scholarly journals Ineffective erythropoiesis in the spleen of a patient with pyruvate kinase deficiency

2003 ◽  
Vol 74 (1) ◽  
pp. 68-72 ◽  
Author(s):  
Shin Aizawa ◽  
Urara Kohdera ◽  
Masaki Hiramoto ◽  
Yutaka Kawakami ◽  
Ken-ichi Aisaki ◽  
...  
Keyword(s):  
Pyruvate Kinase ◽  
Ineffective Erythropoiesis ◽  
Pyruvate Kinase Deficiency

scholarly journals A Proposed Concept for Defective Mitophagy Leading to Late Stage Ineffective Erythropoiesis in Pyruvate Kinase Deficiency

2021 ◽  
Vol 11 ◽  
Author(s):  
Annelies Johanna van Vuren ◽  
Eduard Johannes van Beers ◽  
Richard van Wijk
Keyword(s):  
Pyruvate Kinase ◽  
Late Stage ◽  
Tca Cycle ◽  
Future Research ◽  
Ineffective Erythropoiesis ◽  
Pyruvate Kinase Deficiency ◽  
Regulated Cell Death ◽  
Starting Point ◽  
Reticulocyte Maturation ◽  
Autophagosome Maturation

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.

scholarly journals Evaluation of the Main Regulators of Systemic Iron Homeostasis in Pyruvate Kinase Deficiency

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1993-1993
Author(s):  
Anna Zaninoni ◽  
Roberta Russo ◽  
Roberta Marra ◽  
Elisa Fermo ◽  
Immacolata Andolfo ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Iron Homeostasis ◽  
Advisory Board ◽  
Ineffective Erythropoiesis ◽  
Advisory Committees ◽  
Pyruvate Kinase Deficiency ◽  
Rbc Membrane

Abstract Iron loading anemias are characterized by ineffective erythropoiesis and iron overload. This group of anemias includes thalassemia syndromes, congenital dyserythropoietic anemias (CDA), and some forms of congenital hemolytic anemias. Among them pyruvate kinase deficiency (PKD) has been shown to develop iron overload also in absence of transfusions suggesting dyserythropoietic features. Moreover, severe forms can be misdiagnosed as CDA due to bone marrow abnormalities and ineffective erythropoiesis further supporting this evidences. The hormone erythroferrone (hERFE) is produced by erythroblasts in response to erythropoietin (EPO), and acts by suppressing hepcidin, thereby increasing iron absorption and mobilisation for erythropoiesis demand. The ERFE-hepcidin axis seems to play a crucial role in the pathogenesis of these disorders; an increased erythroferrone release by immature erythroid cells results in hepcidin suppression and secondary iron overload that could finally results in ineffective erythropoiesis and anemia. To investigate the pathophysiological basis of iron overload in PKD, we analysed the levels of hERFE, EPO, hepcidin, and soluble transferrin receptor (sTFR) in a large group of 41 PKD patients equally distributed by gender, age and severity. The results were analysed in comparison with two groups of patients affected by hemolytic anemia with overt dyserythropoiesis (42 patients with CDA type II) and with congenital hemolytic anemia due to RBC membrane defects (51 patients with hereditary spherocytosis [HS]), respectively. Demographic, hematologic, and biochemical features of the three groups of patients are reported in the table. Among the PKD patients, 18/41 were <18 yrs, median Hb level at the time of the study was 9.05g/dL (range 5.5-14.5), 12 underwent splenectomy, 28 ever received at least three transfusions their life, 14 of them transfusion dependent (>6 tx/yrs). Mean ferritin levels at the time of the study were 546 ng/ml (range 59-4990), 15/41 patients requiring chelation therapy for iron overload developed also in absence of transfusions. As expected, CDAII patients showed decreased hepcidin levels (3.74 ng/mL; n.v. 17.25, P<0.001) associated with increased erythropoietin (62.7 IU/L, n.v. 6.5, P=0.01) and hERFE (24.8 ng/mL, n.v. 1, P<0.0001). On the contrary, HS showed increased hepcidin, with less marked increased of ERFE (9.9 ng/mL, P=0.02) and EPO (36.4IU/L, P=0.005). In PKD patients we observed decreased hepcidin levels (7.15 ng/mL, P=0.03)), increased hERFE (18ng/mL, P<0.0001) and EPO (75.6 IU/L, P=0.009). Instead, sTFR was equally increased in the three groups of patients (Figure). Interestingly, by comparing the three groups of patients, PKD showed dyserythropoietic features as evidenced by the observation of intermediate values between HS and CDAII of hepcidin (P=0.007 PKD v CDAII and P=0.0002 PKD vs HS), hEFRE, and sTFR. This study provides the first analysis of the main regulators of systemic iron homeostasis in PK deficiency compared either with the model of a structural RBC defect (HS) or with the typical model of dyserythropoietic anemia with ineffective erythropoiesis, such as CDAII. These data provide evidence of the dyserythropoietic features of PK deficiency, underlining the need of accurate diagnosis and paving the way of novel therapeutic approaches in PK deficiency. Zaninoni A. and Russo R. equally contributed to the study Figure 1 Figure 1. Disclosures Fattizzo: Kira: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Momenta: Honoraria, Speakers Bureau; Annexon: Consultancy; Apellis: Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Barcellini: Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria. Iolascon: Bluebird Bio: Other: Advisory Board; Celgene: Other: Advisory Board. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Sri Lankan girl with a new genetic variant in the PKLR gene causing pyruvate kinase deficiency: a case report

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Ahalyaa Sivashangar ◽  
Lallindra Gooneratne ◽  
Barnaby Clark ◽  
David Rees ◽  
Saroj Jayasinghe ◽  
...  
Keyword(s):  
Case Report ◽  
Pyruvate Kinase ◽  
Genetic Variant ◽  
Asian Population ◽  
Pathogenic Variant ◽  
Sri Lankan ◽  
Recessive Trait ◽  
Case Presentation ◽  
Pyruvate Kinase Deficiency ◽  
Hematological Disorders

Abstract Background Erythrocyte pyruvate kinase is expressed under the control of the PKLR gene located on chromosome 1q21. Pyruvate kinase catalyzes the final steps of the glycolytic pathway and creates 50% of the red cell total adenosine triphosphate. Pyruvate kinase deficiency is the commonest glycolytic defect causing congenital non-spherocytic hemolytic anemia inherited in an autosomal recessive trait in which homozygotes and compound heterozygotes are common. Over 200 mutations have been described in patients with pyruvate kinase deficiency. This case report identifies a new pathogenic variant in PKLR gene detected in a patient with severe pyruvate kinase deficiency. Case presentation A Sri Lankan Sinhalese girl who developed neonatal anemia and jaundice within 24 hours of birth with mild hepatomegaly. She was from a nonconsanguineous marriage and had two siblings who had no hematological disorders. She had repeated admissions due to similar illnesses and at the age of 8 years was found to have pyruvate kinase deficiency associated with a novel homozygous pathogenic variant c.507+1delG in the PKLR gene. Conclusions A novel genetic variant in PKLR gene, consistent with pyruvate kinase deficiency, was detected in a Sri Lankan girl. This genetic variant may be specific to the Asian population and requires further studies.

Six novel variants in the PKLR gene associated with pyruvate kinase deficiency in Argentinian patients

2021 ◽  
Author(s):  
Berenice Milanesio ◽  
Carolina Pepe ◽  
Lucas A. Defelipe ◽  
Silvia Eandi Eberle ◽  
Vanesa Avalos Gomez ◽  
...  
Keyword(s):  
Pyruvate Kinase ◽  
Pyruvate Kinase Deficiency ◽  
Novel Variants

IRON OVERLOAD IN CONGENITAL ERYTHROCYTE PYRUVATE KINASE DEFICIENCY

1980 ◽  
Vol 1 (11) ◽  
pp. 531-532 ◽  
Author(s):  
H. H. Salem ◽  
M. B. Van Der Weyden ◽  
B. G. Firkin
Keyword(s):  
Iron Overload ◽  
Pyruvate Kinase ◽  
Pyruvate Kinase Deficiency

Improving the laboratory diagnosis of pyruvate kinase deficiency

2021 ◽  
Author(s):  
Claire Laas ◽  
Christopher Lambert ◽  
Tania Senior McKenzie ◽  
Ewart Sheldon ◽  
Philip Davidson ◽  
...  
Keyword(s):  
Pyruvate Kinase ◽  
Laboratory Diagnosis ◽  
Pyruvate Kinase Deficiency

scholarly journals Clinically Relevant Gene Editing in Hematopoietic Stem Cells for the Treatment of Pyruvate Kinase Deficiency

2021 ◽  
Author(s):  
Sara Fañanas-Baquero ◽  
Oscar Quintana-Bustamante ◽  
Daniel P. Dever ◽  
Omaira Alberquilla ◽  
Rebeca Sanchez ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Pyruvate Kinase ◽  
Gene Editing ◽  
Hematopoietic Stem ◽  
Pyruvate Kinase Deficiency ◽  
Relevant Gene

scholarly journals Laboratory approach to investigation of anemia with a focus on pyruvate kinase deficiency

2020 ◽  
Vol 42 (S1) ◽  
pp. 107-112
Author(s):  
Archana M. Agarwal ◽  
Anton Rets
Keyword(s):  
Pyruvate Kinase ◽  
Pyruvate Kinase Deficiency

On the molecular basis of pyruvate kinase deficiency II. Role of thiol groups in pyruvate kinase from pyruvate kinase-deficient patients

1974 ◽  
Vol 334 (2) ◽  
pp. 361-367 ◽  
Author(s):  
Th.J.C. Van Berkel ◽  
G.E.J. Staal ◽  
J.F. Koster ◽  
J.G. Nyessen ◽  
L. van Milligen-Boersma
Keyword(s):  
Pyruvate Kinase ◽  
Molecular Basis ◽  
Thiol Groups ◽  
Pyruvate Kinase Deficiency
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