Function and dysfunction

In this issue of Blood, Grace et al characterize the clinical manifestations, disease complications, and response to treatment of 278 patients with pyruvate kinase (PK) deficiency from a 5-country longitudinal natural history study.¹  The availability of such a large genetic and clinical data set of patients with this rare red cell disorder will allow for more robust genotype–phenotype correlations and guide the development of future therapeutic strategies.

During their 120-day life span in circulation, human red cells require energy to maintain vital functions including regulation of cell shape, cell volume, and membrane deformability/stability. The red cell is uniquely dependent on anaerobic conversion of glucose by the Embden-Meyerhof pathway for the generation and storage of high-energy phosphates. Mutations in genes encoding the various enzymes in this pathway lead to loss of cell integrity and thus to hemolytic anemia.² 

PK catalyzes the conversion of phosphoenolpyruvate to pyruvate, generating red cell adenosine triphosphate. It is thus a key component of the glycolytic cycle and of the various metabolic pathways in which PK is involved. Since the description in 1962 by Tanaka et al of nonspherocytic anemia resulting from PK deficiency³  and subsequent documentation of selective reticulocyte destruction in PK deficiency in 1971,⁴  it has emerged that PK deficiency is the most common cause of anemia linked to defective glycolysis. The estimated prevalence is 1 per 20 000 in the Caucasian population,⁵  with more than 160 mutations in the PKLR gene identified.⁶  PK deficiency leads to a reduction in red cell adenosine triphosphate, loss of red cell structural integrity, and splenic sequestration of reticulocytes and red cells. The net result is shortened reticulocyte and red cell lifespan. The degree of anemia can vary widely from a mildly symptomatic anemia to severe anemia requiring blood transfusions. Although the anemia of PK deficiency is well documented, the frequencies of other clinical complications such as jaundice, gall stones, iron overload, thrombosis, and osteopenia have not been determined because many of the published studies are based on small cohorts.

To overcome this limitation, Grace et al established an international, multicenter registry to collect retrospective and prospective clinical data on patients with PK deficiency. Medical history and laboratory and radiological data were collected at enrollment on 254 patients with molecularly confirmed PK deficiency in centers across 5 countries between 2014 and 2017. Detailed analysis of the data gathered enabled the investigators to develop a comprehensive catalog of clinical manifestations, including perinatal complications such as anemia requiring transfusions, hyperbilirubinemia, hydrops, and prematurity. Almost all newborns were treated with phototherapy and nearly one-half required exchange transfusions. Young children were transfused until splenectomy, and ∼60% of the patient cohort underwent splenectomy with 11% developing thrombosis postsplenectomy. The most frequent complications were iron overload (48%) and gall stones (45%). A number of other clinical complications were also systematically cataloged. Exploration of genotype–phenotype association surprisingly showed no evidence of an association between PK enzyme activity and genotype, although an association of genotypes with some of the clinical manifestations was noted. The extensive clinical findings reported by the study lay a firm foundation for the comprehensive understanding of clinical manifestations of PK deficiency and provide valuable insights into the clinical management of these patients.

Although the reported findings represent a comprehensive description of the clinical consequences of PK deficiency in a relatively large cohort of patients, a number of questions remain unanswered. As the investigators state, despite the global efforts in a large number of sites, a limited number of patients were available for detailed and complete data capture. Moreover, there were biases in some of the data gathered and some missing data. Yet, the present study provides new insights that were not previously available regarding the clinical aspects of an important red cell disorder.

What then are the implications of the outlined findings? Although it is clear that the data reveal the diversity and complexity of the clinical manifestations resulting from PK deficiency, what is less clear are the molecular, biochemical, and mechanistic basis for the very large variations in the clinical manifestation among the patients. This issue is of particular concern when it comes to designing optimal clinical management strategies of the individuals affected. In spite of these concerns, the studies of Grace et al represent a significant advance in our understanding of clinical manifestation of PK deficiency and have the potential to develop new and more effective therapeutic strategies.