A brief summary of Pyruvate Kinase Disorder:

Pyruvate kinase deficiency is a rare genetic disorder. It is caused by DNA changes in the pyruvate kinase gene and leads to faster than normal breakdown of red blood cells. This will lead to low red blood cell count (anemia) which can cause symptoms like fatigue, weakness and rapid heartbeat (tachycardia). Most people with pyruvate kinase deficiency lead a healthy life. It is estimated that there are currently 50,000 people with pyruvate kinase deficiency in the United States of America.

 

Symptoms seen in Pyruvate Kinase Deficiency (PKD):

A wide range of symptoms and severity are seen in people with PKD. Some people have very mild symptoms and some cases are life threatening that require blood transfusions to survive. Everyone is different and your care provider will tailor your care management to your specific needs. 

At different stages of life some symptoms may be more likely. Newborns can have a large amount of fluid build-up in tissues and organs (fetal hydrops). Children and adults will experience general symptoms associated with low blood cell count (anemia) : weakness, fatigue, rapid heartbeat (tachycardia), shortness of breath, trouble breathing, dizziness, headaches and pale skin. 

Rarely, patients experience more advanced symptoms like yellow skin (jaundice), enlargement of the spleen (splenomegaly), dark-colored pee, gallstones and iron overload.

When the body is under stress, an episode of low blood cell count can occur, called aplastic crisis. During this crisis, symptoms can be more frequent or worsen in severity.

From a number of research studies by scientists and doctors on pyruvate kinase deficiency, below are lists of symptoms that have been seen in patients with pyruvate kinase deficiency. Different people will have very different symptoms so you may not necessarily have some or any of the below.

It’s sometimes helpful to know what other people have seen just so there’s less uncertainty about what to expect.

Table 1.

General features of pyruvate kinase deficiency

Symptom

Laboratory Findings

·       Fluid build up in infants (fetal hydrops) ·       Weakness ·       Fatigue ·       Rapid heartbeat (tachycardia) ·       Shortness of breath ·       Trouble breathing (dyspnea) ·       Dizziness ·       Headaches ·       Pale skin (pallor) ·       Yellow skin (jaundice) ·       Enlarged spleen (splenomegaly) ·       Dark-colored pee ·       Gallstones  (cholelithiasis) ·       Iron overload ·       Muscle spasms

·       Low amount of red blood cells (anemia) ·       Low level of oxygen carrying proteins (hemoglobulin) ·       Elevated bilirubin (compound of red blood cells) level ·       Elevated count of immature red blood cells (reticulocyte) ·       Low activity of pyruvate kinase enzyme ·       Mutations in pyruvate kinase gene

Here we explain some of the more complicated symptoms :

 

Fluid buildup : Fluid buildup (hydrops) can occur in newborns due to low red blood cell count (anemia). It is a condition in which fluids build up in the organs. Only 20% of unborn babies diagnosed with fluid buildup survive child birth.

Yellow skin : Yellow skin (Jaundice) is a condition in which the skin will take a yellow color. This is due to build up of bilirubin, a key component of red blood cells, due to the rapid death of red blood cells.  

Pale skin :  Pale skin (pallor) can be caused due to a decrease of blood flow, or amount of red blood cells in the blood flow of the skin.

Enlarged spleen : Enlarged spleen (splenomegaly) is a condition in which the spleen grown abnormally large. The spleen is the organ that regulates break down of red blood cells. During periods of increased red blood cell break down, the spleen can grow large. This can be dangerous as the spleen can easily rupture upon hard impacts on the body.

Dark-colored pee : Due to the high amount of breakdown of red blood cells, there is an increased amount of breakdown products that will be excreted in the urine. This can turn the pee dark in color.

Gallstones : Gallstones (cholelithiasis) are small stones build up of cholesterol that will from inside the gallbladder, a small organ under the liver. These can cause discomfort and pain.

Iron overload : Iron overload (hemochromatosis) is caused due to rapid break down of red blood cells. Iron is naturally part of red blood cells and get released upon breakdown of the red blood cell.

 

Diagnosis of Pyruvate Kinase Deficiency:

Prenatal and newborns

If pyruvate kinase deficiency runs in the family, doctors might advise tests before birth. Most commonly, prenatal ultrasound is used to determine fluid buildup in the baby’s body. In addition, the baby’s DNA will be determined to look for genetic defects in the pyruvate kinase deficiency gene (Amniocentesis or chorionic villus sampling).

Children and adults

Doctors will first suspect pyruvate kinase deficiency based on symptoms like fluid build-up in children or weakness, tiredness and yellow skin (jaundice) in adults. 

Doctors will take a blood sample to examine the blood quality. Different findings in the blood can indicate pyruvate kinase deficiency : low amount of red blood cells (anemia), low hemoglobulin level, elevated bilirubin level, elevated reticulocyte count. To make a conclusive diagnosis of pyruvate kinase deficiency, doctors will check the activity of the pyruvate kinase enzyme. Low activity signals pyruvate kinase deficiency. In addition, doctors will perform genetic testing to look for DNA changes in the pyruvate kinase gene.

 

Clinical diagnosis

Prenatal and newborns

·      Ultrasound evaluation of fluid build-up ·      DNA analysis (Amniocentesis / Chorionic villus sampling)

Children and adults

·      Clinical evaluation of common symptoms ·      Blood sample analysis ·      Pyruvate kinase enzyme activity analysis ·      DNA analysis

Management: 

Different options exist to manage pyruvate kinase deficiency disease symptoms and progression.

Early diagnosis : In prenatal, newborns or infants, early diagnosis may be key to proper development and survival. Therefore, it is advised to consult your doctor before pregnancy if pyruvate kinase deficiency runs in your family.

Intrauterine fetal transfusion : To prevent symptoms in a fetus in the womb, intrauterine fetal transfusion can be used. A doctor will inject red blood cells into the fetus in the womb.

Treating low blood cells : As the main cause to many of the symptoms is the low amount of red blood cells, the most advised treatment is to promote red blood cells by supplementation of folic acid or vitamin B. In addition, blood transfusion is used to increase the red blood cell count. Another possibility is to remove a part or the entire spleen (splenectomy) in order to prevent or slow down red blood cell breakdown.

Jaundice : The yellowing of the skin (jaundice) can be treated by ultraviolet (UV) light therapy (phototherapy).

Iron buildup : To slow down and reduce the iron buildup, patients can take medications that send extra iron out of the body in the urine (iron chelation).

Gallstones : To prevent gallstone formation, it is possible to completely remove the gallbladder (cholecystectomy).

Drugs : Mitapivat (pyrukynd) is a tablet drug that can be used to treat pyruvate kinase deficiency. This drug can bind to, and activate, the pyruvate kinase enzyme.

Allogeneic hematopoietic stem cell transplantation (HSCT) : In severe cases, it is possible to receive hematopoietic stem cells from a healthy donor. These cells are capable to make healthy red blood cells.

Gene therapy : Recent advances in gene therapy might make it possible in the future to replace the mutated gene that causes pyruvate kinase deficiency with a healthy gene.

Life Expectancy:

The life of a person with pyruvate kinase deficiency depends on the severity of the case. Most people will live a life of regular length when symptoms are properly managed. Some patients will have no symptoms at all whilst other people’s symptoms may range from mold to severe. Most severe cases can be life-threatening, especially during infancy. These patients require regular blood transfusions to survive.

Resources: 

·       Pyruvate kinase deficiency foundation

www.pkdf.org

·       KidsHealth

Kidshealth.org

·       Metabolic Support UK

United Kingdom

Phone: 0845 241 2173

www.metabolicsupportuk.org

·       Newborn Screening in Your State

Health Resources & Services Administration

www.newbornscreening.hrsa.gov/your-state