Pyruvate kinase deficiency
Encyclopedia
Pyruvate kinase deficiency, also called erythrocyte pyruvate kinase deficiency, is an inherited
metabolic disorder of the enzyme pyruvate kinase
which affects the survival of red blood cell
s and causes them to deform into echinocytes on peripheral blood smears.
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.
essential to glycolysis
. A total lack of this enzyme's activity will be lethal.
through glycolysis
. A deficiency in pyruvate kinase, the enzyme that potentiates the last step of glycolysis (phosphoenolpyruvate converted to pyruvate), results in red blood cells (RBCs) with decreased energy.
The events leading to hemolysis are still not well understood, but it seems that the lack of ATP impairs the Na+/K+-ATPase and other ATP-dependent processes, leading to a cellular loss of K+ and water and an intracellular accumulation of Na+. This cellular swelling is comparable to ischemic changes in which cells denied of O2 suffer from an ATP deficiency. This swelling causes rigidity of the RBC and eventually splenic hemolysis from an inability to distort through splenic sinusoids. Partial splenectomies are sometimes performed as a treatment for anemias due to an underlying inability for RBC deformation (hereditary spherocytosis and pyruvate kinase deficiency). This is usually reserved for severe transfusion-dependent anemias as removal of the spleen confers a susceptibility to encapsulated organisms.
The buildup of reaction intermediates can also increase the level of 2,3-bisphosphoglycerate
(2,3 BPG) in the cells and affect tissue oxygenation. This will cause a "right shift" in the hemoglobin
oxygen saturation curve, implying a decreased oxygen affinity for the hemoglobin and earlier oxygen unloading than under normal conditions. As a result, individuals with pyruvate kinase deficiency may have a greater capacity for physical activity than others with similarly low hemoglobin levels.
from increased bilirubin
.
Treatment can include a blood transfusion
or removal of the spleen
. Treatment is usually effective in reducing the severity of the symptoms.
Heredity
Heredity is the passing of traits to offspring . This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. Through heredity, variations exhibited by individuals can accumulate and cause some species to evolve...
metabolic disorder of the enzyme pyruvate kinase
Pyruvate kinase
Pyruvate kinase is an enzyme involved in glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate to ADP, yielding one molecule of pyruvate and one molecule of ATP.-Reaction:The reaction with pyruvate kinase:...
which affects the survival of red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s and causes them to deform into echinocytes on peripheral blood smears.
Both autosomal
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
dominant and recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
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
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
, following G6PD deficiency.
Causes
A variety of mutations can lead to lowered production, activity, or stability of pyruvate kinase, an enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
essential to glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
. A total lack of this enzyme's activity will be lethal.
Pathophysiology
Erythrocytes manufacture ATPAdenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
through glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
. A deficiency in pyruvate kinase, the enzyme that potentiates the last step of glycolysis (phosphoenolpyruvate converted to pyruvate), results in red blood cells (RBCs) with decreased energy.
The events leading to hemolysis are still not well understood, but it seems that the lack of ATP impairs the Na+/K+-ATPase and other ATP-dependent processes, leading to a cellular loss of K+ and water and an intracellular accumulation of Na+. This cellular swelling is comparable to ischemic changes in which cells denied of O2 suffer from an ATP deficiency. This swelling causes rigidity of the RBC and eventually splenic hemolysis from an inability to distort through splenic sinusoids. Partial splenectomies are sometimes performed as a treatment for anemias due to an underlying inability for RBC deformation (hereditary spherocytosis and pyruvate kinase deficiency). This is usually reserved for severe transfusion-dependent anemias as removal of the spleen confers a susceptibility to encapsulated organisms.
The buildup of reaction intermediates can also increase the level of 2,3-bisphosphoglycerate
2,3-Bisphosphoglycerate
2,3-Bisphosphoglyceric acid is a three-carbon isomer of the glycolytic intermediate 1,3-bisphosphoglyceric acid . 2,3-BPG is present in human red blood cells at approximately 5 mmol/L...
(2,3 BPG) in the cells and affect tissue oxygenation. This will cause a "right shift" in the hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
oxygen saturation curve, implying a decreased oxygen affinity for the hemoglobin and earlier oxygen unloading than under normal conditions. As a result, individuals with pyruvate kinase deficiency may have a greater capacity for physical activity than others with similarly low hemoglobin levels.
Symptoms
The lysis of the RBCs leads to hemolytic anemia and may cause jaundiceJaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
from increased bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
.
Treatment
Most affected individuals do not require treatment. Individuals who are most severely affected may die in utero of anemia or may require blood transfusions or splenectomy, but most of the symptomatology is limited to early life and times of physiologic stress or infection.Treatment can include a blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
or removal of the spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
. Treatment is usually effective in reducing the severity of the symptoms.