Pyruvate kinase deficiency is an inherited metabolic disorder of the enzyme pyruvate kinase which affects the survival of red blood cells. Both autosomal dominant and recessive inheritance have been observed with the disorder; classically, and more commonly, the inheritance is autosomal recessive. Pyruvate kinase deficiency is the second most common cause of enzyme-deficient hemolytic anemia, following G6PD deficiency. Signs and symptoms Symptoms can be extremely varied among those suffering from pyruvate kinase deficiency. The majority of those suffering from the disease are detected at birth while some only present symptoms during times of great physiological stress such as pregnancy, or with acute illnesses (viral disorders). Symptoms are limited to or most severe during childhood. Among the symptoms of pyruvate kinase deficiency are: Mild to severe hemolytic Anemia Cholecystolithiasis Tachycardia Hemochromatosis Icteric sclera Splenomegaly Leg ulcers Jaundice Fatigue Shortness of breath The level of 2,3-bisphosphoglycerate is elevated: 1,3-bisphosphoglycerate, a precursor of phosphoenolpyruvate which is the substrate for Pyruvate kinase, is increased and so the Luebering-Rapoport pathway is overactivated. This led to a rightward shift in the oxygen dissociation curve of hemoglobin (i.e. it decreases the hemoglobin affinity for oxygen): In consequence, patients may tolerate anemia surprisingly well. Cause Pyruvate kinase deficiency is due to a mutation in the PKLR gene. There are four pyruvate kinase isoenzymes, two of which are encoded by the PKLR gene (isoenzymes L and R, which are used in the liver and erythrocytes, respectively). Mutations in the PKLR gene therefore cause a deficiency in the pyruvate kinase enzyme. 180 different mutations have been found on the gene coding for the L and R isoenzymes, 124 of which are single-nucleotide missense mutations. Pyruvate kinase deficiency is most commonly an autosomal recessive trait. Although it is mostly homozygotes that demonstrate symptoms of the disorder, compound heterozygotes can also show clinical signs. Pathophysiology Pyruvate kinase is the last enzyme involved in the glycolytic process, transferring the phosphate group from phosphenol pyruvate to a waiting adenosine diphosphate (ADP) molecule, resulting in both adenosine triphosphate (ATP) and pyruvate. This is the second ATP producing step of the process and the third regulatory reaction. Pyruvate kinase deficiency in the red blood cells results in an inadequate amount of or complete lack of the enzyme, blocking the completion of the glycolytic pathway. Therefore, all products past the block would be deficient in the red blood cell. These products include ATP and pyruvate. Mature erythrocytes