scholarly journals Pyruvate kinase deficiency: epidemiology, molecular analyses and modern diagnostic approaches (literature review)

2020 ◽  
Vol 7 (2) ◽  
pp. 86-93
Author(s):  
A. V. Bankole ◽  
E. A. Chernyak
Keyword(s):  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Molecular Genetic ◽  
Clinical Manifestations ◽  
Diagnostic Methods ◽  
Compound Heterozygous ◽  
Red Cell ◽  
Molecular Genetic Study ◽  
Pyruvate Kinase Deficiency ◽  
Diagnostic Approaches

Red cell pyruvate kinase deficiency is the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Pyruvate kinase is the enzyme involved in the last step of glycolysis – the transfer of a phosphate group from phosphoenolpyruvate producing the enolate of pyruvate and ATP (50 % of total energy ATP of erythrocytes). ATP deficiency directly shortened red cell lifespan. Affected red blood cells are destroyed in the splenic capillaries, leading to the development of chronic hemolytic anemia. It is an autosomal recessive disease, caused by homozygous and compound heterozygous mutations in the PKLR gene. There are no exact data on the incidence of pyruvate kinase deficiency, but the estimated frequency varies from 3: 1,000,000 to 1:20,000. The clinical features of the disease and the severity are highly variable. Diagnosis of pyruvate kinase deficiency is based on the determination of pyruvate kinase activity and molecular genetic study of the PKLR gene. The variety of clinical manifestations, possible complications, as well as the inaccessibility of diagnostic methods complicate the diagnosis.

scholarly journals Diagnostic challenges in pyruvate kinase deficiency

2020 ◽  
Vol 19 (3) ◽  
pp. 90-94
Author(s):  
F. R. Khadzhieva ◽  
S. N. Mushanova ◽  
T. N. Kekeeva ◽  
I. N. Lavrentyeva ◽  
E. V. Raykina
Keyword(s):  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Clinical Case ◽  
Compound Heterozygous ◽  
Red Cell ◽  
Review Of Literature ◽  
Pyruvate Kinase Deficiency ◽  
Analytical Review ◽  
Homozygous Mutations ◽  
Chromosome 1Q21

Red cell pyruvate kinase deficiency is a rare congenital, nonspherocytic hemolytic anemia caused by a glycolytic defect that is due to compound heterozygous or homozygous mutations in the PKLR gene on chromosome 1q21. The article presents analytical review of literature and the clinical case of pyruvate kinase deficiency. Patient's parents agreed to use personal dats and photos in research and publications.

Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3585-3588 ◽  
Author(s):  
Ernest Beutler ◽  
Terri Gelbart
Keyword(s):  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Relative Frequency ◽  
Gene Frequency ◽  
Red Cell ◽  
White Population ◽  
Pyruvate Kinase Deficiency ◽  
Oligonucleotide Hybridization ◽  
Allele Specific ◽  
White Patients

Pyruvate kinase (PK) deficiency is the most common cause of hereditary nonspherocytic hemolytic anemia. The prevalence of this deficiency is unknown, though some estimates have been made based on the frequency of low red cell PK activity in the population. An additional 20 patients with hereditary nonspherocytic hemolytic anemia caused by PK deficiency have been genotyped. One previously unreported mutation 1153C→T (R385W) was encountered. The relative frequency of PK mutations in patients with hemolytic anemia caused by PK deficiency was calculated from the 18 white patients reported here and from 102 patients previously reported in the literature. DNA samples from 3785 subjects from different ethnic groups have been screened for the 4 more frequently encountered mutations—c.1456 C→T(1456T), c.1468 C→T(1468T), c.1484 C→T(1484T), and c.1529 G6A (1529A)—by allele-specific oligonucleotide hybridization. Among white patients the frequency of the 1456T mutation was 3.50 × 10−3; that of the 1529A mutation was 2.03 × 10−3. Among African Americans the frequency of the 1456T mutation was 3.90 × 10−3 The only mutation found in the limited number of Asians tested was 1468T at a frequency of 7.94 × 10−3. Based on the gene frequency of the 1529A mutation in the white population and on its relative abundance in patients with hemolytic anemia caused by PK deficiency, the prevalence of PK deficiency is estimated at 51 cases per million white population. This number would be increased by inbreeding and decreased by failure of patients with PK deficiency to survive.

scholarly journals Decreased Activity and Stability of Pyruvate Kinase in Hereditary Hemolytic Anemia: A Potential Target for Therapy By AG-348 (Mitapivat), an Allosteric Activator of Red Blood Cell Pyruvate Kinase

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3506-3506
Author(s):  
Minke A.E. Rab ◽  
Brigitte A. van Oirschot ◽  
Stephanie van Straaten ◽  
Bart J. Biemond ◽  
Jennifer Bos ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Cell ◽  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Red Blood Cell ◽  
Research Funding ◽  
Reticulocyte Count ◽  
Compound Heterozygous ◽  
Healthy Controls ◽  
Red Cell

Background: Reactive oxygen species (ROS) play an important role in the complex and multifactorial pathophysiology of hereditary hemolytic anemia like sickle cell disease (SCD), β-thalassemia and hereditary xerocytosis (HX). Increased intracellular levels of oxidative stress disrupt normal cell functioning and may contribute to premature red blood cell (RBC) clearance from the circulation. Pyruvate kinase (PK) is a key regulatory enzyme of glycolysis, the cell's main source of energy. Because PK is very sensitive to redox balance we hypothesized that increased levels of oxidative stress in SCD, β-thalassemia and HX impairs proper enzyme function, thereby compromizing RBC energy metabolism. This may contribute to disease pathophysiology. Aims: To investigate if secondary deficiency of PK is common in SCD, thalassemia, and HX, and to investigate if PK in these disorders is able to respond to treatment with the allosteric PK activator AG-348 (mitapivat). Methods: Enzymatic activities of red cell PK and hexokinase (HK) were measured together with PK-thermostability in order to assess relative PK activity and enzyme stability. Purified RBCs were incubated with AG-348 (3.33μM) for 24 hours after which PK activity and ATP response was measured. RBCs of SCD patients were also analyzed with the oxygenscan, a newly developed method that characterizes individual sickling behavior by oxygen gradient ektacytometry (Rab et al, Am J Hematol, 2019). Individual tendency to sickle is reflected by Point-of-Sickling (PoS) that indicates the specific pO2 at which RBCs start to sickle during deoxygenation under shear stress. Results: Thirty-eight patients and 21 healthy controls (HC) were included. The patient cohort consisted of patients homozygous for HbS (HbSS, n=26), patients compound heterozygous for HbS and HbC (HbSC, n=4), β-thalassemia major (regularly transfused, n=3), and hereditary xerocytosis (n=5). Patients showed reticulocytosis and, in line with this, a concomitant increase in HK activity. In contrast however, relative PK activity was decreased significantly compared to HK in HbSS, β-thalassemia and HX patients, but not in HbSC patients (Figure 1A). PK thermostability was significantly decreased compared to healthy controls in HbSS patients and patients with HX (Figure 1B). In HbSC and β-thalassemia patients, PK-thermostability was comparable to HC. PK thermostability strongly correlated with absolute reticulocyte count (ARC), indicating that patients displaying the highest degree of PK instability had the highest reticulocyte count (Figure 1C). This suggests that in general, a higher degree of PK instability is associated with more severe anemia due to a high hemolytic rate. In SCD patients, PK-thermostability inversely correlated with PoS, indicating that decreased PK stability is associated with sickling at higher pO2 (r=-0.646, p<0.001, Figure 1F). When purified RBCs were incubated with 3.33μM of the allosteric PK-activator AG-348, an increase in PK activity was seen in all patients and HCs, with a mean increase of 122% in HbSS (range 111-139%, n=6), 137% in β-thalassemia (n=1), 163% in HX (range 152-174%, n=2) and 143% in HC (range 113-173%, n=9, Figure 1E). Accordingly, ATP-levels increased in all patients and HCs, with a mean increase of 133% in HbSS (range 125-141%, n=5), 144% patient with β-thalassemia (n=1), 121% in HX (range 112-129, n=3), and 132% in HCs (range 101-149%, n=9, Figure 1E). Conclusion: PK enzyme activity and stability is compromised in patients with various forms of hereditary hemolytic anemia. This implies that PK stability and, hence, compromised red cell metabolism could contribute to the complex pathophysiology of these diseases. In SCD patients, reduced PK-thermostability is associated with higher PoS, which we previously have shown to be associated with more severe disease (Rab et al, Am J Hematol, 2019, ASH 2019 abstract ID128870). This is confirmed by the correlation of decreased PK-thermostability with increased reticulocyte count as presented in this study. Current studies are in progress to further substantiate the underlying mechanism(s) involved, and to investigate whether AG-348 may ameliorate clinical features such as hemolysis, sickling tendency and iron overload. Disclosures Rab: RR Mechatronics: Research Funding. Bos:RR Mechatronics: Research Funding. Kosinski:Agios Pharmaceuticals, Inc: Employment, Other: Stakeholder. Kung:Agios Pharmaceuticals, Inc: Employment, Other: Stakeholder. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. van Wijk:Agios Pharmaceuticals: Consultancy, Research Funding; RR Mechatronics: Research Funding.

scholarly journals The variable manifestations of disease in pyruvate kinase deficiency and their management

Haematologica ◽  
2020 ◽  
Vol 105 (9) ◽  
pp. 2229-2239 ◽  
Author(s):  
Hanny Al-Samkari ◽  
Eduard J. Van Beers ◽  
Kevin H.M. Kuo ◽  
Wilma Barcellini ◽  
Paola Bianchi ◽  
...  
Keyword(s):  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Working Group ◽  
Disease Burden ◽  
Extramedullary Hematopoiesis ◽  
Poor Correlation ◽  
Red Cell ◽  
Hematopoietic Stem ◽  
Pyruvate Kinase Deficiency ◽  
High Index Of Suspicion

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.

scholarly journals Management of pyruvate kinase deficiency in children and adults

Blood ◽  
2020 ◽  
Vol 136 (11) ◽  
pp. 1241-1249
Author(s):  
Rachael F. Grace ◽  
Wilma Barcellini
Keyword(s):  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Autosomal Recessive ◽  
Clinical Manifestations ◽  
Extramedullary Hematopoiesis ◽  
Current Treatment ◽  
Treatment Approaches ◽  
Pyruvate Kinase Deficiency ◽  
Chronic Hemolysis ◽  
Chronic Hemolytic Anemia

Abstract 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.

scholarly journals Pyruvate kinase Greensboro. A four-generation study of a high K0.5s (phosphoenolpyruvate) variant [published erratum appears in Blood 1988 Dec;72(6):2082]

Blood ◽  
1988 ◽  
Vol 72 (3) ◽  
pp. 1054-1059 ◽  
Author(s):  
WN Valentine ◽  
WB Herring ◽  
DE Paglia ◽  
MC Steuterman ◽  
RA Brockway ◽  
...  
Keyword(s):  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Clinical Manifestations ◽  
Substrate Affinity ◽  
Red Cell ◽  
Gene Products ◽  
Normal Allele ◽  
Metabolic Phenotypes ◽  
Sulfhydryl Modification ◽  
Nucleotide Specificity

The proband with lifelong hemolytic anemia has a high K0.5s phosphoenolypyruvate (PEP) erythrocyte pyruvate kinase (PK) variant substantially but incompletely normalized by the allosteric modifier fructose-1,6-diphosphate (F-1,6-P2) with conversion of sigmoidal to hyperbolic kinetics. Heterozygotes in four generations express qualitatively identical but less severely abnormal kinetics and lack overt hemolysis. Kinetic abnormalities are closely mimicked by sulfhydryl modification of normal PK. Three distinct clinical and metabolic phenotypes characterize the proband and two sisters: variant PK and hemolytic anemia, variant PK without clinical manifestations or hemolysis, and complete normality. Their mother, whose red cell PK is entirely normal except for a questionably slightly low Vmax, is postulated to express the gene products of nonidentical alleles, one encoding a product with mildly less favorable catalytic characteristics. At low PEP concentrations, the proband and heterozygotes for the PK mutant express only a very small fraction of normal PK activity despite apparent inheritance of one normal allele in the latter. Evidence suggests that disproportionately lowered PK activity may be a property of a heterotetrameric PK. Illusory abnormalities in nucleotide specificity are artifacts of diminished substrate affinity characterizing the mutant PK.

Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3585-3588 ◽  
Author(s):  
Ernest Beutler ◽  
Terri Gelbart
Keyword(s):  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Relative Frequency ◽  
Gene Frequency ◽  
Red Cell ◽  
White Population ◽  
Pyruvate Kinase Deficiency ◽  
Oligonucleotide Hybridization ◽  
Allele Specific ◽  
White Patients

Abstract Pyruvate kinase (PK) deficiency is the most common cause of hereditary nonspherocytic hemolytic anemia. The prevalence of this deficiency is unknown, though some estimates have been made based on the frequency of low red cell PK activity in the population. An additional 20 patients with hereditary nonspherocytic hemolytic anemia caused by PK deficiency have been genotyped. One previously unreported mutation 1153C→T (R385W) was encountered. The relative frequency of PK mutations in patients with hemolytic anemia caused by PK deficiency was calculated from the 18 white patients reported here and from 102 patients previously reported in the literature. DNA samples from 3785 subjects from different ethnic groups have been screened for the 4 more frequently encountered mutations—c.1456 C→T(1456T), c.1468 C→T(1468T), c.1484 C→T(1484T), and c.1529 G6A (1529A)—by allele-specific oligonucleotide hybridization. Among white patients the frequency of the 1456T mutation was 3.50 × 10−3; that of the 1529A mutation was 2.03 × 10−3. Among African Americans the frequency of the 1456T mutation was 3.90 × 10−3 The only mutation found in the limited number of Asians tested was 1468T at a frequency of 7.94 × 10−3. Based on the gene frequency of the 1529A mutation in the white population and on its relative abundance in patients with hemolytic anemia caused by PK deficiency, the prevalence of PK deficiency is estimated at 51 cases per million white population. This number would be increased by inbreeding and decreased by failure of patients with PK deficiency to survive.

Sign in / Sign up

Export Citation Format

Share Document