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pyruvate kinase deficiency

Guillaume Vignon, Roxane Jeanneau, Julien Labrousse, Sébastien Aubrit, Philippe Mottaz, François Carrère, Pierre-Frédéric Augereau, Philippe Aucher, Franck Lellouche
The most frequent causes of hemolytic anemias are immune or infectious diseases, drug induced hemolysis, thrombotic microangiopathies, hereditary spherocytosis, glucose-6-phosphate dehydrogenase or pyruvate kinase deficiencies, thalassemia's and sickle cell disease. Sometimes no cause is found because a rarer etiology is involved. The goal of this review is to remember some unfrequent constitutional or acquired causes and to point out difficulties to avoid wrong interpretations of analysis results.
October 1, 2018: Annales de Biologie Clinique
Eduard J van Beers, Stephanie van Straaten, D Holmes Morton, Wilma Barcellini, Stefan W Eber, Bertil Glader, Hassan M Yaish, Satheesh Chonat, Janet L Kwiatkowski, Jennifer A Rothman, Mukta Sharma, Ellis J Neufeld, Sujit Sheth, Jenny M Despotovic, Nina Kollmar, Dagmar Pospisilova, Christine M Knoll, Kevin Kuo, Yves D Pastore, Alexis A Thompson, Peter E Newburger, Yaddanapudi Ravindranath, Winfred C Wang, Marcin W Wlodarski, Heng Wang, Susanne Holzhauer, Vicky R Breakey, Madeleine Verhovsek, Joachim Kunz, Melissa A McNaull, Melissa J Rose, Heather A Bradeen, Kathryn Addonizio, Anran Li, Hasan Al-Sayegh, Wendy B London, Rachael F Grace
No abstract text is available yet for this article.
September 13, 2018: Haematologica
Victor Bobée, Sylvie Daliphard, Aurélien Schrapp, Agnès Lahary
INTRODUCTION: Development of additional parameters for complete blood count has emerged in recent hematology analyzers, leading to many publications. However, few studies have been conducted on advanced RBC parameters and hemolytic anemias. We investigated the interest of Sysmex unique parameters, MicroR and HypoHe, as well as the immature fraction of reticulocytes (IRF) in combination with complete blood and reticulocyte count, for screening hereditary spherocytosis (HS) and pyruvate kinase deficiency...
September 5, 2018: International Journal of Laboratory Hematology
Vedad Delic, Kenyaria Noble, Sandra Zivkovic, Tam-Anh Phan, Christian Reynes, Yumeng Zhang, Oluwakemi Phillips, Charles Claybaker, Yen Ta, Vinh B Dinh, Josean Cruz, Tomas A Prolla, Patrick C Bradshaw
Mitochondrial DNA mutations accumulate with age and may play a role in stem cell aging as suggested by the premature aging phenotype of mitochondrial DNA polymerase gamma (POLG) exonuclease-deficient mice. Therefore, E1A immortalized murine embryonic fibroblasts (MEFs) from POLG exonuclease-deficient and WT mice were constructed. Surprisingly, when some E1A immortalized MEF lines were cultured in pyruvate containing media they slowly became addicted to the pyruvate. The POLG exonuclease-deficient MEFs were more sensitive to several mitochondrial inhibitors and showed increased reactive oxygen species production under standard conditions...
September 3, 2018: Biology Open
Shubha Ghosh Dastidar, Ganapathy Jagatheesan, Petra Haberzettl, Jasmit Shah, Bradford G Hill, Aruni Bhatnagar, Daniel J Conklin
Hepatic glutathione S-transferases (GSTs) are dysregulated in human obesity, non-alcoholic fatty liver disease (NAFLD) and diabetes. The multifunctional GST Pi isoform (GSTP) catalyzes the conjugation of glutathione with acrolein and inhibits c-Jun NH2-terminal kinase (JNK) activation. Herein, we tested whether GSTP deficiency disturbs glucose homeostasis in mice. Hepatic GST proteins were downregulated by short-term high-fat diet (HFD) in wild type (WT) mice concomitant with increased glucose intolerance, JNK activation, and cytokine mRNAs in the liver...
August 28, 2018: American Journal of Physiology. Endocrinology and Metabolism
Hua Yang, Elizabeth Merica, Yue Chen, Marvin Cohen, Ronald Goldwater, Penelope A Kosinski, Charles Kung, Zheng Jason Yuan, Lee Silverman, Meredith Goldwasser, Bruce A Silver, Sam Agresta, Ann J Barbier
Pyruvate kinase deficiency is a chronic hemolytic anemia caused by mutations in PK-R, a key glycolytic enzyme in erythrocytes. These 2 phase 1 randomized, placebo-controlled, double-blind healthy-volunteer studies assessed the safety, tolerability, and pharmacokinetics/pharmacodynamics of AG-348, a first-in-class allosteric PK-R activator. Twelve sequential cohorts were randomized 2:6 to receive oral placebo or AG-348, respectively, as a single dose (30-2500 mg) in the single-ascending-dose (SAD) study (ClinicalTrials...
August 9, 2018: Clinical Pharmacology in Drug Development
Serena Pagliarani, Sabrina Lucchiari, Gianna Ulzi, Michela Ripolone, Raffaella Violano, Francesco Fortunato, Andreina Bordoni, Stefania Corti, Maurizio Moggio, Nereo Bresolin, Giacomo P Comi
Glycogen disease type III (GSDIII), a rare incurable autosomal recessive disorder due to glycogen debranching enzyme deficiency, presents with liver, heart and skeletal muscle impairment, hepatomegaly and ketotic hypoglycemia. Muscle weakness usually worsens to fixed myopathy and cardiac involvement may present in about half of the patients during disease. Management relies on careful follow-up of symptoms and diet. No common agreement was reached on sugar restriction and treatment in adulthood. We administered two dietary regimens differing in their protein and carbohydrate content, high-protein (HPD) and high-protein/glucose-free (GFD), to our mouse model of GSDIII, starting at one month of age...
October 2018: Biochimica et biophysica acta. Molecular basis of disease
Bo-Yoon Park, Jae-Han Jeon, Younghoon Go, Hye Jin Ham, Jeong-Eun Kim, Eun Kyung Yoo, Woong Hee Kwon, Nam-Ho Jeoung, Yong Hyun Jeon, Seung-Hoi Koo, Byung-Gyu Kim, Ling He, Keun-Gyu Park, Robert A Harris, In-Kyu Lee
In fasting or diabetes, gluconeogenic genes are transcriptionally activated by glucagon stimulation of the cAMP-protein kinase A (PKA)-CREB signaling pathway. Previous work showed pyruvate dehydrogenase kinase (PDK) inhibition in skeletal muscle increases pyruvate oxidation, which limits the availability of gluconeogenic substrates in the liver. However, this study found upregulation of hepatic PDK4 promoted glucagon-mediated expression of gluconeogenic genes, whereas knockdown or inhibition of hepatic PDK4 caused the opposite effect on gluconeogenic gene expression and decreased hepatic glucose production...
October 2018: Diabetes
Sultan Aydin Köker, Yeşim Oymak, Paola Bianchi, Salih Gözmen, Tuba H Karapinar, Elisa Fermo, Raziye C Vergin
Pyruvate kinase deficiency (PKD) is the most common glycolytic defect leading to hemolytic anemia. PKD is caused by the mutations in the PKLR gene; however, the detection of a decreased PK activity should be first measured for rapid diagnosis. We report here the case of a 1-year-old girl with mild hemolysis and PKD. At the time of the study, the patient showed a hemoglobin level of 9.5 g/dL, mean corpuscular volume of 93 fL, reticulocyte of 6.7%, and lactate dehydrogenase of 218 IU/L. Peripheral blood smear showed polychromasia, anisocytosis, tear drop cells, fragmented eyrtrocytes, and target cells...
July 19, 2018: Journal of Pediatric Hematology/oncology
Kristy Zera, Jason Zastre
Vitamin B1, or thiamine is a critical enzyme cofactor required for metabolic function and energy production. Thiamine deficiency (TD) is common in various diseases, and results in severe neurological complications due to diminished mitochondrial function, oxidative stress, excitotoxicity and inflammation. These pathological sequelae result in apoptotic cell death in both neurons and astrocytes in distinct regions, in particular the thalamus and mammillary bodies. Comparable histological injuries in patients with hypoxia/ischemia (H/I) have also been described, suggesting a congruency between the cellular responses to these stresses...
September 15, 2018: Toxicology and Applied Pharmacology
L Song, Y Li, G X Peng, L Zhang, L P Jing, K Zhou, Y Li, L Ye, J P Li, H H Fan, X Zhao, W R Yang, Y Yang, Y P Zhao, Y Z Xiong, Z J Wu, F K Zhang
Clinical data of 19 patients with congenital pyruvate kinase deficiency were analyzed. Insufficient pyruvate kinase confirmed the diagnosis. Laboratory parameters of hemolysis were summarized. In cases of neonatal hyperbilirubinemia and unexplained hemolytic anemia, pyruvate kinase activity and next generation sequencing test may help the early diagnosis.
July 1, 2018: Zhonghua Nei Ke za Zhi [Chinese Journal of Internal Medicine]
James L Coleman, Alvaro Toledo, Jorge L Benach
Borrelia burgdorferi HtrA (HtrABb) is a serine protease that targets damaged or improperly folded proteins. In our previous studies, HtrABb specifically degraded basic membrane protein BmpD, chemotaxis phosphatase CheX, and outer membrane protein P66. In addition, HtrABb degrades virulence factor BB0323 and components of the extracellular matrix fibronectin and aggrecan. A proteomics-based analysis (two-dimensional difference gel electrophoresis [2-D DIGE], liquid chromatography-mass spectrometry [LC-MS]) of an HtrABb-overexpressing strain of B...
July 10, 2018: MBio
Rachael F Grace, Jennifer Cohen, Shayna Egan, Ted Wells, Brooke Witherspoon, Aisling Ryan, Sam S Salek, Susan Bodie, Robert J Klaassen
OBJECTIVES: This study explored how signs and symptoms of pyruvate kinase (PK) deficiency, a rare hemolytic anemia caused by mutations in the PKLR gene, impacts patients' health-related quality of life (HRQoL). METHODS: Interviews with twenty-one adults with PK deficiency in the United States, Netherlands, and Germany were conducted. Participants were asked to describe signs, symptoms, and impacts of the disease on their daily lives. Interviews were transcribed and analyzed using qualitative analysis methods...
June 23, 2018: European Journal of Haematology
Dylan Durie, Tanya S McDonald, Karin Borges
A recent report has found that glucose oxidation and the activity of pyruvate dehydrogenase (PDH) are reduced in the chronic stage of the pilocarpine mouse epilepsy model. This is likely caused by increased phosphorylation by PDH kinase of the E1α subunit of PDH, downregulating its activity. Inhibition of this phosphorylation has not yet been explored as a possible approach to treat epilepsy. Chronic dichloroacetate (DCA, 50 and 100 mg/kg/day) treatment was tested in acute seizure and the chronic pilocarpine models...
September 2018: Epilepsy Research
Rachael F Grace, Bertil Glader
Mature red blood cells are reliant on the glycolytic pathway for energy production and the hexose monophosphate shunt for cell protection from oxidative insults. The most common red blood cell enzyme disorders are characterized by hemolysis but with wide clinical variability. Glucose-6-phosphate dehydrogenase deficiency is the most common red cell enzyme disorder worldwide. Frequent clinical presentations include neonatal jaundice and episodic hemolysis after exposure to oxidative stress. Symptoms of pyruvate kinase deficiency and other glycolytic enzyme disorders include neonatal jaundice, chronic hemolytic anemia, gallstones, and transfusion-related and transfusion-independent iron overload...
June 2018: Pediatric Clinics of North America
Noa Shefer Averbuch, Orna Steinberg-Shemer, Orly Dgany, Tanya Krasnov, Sharon Noy-Lotan, Joanne Yacobovich, Amir A Kuperman, Antonis Kattamis, Ayelet Ben Barak, Batia Roth-Jelinek, Evgeni Chubar, Evelyn Shabad, Gustavo Dufort, Martin Ellis, Ofir Wolach, Idit Pazgal, Abed Abu Quider, Hagit Miskin, Hannah Tamary
BACKGROUND: Most patients with anemia are diagnosed through clinical phenotype and basic laboratory testing. Nonetheless, in cases of rare congenital anemias, some patients remain undiagnosed despite undergoing an exhaustive workup. Genetic testing is complicated by the large number of genes involved in rare anemias and the similarities in the clinical presentation of the different syndromes. OBJECTIVE: We aimed to enhance the diagnosis of patients with congenital anemias by using targeted next-generation sequencing...
September 2018: European Journal of Haematology
Anna Zaninoni, Elisa Fermo, Cristina Vercellati, Dario Consonni, Anna P Marcello, Alberto Zanella, Agostino Cortelezzi, Wilma Barcellini, Paola Bianchi
Chronic hemolytic anemias are a group of heterogeneous diseases mainly due to abnormalities of red cell (RBC) membrane and metabolism. The more common RBC membrane disorders, classified on the basis of blood smear morphology, are hereditary spherocytosis (HS), elliptocytosis, and hereditary stomatocytoses (HSt). Among RBC enzymopathies, the most frequent is pyruvate kinase (PK) deficiency, followed by glucose-6-phosphate isomerase, pyrimidine 5' nucleotidase P5'N, and other rare enzymes defects. Because of the rarity and heterogeneity of these diseases, diagnosis may be often challenging despite the availability of a variety of laboratory tests...
2018: Frontiers in Physiology
Silin Lü, Jiacheng Deng, Huiying Liu, Bo Liu, Juan Yang, Yutong Miao, Jing Li, Nan Wang, Changtao Jiang, Qingbo Xu, Xian Wang, Juan Feng
Inflammation mediated by activated T cells plays an important role in the initiation and progression of hyperhomocysteinemia (HHcy)-accelerated atherosclerosis in ApoE-/- mice. Homocysteine (Hcy) activates T cells to secrete proinflammatory cytokines, especially interferon (IFN)-γ; however, the precise mechanisms remain unclear. Metabolic reprogramming is critical for T cell inflammatory activation and effector functions. Our previous study demonstrated that Hcy regulates T cell mitochondrial reprogramming by enhancing endoplasmic reticulum (ER)-mitochondria coupling...
June 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Nazeer Fataftah, Christina Mohr, Mohammad-Reza Hajirezaei, Nicolaus von Wirén, Klaus Humbeck
BACKGROUND: Low availability of nitrogen (N) severely affects plant growth at different levels, which can be reverted by the resupply of N. To unravel the critical steps in primary metabolism underlying the growth adjustment in response to changes in N availability, transcriptomic and comprehensive metabolite analyses were performed in barley using primary leaves at early and later stages of N deprivation, and after N resupply to N-deficient plants. RESULT: N deficiency in leaves caused differential regulation of 1947 genes, mostly belonging to the functional classes photosynthesis, cell wall degradation, lipid degradation, amino acid degradation, transcription factors, phytohormone metabolism and receptor-like kinases...
May 4, 2018: BMC Plant Biology
Marie-Eve Chartier, Lara Hart, Massimiliano Paganelli, Najma Ahmed, Marc Bilodeau, Fernando Alvarez
Pyruvate kinase deficiency (PKD) is the most common cause of congenital nonspherocytic chronic hemolytic anemia, and patients normally present with mild to severe anemia, unconjugated hyperbilirubinemia, and splenomegaly. Only a few reports of PKD have documented its association with severe, progressive liver failure. In all those cases, the patients died before liver transplant (LT) or immediately after transplant. We report 2 case patients with liver failure associated with PKD who successfully underwent LT and splenectomy: an infant who presented with neonatal cholestasis and a young adult with a severe form of PKD and having been transfusion dependent during childhood...
April 2018: Pediatrics
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