The Experts below are selected from a list of 258 Experts worldwide ranked by ideXlab platform
Paola Bianchi - One of the best experts on this subject based on the ideXlab platform.
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the variable manifestations of disease in Pyruvate Kinase Deficiency and their management
Haematologica, 2020Co-Authors: Hanny Alsamkari, Paola Bianchi, Wilma Barcellini, Eduard J Van Beers, Kevin H M Kuo, Bertil Glader, Maria Del Mar Mañú-pereira, Richard Van Wijk, Andreas Glenthoj, Rachael F GraceAbstract:Pyruvate Kinase Deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia and results in a broad spectrum of disease. The diagnosis of PKD requires a high index of suspicion and judicious use of laboratory tests that may not always be informative, including Pyruvate Kinase enzyme assay and genetic analysis of the PKLR gene. A significant minority of patients with PKD have occult mutations in non-coding regions of PKLR which are missed on standard genetic tests. The biochemical consequences of PKD result in hemolytic anemia due to red cell Pyruvate and ATP Deficiency while simultaneously causing increased red cell 2,3-diphosphoglycerate, which facilitates oxygen unloading. This phenomenon, in addition to numerous other factors such as genetic background and differences in splenic function result in a poor correlation between symptoms and degree of anemia from patient to patient. Red cell transfusions should, therefore, be symptom-directed and not based on a hemoglobin threshold. Patients may experience specific complications, such as paravertebral extramedullary hematopoiesis and chronic debilitating icterus, which require personalized treatment. The decision to perform splenectomy or hematopoietic stem cell transplantation is nuanced and depends on disease burden and long-term outlook given that targeted therapeutics are in development. In recognition of the complicated nature of the disease and its management and the limitations of the PKD literature, an international working group of ten PKD experts convened to better define the disease burden and manifestations. This article summarizes the conclusions of this working group and is a guide for clinicians and investigators caring for patients with PKD.
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addressing the diagnostic gaps in Pyruvate Kinase Deficiency consensus recommendations on the diagnosis of Pyruvate Kinase Deficiency
American Journal of Hematology, 2019Co-Authors: Paola Bianchi, Wilma Barcellini, Elisa Fermo, Bertil Glader, Hitoshi Kanno, Archana M Agarwal, Stefan Eber, James D Hoyer, David J Kuter, Tabita M MaiaAbstract:Pyruvate Kinase Deficiency (PKD) is the most common enzyme defect of glycolysis and an important cause of hereditary, nonspherocytic hemolytic anemia. The disease has a worldwide geographical distribution but there are no verified data regarding its frequency. Difficulties in the diagnostic workflow and interpretation of PK enzyme assay likely play a role. By the creation of a global PKD International Working Group in 2016, involving 24 experts from 20 Centers of Expertise we studied the current gaps in the diagnosis of PKD in order to establish diagnostic guidelines. By means of a detailed survey and subsequent discussions, multiple aspects of the diagnosis of PKD were evaluated and discussed by members of Expert Centers from Europe, USA, and Asia directly involved in diagnosis. Broad consensus was reached among the Centers on many clinical and technical aspects of the diagnosis of PKD. The results of this study are here presented as recommendations for the diagnosis of PKD and used to prepare a diagnostic algorithm. This information might be helpful for other Centers to deliver timely and appropriate diagnosis and to increase awareness in PKD.
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a new variant of pklr gene associated with mild hemolysis may be responsible for the misdiagnosis in Pyruvate Kinase Deficiency
Journal of Pediatric Hematology Oncology, 2019Co-Authors: Sultan Aydin Koker, Paola Bianchi, Elisa Fermo, Yesim Oymak, Salih Gozmen, Tuba Hilkay Karapinar, Raziye Canan VerginAbstract: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. When a biochemical analysis was performed in our patient and her parents who had consanguinity, a decreased PK activity was detected in the patient and her father. After the molecular study of PKLR gene, a new homozygote variant, c.1708G>T (pVal570Leu), was found in our patient and her father. Her father had a misdiagnosis of Gilbert syndrome because he had unconjugated hyperbilirubinemia and not anemia. Her mother was also a carrier of the mutation in heterozygous state. Patients presenting with hemolytic anemia, either severe or mild hemolytic anemia, should be screened for PKD in the first year of life. Patients with mild hemolytic findings can be followed-up with misdiagnoses.
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Six children with Pyruvate Kinase Deficiency from one small town: molecular characterization of the PK-LR gene.
The Journal of pediatrics, 2011Co-Authors: Robert D. Christensen, Paola Bianchi, Hassan M Yaish, Charlotte B. Johnson, Alberto ZanellaAbstract:We identified the Pyruvate Kinase liver/red cell enzyme gene mutation of 8 children previously diagnosed with Pyruvate Kinase Deficiency who were living in a remote town in the western United States. Six were found to be homozygous for the mutation 1529G-A (510 Arg-Gln). Two previously thought to have Pyruvate Kinase Deficiency did not, because they were heterozygous.
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Regulation of iron metabolism through GDF15 and hepcidin in Pyruvate Kinase Deficiency.
British journal of haematology, 2008Co-Authors: Armin Finkenstedt, Paola Bianchi, Igor Theurl, Wolfgang Vogel, Derrick R. Witcher, Victor J. Wroblewski, Anthony T. Murphy, Alberto Zanella, Heinz ZollerAbstract:Iron absorption is inadequately increased in patients with chronic haemolytic anaemia, which is commonly complicated by iron overload. Growth differentiation factor 15 (GDF15) has been identified as a bone marrow-derived factor that abrogates hepcidin-mediated protection from iron overload under conditions of increased erythropoiesis. Increased concentrations of GDF15 have been reported in beta-thalassaemia patients and GDF15 has been found to suppress hepcidin expression in vitro. To further study the interdependencies of iron metabolism and erythropoiesis in vivo, the concentrations of hepcidin and GDF15 were determined in sera from 22 patients with Pyruvate Kinase Deficiency (PKD) and 21 healthy control subjects. In PKD patients, serum hepcidin levels were 13-fold lower than in controls (2.0 ng/ml vs. 26.2 ng/ml) and GDF15 was significantly higher (859 pg/ml vs. 528 pg/ml). Serum hepcidin concentrations correlated positively with haemoglobin and negatively with serum GDF15. These results suggest that GDF15 contributes to low hepcidin expression and iron loading in PKD.
Alberto Zanella - One of the best experts on this subject based on the ideXlab platform.
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Hereditary Xerocytosis due to Mutations in PIEZO1 Gene Associated with Heterozygous Pyruvate Kinase Deficiency and Beta-Thalassemia Trait in Two Unrelated Families
Hindawi Limited, 2017Co-Authors: Elisa Fermo, Alberto Zanella, Cristina Vercellati, Anna Paola Marcello, Anna Zaninoni, Richard Van Wijk, Nadia Mirra, Cristina Curcio, Agostino Cortelezzi, Wilma BarcelliniAbstract:Hereditary xerocytosis (HX) is a rare disorder caused by defects of RBC permeability, associated with haemolytic anaemia of variable degree and iron overload. It is sometimes misdiagnosed as hereditary spherocytosis or other congenital haemolytic anaemia. Splenectomy is contraindicated due to increased risk of thromboembolic complications. We report the clinical, haematological, and molecular characteristics of four patients from two unrelated Italian families affected by HX, associated with beta-thalassemia trait and heterozygous Pyruvate Kinase Deficiency, respectively. Two patients had been splenectomised and displayed thrombotic episodes. All patients had iron overload in the absence of transfusion, two of them requiring iron chelation. The diagnosis of HX was confirmed by LoRRca Osmoscan analysis showing a left-shifted curve. PIEZO1 gene sequencing revealed the presence of mutation p.E2496ELE, showing that this is one of the most frequent mutations in this disease. The concomitant defects did not aggravate the clinical phenotype; however, in one patient, the initial diagnosis of Pyruvate Kinase Deficiency delayed the correct diagnosis of HX for many years and resulted in splenectomy followed by thrombotic complications. The study underlines the importance of a precise diagnosis in HX, particularly in view of splenectomy, and the need of a molecular confirmation of suspected RBC enzymopathy
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erythrocyte Pyruvate Kinase Deficiency 2015 status report
American Journal of Hematology, 2015Co-Authors: Rachael F Grace, Alberto Zanella, Hassan M Yaish, Ellis J Neufeld, Holmes D Morto, Stefa Ebe, Ertil GladeAbstract:Over the last several decades, our understanding of the genetic variation, pathophysiology, and complications of the hemolytic anemia associated with red cell Pyruvate Kinase Deficiency (PKD) has expanded. Nonetheless, there remain significant gaps in our knowledge with regard to clinical care and monitoring. Treatment remains supportive with phototherapy and/or exchange transfusion in the newborn period, regular or intermittent red cell transfusions in children and adults, and splenectomy to decrease transfusion requirements and/or anemia related symptoms. In this article, we review the clinical diversity of PKD, the current standard of treatment and for supportive care, the complications observed, and future treatment directions.Am. J. Hematol. 90:825–830, 2015. © 2015 Wiley Periodicals, Inc.
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Six children with Pyruvate Kinase Deficiency from one small town: molecular characterization of the PK-LR gene.
The Journal of pediatrics, 2011Co-Authors: Robert D. Christensen, Paola Bianchi, Hassan M Yaish, Charlotte B. Johnson, Alberto ZanellaAbstract:We identified the Pyruvate Kinase liver/red cell enzyme gene mutation of 8 children previously diagnosed with Pyruvate Kinase Deficiency who were living in a remote town in the western United States. Six were found to be homozygous for the mutation 1529G-A (510 Arg-Gln). Two previously thought to have Pyruvate Kinase Deficiency did not, because they were heterozygous.
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Regulation of iron metabolism through GDF15 and hepcidin in Pyruvate Kinase Deficiency.
British journal of haematology, 2008Co-Authors: Armin Finkenstedt, Paola Bianchi, Igor Theurl, Wolfgang Vogel, Derrick R. Witcher, Victor J. Wroblewski, Anthony T. Murphy, Alberto Zanella, Heinz ZollerAbstract:Iron absorption is inadequately increased in patients with chronic haemolytic anaemia, which is commonly complicated by iron overload. Growth differentiation factor 15 (GDF15) has been identified as a bone marrow-derived factor that abrogates hepcidin-mediated protection from iron overload under conditions of increased erythropoiesis. Increased concentrations of GDF15 have been reported in beta-thalassaemia patients and GDF15 has been found to suppress hepcidin expression in vitro. To further study the interdependencies of iron metabolism and erythropoiesis in vivo, the concentrations of hepcidin and GDF15 were determined in sera from 22 patients with Pyruvate Kinase Deficiency (PKD) and 21 healthy control subjects. In PKD patients, serum hepcidin levels were 13-fold lower than in controls (2.0 ng/ml vs. 26.2 ng/ml) and GDF15 was significantly higher (859 pg/ml vs. 528 pg/ml). Serum hepcidin concentrations correlated positively with haemoglobin and negatively with serum GDF15. These results suggest that GDF15 contributes to low hepcidin expression and iron loading in PKD.
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Red Cell Pyruvate Kinase Deficiency: Molecular Characterization of 10 New Variants.
Blood, 2004Co-Authors: Elisa Fermo, Paola Bianchi, Cristina Vercellati, Frédéric Cotton, Alberto ZanellaAbstract:PK Deficiency is the most common glycolytic enzyme defect associated with chronic non-spherocytic hemolytic anemia. To date about 150 different mutations have been identified in the PK-LR gene. Among them only one large deletion has been described in Gipsy resulting in the loss of exon 11. We report 10 new variants of LR-PK gene in 8 families with Pyruvate Kinase Deficiency. The entire coding region and intronic flanking regions were analyzed by direct sequencing. The results of the molecular analysis are reported in the table: Mutations reported in bold are new. By comparing the amino acids sequences among several species (cat M1, chicken M, rat L, yeast and human), we found that mutations 661A, 859C, 958A, 1094T and 1209A involve highly conserved residues. Mutation 1209A when present in association with 661A (cases NA and NR) results in a severe clinical pattern with need of transfusion support, whereas in compound heterozygosity with 1456T (case SA, mother of NA and NR) is associated with a less severe clinical pattern. The variant 1706A was found in a patient carrying the polymorphism 1705C at the homozygous level; the mutation in association with the polymorphism determines the aminoacidic substitution Arg596Gln. A deletion of 5006 nucleotides extending from intron 3 to the last 3 nucleotides of exon 10 has been found in an Australian baby dead at birth (case TT); the mutation results in a large cDNA deletion encompassing exon 4 and exon11 included. This is the largest abnormality so far detected in LR-PK gene.
Rachael F Grace - One of the best experts on this subject based on the ideXlab platform.
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Management of Pyruvate Kinase Deficiency in children and adults
Blood, 2020Co-Authors: Rachael F Grace, Wilma BarcelliniAbstract:Pyruvate Kinase Deficiency (PKD) is an autosomal-recessive enzyme defect of the glycolytic pathway that causes congenital nonspherocytic hemolytic anemia. The diagnosis and management of patients with PKD can be challenging due to difficulties in the diagnostic evaluation and the heterogeneity of clinical manifestations, ranging from fetal hydrops and symptomatic anemia requiring lifelong transfusions to fully compensated hemolysis. Current treatment approaches are supportive and include transfusions, splenectomy, and chelation. Complications, including iron overload, bilirubin gallstones, extramedullary hematopoiesis, pulmonary hypertension, and thrombosis, are related to the chronic hemolytic anemia and its current management and can occur at any age. Disease-modifying therapies in clinical development may decrease symptoms and findings associated with chronic hemolysis and avoid the complications associated with current treatment approaches. As these disease-directed therapies are approved for clinical use, clinicians will need to define the types of symptoms and findings that determine the optimal patients and timing for initiating these therapies. In this article, we highlight disease manifestations, monitoring approaches, strategies for managing complications, and novel therapies in development.
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the variable manifestations of disease in Pyruvate Kinase Deficiency and their management
Haematologica, 2020Co-Authors: Hanny Alsamkari, Paola Bianchi, Wilma Barcellini, Eduard J Van Beers, Kevin H M Kuo, Bertil Glader, Maria Del Mar Mañú-pereira, Richard Van Wijk, Andreas Glenthoj, Rachael F GraceAbstract:Pyruvate Kinase Deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia and results in a broad spectrum of disease. The diagnosis of PKD requires a high index of suspicion and judicious use of laboratory tests that may not always be informative, including Pyruvate Kinase enzyme assay and genetic analysis of the PKLR gene. A significant minority of patients with PKD have occult mutations in non-coding regions of PKLR which are missed on standard genetic tests. The biochemical consequences of PKD result in hemolytic anemia due to red cell Pyruvate and ATP Deficiency while simultaneously causing increased red cell 2,3-diphosphoglycerate, which facilitates oxygen unloading. This phenomenon, in addition to numerous other factors such as genetic background and differences in splenic function result in a poor correlation between symptoms and degree of anemia from patient to patient. Red cell transfusions should, therefore, be symptom-directed and not based on a hemoglobin threshold. Patients may experience specific complications, such as paravertebral extramedullary hematopoiesis and chronic debilitating icterus, which require personalized treatment. The decision to perform splenectomy or hematopoietic stem cell transplantation is nuanced and depends on disease burden and long-term outlook given that targeted therapeutics are in development. In recognition of the complicated nature of the disease and its management and the limitations of the PKD literature, an international working group of ten PKD experts convened to better define the disease burden and manifestations. This article summarizes the conclusions of this working group and is a guide for clinicians and investigators caring for patients with PKD.
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safety and efficacy of mitapivat in Pyruvate Kinase Deficiency
The New England Journal of Medicine, 2019Co-Authors: Rachael F Grace, Yaddanapudi Ravindranath, Christian Rose, Mark D Layton, Frederic Galacteros, Wilma Barcellini, Holmes D Morton, Eduard J Van Beers, Hassan M Yaish, Kevin H M KuoAbstract:Abstract Background Pyruvate Kinase Deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of Pyruvate Kinase ...
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How we manage patients with Pyruvate Kinase Deficiency.
British journal of haematology, 2019Co-Authors: Rachael F Grace, D. Mark Layton, Wilma BarcelliniAbstract:Novel therapies in development have brought a new focus on Pyruvate Kinase Deficiency (PKD), the most common congenital haemolytic anaemia due to a glycolytic enzyme Deficiency. With an improved recognition of its clinical presentation and understanding of the diagnostic pathway, more patients are likely to be identified with this anaemia. Complications, including gallstones and non-transfusion-related iron overload, require monitoring for early diagnosis and management. Current management remains supportive with red cell transfusions, chelation and splenectomy. Decisions to transfuse and/or splenectomise must be individualised. Haematopoietic stem cell transplant has been pursued in a small number of patients with mixed outcomes. Novel treatment approaches, which range from a small molecule Pyruvate Kinase activator to gene therapy, may transform the way in which PKD is managed in the future. In this review, we discuss the pathophysiology of PKD and present our approaches to diagnosis, monitoring and management of patients with this anaemia.
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erythrocyte Pyruvate Kinase Deficiency 2015 status report
American Journal of Hematology, 2015Co-Authors: Rachael F Grace, Alberto Zanella, Hassan M Yaish, Ellis J Neufeld, Holmes D Morto, Stefa Ebe, Ertil GladeAbstract:Over the last several decades, our understanding of the genetic variation, pathophysiology, and complications of the hemolytic anemia associated with red cell Pyruvate Kinase Deficiency (PKD) has expanded. Nonetheless, there remain significant gaps in our knowledge with regard to clinical care and monitoring. Treatment remains supportive with phototherapy and/or exchange transfusion in the newborn period, regular or intermittent red cell transfusions in children and adults, and splenectomy to decrease transfusion requirements and/or anemia related symptoms. In this article, we review the clinical diversity of PKD, the current standard of treatment and for supportive care, the complications observed, and future treatment directions.Am. J. Hematol. 90:825–830, 2015. © 2015 Wiley Periodicals, Inc.
Wilma Barcellini - One of the best experts on this subject based on the ideXlab platform.
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Management of Pyruvate Kinase Deficiency in children and adults
Blood, 2020Co-Authors: Rachael F Grace, Wilma BarcelliniAbstract:Pyruvate Kinase Deficiency (PKD) is an autosomal-recessive enzyme defect of the glycolytic pathway that causes congenital nonspherocytic hemolytic anemia. The diagnosis and management of patients with PKD can be challenging due to difficulties in the diagnostic evaluation and the heterogeneity of clinical manifestations, ranging from fetal hydrops and symptomatic anemia requiring lifelong transfusions to fully compensated hemolysis. Current treatment approaches are supportive and include transfusions, splenectomy, and chelation. Complications, including iron overload, bilirubin gallstones, extramedullary hematopoiesis, pulmonary hypertension, and thrombosis, are related to the chronic hemolytic anemia and its current management and can occur at any age. Disease-modifying therapies in clinical development may decrease symptoms and findings associated with chronic hemolysis and avoid the complications associated with current treatment approaches. As these disease-directed therapies are approved for clinical use, clinicians will need to define the types of symptoms and findings that determine the optimal patients and timing for initiating these therapies. In this article, we highlight disease manifestations, monitoring approaches, strategies for managing complications, and novel therapies in development.
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the variable manifestations of disease in Pyruvate Kinase Deficiency and their management
Haematologica, 2020Co-Authors: Hanny Alsamkari, Paola Bianchi, Wilma Barcellini, Eduard J Van Beers, Kevin H M Kuo, Bertil Glader, Maria Del Mar Mañú-pereira, Richard Van Wijk, Andreas Glenthoj, Rachael F GraceAbstract:Pyruvate Kinase Deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia and results in a broad spectrum of disease. The diagnosis of PKD requires a high index of suspicion and judicious use of laboratory tests that may not always be informative, including Pyruvate Kinase enzyme assay and genetic analysis of the PKLR gene. A significant minority of patients with PKD have occult mutations in non-coding regions of PKLR which are missed on standard genetic tests. The biochemical consequences of PKD result in hemolytic anemia due to red cell Pyruvate and ATP Deficiency while simultaneously causing increased red cell 2,3-diphosphoglycerate, which facilitates oxygen unloading. This phenomenon, in addition to numerous other factors such as genetic background and differences in splenic function result in a poor correlation between symptoms and degree of anemia from patient to patient. Red cell transfusions should, therefore, be symptom-directed and not based on a hemoglobin threshold. Patients may experience specific complications, such as paravertebral extramedullary hematopoiesis and chronic debilitating icterus, which require personalized treatment. The decision to perform splenectomy or hematopoietic stem cell transplantation is nuanced and depends on disease burden and long-term outlook given that targeted therapeutics are in development. In recognition of the complicated nature of the disease and its management and the limitations of the PKD literature, an international working group of ten PKD experts convened to better define the disease burden and manifestations. This article summarizes the conclusions of this working group and is a guide for clinicians and investigators caring for patients with PKD.
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safety and efficacy of mitapivat in Pyruvate Kinase Deficiency
The New England Journal of Medicine, 2019Co-Authors: Rachael F Grace, Yaddanapudi Ravindranath, Christian Rose, Mark D Layton, Frederic Galacteros, Wilma Barcellini, Holmes D Morton, Eduard J Van Beers, Hassan M Yaish, Kevin H M KuoAbstract:Abstract Background Pyruvate Kinase Deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of Pyruvate Kinase ...
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How we manage patients with Pyruvate Kinase Deficiency.
British journal of haematology, 2019Co-Authors: Rachael F Grace, D. Mark Layton, Wilma BarcelliniAbstract:Novel therapies in development have brought a new focus on Pyruvate Kinase Deficiency (PKD), the most common congenital haemolytic anaemia due to a glycolytic enzyme Deficiency. With an improved recognition of its clinical presentation and understanding of the diagnostic pathway, more patients are likely to be identified with this anaemia. Complications, including gallstones and non-transfusion-related iron overload, require monitoring for early diagnosis and management. Current management remains supportive with red cell transfusions, chelation and splenectomy. Decisions to transfuse and/or splenectomise must be individualised. Haematopoietic stem cell transplant has been pursued in a small number of patients with mixed outcomes. Novel treatment approaches, which range from a small molecule Pyruvate Kinase activator to gene therapy, may transform the way in which PKD is managed in the future. In this review, we discuss the pathophysiology of PKD and present our approaches to diagnosis, monitoring and management of patients with this anaemia.
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addressing the diagnostic gaps in Pyruvate Kinase Deficiency consensus recommendations on the diagnosis of Pyruvate Kinase Deficiency
American Journal of Hematology, 2019Co-Authors: Paola Bianchi, Wilma Barcellini, Elisa Fermo, Bertil Glader, Hitoshi Kanno, Archana M Agarwal, Stefan Eber, James D Hoyer, David J Kuter, Tabita M MaiaAbstract:Pyruvate Kinase Deficiency (PKD) is the most common enzyme defect of glycolysis and an important cause of hereditary, nonspherocytic hemolytic anemia. The disease has a worldwide geographical distribution but there are no verified data regarding its frequency. Difficulties in the diagnostic workflow and interpretation of PK enzyme assay likely play a role. By the creation of a global PKD International Working Group in 2016, involving 24 experts from 20 Centers of Expertise we studied the current gaps in the diagnosis of PKD in order to establish diagnostic guidelines. By means of a detailed survey and subsequent discussions, multiple aspects of the diagnosis of PKD were evaluated and discussed by members of Expert Centers from Europe, USA, and Asia directly involved in diagnosis. Broad consensus was reached among the Centers on many clinical and technical aspects of the diagnosis of PKD. The results of this study are here presented as recommendations for the diagnosis of PKD and used to prepare a diagnostic algorithm. This information might be helpful for other Centers to deliver timely and appropriate diagnosis and to increase awareness in PKD.
Richard Van Wijk - One of the best experts on this subject based on the ideXlab platform.
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a proposed concept for defective mitophagy leading to late stage ineffective erythropoiesis in Pyruvate Kinase Deficiency
Frontiers in Physiology, 2021Co-Authors: Annelies J Van Vuren, Eduard J Van Beers, Richard Van WijkAbstract:Pyruvate Kinase Deficiency (PKD) is a rare congenital hemolytic anemia caused by mutations in the PKLR gene. Here, we review pathophysiological aspects of PKD, focusing on the interplay between Pyruvate Kinase (PK)-activity and reticulocyte maturation in the light of ferroptosis, an iron-dependent process of regulated cell death, and in particular its key player glutathione peroxidase 4 (GPX4). GPX4 plays an important role in mitophagy, the key step of peripheral reticulocyte maturation and GPX4 Deficiency in reticulocytes results in a failure to fully mature. Mitophagy depends on lipid oxidation, which is under physiological conditions controlled by GPX4. Lack of GPX4 leads to uncontrolled auto-oxidation, which will disrupt autophagosome maturation and thereby perturb mitophagy. Based on our review, we propose a model for disturbed red cell maturation in PKD. A relative GPX4 Deficiency occurs due to glutathione (GSH) depletion, as cytosolic L-glutamine is preferentially used in the form of α-ketoglutarate as fuel for the tricarboxylic acid (TCA) cycle at the expense of GSH production. The relative GPX4 Deficiency will perturb mitophagy and, subsequently, results in failure of reticulocyte maturation, which can be defined as late stage ineffective erythropoiesis. Our hypothesis provides a starting point for future research into new therapeutic possibilities, which have the ability to correct the oxidative imbalance due to lack of GPX4.
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Untargeted metabolic profiling in dried blood spots identifies disease fingerprint for Pyruvate Kinase Deficiency.
Haematologica, 2020Co-Authors: Birgit Van Dooijeweert, Eduard J Van Beers, Wouter W. Van Solinge, Melissa H. Broeks, Nanda M. Verhoeven-duif, Edward E. S. Nieuwenhuis, Marije Bartels, Judith J.m. Jans, Richard Van WijkAbstract:The diagnostic evaluation and clinical characterization of rare hereditary anemia (RHA) is to date still challenging. In particular, there is little knowledge on the broad metabolic impact of many of the molecular defects underlying RHA. In this study we explored the potential of untargeted metabolomics to diagnose a relatively common type of RHA: Pyruvate Kinase Deficiency (PKD). In total, 1903 unique metabolite features were identified in dried blood spot samples from 16 PKD patients and 32 healthy controls. A metabolic fingerprint was identified using a machine learning algorithm, and subsequently a binary classification model was designed. The model showed high performance characteristics (AUC 0.990, 95%CI 0.981-0.999) and an accurate class assignment was achieved for all newly added control (13) and patient samples (6), with the exception of one patient (accuracy 94%). Important metabolites in the metabolic fingerprint included glycolytic intermediates, polyamines and several acyl carnitines. In general, the application of untargeted metabolomics in dried blood spots is a novel functional tool that holds promise for diagnostic stratification and studies on disease pathophysiology in RHA.
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the variable manifestations of disease in Pyruvate Kinase Deficiency and their management
Haematologica, 2020Co-Authors: Hanny Alsamkari, Paola Bianchi, Wilma Barcellini, Eduard J Van Beers, Kevin H M Kuo, Bertil Glader, Maria Del Mar Mañú-pereira, Richard Van Wijk, Andreas Glenthoj, Rachael F GraceAbstract:Pyruvate Kinase Deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia and results in a broad spectrum of disease. The diagnosis of PKD requires a high index of suspicion and judicious use of laboratory tests that may not always be informative, including Pyruvate Kinase enzyme assay and genetic analysis of the PKLR gene. A significant minority of patients with PKD have occult mutations in non-coding regions of PKLR which are missed on standard genetic tests. The biochemical consequences of PKD result in hemolytic anemia due to red cell Pyruvate and ATP Deficiency while simultaneously causing increased red cell 2,3-diphosphoglycerate, which facilitates oxygen unloading. This phenomenon, in addition to numerous other factors such as genetic background and differences in splenic function result in a poor correlation between symptoms and degree of anemia from patient to patient. Red cell transfusions should, therefore, be symptom-directed and not based on a hemoglobin threshold. Patients may experience specific complications, such as paravertebral extramedullary hematopoiesis and chronic debilitating icterus, which require personalized treatment. The decision to perform splenectomy or hematopoietic stem cell transplantation is nuanced and depends on disease burden and long-term outlook given that targeted therapeutics are in development. In recognition of the complicated nature of the disease and its management and the limitations of the PKD literature, an international working group of ten PKD experts convened to better define the disease burden and manifestations. This article summarizes the conclusions of this working group and is a guide for clinicians and investigators caring for patients with PKD.
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Hereditary Xerocytosis due to Mutations in PIEZO1 Gene Associated with Heterozygous Pyruvate Kinase Deficiency and Beta-Thalassemia Trait in Two Unrelated Families
Hindawi Limited, 2017Co-Authors: Elisa Fermo, Alberto Zanella, Cristina Vercellati, Anna Paola Marcello, Anna Zaninoni, Richard Van Wijk, Nadia Mirra, Cristina Curcio, Agostino Cortelezzi, Wilma BarcelliniAbstract:Hereditary xerocytosis (HX) is a rare disorder caused by defects of RBC permeability, associated with haemolytic anaemia of variable degree and iron overload. It is sometimes misdiagnosed as hereditary spherocytosis or other congenital haemolytic anaemia. Splenectomy is contraindicated due to increased risk of thromboembolic complications. We report the clinical, haematological, and molecular characteristics of four patients from two unrelated Italian families affected by HX, associated with beta-thalassemia trait and heterozygous Pyruvate Kinase Deficiency, respectively. Two patients had been splenectomised and displayed thrombotic episodes. All patients had iron overload in the absence of transfusion, two of them requiring iron chelation. The diagnosis of HX was confirmed by LoRRca Osmoscan analysis showing a left-shifted curve. PIEZO1 gene sequencing revealed the presence of mutation p.E2496ELE, showing that this is one of the most frequent mutations in this disease. The concomitant defects did not aggravate the clinical phenotype; however, in one patient, the initial diagnosis of Pyruvate Kinase Deficiency delayed the correct diagnosis of HX for many years and resulted in splenectomy followed by thrombotic complications. The study underlines the importance of a precise diagnosis in HX, particularly in view of splenectomy, and the need of a molecular confirmation of suspected RBC enzymopathy
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partial Pyruvate Kinase Deficiency aggravates the phenotypic expression of band 3 Deficiency in a family with hereditary spherocytosis
American Journal of Hematology, 2015Co-Authors: Rob Van Zwieten, Wouter W. Van Solinge, Brigitte A Van Oirschot, Martijn Veldthuis, Johannes G G Dobbe, Geert J Streekstra, Roger E G Schutgens, Richard Van WijkAbstract:In a family with mild dominant spherocytosis, affected members showed partial band 3 Deficiency. The index patient showed more severe clinical symptoms than his relatives, and his red blood cells displayed concomitant low Pyruvate Kinase activity. We investigated the contribution of partial PK Deficiency to the phenotypic expression of mutant band 3 in this family. Pyruvate Kinase Deficiency and band 3 Deficiency were characterized by DNA analysis. Results of red cell osmotic fragility testing, the results of cell deformability obtained by the Automated Rheoscope and Cell Analyzer and the results obtained by Osmotic Gradient Ektacytometry, which is a combination of these tests, were related to the red cell ATP content. Spherocytosis in this family was due to a novel heterozygous mutation in SLC4A1, the gene for band 3. Reduced PK activity of the index patient was attributed to a novel mutation in PKLR inherited from his mother, who was without clinical symptoms. Partial PK Deficiency was associated with decreased red cell ATP content and markedly increased osmotic fragility. This suggests an aggravating effect of low ATP levels on the phenotypic expression of band 3 Deficiency.
