Addressing the diagnostic gaps in pyruvate kinase deficiency: Consensus recommendations on the diagnosis of pyruvate kinase deficiency

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.

Genotype‐phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency

“…Despite sequencing all exons, intronic flanking regions, and the erythroid promoter of PKLR gene, patients with a clinical phenotype of PK deficiency and low PK enzyme levels are sometime found to have only one PKLR mutation or no mutations at all . Among the 278 initially enrolled participants in the PKD NHS, 21 were considered ineligible for this study due to the inability to demonstrate two pathogenic variants after the exclusion of large deletion performed by long range PCR.…”

“…Discrepancies exist between the published estimated prevalence, and the lower prevalence suggested by data from patient registries and clinical practice. This may be explained by a high number of mildly affected undiagnosed patients and challenges in diagnosing PK deficiency …”

“…With an improved understanding of the relationship between genotype and clinical features, genetic testing has been recommended to assist in determination of expected prognosis and development of an individualized monitoring plan. Recent consensus guidelines on the diagnosis of PK deficiency recommend diagnostic confirmation with genetic testing …”

How we manage patients with pyruvate kinase deficiency

“…Therefore, both enzyme activity and genetic testing are recommended for the diagnosis of PKD. Two approaches are currently adopted: most reference centres perform PKD screening by measuring PK enzymatic activity and confirm a suspected patient with PKD by DNA analysis of the PKLR gene, and a few centres first sequence the PKLR gene by next generation sequencing panels and then confirm the diagnosis by PK enzymatic activity if a novel mutation is found (Bianchi et al , ).…”

Novel PLKR mutations in four families with pyruvate kinase deficiency

“…The normal lifespan of RBCs is 120 days, and Bianchi et al suggested a mininum of 50 days to be considered after transfusion to expect an overestimation of PK activity of about 6%-12% due to donor RBC contamination. 10…”