Red cell pyruvate kinase deficiency: molecular and clinical aspects

Abstract

SummaryRed cell pyruvate kinase (PK) deficiency is the most frequent enzyme abnormality of the glycolytic pathway causing hereditary non-spherocytic haemolytic anaemia. The degree of haemolysis varies widely, ranging from very mild or fully compensated forms, to life-threatening neonatal anaemia and jaundice necessitating exchange transfusions. Erythrocyte PK is synthesized under the control of the PK-LR gene located on chromosome 1. To date, more than 150 different mutations in the PK-LR gene have been associated with PK deficiency. First attempts to delineate the biochemical and clinical consequences of the molecular defect were mainly based on the observation of the few homozygous patients and on the analysis of the three-dimensional structure of the enzyme. More recently, the comparison of the recombinant mutants of human red cell PK with the wild-type enzyme has enabled the effects of amino acid replacements on the enzyme molecular properties to be determined and help to correlate genotype to clinical phenotype.

Fifteen novel mutations inPKLRassociated with pyruvate kinase (PK) deficiency: Structural implications of amino acid substitutions in PK

“…PK-deficient patients suffer from a variable degree of chronic hemolysis. Clinically, they manifest a highly variable phenotype, ranging from severe neonatal jaundice and anemia at birth, severe transfusiondependent chronic hemolysis, or moderate hemolysis with exacerbation during infection, to a fully compensated hemolysis without apparent anemia [Hirono et al, 2001;Zanella et al, 2005]. There is, however, no relationship between the residual enzymatic activity and the severity of hemolysis .…”

Worldwide study of hematopoietic allogeneic stem cell transplantation in pyruvate kinase deficiency

“…The degree of hemolysis can vary widely, from very mild and fully compensated forms to life-threatening anemia with transfusion dependency. 2 The treatment for PKD is mainly supportive, and consists of regular red blood cell transfusions, splenectomy and chelation therapy for iron overload. 3 Hematopoietic allogeneic stem cell transplantation (HSCT) has the potential to cure PKD.…”

Transgenic rescue of hemolytic anemia due to red blood cell pyruvate kinase deficiency

“…29 It is most likely that the incorporation of mutant R-PK subunits into the tetramer may interfere with the full restoration of PK activity in some erythroid cells. Since over 80% of reported R-PK mutations are missense mutations, 2,3 it seems that a gene-replacement strategy which inactivates the endogenous mutant R-PK gene might be required to achieve the complete cure of PK deficiency. …”

“…In addition, the majority of the identified PK gene mutations are missense mutations, 2,3 and previous studies revealed that there were some kinetically aberrant enzymes, which showed normal intracellular stability in erythroid cells. These results suggest that R-PK subunits derived from the transgene might form heterotetramers with aberrant R-PK.…”

“…[1][2][3] Although subjects with PK deficiency show a moderate degree of hemolytic anemia, the most severe cases die in utero 4,5 or are transfusion-dependent. 6 Repeated red blood cell (RBC) transfusions may induce hemochromatosis, 7 and a recent report showed that free hemoglobin caused by intravascular hemolysis might interfere with the biological action of nitric oxide, leading to the development of pulmonary hypertension.…”