What is Pyruvate Kinase Deficiency?
Pyruvate kinase deficiency (PKD) is a condition that typically leads to the breakup of red blood cells, which is the most common sort of defect related to an enzyme involved in the process of breaking down glucose in the body. This disorder can manifest differently in different individuals. Because of this variation, the breakup of red blood cells can range in severity, leading to irreversible damage to cells.
Without fail, PKD results in a specific type of inherited anemia, called non-spherocytic anemia. The symptoms of this disorder can appear anytime, from when a person is a newborn to when they are an adult. Many complications can occur due to anemia caused by the excessive destruction of red blood cells.
What Causes Pyruvate Kinase Deficiency?
Red blood cells, which distribute oxygen throughout the body, rely on a process called glycolysis to function. A vital enzyme in this process is known as pyruvate kinase (PK). This enzyme essentially transforms a molecule called phosphoenolpyruvate into another molecule called pyruvate. This step is crucial as it produces about half of the red blood cell’s energy supply (ATP). Moreover, PK helps produce another molecule called NADH, which is responsible for reducing the levels of a harmful form of hemoglobin. All these changes help red blood cells function more efficiently.
However, in a condition known as PKD (Pyruvate Kinase Deficiency), the efficiency and lifespan of the cells decrease, particularly in younger red blood cells. This deficiency is linked to the PK-LR gene located on chromosome 1q21 and is inherited in what we call an autosomal recessive pattern, meaning both parents must carry and pass on the mutation for the child to be affected.
PKD can occur due to differing mutations in the PK-LR gene, with around 300 known to cause the condition. The most common type of mutations are missense mutations, which means one DNA sequence is replaced by another. Other types of mutations, such as frameshift (where DNA is inserted or deleted), are also possible.
Risk Factors and Frequency for Pyruvate Kinase Deficiency
PKD, a rare condition, was first identified in 1961 and since then, cases have been reported worldwide. Its exact prevalence is unwritten, but it’s estimated to range from 3.2 to 8.5 cases per million people in the Western world. However, in some instances, a prevalence of one in every 20,000 has been reported. PKD is particularly common in Brazil and Tunisia.
Although there isn’t much data on how PKD affects genders differently, certain genetic changes connected to the disease occur more frequently in some communities. This is especially the case in groups like the Pennsylvania Amish and Romani communities. This could be due to a variety of reasons. For one, certain inherited mutations could be passed down from specific migrant couples. Moreover, if people in a community are closely related (consanguinity), it increases the chances of them inheriting and passing on the same genetic changes.
- PKD was first discovered in 1961.
- It is a rare condition, and cases have been reported worldwide.
- The exact number of PKD cases is not known, but it’s estimated to be between 3.2 and 8.5 cases per million people in the West.
- In some cases, one in every 20,000 people is reported to have PKD.
- Certain communities, such as the Pennsylvania Amish and Romani, have higher instances of PKD due to genetic factors.
Signs and Symptoms of Pyruvate Kinase Deficiency
Neonates, or newborns, may display certain symptoms of an as yet unidentified condition. These symptoms may include:
- High levels of bilirubin in the blood and anemia
- Noticeable paleness
- Marred feeding capabilities with frequent pauses
- Tiredness and poor weight gain
- Fast breathing, indicating potential heart failure
- Possibly developing hydrops – an extreme form of swelling in the body – while still in the womb
- Delayed skin healing and difficulty breathing at birth
- Often leading to stillbirth when hydrops complicates
- A “blueberry muffin” rash indicating abnormal blood cell production outside of the bone marrow
- Yellowing of skin and sclerae – the whites of the eyes – indicating jaundice
- Potential kernicterus – a severe kind of brain damage – if severe untreated blood cell destruction is present
Older children and adults can present other symptoms like:
- Poor growth, quick exhaustion, and jaundice
- Potential loss of appetite and dizziness
- Stress triggering bouts of red blood cell destruction
- The skin and whites of the eyes appearing yellow, indicative of jaundice
- An unhealthy pallor to the insides of the eyelids
- Enlarged liver and spleen due to increased red blood cell destruction
- Bony bumps on the forehead due to abnormal blood cell production outside of the bone marrow
- Grown-ups possibly presenting with complications such as gall stones, a type of iron overload disorder, and a severe kind of anemia that happens when the bone marrow fails to make sufficient new blood cells
Testing for Pyruvate Kinase Deficiency
If your baby is showing signs of anemia (low red blood cell count), or hyperbilirubinemia (high levels of bilirubin in the blood), a doctor may carry out specific laboratory tests. The same applies to children with chronic (long-term) anemia and an enlarged spleen. People who require regular blood transfusions also need monitoring.
A complete blood count, which measures different parts of the blood, may be used to assess the severity of anemia. When examining the blood sample (blood smear), the doctor will usually spot normal-color cells, and in some cases, immature red blood cells with uneven shape (echinocytes). Red blood cells of perfectly round shape (spherocytes) are typically not present. Large-sized red blood cells imply a deficiency of a vital vitamin called folate.
The count of immature red blood cells (reticulocytes) does not usually match the extent of red blood cell destruction (hemolysis). The level of an enzyme called lactate dehydrogenase (LDH) elevates in the blood, and haptoglobin, a protein that binds to hemoglobin, decreases. One important test called Coombs’ test, used to identify certain blood disorders, renders negative, the same as another test measuring red blood cell fragility. Lastly, hemoglobin electrophoresis, which differentiates various types of hemoglobin, appears normal.
The main way to diagnose the disease known as Pyruvate Kinase Deficiency (PKD) is by measuring the activity level of an enzyme called pyruvate kinase (PK). Even if PK levels are near normal but PKD is suspected, the doctor may carry out other specific tests. The levels of PK enzyme adjusted for the age of red blood cells, as well as the ratio of PK activity to another enzyme called hexokinase, are found to be low.
A genetic test that identifies changes in the PKLR gene also confirms PKD. The variations present are defined by this test.
People with PKD are at risk of accumulating excess iron in their body. Regular checks with iron studies may detect iron overload. Having high levels of a protein called ferritin in your blood may signal the start of iron overload. Doctors might also use a type of imaging technique, a Magnetic Resonance Imaging (MRI), to identify the storage of iron, in particular circumstances. The MRI technique is especially helpful in selected patients.
Treatment Options for Pyruvate Kinase Deficiency
If you have chronic anemia, supportive care is crucial. This often includes taking folic acid supplements, especially if you’re a child or if you’re pregnant. People with hemolytic crises, which occur when red blood cells are destroyed faster than they can be made, need folic acid supplements too due to extra need for this vitamin. Sometimes, a blood transfusion might be necessary to ease the anemia, but this must be done carefully and appropriately to avoid causing an overload of iron in the body.
If your spleen is very large (a condition known as splenomegaly), a surgical procedure to remove it might be recommended. This also reduces the risk of damaging a swollen spleen. Sometimes, a splenectomy can also help severe anemia. If you had your spleen removed, it’s important to get vaccinated against certain bacteria and also to take preventive antibiotics.
For a condition where too much iron builds up in your body, called hemosiderosis, iron-chelation therapy, which uses medicine to remove excess iron, might be needed. One such drug is desferrioxamine, but this should be stopped if you’re planning to become pregnant.
If you have PKD (Pyruvate Kinase Deficiency) and are pregnant or planning to become pregnant, careful monitoring is important. This includes screening for viral infections and checking your heart function with a test called an echocardiogram. Counseling before undergoing these tests is also essential. You might also need to take folic acid supplements to help prevent certain birth defects. Blood transfusion might be necessary if you have severe anemia symptoms or if your hemoglobin level falls below 8 g/dL. Hemoglobin is a protein in your blood that carries oxygen.
It’s important to be under the care of hematologists (specialists in blood disorders) and obstetricians (specialists in pregnancy and childbirth). If slow fetal growth is suspected, it’s advisable to monitor the baby’s health closely. Sometimes, preterm delivery might happen; this happens in about 10% of the cases.
What else can Pyruvate Kinase Deficiency be?
When a doctor is trying to diagnose PKD (Pyruvate Kinase Deficiency), in addition to the patient’s symptoms, they also look for other conditions that might be causing the patient’s anemia or low red blood cell count. There are several conditions that they may consider:
- Immune hemolysis: This is when the body produces antibodies that destroy red blood cells. One type of immune hemolysis happens when there’s a mix-up in blood groups, like during a blood transfusion. For babies, this can cause serious issues like hydrops fetalis (a severe form of fetal anemia), or can result in neonatal anemia with jaundice for survivors.
- RBC membrane defects: These are inherited conditions, like hereditary spherocytosis, that affect the membrane of red blood cells and can lead to anemia. Doctors can often identify these conditions by looking at a blood smear under a microscope.
- Glucose-6-phosphate dehydrogenase deficiency: This is a genetic disease that often affects males and can cause hemolytic anemia. It’s typically found in people with African-American and Mediterranean ancestry. Certain triggers such as infection, certain medications, and stress can lead to hemolysis in people with this disease.
Finding the right diagnosis often requires not only understanding the patient’s symptoms and condition but also matching that information with lab tests and medical history. It’s not always straightforward, but it’s crucial for the patient’s health.
What to expect with Pyruvate Kinase Deficiency
The outcome of Polycystic Kidney Disease (PKD), a genetic disorder that causes clusters of cysts to develop in your kidneys, can vary greatly from case to case. The severity of the disease and early medical care can greatly influence these outcomes. Severe anemia, a condition in which you lack enough healthy red blood cells to carry adequate oxygen to your body’s tissues, and hemosiderosis, a condition caused by the buildup of iron in the body, are unfavorable conditions and can signal potential risks, especially during pregnancy.
Possible Complications When Diagnosed with Pyruvate Kinase Deficiency
The treatment of PKD, a blood disorder, can lead to a number of complications. These issues include neonatal hyperbilirubinemia, a condition affecting newborns that may appear as jaundice. Additionally, the breaking down of red blood cells, known as hemolysis, can result in an overload of iron in the body and a condition called hemosiderosis.
Gallstones are a common problem for people with PKD, affecting around 30% of patients. These are called pigment gallstones. Moreover, blood transfusions, although helpful, can also cause excessive iron in the body. Thankfully, screening before transfusion has helped decrease the transmission of viruses through blood.
A rare but serious complication can arise from an infection caused by the parvovirus B-19, leading to a condition called aplastic anemia. Another issue can occur when the bone marrow starts producing blood cells in atypical places, resulting in abnormal growths or masses. These are often found in the spine or abdomen and need to be monitored closely.
Lastly, pregnancy can also be difficult for women suffering from PKD, as there could be issues with the baby’s growth.
Typical Complications:
- Neonatal hyperbilirubinemia (jaundice in newborns)
- Hemolysis (breakdown of red blood cells) and hemosiderosis (iron overload)
- Formation of pigment gallstones
- Iron overload from blood transfusions
- Aplastic anemia caused by parvovirus B-19 infection
- Abnormal growths due to production of blood cells in unusual places
- Growth issues during pregnancy
Preventing Pyruvate Kinase Deficiency
Teaching patients consistently about infections is very important. Preventing infections can help reduce episodes of blood cell destruction. Things such as vaccines, preventative folate (a type of B vitamin) and antibiotics are important in disease management. It’s also key to have education before marriage as a preventive measure for Polycystic Kidney Disease (PKD). This education can help prospective couples prepare mentally for the possibility of disease.
It’s also wise to screen partners for carrier status of PKD before the babies are conceived. This means checking if the partner carries the gene for PKD, even if they themselves do not have the disease. This can help in making reproductive decisions. Getting a health check-up and advice before getting pregnant is crucial, too. This can help ensure mom and baby are as healthy as possible throughout the pregnancy.
