Pyruvate kinase deficiency

Pyruvate kinase deficiency is an inherited disorder that affects red blood cells, which carry oxygen to the body’s tissues. People with pyruvate kinase deficiency have a condition known as chronic hemolytic anemia, in which red blood cells are broken down (undergo hemolysis) prematurely, resulting in a shortage of red blood cells (anemia). Specifically, pyruvate kinase deficiency is a common cause of a type of inherited hemolytic anemia called hereditary nonspherocytic hemolytic anemia. In hereditary nonspherocytic hemolytic anemia, the red blood cells do not assume a spherical shape as they do in some other forms of hemolytic anemia.

There are many different types of enzyme-related defects of the red blood cell that can cause hemolytic anemia. Pyruvate kinase deficiency is the second most common cause, after glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Chronic hemolytic anemia can lead to unusually pale skin (pallor), yellowing of the eyes and skin (jaundice), extreme tiredness (fatigue), shortness of breath (dyspnea), and a rapid heart rate (tachycardia). An enlarged spleen (splenomegaly), an excess of iron in the blood, and small pebble-like deposits in the gallbladder or bile ducts (gallstones) are also common in this disorder.

In people with pyruvate kinase deficiency, hemolytic anemia and associated complications may range from mild to severe. Some affected individuals have few or no symptoms. Severe cases can be life-threatening in infancy, and such affected individuals may require regular blood transfusions to survive. The symptoms of this disorder may get worse during an infection or pregnancy.

Pyruvate kinase deficiency is the most common inherited cause of nonspherocytic hemolytic anemia. More than 500 affected families have been identified, and studies suggest that the disorder may be underdiagnosed because mild cases may not be identified.

Pyruvate kinase deficiency is found in people of all ethnic backgrounds. Pyruvate kinase deficiency prevalence has been estimated at 1 in 20,000 people of European descent. Pyruvate kinase deficiency is more common in the Old Order Amish population of Pennsylvania.

Mild pyruvate kinase deficiency cases require no treatment. People with severe anemia may need blood transfusions. In newborns with dangerous levels of jaundice, a health care provider may recommend an exchange transfusion. Surgical removal of the spleen (splenectomy) may also be necessary to help reduce the destruction of red blood cells. However, this does not help in all cases. With small children, this is delayed as long as possible to allow the immune system to mature. Other treatment is symptomatic and supportive. Someone who had a splenectomy should receive the pneumococcal vaccine at recommended intervals. They also should receive preventive antibiotics until age 5 ¹.

What causes pyruvate kinase deficiency?

Pyruvate kinase deficiency is caused by mutations in the PKLR gene. The PKLR gene is located on chromosome 1 (1q21). The PKLR gene is active in the liver and in red blood cells, where it provides instructions for making an enzyme called pyruvate kinase. The pyruvate kinase enzyme is involved in a critical energy-producing process known as glycolysis. During glycolysis, the simple sugar glucose is broken down to produce adenosine triphosphate (ATP), the cell’s main energy source.

PKLR gene mutations result in reduced pyruvate kinase enzyme function, causing a shortage of ATP in red blood cells and increased levels of other molecules produced earlier in the glycolysis process. The abnormal red blood cells are gathered up by the spleen and destroyed, causing hemolytic anemia and an enlarged spleen. A shortage of red blood cells to carry oxygen throughout the body leads to fatigue, pallor, and shortness of breath. Iron and a molecule called bilirubin are released when red blood cells are destroyed, resulting in an excess of these substances circulating in the blood. Excess bilirubin in the blood causes jaundice and increases the risk of developing gallstones.

Pyruvate kinase deficiency may also occur as an effect of other blood diseases, such as leukemia. These cases are called secondary pyruvate kinase deficiency and are not inherited.

Pyruvate kinase deficiency inheritance pattern

Pyruvate kinase deficiency is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

It is rare to see any history of autosomal recessive conditions within a family because if someone is a carrier for one of these conditions, they would have to have a child with someone who is also a carrier for the same condition. Autosomal recessive conditions are individually pretty rare, so the chance that you and your partner are carriers for the same recessive genetic condition are likely low. Even if both partners are a carrier for the same condition, there is only a 25% chance that they will both pass down the non-working copy of the gene to the baby, thus causing a genetic condition. This chance is the same with each pregnancy, no matter how many children they have with or without the condition.

• If both partners are carriers of the same abnormal gene, they may pass on either their normal gene or their abnormal gene to their child. This occurs randomly.
• Each child of parents who both carry the same abnormal gene therefore has a 25% (1 in 4) chance of inheriting a abnormal gene from both parents and being affected by the condition.
• This also means that there is a 75% ( 3 in 4) chance that a child will not be affected by the condition. This chance remains the same in every pregnancy and is the same for boys or girls.
• There is also a 50% (2 in 4) chance that the child will inherit just one copy of the abnormal gene from a parent. If this happens, then they will be healthy carriers like their parents.
• Lastly, there is a 25% (1 in 4) chance that the child will inherit both normal copies of the gene. In this case the child will not have the condition, and will not be a carrier.

Figure 1 illustrates autosomal recessive inheritance. The example below shows what happens when both dad and mum is a carrier of the abnormal gene, there is only a 25% chance that they will both pass down the abnormal gene to the baby, thus causing a genetic condition.

Figure 1. Pyruvate kinase deficiency autosomal recessive inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

Pyruvate kinase deficiency symptoms

The signs and symptoms of pyruvate kinase deficiency may vary greatly from person to person, but usually include the breakdown of red blood cells resulting in hemolytic anemia, a yellowing of the whites of the eyes (icterus), fatigue, lethargy, recurrent gallstones, jaundice, and pale skin (pallor). An excess of young red blood cells (reticulocytes) usually occurs. The anemia is chronic and may vary from mild to severe. Enlargement of the spleen (splenomegaly) may occur, and gallstones may sometimes develop. After infections, the anemia tends to become more severe. In rare cases, leg ulcers may develop.

Symptoms of pyruvate kinase deficiency include:

• Low count of healthy red blood cells (anemia)
• Swelling of the spleen (splenomegaly)
• Yellow color of the skin, mucous membranes, or white part of the eyes (jaundice)
• Neurologic condition, called kernicterus, that affects the brain
• Fatigue, lethargy
• Pale skin (pallor)
• In infants, not gaining weight and growing as expected (failure to thrive)
• Gallstones, usually in the teens and older

In more severe cases, the first signs and symptoms may appear in utero in the form of hydrops fetalis, a condition in which abnormal amounts of fluid build up in two or more body areas of the fetus. Newborns may present with prolonged jaundice and anemia. Older children may be pale (due to anemia) and have intermittent episodes of jaundice. Mild cases may escape detection until adulthood. Although the anemia tends to stabilize in adulthood, episodes of anemia may occur with acute infections, stress, and pregnancy.

Pyruvate kinase deficiency diagnosis

Your health care provider will perform a physical exam and ask about and check for symptoms such as an enlarged spleen. If pyruvate kinase deficiency is suspected, tests that will likely be ordered include:

• Bilirubin in the blood. Tests for the presence of bile salts (bilirubin) are used to determine whether the gall bladder is involved.
• CBC (complete blood count), differential blood counts, and reticulocyte counts
• Genetic testing for mutation in the pyruvate kinase gene
• Haptoglobin blood test
• Osmotic fragility
• Pyruvate kinase activity
• Stool urobilinogen

DNA analysis may be ordered to confirm the diagnosis.

Pyruvate kinase deficiency treatment

Mild pyruvate kinase deficiency cases require no treatment. People with severe anemia may need blood transfusions. Removing the spleen (splenectomy) may help reduce the destruction of red blood cells. But, this does not help in all cases. With small children, this is delayed as long as possible to allow the immune system to mature. In newborns with a dangerous level of jaundice, your child’s doctor may recommend an exchange transfusion. This procedure involves slowly removing the infant’s blood and replacing it with fresh donor blood or plasma.

Someone who had a splenectomy should receive the pneumococcal vaccine at recommended intervals. They also should receive preventive antibiotics until age 5.

Pyruvate kinase deficiency prognosis

Pyruvate kinase deficiency prognosis varies. Some people have few or no symptoms. Others have severe symptoms. Treatment can usually make symptoms less severe. Some patients present with a mild, compensated, chronic hemolytic anemia that does not require medical intervention; others present with a severe hemolytic anemia that, in most cases, requires only transfusions during childhood.

Complications associated with pyruvate kinase deficiency include the following:

• Cholecystolithiasis is common in the first decade of life in children with severe anemia
• Splenectomy increases the risk of sepsis by encapsulated bacteria in children and the risk of thromboembolic disease in adults ²
• Sudden worsening of anemia associated with viral infections (eg, parvovirus B19) can occur, leading to a transient decrease in red cell production (ie, aplastic crisis)
• Severe anemia may result in heart failure
• Ischemic stroke has been reported in previously undiagnosed young adults with pyruvate kinase deficiency ³
• Multiple transfusion therapy can cause iron overload ⁴
• Blood transfusions expose a person to the risk of contracting certain infections that are not well detected (eg, human immunodeficiency virus (HIV) disease, hepatitis C)
• Repeated transfusions during pregnancy increase the risk of alloimmunization, which may lead to fetal complications

Morbidity in the newborn with pyruvate kinase deficiency is usually the result of severe anemia, hyperbilirubinemia, or both combined with the adverse effects associated with the management of such conditions. A report from the Netherlands described a fatal outcome in 2 newborns who suffered liver failure as a result of very severe pyruvate kinase–deficient hemolytic anemia. No other explanation for the liver failure was identified ⁵.

References

1. Pyruvate kinase deficiency. https://medlineplus.gov/ency/article/001197.htm
2. Chou R, DeLoughery TG. Recurrent thromboembolic disease following splenectomy for pyruvate kinase deficiency. Am J Hematol. 2001 Jul. 67(3):197-9.
3. Pincus M, Stark RA, O’Neill JH. Ischaemic stroke complicating pyruvate kinase deficiency. Intern Med J. 2003 Sep-Oct. 33(9-10):473-4.
4. Andersen FD, d’Amore F, Nielsen FC, van Solinge W, Jensen F, Jensen PD. Unexpectedly high but still asymptomatic iron overload in a patient with pyruvate kinase deficiency. Hematol J. 2004. 5(6):543-5.
5. Raphaël MF, Van Wijk R, Schweizer JJ, Schouten-van Meeteren NA, Kindermann A, van Solinge WW, et al. Pyruvate kinase deficiency associated with severe liver dysfunction in the newborn. Am J Hematol. 2007 Nov. 82(11):1025-8.