild hyperammonemia and hypoglutaminemia, but a pronounced decrease in the whole-body muscle-to-fat ratio with increased myostatin expression in muscle. Using GS-KO/Liver and control mice, and stepwise increments of enterally infused ammonia, we show that ∼35% of this ammonia is detoxified by hepatic GS and ∼35% by urea-cycle enzymes, while ∼30% is not cleared by the liver, independent of portal ammonia concentrations ≤2 mmol/L...
September 19, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Masahiro Emura, Kazunari Tsuchihashi, Yosuke Shimizu, Sojun Kanamaru, Shun Matoba, Noriyuki Ito
We present here a rare case of hyperammonemia without liver dysfunction or portal-systemic shunting. The patient was an 80-year-old woman with a history of neurogenic bladder. She was admitted to a nearby hospital for vomiting, diarrhea and consciousness disturbance. Two days after admission, she was transferred to our hospital because of persistant consciousness disturbance. Laboratory data revealed hyperammonemia, but there was no indication of liver dysfunction. Moreover abdominal computed tomography did not reveal any clear finding of liver disease or portal-systemic shunting, but we noted multiple large bladder diverticula...
August 2016: Hinyokika Kiyo. Acta Urologica Japonica
Xiaopeng Guo, Lu Gao, Wei Lin, Yue Wu, Qiang Wang, Bing Xing, Zhiqin Xu
BACKGROUND: Antiepileptic drugs (AEDs) are increasingly used prophylactically during the perioperative period to prevent epilepsy in patients undergoing craniotomy. Evidence concerning the use of AEDs and the incidence, extent and risk factors of hyperammonemia induced by different types of AEDs is lacking. METHODS: Patients were divided into groups with 3 different AED regimens, levetiracetam, valproate and carbamazepine regimens, and the blood ammonia concentration and liver and coagulation functions were assessed during the perioperative period...
November 1, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
Keiko Kanamori
In vivo (15)N MRS has made a unique contribution to kinetic studies of the individual pathways that control glutamate flux in the rat brain. This review covers the following topics: (1) the advantages and limitations of in vivo (15)N MRS and its indirect detection through coupled (1)H; (2) kinetic methods; (3) major findings from our and other laboratories in the areas: (a) the uptake of the neurotransmitter glutamate from the extracellular fluid into glia; (b) the metabolism of glutamate to glutamine; (c) glutamine transport to the extracellular fluid; (d) hydrolysis of neuronal glutamine to glutamate; and (e) contribution of transamination from leucine to replenish the glutamate nitrogen...
August 28, 2016: Analytical Biochemistry
Rachel A Stern, Srinivasan Dasarathy, Paul E Mozdziak
Increased myostatin expression, resulting in muscle loss, has been associated with hyperammonemia in mammalian models of cirrhosis. However, there is evidence that hyperammonemia in avian embryos results in a reduction of myostatin expression, suggesting a proliferative myogenic environment. The present in vitro study examines species differences in myotube and liver cell response to ammonia using avian and murine-derived cells. Primary myoblasts and liver cells were isolated from embryonic day 15 and 17 chick embryos to be compared with mouse myoblasts (C2C12) and liver (AML12) cells...
August 29, 2016: In Vitro Cellular & Developmental Biology. Animal
Eiman H Al Kaabi, Ayman W El-Hattab
The urea cycle is the main pathway for the disposal of excess nitrogen. Carbamoylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of urea cycle, is activated by N-acetylglutamate (NAG), and thus N-acetylglutamate synthase (NAGS) is an essential part of the urea cycle. Although NAGS deficiency is the rarest urea cycle disorder, it is the only one that can be specifically and effectively treated by a drug, N-carbamylglutamate, a stable structural analogous of NAG that activates CPS1. Here we report an infant with NAGS deficiency who presented with neonatal hyperammonemia...
September 2016: Molecular Genetics and Metabolism Reports
Boby Varkey Maramattom, Rajat Raja, Anuroop Balagopal
Urea cycle disorders (UCD) are very rare metabolic disorders that present with encephalopathy and hyperammonemia. Of the UCDs, Arginase deficiency (ARD) is the rarest and presents in childhood with a progressive spastic diplegia or seizures. Acute presentation in adulthood is extremely unusual.[1] We present the first case of adult onset ARD presenting with encephalopathy and diffusion weighted MRI findings that resembled a moustache in the midbrain.
July 2016: Annals of Indian Academy of Neurology
Sunita Bijarnia-Mahay, Vivek Jain, Rajiv Kumar Bansal, Gummadi Maheshwar Reddy, Johannes Haberle
BACKGROUND: Lysinuric protein intolerance is an inherited disorder of transport of cationic amino acids, causing amino aciduria. CASE CHARACTERISTICS: A 3-year-old boy with 12 month history of episodic change in behavior (decreased sleep, poor interaction), stunted growth and hyperammonemia. OUTCOME: Genetic analysis revealed a homozygous mutation, c.158C>T (p.Ser53Leu) in exon 1 of SLC7A7 gene. With appropriate management of hyperammonemia episodes, his neurodevelopmental outcome is normal...
August 8, 2016: Indian Pediatrics
Dae J Kang, Genta Kakiyama, Naga S Betrapally, Jeremy Herzog, Hiroshi Nittono, Phillip B Hylemon, Huiping Zhou, Ian Carroll, Jing Yang, Patrick M Gillevet, Chunhua Jiao, Hajime Takei, William M Pandak, Takashi Iida, Douglas M Heuman, Sili Fan, Oliver Fiehn, Takao Kurosawa, Masoumeh Sikaroodi, R B Sartor, Jasmohan S Bajaj
OBJECTIVES: Rifaximin has clinical benefits in minimal hepatic encephalopathy (MHE) but the mechanism of action is unclear. The antibiotic-dependent and -independent effects of rifaximin need to be elucidated in the setting of MHE-associated microbiota. To assess the action of rifaximin on intestinal barrier, inflammatory milieu and ammonia generation independent of microbiota using rifaximin. METHODS: Four germ-free (GF) mice groups were used (1) GF, (2) GF+rifaximin, (3) Humanized with stools from an MHE patient, and (4) Humanized+rifaximin...
2016: Clinical and Translational Gastroenterology
Gangarao Davuluri, Allawy Allawy, Samjhana Thapaliya, Julie H Rennison, Dharmvir Singh, Avinash Kumar, Yana Sandlers, David R Van Wagoner, Chris A Flask, Charles Hoppel, Takhar Kasumov, Srinivasan Dasarathy
Ammonia is a cytotoxic metabolite that is removed primarily by hepatic ureagenesis in humans. Hyperammonemia occurs in advanced hepatic, cardiac, pulmonary disease, and in urea cycle enzyme deficiencies. Increased skeletal muscle ammonia uptake and metabolism are the major mechanism of non-hepatic ammonia disposal. Non-hepatic ammonia disposal occurs in the mitochondria via glutamate synthesis from α-ketoglutarate resulting in cataplerosis. We show skeletal muscle mitochondrial dysfunction during hyperammonemia in a comprehensive array of human, rodent and cellular models...
August 25, 2016: Journal of Physiology
Hersh Patel, Jung Kim, Tessa Kate Huncke
Citrullinemia type I is a rare autosomal recessive genetic condition that causes reduced activity of the enzyme, argininosuccinate synthase, which is needed for proper urea metabolism. The end result is hyperammonemia which can cause life-threatening neurologic symptoms and global developmental delay. Previous case reports of the anesthetic management of patients with citrullinemia describe delayed recovery possibly related to elevated ammonia levels postoperatively or choice of intraoperative anesthetics which have included narcotics...
September 2016: Journal of Clinical Anesthesia
Caroline Unsinn, Anibh Das, Vassili Valayannopoulos, Eva Thimm, Skadi Beblo, Alberto Burlina, Vassiliki Konstantopoulou, Sebene Mayorandan, Pascale de Lonlay, Jörg Rennecke, Jens Derbinski, Georg F Hoffmann, Johannes Häberle
BACKGROUND: Urea cycle disorders (UCDs) are rare inherited metabolic defects of ammonia detoxification. In about half of patients presenting with a UCD, the first symptoms appear within a few days after birth. These neonatal onset patients generally have a severe defect of urea cycle function and their survival and outcome prognoses are often limited. To understand better the current situation of neonatal onset in UCDs, we have performed a multicentre, retrospective, non-interventional case series study focussing on the most severe UCDs, namely defects of carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), and argininosuccinate synthetase (ASS)...
2016: Orphanet Journal of Rare Diseases
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