What is pyruvate kinase deficiency?

Pyruvate Kinase Deficiency: A Comprehensive Overview

Pyruvate kinase deficiency (PKD) is the most frequent enzyme abnormality of the glycolytic pathway and the most common cause of hereditary nonspherocytic hemolytic anemia, characterized by ATP depletion in red blood cells leading to chronic hemolysis of variable severity. 1

Definition and Pathophysiology

• PKD is an autosomal recessive disorder caused by mutations in the PKLR gene, resulting in defective pyruvate kinase enzyme activity 1
• The enzyme catalyzes one of the two major steps of ATP production in red blood cells, converting phosphoenolpyruvate to pyruvate while generating ATP 1
• Since mature RBCs lack mitochondria, they are completely dependent on glycolysis for ATP production to maintain cell integrity and critical functions 1
• PKD leads to ATP depletion, affecting cell viability, and causes accumulation of glycolytic intermediates (2-phosphoglycerate, 3-phosphoglycerate, and 2,3-DPG) up to 3-fold normal levels 1
• Increased 2,3-DPG causes a rightward shift in the oxygen dissociation curve, allowing patients to tolerate anemia better than expected 2

Epidemiology

• PKD has a worldwide geographical distribution with no precise prevalence figures 1
• Estimated prevalence in Caucasian populations ranges from 1:100,000 to 5:100,000 1
• The discrepancy in prevalence estimates is likely due to underdiagnosis of mildly affected patients 1
• Over 600 families and more than 300 mutations in the PKLR gene have been reported in the literature 1

Genetics and Molecular Basis

• Four PK isozymes exist in mammalian tissues 1:

  • L-type: expressed in liver, renal cortex, and small intestine
  • R-type: expressed in erythrocytes
  • M1-type: expressed in skeletal muscle, heart, and brain
  • M2-type: expressed in leukocytes, platelets, and various tissues

• The L-type and R-type isozymes are encoded by the PKLR gene under tissue-specific promoters 1

• The M1 and M2 isozymes are encoded by the PKM gene through alternative mRNA splicing 1

• During erythroid differentiation, the M2 isoenzyme is progressively replaced by the R-type isoform 1

• PKD is transmitted as an autosomal recessive trait, with clinical symptoms confined to compound heterozygous and homozygous patients 1

Clinical Manifestations

• Clinical presentation varies widely, from severe neonatal anemia requiring lifelong transfusions to fully compensated hemolysis 3, 4
• Common manifestations include 1, 4:
  • Chronic hemolytic anemia of variable severity
  • Jaundice
  • Splenomegaly
  • Gallstones
  • Iron overload (even in transfusion-independent patients)
• Severe cases may present with neonatal indirect hyperbilirubinemia 1, 5
• Disease phenotype is heterogeneous and changes over time, with different transfusion requirements and complication rates in children versus adults 3, 6
• Complications can include 4, 6:
  • Extramedullary hematopoiesis
  • Pulmonary hypertension
  • Thrombosis
  • Iron overload
  • Bilirubin gallstones

Diagnosis

• PKD should be suspected in patients with 1, 5:

  • Variable chronic anemia with normal or near-normal red cell morphology
  • Splenomegaly and/or jaundice
  • Transfusion-dependent hemolytic anemia of unknown etiology
  • Unexplained severe neonatal indirect hyperbilirubinemia
  • High reticulocyte count in splenectomized patients without diagnosis

• Diagnostic approach includes 1, 5:

  1. Complete blood count and RBC morphology
  2. Markers of hemolysis (reticulocyte count, LDH, unconjugated bilirubin, haptoglobin)
  3. Exclusion of acquired causes of hemolysis and hemoglobinopathies
  4. PK enzyme activity assay by spectrophotometry
  5. Molecular studies of the PKLR gene

• Blood testing for PK enzyme activity should be delayed at least 50 days after transfusion to minimize the effect of donor red cells 2, 6

• In transfusion-dependent patients, enzyme activity results should be interpreted with caution as donor contamination can lead to falsely normal levels 2, 6

Management

• Treatment is primarily supportive and includes 3, 4:

  • Folic acid supplementation
  • Red blood cell transfusions based on symptoms rather than fixed hemoglobin thresholds
  • Splenectomy (though less effective than in membrane defects)
  • Iron chelation therapy for iron overload

• Patients with PKD require irradiated blood components to prevent transfusion-associated graft-versus-host disease 2

• Regular monitoring is essential, with hematology visits at least every 6 months regardless of transfusion status 5, 4

• Novel therapies include 3, 7:

  • Mitapivat, an oral allosteric activator of wild-type and mutant RBC PK enzymes (recently approved)
  • Gene therapy (in development)

• Response to mitapivat varies based on genotype, with patients carrying non-missense mutations showing poorer response 7

Prognosis

• Prognosis is variable and depends on disease severity, transfusion requirements, and development of complications 4, 6
• Patients with PKD may tolerate anemia better than expected due to increased 2,3-DPG levels 2
• Early diagnosis and appropriate management can improve quality of life and reduce complications 5, 7