Pyruvate+Kinase+Deficiency

PYRUVATE KINASE DEFICIENCY Pyruvate kinase deficiency is caused by a mutation in the PKLR gene. This condition is an autosomal recessive inheritance, meaning both parents are carriers. The Gene is active in the liver and red blood cells, where it provides instructions for making an enzyme called pyruvate kinase. The enzyme is in a critical energy producing process, known as glycolysis. Glycolysis produces ATP, which is the cells primary energy source. The mutation causes a shortage of ATP in red blood cells and a buildup of the molecules in glycolysis pervious to pyruvate kinase. The spleen gathers up the abnormal blood cells and destroys them, causing the spleen to enlarge. The shortage of red blood cells causes fatigue, pallor, and shortness of breath. When the red blood cells are destroyed, iron and bilirubin are released. The excess bilirubin causes jaundice as well as an increased risk of gall stones. Symptoms vary from severe to mild. Severe cases can be life threatening in infancy, sometimes requiring regular blood transfusions to survive. Symptoms may get worse during infection or pregnancy. Pyruvate kinase can also be induced by other blood diseases such as leukemia, these cases are not inherited.

Fact Sheet Disease: Pyruvate Kinase Deficiency Root of the Disease: Mutation of the PKLR gene, causing a reduced function of the enzyme pyruvate kinase. The inheritance pattern is autosomal recessive. Affected Cells: Red blood cells and the liver don’t produce the enzyme pyruvate kinase. Historical Background: Estimated to affect 1/20,000 people in the general white population. More common in the Old Order Amish population of Pennsylvania. Valentine first reported pyruvate kinase deficiency in 3 patients, in 1961. Common Symptoms: anemia, fatigue, pallor, shortness of breath, jaundice, and an increased risk of gall stones. Standard Treatments: medicines such as corticosteroids, rituximab, and cyclosporine. Folic acid supplements are also used. For severe cases blood transfusions and splenectomy may be necessary. Iron chelation may be required because of the excess iron in circulation. Current research: Young cells exhibit more pyruvate kinase activity than older cells. This suggests that the younger cells require more ATP, meaning that young PK-deficient cells are more severely compromised by their deficiency than the older cells. The Fe organ scans showed that the spleen and the liver were major sites of death of the newly formed cells. As the PK activity in a reticulocyte approaches a critically low level, the ATP production of the cell becomes dependent on the mitochondrial metabolism. When the cell emerges from the marrow, they may be detained by the spleen. The pressure of the oxygen in the splenic pulp blood is insufficient for the mitochondrial metabolism. This causes the ATP levels to drop rapidly and the cell loses potassium and water. The cell becomes dehydrated, viscous, and spiculated and is either destroyed by the spleen or, if it emerges from that organ it is so compromised that it is soon destroyed by the liver. Citations: Mentzer, William C., Robert L. Baehner, Holger Schmidt-Schönbein, Stephen H. Robinson, and David G. Nathan. "Selective Reticulocyte Destruction in Erythrocyte Pyruvate Kinase Deficiency." //Journal of Clinical Investigation// 50.3 688-99.