NORD gratefully acknowledges Rachael Grace, MD, MMSc, Assistant Professor of Pediatrics, Harvard Medical School, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, for assistance in the preparation of this report.
Pyruvate kinase deficiency (PKD) is a rare genetic disorder characterized by the premature destruction of red bloods, which is called hemolytic anemia. Anemia is a general term for when there are low levels of red blood cells in the bloodstream, and hemolytic (or hemolysis) means that the red blood cells break down prematurely. Red blood cells are formed in the bone marrow and then are released into the bloodstream. When the youngest red cells are first released into the bloodstream, they are called reticulocytes. Red blood cells travel throughout the body delivering oxygen to the tissues. Healthy red blood cells last approximately 120 days.
PKD is caused by alterations (mutations) in the PKLR gene, which lead to a deficiency of the enzyme pyruvate kinase. These genetic alterations are inherited in an autosomal recessive manner. Pyruvate kinase is an enzyme that helps cells turn sugar (glucose) into energy (called adenosine triphosphate, ATP) in a process called glycolysis. Red cells rely on this process for energy, and so, pyruvate kinase deficiency leads to a deficiency in energy and to premature red cell destruction (hemolysis). Instead of lasting 120 days, red cells with pyruvate kinase deficiency last only a few days to weeks.
The severity of PKD can vary greatly. In some people, it may cause mild symptoms; while in others more severe symptoms may develop.
Symptoms from pyruvate kinase deficiency can be highly variable. How it affects one person can be significantly different from how it affects another person. In some instances, the disorder can be life-threatening at birth. Other individuals may have mild or no symptoms of the disorder and go undiagnosed into adulthood. Others may develop symptoms during childhood or as adults. The main finding, hemolytic anemia, is a chronic, lifelong condition.
Before birth, some developing fetuses with anemia can develop a condition called fetal hydrops. This is a serious condition in which large amounts of fluid builds up in the tissues and organs of the fetus. It develops because the heart has to pump a greater volume of blood to deliver oxygen than normal because of anemia. Anemia in the developing fetus can also lead to premature birth.
At birth, some infants may have significant anemia and severe jaundice, which is yellowing of the skin and the whites of the eyes. Jaundice is caused by high levels of bilirubin in the body. Normally, when old or damaged red blood cells are broken down in the spleen, bilirubin is released into the bloodstream. This type of bilirubin is called unconjugated (or indirect) bilirubin. The unconjugated bilirubin is taken up by your liver cells, converted to conjugated bilirubin and excreted into the intestines and then into the stools. With hemolysis, an excess of bilirubin is released into the bloodstream and the liver cannot keep up with the conjugation process. Unlike children and adults with elevated bilirubin levels, high bilirubin levels in infants can lead to kernicterus, a neurologic condition characterized by the accumulation of toxic levels of bilirubin. High bilirubin levels in newborns require aggressive treatment to attempt to avoid the risk of kernicterus.
Children and Adults
The most common finding in children and adults is anemia. Anemia can cause tiredness, fatigue, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing (dyspnea), shortness of breath, and cardiac symptoms.
The degree of jaundice or scleral icterus is linked to the amount of total unconjugated bilirubin. This is determined both by the degree of hemolysis and by an individual’s ability to metabolize bilirubin, which is genetically determined. People with Gilbert syndrome have an inherited condition (two copies of a non-working gene) that reduces the production of an enzyme involved in the processing of bilirubin in the liver. Gilbert syndrome is common, so it is possible for someone to inherit both PKD and Gilbert syndrome. Children and adults with PKD can develop gallstones. Gallstones are small, hard masses that form in the gallbladder and block the bile ducts and cause pain. Gallstones are a frequent complication in children and adults with PKD because of the increased unconjugated bilirubin. The risk of gallstones is life-long due to ongoing hemolysis.
Affected individuals can also develop an enlarged spleen (splenomegaly). One function of the spleen is to filter red blood cells. The spleen becomes enlarged because it filters out the abnormal red blood cells. An enlarged spleen does not typically cause pain.
Hemolytic episodes develop in the presence of stressors or triggers of hemolysis, which most often are infections and, therefore, more frequent in childhood. Pregnancy can also be a common hemolytic trigger. During these episodes, an individual’s symptoms worsen, such as fatigue, paleness, scleral icterus, jaundice and/or dark urine. An aplastic crisis is caused by parvovirus B19 infection (also called Fifth disease). This commonly causes a high fever and facial rash. In individuals with PKD, parvovirus infection reduces or stops reticulocyte production in the bone marrow and thereby decreases the hemoglobin level. Aplastic crises in individuals with PKD often require a blood transfusion.
Iron overload is one of the most common findings in patients with PKD. Iron overload can occur both in individuals who receive blood transfusions and in those who have never been transfused. Iron overload is the abnormal accumulation of iron in various organs of the body most commonly in the liver, but iron loading can also occur in the heart and hormone-producing organs (endocrine organs). Iron loading is not associated with symptoms until a significant amount of iron is deposited, so it is important to monitor iron studies regularly in individuals with PKD.
Other complications can occur in PKD. Adolescents and adults can have weakened bones with an increased risk of bone fractures. Adults can develop skin sores (ulcers), typically around the ankles. Other less common complications include high blood pressure in the arteries in the lungs and the right side of the heart (pulmonary hypertension) and blood cell production outside of the bone marrow (extramedullary hematopoiesis).
Pyruvate kinase deficiency is caused by an alteration in the PKLR gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent.
The PKLR gene contains instructions for creating (encoding) a specialized protein (enzyme) known as pyruvate kinase. Because this gene is altered, there is a deficiency of functional pyruvate kinase enzyme. Red blood cells use several enzymes to ensure proper energy production. Energy is produced through a chemical process called glycolysis. Glycolysis is a chemical pathway in which glucose is broken down to produce energy for the cell. Pyruvate kinase enzyme breaks down a chemical compound called adenosine triphosphate (ATP). Because this enzyme is deficient, there is a lack of ATP. This leads to dehydration of red blood cells and abnormal red cell shapes. The altered red blood cell has a shortened lifespan leading to hemolytic anemia. As the altered red cells are destroyed, new red cells (reticulocytes) are created, creating a balance of increased red cell destruction and increased red cell production.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but, with the carrier state for PKD, will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. Most individuals with PKD have different variants affecting each copy of the disease genes (compound heterozygotes).
Pyruvate kinase deficiency is a rare disorder that affects both men and women. The frequency of the disorder is unknown, although one estimate suggests that approximately 1 in 20,000 Caucasian people develop the disorder. In clinical practice, the frequency is closer to 1 in 1,000,000 people. PKD has been identified most commonly in Europe. However, rare disorders like PKD often go misdiagnosed or undiagnosed making it difficult to determine their true frequency in the general population.
A diagnosis of pyruvate kinase deficiency is based upon identification of characteristic symptoms (e.g. active hemolysis), a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests.
Clinical Testing and Workup
Initial lab tests may be performed to determine that anemia is present and whether it is due to hemolysis. Signs of hemolysis include a low hemoglobin level, an elevated unconjugated bilirubin level, an elevated reticulocyte count, and low levels of haptoglobin in the blood.
The standard diagnostic test for PKD is to measure the activity of the pyruvate kinase enzyme in red blood cells. Low activity of this enzyme is indictive of the disorder. This test is only run at specialized laboratories; most clinics and hospitals send this test to be run at these specialized centers.
Molecular genetic testing helps to confirm a diagnosis of PKD. Molecular genetic testing can detect mutations in the PKLR gene known to cause the disorder. This test is only run at specialized laboratories; most clinics and hospitals send this test to be run at these specialized centers.
Treatment may require the coordinated efforts of a team of specialists. Pediatricians or general internists, physicians who specialize in diagnosing and treating blood disorders (hematologists), and other healthcare professionals may need to systematically and comprehensively plan treatment. Symptoms vary between patients so an individualized treatment plan should be developed.
Genetic counseling is recommended for affected individuals and their families.
A blood transfusion may be necessary for the developing fetus (intrauterine transfusion) if fetal hydrops develops or there are signs of poor growth related to anemia during pregnancy . Most newborns with PKD will develop jaundice because of the breakdown of red cells and the inability of their immature livers to conjugate bilirubin. Some affected infants may require phototherapy for bilirubinemia. During this procedure, intense light is focused on the bare skin, while the eyes are shielded. This helps to speed up the bilirubin metabolism and excretion. In some newborns with severe jaundice, an exchange transfusion may be necessary. An exchange transfusion is when an individual’s blood is removed and replaced by a donor’s blood.
Infants, Children, and Adults
In infants, children, and adults with PKD, blood transfusions may be used. The decision to transfuse is not based on the level of hemoglobin, but, rather, how an individual is tolerating the hemolytic anemia. The goal is to avoid transfusions if possible, but they may be necessary, particularly in the first years of life, to support growth and development and avoid symptoms, such as fatigue or poor feeding. In older children and adults, there are no standard criteria or schedule for transfusions, especially since the symptoms differ so widely between individuals. For individuals with daily symptoms from anemia, regular blood transfusions may be recommended. Others may only be transfused for acute infections or in pregnancy. Other individuals may never have a blood transfusion.
Red cell transfusions cause a buildup of iron over time. The body does not have a mechanism for getting rid of iron and so with repeated red cell transfusions, iron begins to deposit in the liver. Iron overload occurs commonly in individuals with PKD, even in the absence of red cell transfusions, through increased absorption from the diet. Chelation agents bind with iron to form substances that can be excreted from the body easily. Phlebotomy (regular removal of blood) can be used to unload iron from the body but is often not well-tolerated in individuals with anemia.
Sometimes, the surgical removal of the spleen (splenectomy) may be recommended. Removal the spleen may be considered if individuals require frequent blood transfusions or have frequent symptoms from anemia. Splenectomy, both open surgical and laparoscopic, has led to a partial improvement of the anemia in most individuals. However, this surgical procedure carries potential risks such as life-threatening bloodstream infections and blood clot formation (thrombosis), which are weighed against the potential benefits of splenectomy in each individual. Given the risk of infection after splenectomy, most individuals wait until at least the age of 5 years before proceeding with splenectomy. It is also important that individuals receive additional vaccines prior to splenectomy, take prophylactic antibiotics after splenectomy, and follow strict fever guidelines.
Supportive care can include gallbladder monitoring due to risk of gallstones. Gallbladder removal (cholecystectomy) is pursued in individuals with symptomatic gallstones and in individuals at the time of splenectomy. Folic acid supplementation, which supports increased red cell production, is often prescribed. Vitamin D, calcium, and exercise may be important for bone health.
Allogeneic hematopoietic stem cell transplantation (HSCT) can cure PKD. This has been pursued in a limited number of individuals, particularly individuals who require chronic blood transfusions. In allogeneic stem cell transplantation, affected individuals, after treatment with chemotherapy, receive hematopoietic stem cells from a healthy donor. This is a major medical procedure that carries significant risk, including dying from complications related to transplant. Only a small number of individuals with PKD have undergone HSCT in Europe and Asia. Most doctors think the risk-benefit ratio is in favor of splenectomy over HSCT. More research is necessary to determine the long-term safety and effectiveness of this therapy for certain individuals with PKD.
Gene therapy is being studied as an approach to therapy for individuals with pyruvate kinase deficiency. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of the active enzyme. Given the permanent transfer of the normal gene, it could theoretically lead to a “cure”. However, at this time, this is under consideration as a research therapy only.
Researchers are also studying a compound called mitapivat (AG-348) that acts to increase the activity of the pyruvate kinase enzyme in red blood cells. Initial studies have shown that this twice daily, oral compound may be both effective and well tolerated. In the initial study, mitapivat raised the hemoglobin at least 1 g/dL in about 50% of the adult participants in the trial. The hemoglobin response is more likely in patients with certain PKLR genotypes. More research is necessary to determine the long-term safety and effectiveness of mitapivat for individuals with PKD.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
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Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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Pyruvate Kinase Deficiency: Understanding and living with PKD
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