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  • Writer's pictureThe Rare360 Editorial Team

Beyond the Bloodstream: Understanding Pyruvate Kinase Deficiency (PKD)

Close up of a doctor and patient hands while discussing medical records after health examination.

Pyruvate kinase deficiency (PKD) is a rare genetic disorder characterized by the premature destruction of red blood cells (RBCs).  It is an inherited metabolic disorder which is caused by a mutation in the PKLR gene, which is found in both liver and red blood cells. The PKLR gene contains instructions to make the pyruvate kinase enzyme, essential for red blood cells to convert sugar into energy through the glycolysis process.

 

However, when a mutation disrupts the gene's structure, it hinders the accurate coding for the pyruvate kinase enzyme, resulting in an enzymatic deficiency. The deficiency of pyruvate kinase leads to breaking down of the red blood cells faster than the body can replace them. This accelerated destruction leads to a lower count of RBCs in the bloodstream, a condition known as hemolytic anemia.

 

Typically, healthy RBCs have a lifespan of approximately 120 days, but in individuals with PKD, this is drastically reduced to a mere few days or weeks. Given that RBCs play a crucial role in transporting oxygen throughout the body, a deficiency in pyruvate kinase translates to insufficient oxygen delivery to other cells. This deficiency manifests in common symptoms associated with anemia, illustrating the far-reaching consequences of PKD on overall health.

 

This rare condition is estimated to affect three to eight individuals per 1,000,000 people, with no biological sex-based prevalence. It is a global phenomenon, impacting individuals from various parts of the world. While most mutations are rare, specific amino acid changes may be more prevalent in certain populations, including the Amish community, the Romany population, and some Mediterranean countries.

 

According to a systematic literature review published in 2020, the prevalence of clinically diagnosed PKD is likely between 3.2 and 8.5 per million in Western populations. However, the overall prevalence, considering both diagnosed and undiagnosed cases, could potentially be as high as 51 per million. Research indicates that the condition might be significantly underdiagnosed due to the challenge of identifying mild cases.


Exploring Pyruvate Kinase Deficiency Symptoms

The symptoms of Pyruvate Kinase Deficiency (PKD) can vary widely, with diverse presentations and impacts on individuals. From life-threatening conditions at birth to subtle or even asymptomatic cases that may go unnoticed until adulthood, PKD showcases a spectrum of manifestations. The condition is more noticeable in childhood, often showing signs of improvement in adulthood.


People living with PKD may exhibit common anemia symptoms like fatigue, weakness, and shortness of breath, particularly during childhood. However, symptoms may remain subtle or unnoticed until the body undergoes stress, such as during pregnancy, viral infections, or injury, in adulthood.

 

Some of the common symptoms associated with PKD include:

  • Mild to severe hemolytic Anemia: The hallmark symptom of PKD, hemolytic anemia, stems from the accelerated breakdown of red blood cells, resulting in a diminished count. This reduction in healthy red blood cells impairs the oxygen-carrying capacity of the blood.

  • Weakness and fatigue: The constant breakdown of red blood cells contributes to fatigue and weakness, as the body struggles to maintain an adequate supply of oxygen to sustain energy levels.

  • Rapid heartbeat (tachycardia): The heart may respond to decreased oxygen availability by beating faster, attempting to compensate for the insufficient oxygen supply to the body's tissues.

  • Shortness of breath and trouble breathing: Insufficient oxygen delivery to the body's organs and tissues can lead to shortness of breath and difficulty breathing, particularly during exertion or stress.

  • Dizziness: Decreased oxygen to the brain may result in dizziness, highlighting the impact of PKD on neurological function.

  • Headaches: Lack of oxygen in the body can lead to headaches, indicating the broader consequences of impaired oxygen transport.

  • Pale skin (pallor): Decreased red blood cell count results in pallor, as the skin reflects the diminished oxygen-carrying capacity of the blood.

  • Jaundice: Jaundice, characterized by yellowing of the skin and eyes, occurs when the liver struggles to process the byproducts of red blood cell breakdown, further illustrating the systemic effects of PKD.

  • Recurrent gallstones: Excess bilirubin, a byproduct of red blood cell breakdown, can lead to the formation of gallstones, contributing to additional complications associated with PKD.

  • Splenomegaly (Enlarged spleen): The spleen is responsible for filtering red blood cells. It enlarges in response to the increased workload caused by the rapid breakdown of red blood cells.

  • Kernicterus: Kernicterus, a neurologic condition affecting the brain, may occur due to the accumulation of bilirubin, a byproduct of red blood cell breakdown. This condition underscores the systemic consequences of PKD.

  • Leg ulcers: Chronic breakdown of red blood cells can lead to reduced oxygen supply to tissues, resulting in skin complications like leg ulcers. These ulcers are indicative of the vascular challenges associated with PKD.

  • Iron overload: Frequent blood transfusions, a common treatment for severe cases of PKD, can result in iron overload, necessitating careful management to prevent further complications.

Research is being conducted in order to gain a better understanding as to how PKD impacts people's lives. If you or a loved one is suspected to have or has been diagnosed with PKD, you have the opportunity to include your perspectives, insights and experiences (P.I.E.) by subscribing to the Rare360 P.I.E. Program.

Diagnostic Tools for Pyruvate Kinase Deficiency: Navigating the Complexity of Diagnosis

The journey to diagnose Pyruvate Kinase Deficiency (PKD) involves a careful exploration of genetic markers, blood parameters, and advanced prenatal screening techniques. Below are various diagnostic tools and procedures used to diagnose PKD:

  • Prenatal Screening: Signs of PKD may be detectable during a prenatal ultrasound, especially if there is fluid build-up in multiple parts of the fetus's body, a condition known as hydrops fetalis. If hydrops fetalis is observed, additional tests such as amniocentesis or chorionic villus sampling may be recommended. These procedures involve collecting samples of amniotic fluid or placental tissue to analyze the genetic material for PKLR gene mutations.

  • Full Blood Counts and Reticulocyte Counts: These tests provide a comprehensive analysis of blood components, including red blood cells and reticulocytes (young, immature red blood cells). Abnormalities in these counts can support the diagnosis of PKD.


Blood samples for Pyruvate Kinase test for pyruvate kinase deficiency.
  • PK Test (Pyruvate Kinase Test): The PK test is a standard diagnostic tool for PKD. It measures the activity of pyruvate kinase per unit of hemoglobin in red blood cells. A low activity level indicates a potential deficiency of pyruvate kinase, contributing to the diagnosis of PKD.


  • Direct Enzyme Assays: These assays directly determine the levels of pyruvate kinase in erythrocytes, which are red blood cells separated by density centrifugation. This method contributes to a more precise evaluation of enzyme levels.

  • Direct DNA Sequencing: Utilizing DNA sequencing techniques helps identify specific genetic mutations responsible for PKD. This is crucial for confirming the genetic basis of the deficiency.

Diagnosing PKD can be challenging due to the intricacies of the diagnostic process and the diverse clinical manifestations observed in affected individuals. The heterogeneity of symptoms and genetic mutations necessitates a multidimensional approach to accurately identify and confirm PKD.


It's important to collaborate closely with healthcare providers, especially in cases where anemia symptoms are present, and there's a family history of anemia or PKD. This collaborative approach enhances the accuracy of diagnosis and facilitates appropriate management strategies for individuals with PKD.


Tailoring Treatment for Pyruvate Kinase Deficiency: A Collaborative Approach

The management of Pyruvate Kinase Deficiency (PKD) is as diverse as the symptoms it presents. A collaborative effort involving pediatricians, hematologists, and other healthcare specialists is essential to tailor treatment plans to individual needs. Given the variation in symptom severity, an individualized approach is crucial.


The treatment plan for individuals living with PKD depends on the severity and when the condition is diagnosed.

 

For Fetuses and Newborns

  • Intrauterine fetal transfusion: When a fetus exhibits a low red blood cell count, an intrauterine transfusion may be administered. A healthcare provider injects red blood cells from a donor into the fetus during this procedure.

  • Phototherapy: Jaundice commonly manifests in most newborns with Pyruvate Kinase (PK) deficiency due to the accelerated breakdown of red blood cells and the underdeveloped capacity of their immature livers to conjugate bilirubin. In cases where infants are significantly affected, phototherapy becomes a recommended intervention for hyperbilirubinemia. This therapeutic procedure involves directing intense light onto the exposed skin, with careful shielding of the eyes. The objective is to enhance the metabolism and excretion of bilirubin, aiding in the resolution of jaundice.

  • Exchange transfusion: Infants experiencing severe jaundice may necessitate an exchange transfusion, a medical procedure involving the replacement of their blood with that of a donor.


For Infants, Children and Adults

  • Blood transfusions: In severe instances, individuals may need lifelong blood transfusions to compensate for a low red blood cell count. The frequency of blood transfusions might be higher during infancy and childhood but could diminish as one reaches adulthood.

  • Mitapivat (Pyrukynd): Mitapivat, an FDA-approved tablet as of February 2022, is utilized in the treatment of pyruvate kinase deficiency and hemolytic anemia. Mitapivat activates an enzyme called pyruvate kinase-R, which red blood cells use to convert sugars into energy. It's the first approved treatment for pyruvate kinase deficiency, a rare, inherited disorder that causes red blood cells to break down quickly. The FDA underscored the caution that an abrupt stoppage of mitapivat may exacerbate premature red blood cell destruction.

  • Folic acid supplements: Folic acid plays a pivotal role in red blood cell production within your body. Prescribed as a supplement, folic acid supplementation promotes heightened red cell production. Additionally, maintaining adequate levels of Vitamin D, calcium, and incorporating regular exercise is crucial for optimal bone health in people living with PKD.

  • Iron chelation: Frequent red cell transfusions result in an accumulation of iron over time, leading to iron overload. The body lacks a natural mechanism to eliminate excess iron, and with repetitive transfusions, iron deposits can form in the liver. Iron overload is prevalent in individuals with PK deficiency, even without red cell transfusions, due to heightened iron absorption from the diet. Chelation agents form compounds with iron, facilitating their excretion from the body. While phlebotomy (regular blood removal) can be employed to reduce iron levels, it is often poorly tolerated in individuals with anemia.

  • Splenectomy (spleen removal): The consideration for splenectomy arises when individuals experience frequent blood transfusions or frequent symptoms from anemia. Splenectomy, whether performed through open surgical or laparoscopic methods, has resulted in a partial improvement of anemia in most individuals, though not universally. However, this surgical intervention entails potential risks, including life-threatening bloodstream infections and blood clot formation (thrombosis), which are carefully assessed against the potential benefits on a case-by-case basis. Due to the risk of infection post-splenectomy, most individuals opt to undergo this procedure after reaching at least 5 years of age. It is crucial for individuals to receive additional vaccines, such as the pneumococcal vaccine, before splenectomy, take prophylactic antibiotics afterward, and adhere to strict fever guidelines.

  • Cholecystectomy (gallbladder removal): Supportive care encompasses monitoring the gallbladder due to the risk of gallstones. The removal of the gallbladder (cholecystectomy) is considered for individuals with symptomatic gallstones and those undergoing splenectomy.


Exploring Future Avenues: Innovations in PK Deficiency Treatment

Researchers are currently testing new treatments for pyruvate kinase deficiency, including:

  • Allogeneic hematopoietic stem cell transplantation (HSCT): Allogeneic hematopoietic stem cell transplantation (HSCT) holds the potential to cure PK deficiency and has been explored in a limited number of individuals, particularly those requiring chronic blood transfusions. In allogeneic stem cell transplantation, individuals affected by PK deficiency undergo chemotherapy treatment before receiving hematopoietic stem cells from a healthy donor. Despite its promise, this is a major medical procedure fraught with significant risks. Further research is imperative to ascertain the long-term safety and effectiveness of this therapeutic approach.

  • PK deficiency gene therapy: Research into gene therapy as a therapeutic approach for individuals with PK deficiency is ongoing. In this innovative treatment, the faulty gene in a patient is replaced with a normal gene, facilitating the production of the active enzyme. Theoretically, this permanent transfer of the normal gene could result in a potential "cure." It's important to note that, as of now, gene therapy for PK deficiency is still in the experimental stages and is being considered primarily as a research-based therapeutic option.

 

Conclusion

In conclusion, Pyruvate Kinase Deficiency (PKD) stands as a complex genetic disorder with a spectrum of manifestations, ranging from subtle symptoms to life-threatening conditions. The impact of PKD on red blood cells and overall health underscores the importance of comprehensive understanding, early detection, and tailored management strategies.


Symptomatically, PKD presents challenges across the lifespan, from neonatal manifestations requiring immediate intervention to milder cases that may go undiagnosed until adulthood. The diverse array of symptoms, including hemolytic anemia, neurological conditions like kernicterus, and complications like gallstones, necessitates a nuanced diagnostic approach.


The diagnostic journey involves meticulous genetic exploration, blood parameter assessments, and prenatal screening techniques. The challenge lies in the heterogeneity of clinical manifestations and the complexity of genetic mutations, making a multidimensional diagnostic approach essential.


Once diagnosed, the management of PKD requires a collaborative effort from a multidisciplinary healthcare team. The treatment plan is tailored to the severity of symptoms and the age at which the condition is identified. Innovative treatments, such as the FDA-approved mitapivat, provide hope for modifying the course of PKD, while investigational approaches like gene therapy and allogeneic hematopoietic stem cell transplantation offer potential avenues for a cure.


In navigating the complexities of PKD, individuals, families, and healthcare providers play crucial roles. As research advances and awareness grows, the landscape of PKD management evolves, promising improved outcomes and quality of life for those affected. Continued research, early detection, and collaborative care remain integral in enhancing the prognosis and well-being of individuals living with PKD.


Research is being conducted in order to gain a better understanding as to how PKD impacts people's lives. If you or a loved one is suspected to have or has been diagnosed with PKD, you have the opportunity to include your perspectives, insights and experiences (P.I.E.) by subscribing to the Rare360 P.I.E. Program.

 

References 

  1. https://my.clevelandclinic.org/health/diseases/23419-pyruvate-kinase-deficiency

  2. https://ashpublications.org/blood/article/136/11/1241/461550/Management-of-pyruvate-kinase-deficiency-in

  3. https://ashpublications.org/hematology/article/2023/1/97/506488/Pyruvate-kinase-activators-for-treatment-of

  4. https://www.stanfordchildrens.org/en/service/stem-cell-transplantation/conditions/pyruvate-kinase-deficiency

  5. https://europepmc.org/article/MED/32279356

  6. https://www.childrenshospital.org/conditions/pk-deficiency#diagnosis--treatments

  7. https://www.aabb.org/news-resources/news/article/2022/02/18/fda-approves-new-treatment-for-hemolytic-anemia-in-adults-with-pk-deficiency

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  9. https://www.webmd.com/a-to-z-guides/pyruvate-kinase-deficiency#1-6

  10. https://www.ncbi.nlm.nih.gov/books/NBK560581/

  11. https://www.sciencedirect.com/topics/medicine-and-dentistry/pyruvate-kinase-deficiency

  12. https://thalassaemia.org.cy/pk-deficiency/#_ftn1

  13. https://rarediseases.org/rare-diseases/pyruvate-kinase-deficiency

  14. https://medlineplus.gov/genetics/condition/pyruvate-kinase-deficiency/

  15. https://kidshealth.org/en/parents/pyruvate-kinase-deficiency.html

  16. https://en.wikipedia.org/wiki/Pyruvate_kinase_deficiency

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