Hereditary erythrocyte adenylate kinase deficiency: a defect of multiple phosphotransferases?

Blood ◽  
1991 ◽  
Vol 77 (12) ◽  
pp. 2774-2784 ◽  
Author(s):  
NA Lachant ◽  
CR Zerez ◽  
J Barredo ◽  
DW Lee ◽  
SM Savely ◽  
...  
Keyword(s):  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Adenosine Triphosphate ◽  
Adenylate Kinase ◽  
Adenine Nucleotides ◽  
Alternative Pathway ◽  
Young Age ◽  
Per Se ◽  
Chronic Hemolytic Anemia ◽  
Phosphoribosylpyrophosphate Synthetase

Abstract Adenylate kinase (AK) modulates the interconversion of adenine nucleotides (AMP + adenosine triphosphate----2 ADP). We evaluated the fifth kindred with hereditary erythrocyte (RBC) AK deficiency. The proband had chronic hemolytic anemia. Her RBC had undetectable AK activity when measured spectrophotometrically, whereas those of her parents had half-normal AK activity. AK electrophoresis showed only AK- 1 in the parents. The activities of pyruvate kinase and phosphoribosylpyrophosphate synthetase were decreased given the young age of the proband's RBC. Despite the absence of spectrophotometric AK activity, the proband's RBC were able to incorporate 14C-adenine into 14C-adenine nucleotides at 50% of the rate expected for her young RBC population, suggesting the possibility of an alternative pathway for the formation of ADP from AMP. Normal hemolysate had AMP:guanosine triphosphate (GTP) phosphotransferase activity, which produced ADP at 8% to 9% of the rate of AK (6.8 +/- 0.8 IU/mL RBC). AMP:GTP phosphotransferase activity was not detectable in the proband's or parent's hemolysates. These additional biochemical defects in the AK- deficient RBC further support the concept that AK deficiency per se may not cause hemolytic anemia. We propose that defects occur in multiple phosphotransferases in the AK-deficient RBC and that these other biochemical defects may produce deleterious lesions that promote the shortened RBC survival in AK deficiency.

scholarly journals Hereditary erythrocyte adenylate kinase deficiency: a defect of multiple phosphotransferases?

Blood ◽  
1991 ◽  
Vol 77 (12) ◽  
pp. 2774-2784 ◽  
Author(s):  
NA Lachant ◽  
CR Zerez ◽  
J Barredo ◽  
DW Lee ◽  
SM Savely ◽  
...  
Keyword(s):  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Adenosine Triphosphate ◽  
Adenylate Kinase ◽  
Adenine Nucleotides ◽  
Alternative Pathway ◽  
Young Age ◽  
Per Se ◽  
Chronic Hemolytic Anemia ◽  
Phosphoribosylpyrophosphate Synthetase

Adenylate kinase (AK) modulates the interconversion of adenine nucleotides (AMP + adenosine triphosphate----2 ADP). We evaluated the fifth kindred with hereditary erythrocyte (RBC) AK deficiency. The proband had chronic hemolytic anemia. Her RBC had undetectable AK activity when measured spectrophotometrically, whereas those of her parents had half-normal AK activity. AK electrophoresis showed only AK- 1 in the parents. The activities of pyruvate kinase and phosphoribosylpyrophosphate synthetase were decreased given the young age of the proband's RBC. Despite the absence of spectrophotometric AK activity, the proband's RBC were able to incorporate 14C-adenine into 14C-adenine nucleotides at 50% of the rate expected for her young RBC population, suggesting the possibility of an alternative pathway for the formation of ADP from AMP. Normal hemolysate had AMP:guanosine triphosphate (GTP) phosphotransferase activity, which produced ADP at 8% to 9% of the rate of AK (6.8 +/- 0.8 IU/mL RBC). AMP:GTP phosphotransferase activity was not detectable in the proband's or parent's hemolysates. These additional biochemical defects in the AK- deficient RBC further support the concept that AK deficiency per se may not cause hemolytic anemia. We propose that defects occur in multiple phosphotransferases in the AK-deficient RBC and that these other biochemical defects may produce deleterious lesions that promote the shortened RBC survival in AK deficiency.

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.

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 Additional Kinetic Distinctions Between Normal Pyruvate Kinase and a Mutant Isozyme From Human Erythrocytes. Correction of the Kinetic Anomaly by Fructose-1,6-diphosphate

Blood ◽  
1971 ◽  
Vol 37 (3) ◽  
pp. 311-315 ◽  
Author(s):  
DONALD E. PAGLIA ◽  
WILLIAM N. VALENTINE
Keyword(s):  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Human Erythrocytes ◽  
Kinetic Characteristics ◽  
Low Concentrations ◽  
Mutant Forms ◽  
Chronic Hemolytic Anemia

Abstract Several cases have been reported in which chronic hemolytic anemia was thought to be secondary to the same mutant isozyme of erythrocyte PK. In crude hemolysates from one of these cases, defective kinetic characteristics of the isozyme were found to be completely correctable in vitro by low concentrations of the PK activator, fructose-1,6-diphosphate. The patterns of response to the activator further distinguished this isozyme from normal PK and suggested that the isozymes in these cases, previously thought to be identical, more probably represent three subtly distinct mutant forms.

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

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.

LEUKOCYTES AND FETAL MALNUTRITION

PEDIATRICS ◽  
1973 ◽  
Vol 51 (5) ◽  
pp. 926-928
Author(s):  
Hamish N. Munro
Keyword(s):  
Energy Metabolism ◽  
Young Children ◽  
Vitamin C ◽  
Pyruvate Kinase ◽  
Adenosine Triphosphate ◽  
Adenylate Kinase ◽  
Human Origin ◽  
Essential Nutrients ◽  
Protein Calorie Malnutrition ◽  
Fetal Malnutrition

Leukocytes are among the few cells of human origin that can be relatively easily obtained from the living subject. For this reason, they have been periodically used to measure the tissue status of enzymes, metabolites, and essential nutrients such as vitamin C. Some years ago, Metcoff and his colleagues1,2 related changes in the energy metabolism of leukocytes to the degree of postnatal malnutrition of young children. They were able to demonstrate a deficit in the capacity for generation of adenosine triphosphate (ATP) in the leukocytes of infants with protein-calorie malnutrition and correlated this with reduced activities of the enzymes pyruvate kinase and adenylate kinase which are involved in the metabolism of ATP formed by glycolysis, the predominating energy-generating process in leukocytes.

Coexistence of Congenital Red Cell Pyruvate Kinase Deficiency and Hereditary Stomatocytosis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1738-1738
Author(s):  
Anna P. Marcello ◽  
Cristina Vercellati ◽  
Elisa Fermo ◽  
Paola Bianchi ◽  
Wilma Barcellini ◽  
...  
Keyword(s):  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Peripheral Blood ◽  
Blood Smear ◽  
Reference Range ◽  
Peripheral Blood Smear ◽  
Red Cell ◽  
Normal Range ◽  
History Of ◽  
Chronic Hemolytic Anemia

Abstract We describe a case of chronic hemolytic anemia due to the co-presence of pyruvate kinase (PK) deficiency and Hereditary Stomatocytosis (HSto). The propositus was a 30 years old adopted male with no known family history; he had severe neonatal jaundice requiring exchange transfusion, followed by a life-long history of moderate to severe chronic hemolytic anemia (Hb 7–10 g/dL), with jaundice and splenomegaly. At the age of 6 months hemoglobin screening was made and a beta trait was found. At the age of 20 splenectomy and cholecystectomy were performed. Surgery resulted in an increase of 1.5 g/dL in haemoglobin, and in a conspicuous rise of reticulocytes (from 125×109/L to 562×109/L). Two thrombotic events occurred thereafter, the former 6 days after surgery, and the latter two years later, during a toxoplasmosis infection. At the time of the study Hb was 10.8 g/dL, MCV 82.2 fL, reticulocytes 562×109/L, unconjugated bilirubin 2.19 mg/dL, LDH 335 U/L, haptoglobin <20 mg/dL, serum ferritin 342 ng/mL and transferrin saturation 71%. The peripheral blood smear examination showed the presence of echinocytes (13%), stomatocytes (11%), acantocytes (10%), schistocytes (7%), elliptocytes (6%), spherocytes (4%), target cells (4%) and a few erythroblasts. Erythrocyte osmotic fragility was decreased; screening test for unstable hemoglobins and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) of red cell membrane gave normal results. The study of the most important red cell enzymes revealed reduced PK activity (6.0 UI/gHb, normal range 11.1–15.59 UI/gHb) and thermal stability (43%, normal range 57–100%). Direct sequencing of PK-LR gene showed a compound heterozygosity for mutation 1456T (Arg486Trp) and the new variant −73g>c. Mutation −73g>c occurs in the most proximal of the four GATA motifs in the R-type promoter region and possibly result in a decrease of mRNA synthesis, as already reported for the variant −72a>g (Manco et al, 2000). Molecular analysis of HFE gene showed heterozygosity for H63D mutation. The history of post splenectomy thrombosis and the presence of stomatocytes in peripheral blood smear prompted us to investigate for the coexistence of hereditary stomatocytosis. The determination of plasma potassium and sodium concentration revealed an increase in intracellular sodium (16.3 mmol/LRBC, reference range 5.0–12.0) and a decrease in intracellular potassium (74.73 mmol/LRBC, reference range 90–103), suggestive for a diagnosis of dehydrated HSto, or hereditary xerocytosis. This defect likely accounts for the thrombophilic state in this case, since HSto is known to be associated with hypercoagulability, particulary after splenectomy.

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