Pyruvate kinase deficiency

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Pyruvate kinase deficiency
Other namesErythrocyte pyruvate kinase deficiency [1]
Phosphoenolpyruvic acid.svg
Phosphoenolpyruvate
Specialty Hematology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Anemia, tachycardia [2]
CausesMutation in PKLR gene [3]
Diagnostic method Physical exam, CBC [4]
TreatmentBlood transfusion [4]

Pyruvate kinase deficiency is an inherited metabolic disorder of the enzyme pyruvate kinase which affects the survival of red blood cells. [4] [5] Both autosomal dominant and recessive inheritance have been observed with the disorder; classically, and more commonly, the inheritance is autosomal recessive. Pyruvate kinase deficiency is the second most common cause of enzyme-deficient hemolytic anemia, following G6PD deficiency. [6]

Contents

Signs and symptoms

Gallstones Gallstones.PNG
Gallstones

Symptoms can be extremely varied among those suffering from pyruvate kinase deficiency. The majority of those suffering from the disease are detected at birth while some only present symptoms during times of great physiological stress such as pregnancy, or with acute illnesses (viral disorders). [7] Symptoms are limited to or most severe during childhood. [2] Among the symptoms of pyruvate kinase deficiency are: [2]

The level of 2,3-bisphosphoglycerate is elevated: 1,3-bisphosphoglycerate, a precursor of phosphoenolpyruvate which is the substrate for Pyruvate kinase, is increased and so the Luebering-Rapoport pathway is overactivated. This led to a rightward shift in the oxygen dissociation curve of hemoglobin (i.e. it decreases the hemoglobin affinity for oxygen): In consequence, patients may tolerate anemia surprisingly well. [8]

Cause

Pyruvate kinase deficiency is due to a mutation in the PKLR gene. There are four pyruvate kinase isoenzymes, two of which are encoded by the PKLR gene (isoenzymes L and R, which are used in the liver and erythrocytes, respectively). Mutations in the PKLR gene therefore cause a deficiency in the pyruvate kinase enzyme. [3] [9]

180 different mutations have been found on the gene coding for the L and R isoenzymes, 124 of which are single-nucleotide missense mutations. [10] Pyruvate kinase deficiency is most commonly an autosomal recessive trait. [11] Although it is mostly homozygotes that demonstrate symptoms of the disorder, [2] compound heterozygotes can also show clinical signs. [10]

Pathophysiology

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ATP-3D

Pyruvate kinase is the last enzyme involved in the glycolytic process, transferring the phosphate group from phosphenol pyruvate to a waiting adenosine diphosphate (ADP) molecule, resulting in both adenosine triphosphate (ATP) and pyruvate. This is the second ATP producing step of the process and the third regulatory reaction. [7] [12] Pyruvate kinase deficiency in the red blood cells results in an inadequate amount of or complete lack of the enzyme, blocking the completion of the glycolytic pathway. Therefore, all products past the block would be deficient in the red blood cell. These products include ATP and pyruvate. [2]

Mature erythrocytes lack a nucleus and mitochondria. Without a nucleus, they lack the ability to synthesize new proteins so if anything happens to their pyruvate kinase, they are unable to generate replacement enzymes throughout the rest of their life cycle. Without mitochondria, erythrocytes are heavily dependent on the anaerobic generation of ATP during glycolysis for nearly all of their energy requirements. [13]

With insufficient ATP in an erythrocyte, all active processes in the cell come to a halt. Sodium potassium ATPase pumps are the first to stop. Since the cell membrane is more permeable to potassium than sodium, potassium leaks out. Intracellular fluid becomes hypotonic, water moves down its concentration gradient out of the cell. The cell shrinks and cellular death occurs, this is called 'dehydration at cellular level'. [2] [14] This is how a deficiency in pyruvate kinase results in hemolytic anaemia, the body is deficient in red blood cells as they are destroyed by lack of ATP at a larger rate than they are being created. [15]

Diagnosis

The diagnosis of pyruvate kinase deficiency can be done by full blood counts (differential blood counts) and reticulocyte counts. [16] Other methods include direct enzyme assays, which can determine pyruvate kinase levels in erythrocytes separated by density centrifugation, as well as direct DNA sequencing. For the most part when dealing with pyruvate kinase deficiency, these two diagnostic techniques are complementary to each other as they both contain their own flaws. Direct enzyme assays can diagnose the disorder and molecular testing confirms the diagnosis or vice versa. [6] Furthermore, tests to determine bile salts (bilirubin) can be used to see whether the gall bladder has been compromised. [16]

Treatment

Most affected individuals with pyruvate kinase deficiency do not require treatment. Those individuals who are more severely affected may die in utero of anemia or may require intensive treatment. With these severe cases of pyruvate kinase deficiency in red blood cells, treatment is the only option, there is no cure. However, treatment is usually effective in reducing the severity of the symptoms. [12] [17]

The most common treatment is blood transfusions, especially in infants and young children. This is done if the red blood cell count has fallen to a critical level. [11] The transplantation of bone marrow has also been conducted as a treatment option. [9]

There is a natural way the body tries to treat this disease. It increases the erythrocyte production (reticulocytosis) because reticulocytes are immature red blood cells that still contain mitochondria and so can produce ATP via oxidative phosphorylation. [13] Therefore, a treatment option in extremely severe cases is to perform a splenectomy. This does not stop the destruction of erythrocytes but it does help increase the amount of reticulocytes in the body since most of the hemolysis occurs when the reticulocytes are trapped in the hypoxic environment of the spleen. This reduces severe anemia and the need for blood transfusions. [2]

Mitapivat was approved for medical use in the United States in February 2022. [18]

Epidemiology

Pyruvate kinase deficiency happens worldwide, however northern Europe, and Japan have many cases. The prevalence of pyruvate kinase deficiency is around 51 cases per million in the population (via gene frequency). [12] [19]

See also

Related Research Articles

<span class="mw-page-title-main">Hemolysis</span> Rupturing of red blood cells and release of their contents

Hemolysis or haemolysis, also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid. Hemolysis may occur in vivo or in vitro.

<span class="mw-page-title-main">Anemia</span> Reduced ability of blood to carry oxygen

Anemia or anaemia is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin available for oxygen transport, or abnormalities in hemoglobin that impair its function.

<span class="mw-page-title-main">Glucose-6-phosphate dehydrogenase deficiency</span> Medical condition

Glucose-6-phosphate dehydrogenase deficiency (G6PDD), also known as favism, is the most common enzyme deficiency anemia worldwide. It is an inborn error of metabolism that predisposes to red blood cell breakdown. Most of the time, those who are affected have no symptoms. Following a specific trigger, symptoms such as yellowish skin, dark urine, shortness of breath, and feeling tired may develop. Complications can include anemia and newborn jaundice. Some people never have symptoms.

<span class="mw-page-title-main">Hereditary spherocytosis</span> Genetic disorder causing red blood cells to be spherical

Hereditary spherocytosis (HS) is a congenital hemolytic disorder wherein a genetic mutation coding for a structural membrane protein phenotype causes the red blood cells to be sphere-shaped (spherocytosis), rather than the normal biconcave disk shape. This abnormal shape interferes with the cells' ability to flex during blood circulation, and also makes them more prone to rupture under osmotic stress, mechanical stress, or both. Cells with the dysfunctional proteins are degraded in the spleen, which leads to a shortage of erythrocytes and results in hemolytic anemia.

<span class="mw-page-title-main">Pyruvate kinase</span> Class of enzymes

Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyruvate kinase was inappropriately named before it was recognized that it did not directly catalyze phosphorylation of pyruvate, which does not occur under physiological conditions. Pyruvate kinase is present in four distinct, tissue-specific isozymes in animals, each consisting of particular kinetic properties necessary to accommodate the variations in metabolic requirements of diverse tissues.

<span class="mw-page-title-main">Hemolytic anemia</span> Reduced oxygen-carrying ability of the blood due to breakdown of red blood cells

Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels or elsewhere in the human body (extravascular). This most commonly occurs within the spleen, but also can occur in the reticuloendothelial system or mechanically. Hemolytic anemia accounts for 5% of all existing anemias. It has numerous possible consequences, ranging from general symptoms to life-threatening systemic effects. The general classification of hemolytic anemia is either intrinsic or extrinsic. Treatment depends on the type and cause of the hemolytic anemia.

<span class="mw-page-title-main">Phosphofructokinase deficiency</span> Medical condition

Phosphofructokinase deficiency is a rare muscular metabolic disorder, with an autosomal recessive inheritance pattern. It is characterized as a deficiency in the Phosphofructokinase (PFK) enzyme throughout the body, including the skeletal muscles and red blood cells. Phosphofrucotkinase is an enzyme involved in the glycolytic process. The lack of PFK blocks the completion of the glycolytic pathway. Therefore, all products past the block would be deficient, including Adenosine triphosphate (ATP).

<span class="mw-page-title-main">Microcytic anemia</span> Medical condition

Microcytic anaemia is any of several types of anemia characterized by smaller than normal red blood cells. The normal mean corpuscular volume is approximately 80–100 fL. When the MCV is <80 fL, the red cells are described as microcytic and when >100 fL, macrocytic. The MCV is the average red blood cell size.

<span class="mw-page-title-main">Hereditary stomatocytosis</span> Medical condition

Hereditary stomatocytosis describes a number of inherited, mostly autosomal dominant human conditions which affect the red blood cell and create the appearance of a slit-like area of central pallor (stomatocyte) among erythrocytes on peripheral blood smear. The erythrocytes' cell membranes may abnormally 'leak' sodium and/or potassium ions, causing abnormalities in cell volume. Hereditary stomatocytosis should be distinguished from acquired causes of stomatocytosis, including dilantin toxicity and alcoholism, as well as artifact from the process of preparing peripheral blood smears.

Reticulocytopenia is the medical term for an abnormal decrease in circulating red blood cell precursors (reticulocytes) that can lead to anemia due to resulting low red blood cell (erythrocyte) production. Reticulocytopenia may be an isolated finding or it may not be associated with abnormalities in other hematopoietic cell lineages such as those that produce white blood cells (leukocytes) or platelets (thrombocytes), a decrease in all three of these lineages is referred to as pancytopenia.

Glutathione synthetase deficiency (GSD) is a rare autosomal recessive metabolic disorder that prevents the production of glutathione. Glutathione helps prevent damage to cells by neutralizing harmful molecules generated during energy production. Glutathione also plays a role in processing medications and cancer-causing compounds (carcinogens), and building DNA, proteins, and other important cellular components.

<span class="mw-page-title-main">Aldolase A deficiency</span> Medical condition

Aldolase A deficiency is an autosomal recessive metabolic disorder resulting in a deficiency of the enzyme aldolase A; the enzyme is found predominantly in red blood cells and muscle tissue. The deficiency may lead to hemolytic anaemia as well as myopathy associated with exercise intolerance and rhabdomyolysis in some cases.

<span class="mw-page-title-main">Lactate dehydrogenase</span> Class of enzymes

Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of pyruvate to lactate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from one molecule to another.

<span class="mw-page-title-main">Pyruvate kinase PKLR</span> Protein-coding gene in the species Homo sapiens

Pyruvate kinase PKLR is an enzyme that in humans is encoded by the PKLR gene.

<span class="mw-page-title-main">Hexokinase deficiency</span> Medical condition

Hexokinase deficiency is an extremely rare autosomal recessive condition that falls under the category of erythroenzymopathies, or defects in red cell enzymes. Hexokinase deficiency manifests is associated with chronic nonspherocytic hemolytic anemia. Hemolytic anemia seems to be the only clinical sign of hexokinase deficiency. In 1967 the first case of hexokinase deficiency was described by Valentine et al, since then, less than 50 cases have been reported.

<span class="mw-page-title-main">Inborn errors of carbohydrate metabolism</span> Medical condition

Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.

Normocytic anemia is a type of anemia and is a common issue that occurs for men and women typically over 85 years old. Its prevalence increases with age, reaching 44 percent in men older than 85 years. The most common type of normocytic anemia is anemia of chronic disease.

<span class="mw-page-title-main">6-phosphogluconate dehydrogenase deficiency</span> Medical condition

6-Phosphogluconate dehydrogenase deficiency, or partial deficiency, is an autosomal hereditary disease characterized by abnormally low levels of 6-phosphogluconate dehydrogenase (6PGD), a metabolic enzyme involved in the Pentose phosphate pathway. It is very important in the metabolism of red blood cells (erythrocytes). 6PDG deficiency affects less than 1% of the population, and studies suggest that there may be race variant involved in many of the reported cases. Although it is similar, 6PDG deficiency is not linked to glucose-6-phosphate dehydrogenase (G6PD) deficiency, as they are located on different chromosomes. However, a few people have had both of these metabolic diseases.

Congenital hemolytic anemia (CHA) is a diverse group of rare hereditary conditions marked by decreased life expectancy and premature removal of erythrocytes from blood flow. Defects in erythrocyte membrane proteins and red cell enzyme metabolism, as well as changes at the level of erythrocyte precursors, lead to impaired bone marrow erythropoiesis. CHA is distinguished by variable anemia, chronic extravascular hemolysis, decreased erythrocyte life span, splenomegaly, jaundice, biliary lithiasis, and iron overload. Immune-mediated mechanisms may play a role in the pathogenesis of these uncommon diseases, despite the paucity of data regarding the immune system's involvement in CHAs.

Human genetic resistance to malaria refers to inherited changes in the DNA of humans which increase resistance to malaria and result in increased survival of individuals with those genetic changes. The existence of these genotypes is likely due to evolutionary pressure exerted by parasites of the genus Plasmodium which cause malaria. Since malaria infects red blood cells, these genetic changes are most common alterations to molecules essential for red blood cell function, such as hemoglobin or other cellular proteins or enzymes of red blood cells. These alterations generally protect red blood cells from invasion by Plasmodium parasites or replication of parasites within the red blood cell.

References

  1. ↑ Online Mendelian Inheritance in Man (OMIM): 266200
  2. 1 2 3 4 5 6 7 "Pyruvate Kinase Deficiency Clinical Presentation: History and Physical Examination". emedicine.medscape.com. Retrieved 2015-11-11.
  3. 1 2 "Pyruvate kinase deficiency". Genetics Home Reference. 2015-11-09. Retrieved 2015-11-11.
  4. 1 2 3 "Pyruvate kinase deficiency: MedlinePlus Medical Encyclopedia". www.nlm.nih.gov. Retrieved 2015-11-11.
  5. ↑ "Pyruvate kinase deficiency | Disease | Overview | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 2015-09-05. Retrieved 2015-11-11.
  6. 1 2 Gallagher, Patrick G.; Glader, Bertil (2016-05-01). "Diagnosis of Pyruvate Kinase Deficiency". Pediatric Blood & Cancer. 63 (5): 771–772. doi:10.1002/pbc.25922. ISSN   1545-5017. PMID   26836632. S2CID   42964783.
  7. 1 2 Gordon-Smith, E.C. (1974). "Pyruvate kinase deficiency". Journal of Clinical Pathology. s3-8 (1): 128–133. doi:10.1136/jcp.27.suppl_8.128. PMC   1347209 . PMID   4536359.
  8. ↑ al.], Ronald (2013). Hematology basic principles and practice (6th ed.). Philadelphia, PA: Saunders/Elsevier. p. 703. ISBN   9781455740413.
  9. 1 2 Zanella, Alberto; Fermo, Elisa; Bianchi, Paola; Valentini, Giovanna (2005-07-01). "Red cell pyruvate kinase deficiency: molecular and clinical aspects". British Journal of Haematology. 130 (1): 11–25. doi: 10.1111/j.1365-2141.2005.05527.x . ISSN   1365-2141. PMID   15982340.
  10. 1 2 Christensen, Robert D.; Yaish, Hassan M.; Johnson, Charlotte B.; Bianchi, Paola; Zanella, Alberto (October 2011). "Six Children with Pyruvate Kinase Deficiency from One Small Town: Molecular Characterization of the PK-LR Gene". The Journal of Pediatrics. 159 (4): 695–697. doi:10.1016/j.jpeds.2011.05.043. PMID   21784452.
  11. 1 2 Zanella, A.; Bianchi, P.; Fermo, E. (2007-06-01). "Pyruvate kinase deficiency". Haematologica. 92 (6): 721–723. doi: 10.3324/haematol.11469 . ISSN   0390-6078. PMID   17550841.
  12. 1 2 3 "Pyruvate Kinase Deficiency. Information about PKD | Patient". Patient. 19 August 2011. Retrieved 2015-11-11.
  13. 1 2 Wijk, Richard van; Solinge, Wouter W. van (2005-12-15). "The energy-less red blood cell is lost: erythrocyte enzyme abnormalities of glycolysis". Blood. 106 (13): 4034–4042. doi: 10.1182/blood-2005-04-1622 . ISSN   0006-4971. PMID   16051738.
  14. ↑ Haematology Made Easy. AuthorHouse. 2013-02-06. p. 181. ISBN   9781477246511.
  15. ↑ Jacobasch, Gisela; Rapoport, Samuel M. (1996-04-01). "Chapter 3 Hemolytic anemias due to erythrocyte enzyme deficiencies". Molecular Aspects of Medicine. 17 (2): 143–170. doi:10.1016/0098-2997(96)88345-2. PMID   8813716.
  16. 1 2 Disorders, National Organization for Rare (2003-01-01). NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. p. 496. ISBN   9780781730631.
  17. ↑ Davey, Patrick (2010-02-01). Medicine at a Glance. John Wiley & Sons. p. 341. ISBN   9781405186162.
  18. ↑ "Agios Announces FDA Approval of Pyrukynd (mitapivat) as First Disease-Modifying Therapy for Hemolytic Anemia in Adults with Pyruvate Kinase Deficiency" (Press release). Agios Pharmaceuticals. 17 February 2022. Retrieved 19 February 2022– via GlobeNewswire.
  19. ↑ Beutler, Ernest; Gelbart, Terri (2000). "Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population" (PDF). Blood. 95 (11): 3585–3588. doi:10.1182/blood.V95.11.3585. PMID   10828047. Archived from the original (PDF) on 2017-08-21. Retrieved 2016-11-25.

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