ABSTRACT
Pyruvate kinase deficiency (PKD) is the most common enzyme defect of glycolysis and an important cause of hereditary, nonspherocytic hemolytic anemia. The disease has a worldwide geographical distribution but there are no verified data regarding its frequency. Difficulties in the diagnostic workflow and interpretation of PK enzyme assay likely play a role. By the creation of a global PKD International Working Group in 2016, involving 24 experts from 20 Centers of Expertise we studied the current gaps in the diagnosis of PKD in order to establish diagnostic guidelines. By means of a detailed survey and subsequent discussions, multiple aspects of the diagnosis of PKD were evaluated and discussed by members of Expert Centers from Europe, USA, and Asia directly involved in diagnosis. Broad consensus was reached among the Centers on many clinical and technical aspects of the diagnosis of PKD. The results of this study are here presented as recommendations for the diagnosis of PKD and used to prepare a diagnostic algorithm. This information might be helpful for other Centers to deliver timely and appropriate diagnosis and to increase awareness in PKD.
Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/diagnosis , Pyruvate Kinase/deficiency , Pyruvate Metabolism, Inborn Errors/diagnosis , Anemia, Hemolytic, Congenital Nonspherocytic/blood , Anemia, Hemolytic, Congenital Nonspherocytic/genetics , Anemia, Hemolytic, Congenital Nonspherocytic/physiopathology , Artifacts , Blood Cell Count , Blood Preservation , DNA Mutational Analysis , Erythrocytes/enzymology , False Negative Reactions , False Positive Reactions , Humans , Pyruvate Kinase/blood , Pyruvate Kinase/genetics , Pyruvate Metabolism, Inborn Errors/blood , Pyruvate Metabolism, Inborn Errors/genetics , Pyruvate Metabolism, Inborn Errors/physiopathology , Reference Values , Reticulocytes , Sensitivity and Specificity , Sequence Analysis, DNA , Spectrophotometry , Time FactorsABSTRACT
Congenital erythrocytosis (CE), or congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and results from mutations in the Epo receptor gene (EPOR). Secondary CE arises from conditions causing tissue hypoxia and results in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (HBB, HBA mutations), decreased production of 2,3-bisphosphoglycerate due to BPGM mutations, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1, and EGLN1). Depending on the affected gene, CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo. Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients. With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr-Euronet developed a comprehensive Internet-based database focusing on the registration of clinical history, hematological, biochemical, and molecular data (http://www.erythrocytosis.org/). In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database.
