pyruvate kinase deficiency

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Pyruvate Kinase Deficiency



Pyruvate kinase deficiency (PKD) is part of a group of disorders called hereditary nonspherocytic hemolytic anemias. Hereditary nonspherocytic anemias are rare genetic conditions that affect the red blood cells. PKD is caused by a deficiency in the enzyme, pyruvate kinase. Although PKD is the second most common of the hereditary nonspherocytic anemias, it is still rare, with the incidence estimated to be 51 cases per million in the Caucasian population.


In PKD, there is an functional abnormality with the enzyme, pyruvate kinase. Usually, pyruvate kinase acts as a catalyst in the glycolysis pathway, and is considered an essential component in this pathway. Glycolysis is the method by which cells produce their own energy. A problem with any of the key components in glycolysis can alter the amount of energy produced. In the red blood cells, glycolysis is the only method available to produce energy. Without the proper amount of energy, the red blood cells do not function normally. Since pyruvate kinase is one of the key components in glycolysis, when there is a problem with this enzyme in the red blood cells, there is a problem with the production of energy, causing the red blood cells not to function properly.
There are four different forms of the pyruvate kinase enzyme in the human body. These forms, called isozymes, all perform the same function but each isozyme of pyruvate kinase is structurally different and works in different tissues and organs. The four isozymes of pyruvate kinase are labeled M1, M2, L, and R. The isozyme M1 is found in the skeletal muscle and brain, isozyme M2 can be found in most fetal and adult tissues, isozyme L works in the liver, and isozyme R works in the red blood cells. In PKD, only the pyruvate kinase isozyme found in red blood cells, called PKR, is abnormal. Therefore, PKD only affects the red blood cells and does not directly affect the energy production in the other organs and tissues of the body.
In general, PKD not does appear to affect one gender more than another or be more common in certain regions. However, there are studies of an Amish group in Pennsylvania where a severe form of PKD is more common. As previously mentioned, the three mutations found in the PKLR gene have been linked to individuals of specific decents. Caucasians of northern and central European decent are more likely to have the 1529A mutations, individuals of southern European descent usually have the 1456T mutation, and individuals of Asian descent are more likely to have the 1468T mutation.

Causes and symptoms

There are two PK genes and each gene produces two of the four isozymes of pyruvate kinase. The M1 and M2 isozymes are produced by the pyruvate kinase gene called PKM2 and pyruvate kinase isozymes, L and R, are products of the pyruvate kinase gene, PKLR. The PKLR gene is located on chromosome 1, on the q arm (the top half of the chromosome), in region 21 (written as 1q21). As of 2001, there have been over 125 different mutations described in the PKLR gene that have been detected in individuals with PKD.
PKD is mainly inherited in an autosomal recessive manner. There have been a few families where it appeared that PKD was inherited in either an autosomal dominant manner or where the carriers of PKD exhibited mild problems with their red blood cells. As with all autosomal recessive conditions, affected individuals have a mutation in both pair of genes. Most individuals with PKD are compound heterozygotes, meaning that each PKLR gene in a pair contains a different mutation. There are individuals who have the same mutation on each PKLR gene, but these individuals tend to be children of parents who are related to each other.
There are three mutations in the PKLR gene called, 1529A, 1456T, and 1468T, that are seen more frequently in individuals with PKD than the other mutations. The mutation 1529A is most frequently seen in Caucasians of northern and central European descent and is the most common mutation seen in PKD. The mutation 1456T is more common in individuals of southern European descent and the mutation 1468T is more common in individuals of Asian descent.
In general, the more severe the PKD, the earlier in life symptoms tend to be detected. Individuals with the more severe form of PKD often show symptoms soon after birth, but most individuals with PKD begin to exhibit symptoms during infancy or childhood. In individuals with the more mild form of PKD, the condition is sometimes not diagnosed until late adulthood, after an acute illness, or during a pregnancy evaluation.
For most of the mutations seen in the PKLR gene, no correlation between the specific mutation and the severity of the disorder has been observed. However, for two of the mutations, there has been speculation on their effect on the severity of PKD. When the mutation 1456T has been seen in the homozygous state (when both PKLR genes contain the same mutation), those rare individuals experienced very mild symptoms of PKD. Also, there have been individuals who were homozygous for the 1529A mutation. These individuals had a very severe form of PKD. Therefore, it is thought that the 1456T mutation is associated with a milder form of the disease and the 1529A mutation is associated with a more severe form of the disease. It is not known how these mutations affect the severity of PKD when paired with different mutations.
Symptoms of PKD are similar to those symptoms seen in individuals who have long-term hemolytic anemia. The more common symptoms include variable degrees of jaundice (a yellowish pigment of the skin), slightly to moderately enlarged spleen (splenomegaly), and increased incidence of gallstones. Other physical effects of PKD can include smaller head size and the forehead appearing prominent and rounded (called frontal bossing). If a child with PKD has their spleen removed, their growth tends to improve. Even within the same family, individuals can have different symptoms and severity of PKD.
In individuals with PKD, the red blood cells are taken out of their circulation earlier than normal (shorten life-span). Because of this, individuals with PKD will have hemolytic anemia. Additionally, the anemia or other symptoms of PKD may worsen during a sudden illness or pregnancy.


A diagnosis of PKD can be made by measuring the amount of pyruvate kinase in red blood cells. Individuals with PKD tend to have 5-25% of the normal amount of pyruvate kinase. Carriers of PKD also can have less pyruvate kinase in their red blood cells, approximately 40-60% of the normal value. However, there is an overlap between the normal range of pyruvate kinase and the ranges seen with carriers of PKD. Therefore, measuring the amount of pyruvate kinase in the red blood cells is not a good method of detecting carriers of PKD. If the mutations causing PKD in a family are known, it may be possible to perform mutation analysis to determine carrier status of an individual and to help diagnose individuals with PKD.


In the severest cases, individuals with PKD will require multiple blood transfusions. In some of those cases, the spleen may be removed (splenectomy). Red blood cells are normally removed from circulation by the spleen. By removing an individual's spleen (usually a child), the red blood cells are allowed to stay in circulation longer than normal; thereby, reducing the severity of the anemia. After a splenectomy, or once an individual with PKD is older, the number of transfusions tends to decrease.


The prognosis of PKD is extremely variable. Early intervention and treatment of symptoms frequently improves the individual's health. Without treatment, individuals may experience severe complications that may become lethal. Individuals with a mild form of PKD may appear to have no symptoms at all.

Key terms

Anemia — When the amount of red blood cells is less than normal.
Catalyst — A substance that causes the next step in a pathway or reaction to occur, but is not physically changed by the process.
Compound heterozygotes — Individuals who have one gene in a pair with one mutation and the other gene in the pair has a different mutation.
Enzyme — A protein produced by cells that acts as a catalyst to allow a change or function to occur.
Glycolysis — The pathway in which a cell breaks down glucose into energy.
Hemolytic anemia — Anemia that results from red blood cells being destroyed sooner than normal.
Heterozygote/Heterozygotes — Are individuals who have one gene in a pair that has a mutation while the other gene in the pair is unaffected.
Homozygote/Homozygotes — Are individuals who have both genes in a pair with the same mutation.
Homozygous — When both genes in a pair have the same mutation.
Isozyme/Isoenzyme — Are a group of enzymes that perform the same function, but are different from one another in their structure or how they move.
Mutation — A change in the gene that causes it to alter its function
Nonspherocytic — Literally means not sphereshaped. Often in inherited hemolytic anemias, the red blood cells are sphere-shaped. In Nonspherocytic Hemolytic Anemias, the red blood cells are not sphere-shaped.



Beutler, Ernest, and Terri Gelbart. "Estimating the Prevalence of Pyruvate Kinase Deficiency from the Gene Frequency in the General White Population." Blood 95 (June 2000): 3585-3588.
Kugler, W., et. al. "Eight Novel Mutations and Consequences of mRNA and Protein Level in Pyruvate Kinase Deficient Patients with Nonspherocytic Hemolytic Anemia." Human Mutation 15 (2000): 261-272.


NIH/National Heart, Lung, and Blood Institute. 31 Center Drive.


"Entry 266200: Pyruvate Kinase Deficiency of Erythrocyte." OMIM—Online Mendelian Inheritance in Man.
Gale Encyclopedia of Medicine. Copyright 2008 The Gale Group, Inc. All rights reserved.

py·ru·vate ki·nase de·fi·cien·cy

a disorder in which there is a deficiency of pyruvate kinase in red blood cells; characterized by hemolytic anemia varying in degree from one patient to another; autosomal recessive inheritance, caused by mutation in the pyruvate kinase liver and red blood cell gene (PKLR) on chromosome 1 q.
Farlex Partner Medical Dictionary © Farlex 2012

pyruvate kinase deficiency

Hematology An AR condition affecting Nothern Europeans and the Amish; lack of PK in RBCs results in chronic hemolytic anemia and release of free Hb into the circulation;13 present in the neonatal period with jaundice requiring phototherapy; in older children, PKD ranges in severity from asymptomatic, to requiring blood transfusions, to jaundice and splenomegaly Clinical Mild to severe hemolysis, jaundice, anemia Lab ↑ 2,3-DPG, ↓ PK activity, ↓ ATP in RBCs Management Transfusions, splenectomy
McGraw-Hill Concise Dictionary of Modern Medicine. © 2002 by The McGraw-Hill Companies, Inc.
References in periodicals archive ?
Mitapivat is an investigational, first-in-class, oral, small molecule allosteric activator of wild-type and a variety of mutated pyruvate kinase-R (PKR) enzymes that directly targets the underlying metabolic defect in PK deficiency, a rare, potentially debilitating, hemolytic anemia.
'The DRIVE PK study is the first clinical trial in adults with PK deficiency, which is a rare disease characterized by chronic hemolysis and long-term serious complications.
Mitapivat is an investigational, oral, small molecule allosteric activator of wild-type and a variety of mutated pyruvate kinase-R, or PKR, enzymes that directly targets the underlying metabolic defect in PK deficiency, a rare, potentially debilitating, hemolytic anemia.
AII.1 displayed chronic haemolysis and jaundice since infancy; she was diagnosed with PK deficiency on the basis of decreased enzyme activity and splenectomised in 1979 at the age of 21.
On that occasion, Hb levels were 12.5 g/dL, reticulocytes were 316 x [10.sup.9]/L, unconjugated bilirubin was 5.9 mg/dL, and serum ferritin was 723 ng/ml; PK activity was slightly decreased (10.2 IU/gHb, normal values 13.3 [+ or -] 2.29); however, because of family history he was diagnosed with PK deficiency. Physical examination revealed scleral jaundice and splenomegaly.
Based on the data, the company intends to begin a Phase II clinical trial in patients with PK deficiency in the first half of 2015.
Agios chief medical officer Dr Chris Bowden said: "We are pleased to achieve another milestone in the clinical program for AG-348, the first medicine in development designed to treat the underlying cause of PK deficiency.
Patients present with jaundice in the neonatal period in hereditary spherocytosis, alpha thalassemia and G6PD and PK deficiency, whereas the first findings generally appear after the 4-[]month in beta thalassemia.
We describe the implementation of a PK assay and document the first mutation underlying PK deficiency in a South African patient who presented with a haemolytic episode following ARV (antiretroviral) prophylaxis.
'On the clinical side, we continued to broaden our IDH program into earlier lines of AML therapy and expand our PKR programs into new disease areas while enrolling the PK deficiency pivotal studies.
In addition, we continue to activate new sites globally for our pivotal PK deficiency program and accrue patients in the dose-escalation portion of the Phase 1 study in MTAP-deleted tumors.
The purpose of this Phase 3, 1:1 randomized, double-blind, placebo-controlled global trial is to evaluate the efficacy and safety of treatment with AG-348 in approximately 80 adults with PK deficiency across approximately 35 sites in 15 countries.