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Pyruvate Kinase Deficiency, Genetic Testing

Pyruvate kinase deficiency (PKD) is a rare genetic disorder that affects red blood cells, leading to hemolytic anemia. Pyruvate kinase is an enzyme involved in glycolysis, a critical pathway for cell energy production. In PKD, a deficiency of pyruvate kinase impairs the ability of red blood cells to generate sufficient energy, resulting in premature destruction (hemolysis). The prevalence of PKD is estimated to be between 1:20.000 and 1:300.000 in Caucasian populations and increases in malaria-endemic areas, where it may have an advantage because it confers some protection against malaria.

Pyruvate kinase deficiency genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

The key features of pyruvate kinase deficiency are:

  • Hemolytic Anemia: The primary characteristic of PKD is hemolytic anemia, which occurs when red blood cells break down more rapidly than the body can replace them. This leads to a shortage of red blood cells, causing symptoms such as fatigue, weakness, pallor, and jaundice (yellowing of the skin and eyes).
  • Genetic Basis: PKD is inherited in an autosomal recessive manner, meaning individuals with PKD inherit mutated copies of the PKLR gene from both parents. The PKLR gene provides instructions for making pyruvate kinase.
  • Variability in Severity: The severity of symptoms can vary widely among individuals with PKD. Some may have mild anemia and experience few or no symptoms, while others may have more severe forms of the condition with significant health challenges.
  • Symptoms: In addition to anemia-related symptoms, individuals with PKD may experience splenomegaly (spleen enlargement) as the spleen works to remove and break down the abnormal red blood cells.
  • Diagnosis involves blood tests, including a complete blood count (CBC), to assess red blood cell counts and levels of hemoglobin and bilirubin. Additional tests, such as enzyme assays and genetic testing, may be performed to confirm the diagnosis of pyruvate kinase deficiency.
  • Treatment: Treatment of PKD is often supportive and may include blood transfusions to manage severe anemia. In some cases, splenectomy (surgical removal of the spleen) may be considered to reduce the rate of red blood cell destruction. Folic acid supplementation is often recommended to support the production of new red blood cells.
  • Genetic Counseling: Because PKD is inherited, genetic counseling is essential for affected individuals and their families. It can help assess the risk of recurrence in future pregnancies and provide information about available testing options.

While there is no cure for pyruvate kinase deficiency, ongoing medical management, and supportive care can help alleviate symptoms and improve the quality of life for affected individuals. Early diagnosis and appropriate medical interventions are crucial for optimizing outcomes.

More Information

Pyruvate kinase deficiency is caused by mutations in the gene that controls PK expression, known as PKLR, which is located on chromosome 1q21. Pyruvate kinase deficiency follows an autosomal recessive inheritance pattern. Individuals with two copies of the same PKLR mutation or who carry two or more different pathogenic PKLR alleles (compound heterozygotes) may develop pyruvate kinase deficiency.

Mature red blood cells depend on ATP production from glycolysis. Homozygous or compound heterozygous loss-of-function mutations in the PKLR gene result in altered erythrocyte ATP production.

The molecules involved in erythrocyte ATP synthesis are ATPases located in the membrane. They regulate sodium exchange for potassium, which is essential for maintaining membrane integrity and function. ATP deficiency appears to reduce the membrane maintenance capacity of erythrocytes and decrease their deformability, resulting in shortened lifespans and destruction of erythrocytes in the spleen.

The consequence of pyruvate kinase deficiency in hemolytic anemia due to pyruvate and ATP deficiency in erythrocytes simultaneously causes an increase of 2,3-diphosphoglycerate (2,3-DPG) in erythrocytes. 2,3-DPG is produced upstream in the glycolytic pathway, regulates the amount of oxygen the body receives, and facilitates the release of oxygen from hemoglobin to the tissues.

The most common PKLR variants are listed below:

The nonsense variant c.1529G>A (p.Arg510Gln, R510Q) is considered the most common pyruvate kinase deficiency variant in northern Europe and the United States. It has been found in homozygosis and compound heterozygosis. The Arg510Gln substitution results in PK enzyme instability and increases susceptibility to ATP inhibition.

The c.1456C>T (p.Arg486Trp, R486W) is also frequent in southern European Caucasians. The R486W variant does not affect protein stability but does affect protein function.

The nonsense variant c.1436G>A (p.Arg479His, R479H) is common in Amish communities but can also be found in other populations. It has been observed that c.1436G>A is one of the most frequent variants in Indian patients, and it has been found in both homozygosis and compound heterozygosis.

The c.721G>T (p.Glu241Ter, E241*) is a nonsense variant that introduces a premature stop codon. It is frequently found in Spanish patients and is usually combined with another PKLR gene variant.

Pyruvate kinase deficiency genetic testing analyzes the 4 most frequent pathogenic mutations of the PKLR gene.

The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).

Additional information
Results Time4 - 5 Weeks
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