Pyruvate kinase deficiency is caused by mutations in the gene that encodes the enzyme pyruvate kinase, specifically the PKLR gene. This enzyme plays a crucial role in the glycolysis pathway, which is the process cells use to break down glucose for energy. Pyruvate kinase catalyzes the final step of glycolysis, converting phosphoenolpyruvate (PEP) into pyruvate while generating ATP, the cell’s energy currency. When pyruvate kinase is deficient or dysfunctional due to genetic mutations, this step is impaired, leading to a shortage of ATP in red blood cells.
Red blood cells rely heavily on glycolysis for energy because they lack mitochondria, which means they cannot generate ATP through oxidative phosphorylation. Without sufficient ATP, red blood cells lose their ability to maintain their shape and membrane integrity, causing them to become fragile and prone to premature destruction—a process called hemolysis. This results in hemolytic anemia, the primary clinical manifestation of pyruvate kinase deficiency.
The mutations in the PKLR gene that cause pyruvate kinase deficiency are inherited in an autosomal recessive pattern, meaning a person must inherit two defective copies of the gene (one from each parent) to develop the condition. These mutations can vary widely, including missense mutations (which change a single amino acid in the enzyme), nonsense mutations (which create a premature stop codon), insertions, deletions, or splice site mutations that affect how the gene’s RNA is processed. Each mutation can affect the enzyme’s stability, activity, or ability to bind substrates and cofactors, leading to varying degrees of enzyme deficiency and clinical severity.
Because pyruvate kinase is essential for energy production in red blood cells, its deficiency disrupts the balance of glycolytic intermediates and reduces ATP availability. This energy deficit impairs the function of ion pumps in the red blood cell membrane, leading to an imbalance of ions and water, causing the cells to become dehydrated and rigid. These abnormal red blood cells are then recognized and removed by the spleen, contributing to anemia and related symptoms such as fatigue, jaundice, and an enlarged spleen.
In some cases, pyruvate kinase deficiency may also trigger compensatory mechanisms such as increased production of 2,3-bisphosphoglycerate (2,3-BPG), which helps release oxygen from hemoglobin more readily to tissues, partially offsetting the effects of anemia. However, this compensation does not correct the underlying energy deficit.
The severity of pyruvate kinase deficiency can vary widely depending on the specific mutations and their impact on enzyme function. Some individuals may experience mild anemia with few symptoms, while others may have severe, chronic hemolytic anemia requiring regular medical intervention. Newborns with severe deficiency may present with jaundice and require blood transfusions early in life.
In summary, pyruvate kinase deficiency is caused by inherited mutations in the PKLR gene that impair the function of the pyruvate kinase enzyme in red blood cells. This leads to decreased ATP production, red blood cell fragility, and hemolytic anemia. The genetic nature of the disorder means it is passed down through families, and the specific mutations determine the severity of the disease.
