Pyruvate Kinase Deficiency Anaemia

Pyruvate kinase deficiency anaemia is a rare inherited blood disorder where red blood cells break down too quickly, causing a shortage of healthy cells to carry oxygen throughout the body. The condition affects people from birth, but symptoms can range from severe and life-threatening in newborns to so mild that they go unnoticed until adulthood.

Table of contents

• What is pyruvate kinase deficiency anaemia?
• What causes the condition?
• Signs and symptoms
• How common is the condition?
• How is it diagnosed?
• Treatment and management
• Living with the condition

What is pyruvate kinase deficiency anaemia?

PK deficiency, PKD, erythrocyte pyruvate kinase deficiency

Pyruvate kinase deficiency anaemia is a condition where the body’s red blood cells break down faster than they should. Red blood cells are responsible for carrying oxygen to all parts of your body. When these cells break down too quickly, you end up with too few red blood cells, a condition called anaemia (not having enough red blood cells).^[1][2]

This disorder is specifically described as hereditary nonspherocytic hemolytic anemia, which means it’s an inherited form of anaemia where red blood cells are destroyed but don’t take on a round, spherical shape like they do in some other types of blood disorders.^[2]

To understand this condition, you need to know about pyruvate kinase, an enzyme (a special protein that helps chemical reactions happen in your body). Your red blood cells need this enzyme to make energy. The enzyme helps convert a substance called glucose (a type of sugar) into adenosine triphosphate or ATP, which is the main energy source for red blood cells. In fact, this single step in the energy-making process produces about 50% of the ATP that red blood cells need.^[1][4]

When you don’t have enough pyruvate kinase, your red blood cells can’t make enough energy to survive and maintain their shape. Instead of living for their normal lifespan of about 120 days, these weakened cells break down after only a few days to weeks. The spleen, an organ in your abdomen that normally filters old blood cells, removes these damaged cells from circulation.^[4][6]

• Red blood cells
• Spleen
• Liver
• Bone marrow

What causes the condition?

Pyruvate kinase deficiency is caused by changes or errors (called mutations) in a gene called PKLR. This gene is located on chromosome 1 and provides instructions to your red blood cells on how to make the pyruvate kinase enzyme.^[1][2]

Think of genes as instruction manuals that tell your cells what to do. When there’s an error in the PKLR gene, it prevents your red blood cells from making enough pyruvate kinase enzyme. As a result, your red blood cells can’t produce the ATP energy they need to survive, so they break down too soon.^[3]

The condition follows what’s called autosomal recessive inheritance. This means you must inherit two faulty copies of the PKLR gene to have the condition—one from each of your biological parents. Each parent carries one normal gene and one faulty gene. Unless they’ve had genetic testing, parents typically don’t know they carry a faulty gene because having just one normal copy is enough to prevent them from having symptoms.^[3][9]

When both parents are carriers, there’s a 1 in 4 (25%) chance with each pregnancy that they will both pass the faulty gene to their child, causing pyruvate kinase deficiency. People who have the condition are either homozygotes (meaning they inherited the same mutation from both parents) or compound heterozygotes (meaning they inherited two different mutations, one from each parent).^[1]

Scientists have identified about 300 different mutations in the PKLR gene that can cause this condition. The majority of these are missense mutations, where a single building block of the gene is changed. However, other types of mutations including frameshift, deletion, and insertion mutations have also been reported.^[1][6]

Signs and symptoms

Pyruvate kinase deficiency is present from birth, but when symptoms become noticeable varies greatly from person to person. Some affected newborns have severe symptoms that require lifesaving treatment, while other people may have mild or no symptoms and aren’t diagnosed until late childhood or even adulthood.^[3][4]

The main symptom is chronic hemolytic anemia, which is ongoing anaemia caused by red blood cells breaking down. This leads to common anaemia symptoms including:^[2][3]

• Extreme tiredness and weakness (fatigue)
• Rapid heartbeat (tachycardia)
• Shortness of breath (dyspnea)
• Unusually pale skin (pallor)
• Dizziness
• Headaches

In infants, symptoms may include being fussy and having trouble feeding. Children may have low energy and trouble keeping up with other children during play or exercise, and may experience slow growth.^[8][12]

Other signs happen when waste products from destroyed red blood cells build up in your body. These include:^[2][3]

• Yellowing of the skin and the whites of the eyes (jaundice)
• An enlarged spleen (splenomegaly)—the spleen works harder to remove the damaged blood cells, causing it to get bigger
• Dark-colored urine
• Small pebble-like deposits called gallstones in the gallbladder or bile ducts
• Excess iron in the blood

The symptoms can worsen during times of physical stress on the body, such as during pregnancy, when you have an infection, or after an injury. If the anaemia becomes very severe, it’s called an aplastic crisis.^[3][8]

An interesting aspect of this condition is that some people tolerate their anaemia surprisingly well. This is because the level of a substance called 2,3-bisphosphoglycerate (or 2,3-DPG) increases in the affected red blood cells. This substance helps red blood cells release oxygen more easily to body tissues, which means that even with fewer red blood cells, the body’s tissues can still get adequate oxygen.^[6][7]

How common is the condition?

Pyruvate kinase deficiency is considered rare. It is the most common inherited cause of nonspherocytic hemolytic anaemia and the most common enzyme-related defect that causes red blood cell destruction.^[1][2]

The true number of people affected is unknown, partly because mild cases may not be identified. More than 500 affected families have been identified worldwide. The estimated prevalence ranges from 3 to 8 cases per million people in Western populations, though some reports suggest it may be as common as 1 in 20,000 people.^[1][2]

The condition affects people of all ethnic groups and is found worldwide. However, it’s more common in certain populations. People of northern European descent are more commonly diagnosed, and the condition is particularly widespread in certain Amish communities in Pennsylvania and Ohio. Higher frequencies of specific mutations have also been found in the Romani (Romany) population, in some Mediterranean countries, and in Brazil and Tunisia.^[1][3][4]

The higher frequency in certain communities can be explained by what’s called a founder effect, where mutations have been traced back to specific migrant couples. In addition, consanguinity (when parents are related to each other) increases the risk of children inheriting two copies of the faulty gene.^[1]

The condition affects men and women equally.^[4]

How is it diagnosed?

Diagnosing pyruvate kinase deficiency requires careful attention because the symptoms can be similar to other blood disorders. Your doctor will first ask about your symptoms and whether family members have similar symptoms, then perform a physical examination.^[8][12]

The diagnostic process typically involves several blood tests:^[4][8]

• Complete blood count—to check for anaemia and look at your red blood cell characteristics
• Tests for hemolytic anaemia—to look for signs that red blood cells are breaking down, such as increased bilirubin levels and changes in other blood markers
• Pyruvate kinase enzyme activity test—measures the amount of pyruvate kinase enzyme in your red blood cells
• Genetic testing—analyzes your PKLR gene to identify specific mutations

However, diagnosing this condition can be challenging. The enzyme activity test may not always be informative because some mutations affect the enzyme in ways that aren’t easily detected by standard tests. Additionally, a significant minority of patients have hidden mutations in non-coding regions of the PKLR gene that are missed on standard genetic tests.^[7]

Doctors might do tests before birth if a prenatal ultrasound shows fluid buildup in the baby’s body (which can be a sign of the condition) or if pyruvate kinase deficiency runs in the family. The prenatal tests used are amniocentesis (testing fluid from around the baby) or chorionic villus sampling (testing a small piece of the placenta).^[8][12]

Treatment and management

Treatment for pyruvate kinase deficiency depends on how severe your symptoms are. For people with mild to moderate disease, care is mainly supportive and focused on managing symptoms.^[11][13]

Supportive care

Basic supportive measures include:^[10][13]

• Folic acid and vitamin B supplements—help prevent deficiencies that can occur from increased red blood cell production
• Monitoring and regular check-ups—to track your blood counts and watch for complications
• Avoiding certain activities—high-impact contact sports should be avoided if you have significant splenomegaly (enlarged spleen)

Red blood cell transfusions

Blood transfusions may be necessary if your hemoglobin level falls significantly or if you develop severe symptoms. The decision to transfuse should be based on your symptoms, not just on a specific hemoglobin number. Some people tolerate lower hemoglobin levels better than others because of the increased 2,3-DPG in their red blood cells.^[7][10]

Transfusions are more common in young children. About 53% of patients younger than 5 years require regular transfusions, while approximately 31% of those aged 5-12 years need them. Newborns with severe symptoms may require phototherapy (light therapy) for jaundice or even exchange transfusions.^[11]

People who receive frequent transfusions may need iron chelation therapy—treatment to remove excess iron that builds up in the body from the transfused blood.^[8][11]

Splenectomy

Splenectomy (surgical removal of the spleen) may be recommended for patients with severe anaemia or symptoms from an enlarged spleen. About 59% of patients in one large study had undergone splenectomy. After the procedure, most patients experienced an increase in hemoglobin levels and 90% had decreased transfusion needs.^[1][10]

However, splenectomy is only partially effective because the liver continues to remove damaged red blood cells. The decision to have this surgery must be carefully considered because the spleen plays an important role in fighting infections. People without a spleen have a lifelong increased risk of serious infections from certain bacteria, including pneumococcus, meningococcus, and haemophilus.^[19]

For this reason, surgery in children should be delayed when possible until they are at least 5 years old. Before splenectomy, patients must receive appropriate vaccinations against these bacteria, and they may need to take preventive antibiotics for life.^[19]

Medication treatment

In February 2022, a medication called mitapivat (brand name Pyrukynd) became the first disease-modifying treatment approved specifically for pyruvate kinase deficiency in adults. Mitapivat is an oral medication that works by activating the pyruvate kinase enzyme, helping it work better even when it’s damaged by mutations.^[11][17]

Mitapivat has shown good results in many patients, including increased hemoglobin levels, improvements in markers of red blood cell breakdown, reduced or eliminated need for transfusions, and improvements in fatigue. However, not all patients respond to this medication. In particular, patients carrying certain types of mutations (non-missense mutations) may not benefit from treatment with mitapivat.^[17]

Other treatment options

Hematopoietic stem cell transplantation (bone marrow transplant) has been reported in isolated cases, but it is not considered a standard therapy due to the extensive risks involved and incomplete results.^[1][11]

Gene therapy for pyruvate kinase deficiency is being studied in research settings and has shown encouraging results in early studies, though it is not yet available as a treatment option.^[11]

Living with the condition

Pyruvate kinase deficiency is a lifelong condition, but the outlook varies greatly depending on the severity of your symptoms. Most people with pyruvate kinase deficiency can lead healthy, active lives, especially with proper management and care from a hematologist (blood specialist).^[3][8]

Many symptoms improve as children grow into adulthood. Some adults experience symptoms only when their body is under stress, such as during a viral illness, pregnancy, or other health challenges.^[8][12]

It’s important to maintain regular follow-up with your healthcare team to monitor your condition, watch for complications, and adjust your treatment plan as needed. With the introduction of new targeted medications like mitapivat, treatment options continue to improve for people living with this condition.^[17]

Pregnant women with pyruvate kinase deficiency need careful monitoring, as hemoglobin levels may decline during pregnancy. However, uncomplicated pregnancies and deliveries have been reported even with significant anaemia.^[11]

Families affected by pyruvate kinase deficiency may benefit from genetic counseling to understand the inheritance pattern and risks for future children. Support groups and patient advocacy organizations can also provide valuable resources and connections to others living with the condition.^[8]