What is Pyruvate Kinase Deficiency? Let's talk about it simply!

Today we are going to talk about a rare, but very important genetic condition. This is called `Pyruvate Kinase Deficiency`. Imagine, there is a special enzyme in our body that helps red blood cells make energy, and it is called `Pyruvate Kinase`. So, when there is not enough of this enzyme in the body (that is what is called a deficiency), those red blood cells do not have the strength to do their job properly, and they start to break down quickly before new red blood cells can be produced.

These red blood cells carry oxygen throughout our bodies. So when red blood cells are reduced due to Pyruvate Kinase Deficiency, other cells in the body do not get enough oxygen. As a result, you may develop symptoms of anemia. This is a condition that is present from birth and lasts throughout your life. This means that you will have to be under the supervision of a hematologist throughout your life. However, these symptoms can vary from person to person.

What are the symptoms of Pyruvate Kinase Deficiency?

The most common symptoms of anemia in this condition are:

• Feeling very tired: This means feeling constantly tired, even doing the smallest thing.
• Palpitations: Feeling like your chest is pounding even when you are just standing still.
• Shortness of breath: Feeling short of breath even with a little exertion.
• Pale skin: When the body loses blood, the skin changes color, right?
• Dizziness: A feeling of spinning, sometimes like you're going to fall.
• Headache : Frequent headaches.

In addition to these anemia symptoms, other symptoms may occur due to the accumulation of waste products from broken red blood cells in the body. Let's see what they are:

• Jaundice: A yellowing of the skin and whites of the eyes. This is caused by a build-up of a substance called bilirubin, which comes from broken down red blood cells.
• Enlarged Spleen: The spleen is an organ in our body that stores broken red blood cells. So when there is too much cell damage, the spleen can become enlarged.
• Dark urine: Urine that is darker than normal.

At what age do symptoms usually appear?

Although Pyruvate Kinase Deficiency (PK Deficiency) is a condition that is present at birth, the time it takes for symptoms to appear depends on the severity of your condition.

Imagine, some newborns have such severe symptoms that they need immediate life-saving treatment. Younger babies may cry a lot, refuse to feed, and stop playing. Older children may complain of being tired all the time and lose interest in running around and playing. Some adults may not even know they have the condition until it is a major stressor—for example, during pregnancy, a serious infection, or an injury.

Why does this `Pyruvate Kinase Deficiency` occur?

This is a genetic disease that is passed down from generation to generation due to a defect in a gene called `(PKLR)`. Think of it like our genes are like a book that tells our cells "do this, do that". Your `(PKLR)` gene tells red blood cells how to make an enzyme called `Pyruvate Kinase`. This `Pyruvate Kinase` enzyme helps red blood cells make `Adenosine Triphosphate` (ATP)`, an energy source.

So, in a person with `Pyruvate Kinase Deficiency` (PK Deficiency), due to a defect in the `(PKLR)` gene, red blood cells are unable to produce enough `Pyruvate Kinase` enzyme. Therefore, red blood cells are unable to produce the `(ATP)` energy they need to survive. As a result, those cells break down quickly. Then the number of red blood cells in the body decreases. This is called `Hemolytic Anemia` , which means anemia caused by the breakdown of red blood cells.

How genes are transmitted: `(Autosomal Recessive Inheritance)`

To develop `Pyruvate Kinase Deficiency` (PK Deficiency), you must inherit two defective `PKLR` genes . One from your mother and one from your father. This is what we call `Autosomal Recessive Inheritance` in medicine. For this to happen, both parents must have one normal `PKLR` gene and one defective `PKLR` gene. However, unless they have had genetic testing, they may not know that they have this defective gene or that they can pass it on to their children.

For such a pair of parents, there is a one in four (25%) chance that their child will inherit both defective `(PKLR)` genes and have a `Pyruvate Kinase Deficiency`.

Who is at higher risk for this condition?

Pyruvate kinase deficiency (PK Deficiency) is a genetic condition that is passed down from parent to child, and is more common in certain ethnic groups. It is most commonly diagnosed in people of Northern European descent. It is also relatively common in some Amish communities in Pennsylvania and Ohio.

Is there a way to reduce the risk?

We cannot prevent inherited genetic conditions. However, you can test your risk of having a child with Pyruvate Kinase Deficiency. If you or your partner has a family history of this condition, it is a good idea to talk to a genetic counselor. They can explain the DNA tests that are available and can help you understand the possible consequences during pregnancy.

What complications can occur due to this condition?

Some people only discover they have Pyruvate Kinase Deficiency after complications arise. Such complications include:

• Gallstones: Gallstones can form in the gallbladder.
• Iron overload: Iron overload can occur due to illness or frequent blood transfusions.
• Non-healing wounds on the legs (`(Leg Ulcers)`).
• Pulmonary Hypertension: Increased pressure in the blood vessels connected to the lungs.
• Weakening of bones: This increases the risk of fractures and the risk of developing diseases like osteoporosis as we age.
• Complications during pregnancy: things like miscarriages, premature births, etc.

Pregnancy is a time of great stress for the body. This can lead to new or worsening symptoms of pyruvate kinase deficiency (PK Deficiency). It can also affect the unborn baby. However, pregnancy complications are rare. If you are pregnant, your obstetrician and gynecologist will work with your hematologist to keep you and your baby safe.

How do doctors diagnose this disease?

If a baby in the womb has symptoms of Pyruvate Kinase Deficiency, they can sometimes be seen during an ultrasound scan before birth. If this is suspected, doctors can test for the condition. For example, fluid buildup in the fetus's body (Hydrops Fetalis) is one warning sign.

If you or your child has symptoms of pyruvate kinase deficiency (PK Deficiency), a doctor will order several blood tests. These tests will look for:

• Anemia: This blood test checks to see if you have hemolytic anemia. Since anemia can have many causes, this blood test also helps rule out other causes.
• Whether the activity of the `pyruvate kinase` enzyme is low: Biochemical tests can measure how active your `pyruvate kinase` enzyme is. In `pyruvate kinase deficiency`, its activity is low.
• Whether there is a mutation in the `(PKLR)` gene: Molecular tests can detect the defects in the `(PKLR)` gene that cause this disease.

How is Pyruvate Kinase Deficiency treated?

Treatment depends on how severe your symptoms are and when the disease was diagnosed.

For fetuses and newborns in the womb

Fetuses and newborns with Pyruvate Kinase Deficiency may require life-saving treatment. Examples:

• Intrauterine Fetal Transfusion: A fetus with pyruvate kinase deficiency (PK Deficiency) may need treatment before birth. In this procedure, red blood cells from a donor are injected into the fetus.
• Phototherapy: This helps break down a waste product called bilirubin that builds up in the newborn's body. Jaundice develops when bilirubin builds up.
• Exchange Transfusion: Newborn babies with severe jaundice may need this treatment. Here, the baby's blood is replaced with blood from a donor.

For babies, children and adults

These treatments can control anemia symptoms and prevent complications caused by pyruvate kinase deficiency (PK deficiency).

• Blood Transfusions: You may need blood transfusions throughout your life to replace your low red blood cell count. However, some people may need regular blood transfusions as they grow older, but this need may disappear as they get older.
• Mitapivat (Pyrukynd®): This is a new drug used to treat Pyruvate Kinase Deficiency and Hemolytic Anemia in adults. The US Food and Drug Administration (FDA) approved it in 2022.
• Folic Acid Supplements: Folic acid is a nutrient that helps the body make red blood cells. If you don't get enough folic acid from the foods you eat, you may need to take a supplement.
• Iron Chelation Therapy: Iron overload can build up in the body, either due to the disease itself or due to frequent blood transfusions. This therapy removes excess iron.
• Spleen Removal (Splenectomy): Your spleen is a place where broken red blood cells are stored. When you have Pyruvate Kinase Deficiency, it can become too large. If this happens, a doctor may need to remove it.
• Gallbladder Removal (Cholecystectomy): Pyruvate Kinase Deficiency can cause gallstones to form. If they cause problems, your doctor may recommend removing your gallbladder.

Researchers are also investigating new treatments, including:

• Stem Cell Transplant: In this procedure, you receive stem cells from a donor. These cells then develop into healthy red blood cells.
• Gene Therapy: This involves replacing the defective gene that causes Pyruvate Kinase Deficiency with a healthy gene.

When should you see a doctor?

You will need to see your hematologist regularly to check your red blood cell levels. They will also check for complications such as iron overload.

They will tell you what follow-up care you need based on your condition. Therefore, it is very important to follow your doctor's instructions.

What can you expect when living with this condition?

Your experience will depend on your symptoms and treatment. The complications of pyruvate kinase deficiency (PK Deficiency) can also affect your experience. Also, your experience may change over the course of your life. For example, children who needed frequent blood transfusions as children may no longer need them as adults. Some adults may not have symptoms until they have a serious health problem.

Your doctor is the best person to explain how Pyruvate Kinase Deficiency will affect your long-term health.

If you have pyruvate kinase deficiency (PK Deficiency), your doctor will monitor you very closely. You will need regular tests to make sure you have enough red blood cells. You may need blood transfusions to prevent severe anemia. Or, you may not need any treatment at all. There is no definitive answer to your experience with this condition. The most important thing is to get diagnosed and get the right care from a specialist. Your red blood cells are your lifeblood. Having enough of them is essential for your well-being.

Finally, remember this.

Pyruvate Kinase Deficiency is a complex and potentially life-long condition. But don't worry. With the right diagnosis, treatment, and expert advice, you can live with this condition successfully. If you or someone you know has these symptoms, see a doctor right away. Remember, the sooner you are diagnosed, the better your chances are of getting treatment and reducing complications. You are not alone, and there are doctors and healthcare providers to help you on this journey.

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