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 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 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.

NEUROENDOCRINE TUMORS OF THE PANCREAS: ETIOLOGY, PATHOGENESIS, DIAGNOSIS, AND CURRENT TREATMENT APPROACHES

2018 ◽  
Vol 64 (6) ◽  
pp. 830-839
Author(s):  
Temuri Morgoshiya
Keyword(s):  
Neuroendocrine Tumors ◽  
Clinical Manifestations ◽  
Gastrointestinal Hormones ◽  
Current Treatment ◽  
High Potential ◽  
Long Term Results ◽  
Considerable Part ◽  
Treatment Approaches ◽  
By Products

The overview of literature on modem classification issues, diagnostics and treatments of neuroendocrinal tumors of a pancreas is provided. According to modern views all neuroendocrinal tumors of a pancreas having clinical manifestations (in the form of the syndromes caused by products of specific hormones; increases in level of hormones in blood of patients without clinical manifestations; in the form of signs of existence of volume education in various departments of PZh) and/or the researches (more than 5 mm) revealed by means of beam methods are malignant in the biology as they have high potential to innidiation. In article it is shown that a considerable part of neuroendocrinal tumors of a pancreas are nonfunctioning, i.e. not cosecreting various gastrointestinal hormones and polypeptides in blood and thereof not followed characteristic clinical manifestations. It is noted that diagnostics of neuroendocrinal tumors of a pancreas is extremely difficult task on which solution the choice of a method of treatment and its long-term results depends...

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.

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.

Sign in / Sign up

Export Citation Format

Share Document