Pyruvate Kinase Deficiency: Symptoms, Types, Causes and Treatment

Pyruvate kinase deficiency (PKD) is a rare but important inherited condition that affects the red blood cells’ ability to produce energy. This leads to chronic hemolytic anemia—a state where red blood cells are destroyed faster than they are made—often causing a wide variety of symptoms and complications. Understanding PKD can be life-changing for affected individuals and their families, as advances in diagnosis and treatment are improving patient outcomes. In this article, we’ll look closely at the symptoms, types, causes, and modern treatments for pyruvate kinase deficiency, using the most current research evidence.

Symptoms of Pyruvate Kinase Deficiency

Living with pyruvate kinase deficiency can mean facing a spectrum of symptoms, from mild fatigue to severe anemia and its complications. The clinical presentation is highly variable—even among people with the same genetic mutations. Recognizing the signs early is crucial for timely diagnosis and better management of the disease.

Symptom	Description	Severity Range	Sources
Anemia	Fatigue, pallor, weakness	Mild to severe	1 4 5 7
Jaundice	Yellowing of skin/eyes due to high bilirubin	Intermittent to chronic	1 4 7
Gallstones	Abdominal pain, nausea from bilirubin stones	Common complication	7 11
Splenomegaly	Enlarged spleen, abdominal fullness	Variable	1 7
Iron Overload	Excess iron in organs, can cause organ damage	Progressive, cumulative	7 9 11
Fatigue	Persistent tiredness, reduced quality of life	Mild to severe	8

Table 1: Key Symptoms

Variability and Complexity in Symptoms

Pyruvate kinase deficiency does not affect everyone in the same way. The hallmark is chronic hemolytic anemia, but the clinical picture can be quite diverse 1 4 5 7:

• Fatigue and Weakness: Due to anemia, people often experience significant tiredness, shortness of breath, and reduced exercise tolerance.
• Jaundice and Icterus: Yellowing of the skin and eyes is common, sometimes persistent, due to the increased breakdown of red blood cells producing excess bilirubin.
• Gallstones: The high bilirubin levels can lead to the formation of gallstones, which may cause abdominal pain or require surgical removal 7 11.
• Splenomegaly: An enlarged spleen can occur as it works to filter the abnormal red blood cells, potentially leading to abdominal discomfort or a palpable mass.
• Iron Overload: Repeated destruction of red blood cells and transfusions can cause iron to accumulate in the body, risking damage to the liver, heart, and other organs 7 9 11.
• Other Complications: Some patients develop rare but serious problems like extramedullary hematopoiesis (blood cell production outside the marrow), leg ulcers, or pulmonary hypertension 1 7.

Impact on Quality of Life

Symptoms such as chronic fatigue and anemia can greatly affect daily life, including school, work, and physical activity. Children and adults with PKD often report lower health-related quality of life and increased fatigue 8. The unpredictable nature of the disease means that some patients may have long symptom-free periods, while others need regular medical care.

Types of Pyruvate Kinase Deficiency

Pyruvate kinase deficiency is not a one-size-fits-all diagnosis. Its clinical and genetic diversity means that patients can be grouped by severity, genetic background, and specific complications.

Type/Group	Defining Features	Typical Severity	Sources
Mild	Subtle or compensated anemia, few symptoms	Mild	7 6 3
Moderate	Symptomatic anemia, occasional transfusions	Moderate	7 6
Severe	Early-onset, regular transfusions needed	Severe	7 3
Genotypic	Homozygous or compound heterozygous mutations	Variable	3 6 7

Table 2: Types and Severity Groups

Clinical Severity Groups

PKD can be categorized based on anemia severity and transfusion needs 7 6:

• Mild or Compensated: Some individuals have minimal symptoms, with their bodies adapting to the chronic anemia. They may never require transfusions.
• Moderate: These patients experience clear symptoms and may need transfusions during stress or illness.
• Severe: The most affected group often presents early in life, sometimes as newborns, and needs regular transfusions to survive.

Genetic and Molecular Heterogeneity

Over 300 different mutations in the PKLR gene have been identified, mostly inherited in an autosomal recessive manner 6 7 3. Types include:

• Homozygous mutations: Both gene copies are the same mutation. Severity is variable.
• Compound heterozygous: Two different mutations, one on each gene copy. This is the most common form and can be associated with a broad spectrum of disease 3 6 7.

Certain mutations (such as non-missense types—those causing early protein truncation or splicing defects) are linked to more severe disease, with lower hemoglobin, more transfusions, and higher risk of complications 3.

Phenotypic Spectrum and Overlap

Interestingly, even siblings with the same mutations may differ in symptoms and severity, underlining the influence of other genetic or environmental factors 3. There is also no clear correlation between genotype and complications during pregnancy or the newborn period.

Causes of Pyruvate Kinase Deficiency

Uncovering the cause of PKD leads us deep into the genetics of red blood cell metabolism. Understanding these mechanisms is key to developing better diagnostics and therapies.

Cause	Description	Impact	Sources
PKLR Gene Mutations	Over 300 known mutations cause PKD	Enzyme deficiency	3 6 7
Autosomal Recessive	Inheritance from both parents	Family risk	4 5 7
Enzyme Dysfunction	Impaired glycolysis, ATP depletion	Hemolytic anemia	1 10
Modifier Factors	Genetic/environmental modifiers	Variable severity	1 3 7

Table 3: Causes of PKD

The Genetic Basis

• PKLR Gene: The root cause of PKD is mutations in the PKLR gene, which encodes pyruvate kinase, a critical enzyme in red blood cell energy production 3 6 7.
  • Types of Mutations: These include missense (single amino acid changes), nonsense (early stop codons), splicing errors, deletions, and promoter variants 3.
  • Homozygosity and Compound Heterozygosity: Most patients inherit two defective gene copies, either identical (homozygous) or different (compound heterozygous) 3 6.
• Inheritance Pattern: The disorder follows an autosomal recessive inheritance, meaning both parents must be carriers for a child to be affected 4 5 7.

Biochemical Consequences

• Enzyme Dysfunction: Pyruvate kinase is essential for glycolysis, the process by which red blood cells generate ATP (energy). Defective enzyme means less ATP, causing red cells to be fragile and prone to breakdown (hemolysis) 1 10.
• Compensatory Mechanisms: Interestingly, the defective enzyme also causes a build-up of 2,3-diphosphoglycerate, which helps tissues extract more oxygen from hemoglobin—this partially compensates for the anemia 1.

Modifier Genes and Environmental Influences

• Variable Severity: The same genetic mutations can result in very different disease courses, likely due to other genes, splenic function, and environmental factors 1 3 7.
• Occult Mutations: Some patients may have mutations in non-coding regions that are missed by standard tests, complicating diagnosis 1.

Treatment of Pyruvate Kinase Deficiency

While PKD remains a complex and lifelong condition, treatment strategies are evolving rapidly. Supportive care, targeted therapies, and even gene therapy are offering new hope for patients.

Treatment	Purpose/Mechanism	Suitability/Indications	Sources
Supportive Care	Transfusions, iron chelation, symptom relief	All severity groups	1 11 7
Splenectomy	Removes spleen to reduce red cell destruction	Selected moderate/severe	1 11 7
HSCT (Transplant)	Potential cure via stem cell replacement	Rare, severe cases	1 11 9
Mitapivat (AG-348)	Activates mutant PK enzyme, boosts ATP	Adults with certain mutations	8 10 12
Gene Therapy	Corrects genetic defect in stem cells	Experimental, future option	9 11

Table 4: PKD Treatment Options

Supportive Management

• Red Cell Transfusions: Used as needed for symptomatic anemia, not solely based on hemoglobin levels 1.
• Iron Chelation: Chronic transfusions and hemolysis can cause iron overload, so chelation therapy is often necessary 7 9 11.
• Monitoring and Managing Complications: Regular assessment for gallstones, iron overload, and other complications is essential 11.

Surgical Approaches

• Splenectomy: Removing the spleen can reduce the destruction of red blood cells and decrease transfusion needs, but it carries risks (infections, thrombosis), so the decision must be individualized 1 11 7.
• Cholecystectomy: Gallbladder removal may be needed if gallstones become problematic 7.

Curative and Emerging Therapies

• Hematopoietic Stem Cell Transplantation (HSCT): Allogeneic bone marrow transplant can cure PKD in selected severe cases but is only considered when other options fail due to risks of rejection and complications 1 11 9.
• Mitapivat (AG-348): This oral drug is a small-molecule activator of the pyruvate kinase enzyme. Clinical trials have shown that mitapivat can increase hemoglobin levels and improve markers of hemolysis in about half of adult patients, especially those with at least one missense mutation 8 10 12.
  • Benefits: Rapid and sustained increase in hemoglobin, well-tolerated with mainly mild, transient side effects 8.
  • Limitations: Not effective in patients with very low or no residual enzyme protein 10.
• Gene Therapy: Still experimental but promising, gene therapy aims to correct the PKLR gene in the patient’s own stem cells. Early animal studies show normalization of red blood cell function and reversal of disease symptoms 9 11.

Personalized and Future Approaches

The variety in disease expression means that management must be tailored to each patient—considering symptoms, complications, genetic background, and treatment goals. New therapies, especially those targeting the genetic root or enzyme function, are expected to transform PKD care in coming years 1 11.

Conclusion

Pyruvate kinase deficiency is a highly variable and complex inherited condition with a growing range of treatment options. Here’s what we covered:

• Symptoms: Range from mild fatigue and anemia to severe complications like gallstones and iron overload; symptoms and severity can vary greatly between patients—even those with the same mutation.
• Types: Classified by clinical severity and genetic background, with over 300 PKLR mutations identified.
• Causes: Mutations in the PKLR gene disrupt red blood cell energy production, causing hemolytic anemia; inheritance is autosomal recessive.
• Treatment: Supportive care is standard, but new targeted therapies (like mitapivat) and experimental gene therapy offer hope for the future.

Staying informed about pyruvate kinase deficiency and advances in its management is crucial for patients, families, and healthcare providers. As research continues, the outlook for those affected by PKD is brighter than ever.