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.

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 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 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 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

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.

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

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 ◽  
Hemolytic Anemia ◽  
Gene Editing ◽  
Autosomal Recessive Disorder ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem ◽  
Pyruvate Kinase Deficiency ◽  
Relevant Gene

ABSTRACTPyruvate Kinase Deficiency (PKD) is an autosomal recessive disorder caused by mutations in the PKLR gene, which constitutes the main cause of chronic non-spherocytic hemolytic anemia. PKD incidence is estimated in 1 in 20,000 people worldwide. The PKLR gene encodes for the erythroid pyruvate kinase protein (RPK) implicated in the last step of the anaerobic glycolysis in red blood cells. The defective enzyme fails to maintain normal erythrocyte ATP levels, producing severe hemolytic anemia, and can be fatal in severe patients. The only curative treatment for PKD is allogeneic hematopoietic stem and progenitor cells (HSPC) transplantation, so far. However, HSPC transplant is associated with a significant morbidity and mortality, especially in PKD patients. Here, we address the correction of PKD through precise gene editing at the PKLR endogenous locus to keep the tight regulation of RPK enzyme during erythropoiesis. We combined CRISPR/Cas9 system and rAAVs for donor matrix delivery to build an efficient and safe system to knock-in a therapeutic donor at the translation start site of the RPK isoform in human hematopoietic progenitors. Edited human hematopoietic progenitors efficiently reconstituted human hematopoiesis in primary and secondary immunodeficient recipient mice. Moreover, erythroid cells derived from edited PKD-HSPCs restored normal levels of ATP, demonstrating the restoration of RPK function in PKD erythropoiesis after gene editing. Our gene editing strategy may represent a lifelong therapy to restore RPK functionality in RBCs of patients and correct PKD.Single Sentence SummaryClinically relevant gene editing in hematopoietic stem cells for the treatment of 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 Impaired erythrocyte phosphoribosylpyrophosphate formation in hemolytic anemia due to pyruvate kinase deficiency

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 500-506 ◽  
Author(s):  
CR Zerez ◽  
MD Wong ◽  
NA Lachant ◽  
KR Tanaka
Keyword(s):  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Adenosine Triphosphate ◽  
Pyridine Nucleotide ◽  
Pentose Phosphate ◽  
Atp Depletion ◽  
Pyridine Nucleotides ◽  
Pyruvate Kinase Deficiency ◽  
Nucleotide Content ◽  
Pentose Phosphate Shunt

Abstract RBCs from patients with hemolytic anemia due to pyruvate kinase (PK) deficiency are characterized by a decreased total adenine and pyridine nucleotide content. Because phosphoribosylpyrophosphate (PRPP) is a precursor of both adenine and pyridine nucleotides, we investigated the ability of intact PK-deficient RBCs to accumulate PRPP. The rate of PRPP formation in normal RBCs (n = 11) was 2.89 +/- 0.80 nmol/min.mL RBCs. In contrast, the rate of PRPP formation in PK-deficient RBCs (n = 4) was markedly impaired at 1.03 +/- 0.39 nmol/min.mL RBCs. Impaired PRPP formation in these cells was not due to the higher proportion of reticulocytes. To study the mechanism of impaired PRPP formation, PK deficiency was simulated by incubating normal RBCs with fluoride. In normal RBCs, fluoride inhibited PRPP formation, caused adenosine triphosphate (ATP) depletion, prevented 2,3-diphosphoglycerate (DPG) depletion, and inhibited pentose phosphate shunt (PPS) activity. These results together with other data suggest that impaired PRPP formation is mediated by changes in ATP and DPG concentration, which lead to decreased PPS and perhaps decreased hexokinase and PRPP synthetase activities. Impaired PRPP formation may be a mechanism for the decreased adenine and pyridine nucleotide content in PK-deficient RBCs.

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