pyruvate kinase deficiency

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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).{{Cite journal|last=Gordon-Smith|first=E.C.|year=1974|title=Pyruvate kinase deficiency|url= |journal=Journal of Clinical Pathology|volume=s3-8|issue=1|pages=128–133|doi=10.1136/jcp.27.suppl_8.128|pmid=4536359|pmc=1347209}} Symptoms are limited to or most severe during childhood. Among the symptoms of pyruvate kinase deficiency are:{{Cite web|title = Pyruvate Kinase Deficiency Clinical Presentation: History and Physical Examination|url = http://emedicine.medscape.com/article/2196589-clinical|website = emedicine.medscape.com|access-date = 2015-11-11}}

• Mild to severe hemolytic anemia
• Cholecystolithiasis
• Tachycardia
• Hemochromatosis
• Icteric sclera
• Splenomegaly
• Leg ulcers
• Jaundice
• Fatigue
• Shortness of breath

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.{{cite book|last1=al.]|first1=Ronald |title=Hematology basic principles and practice|date=2013|publisher=Saunders/Elsevier|location=Philadelphia, PA|isbn=9781455740413|page=703|edition= 6th}}

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.{{Cite web|url=http://ghr.nlm.nih.gov/condition/pyruvate-kinase-deficiency|title=Pyruvate kinase deficiency|date=2015-11-09|website=Genetics Home Reference|access-date=2015-11-11}}

180 different mutations have been found on the gene coding for the L and R isoenzymes, 124 of which are single-nucleotide missense mutations.{{Cite journal|last1=Christensen|first1=Robert D.|last2=Yaish|first2=Hassan M.|last3=Johnson|first3=Charlotte B.|last4=Bianchi|first4=Paola|last5=Zanella|first5=Alberto|title=Six Children with Pyruvate Kinase Deficiency from One Small Town: Molecular Characterization of the PK-LR Gene|journal=The Journal of Pediatrics|volume=159|issue=4|pages=695–697|doi=10.1016/j.jpeds.2011.05.043|pmid=21784452|date=October 2011}} Pyruvate kinase deficiency is most commonly an autosomal recessive trait. Although it is mostly homozygotes that demonstrate symptoms of the disorder, compound heterozygotes can also show clinical signs.

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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. 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.

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.

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'.{{Cite book|url=https://books.google.com/books?id=UCDcZFUo0YIC|title=Haematology Made Easy|date=2013-02-06|publisher=AuthorHouse|isbn=9781477246511|page=181|language=en}} 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.{{Cite journal|last1=Jacobasch|first1=Gisela|last2=Rapoport|first2=Samuel M.|date=1996-04-01|title=Chapter 3 Hemolytic anemias due to erythrocyte enzyme deficiencies|journal=Molecular Aspects of Medicine|volume=17|issue=2|pages=143–170|doi=10.1016/0098-2997(96)88345-2|pmid=8813716}}

The diagnosis of pyruvate kinase deficiency can be done by full blood counts (differential blood counts) and reticulocyte counts.{{Cite book|url=https://books.google.com/books?id=99YPDvFWBB0C|title=NORD Guide to Rare Disorders|last=Disorders|first=National Organization for Rare|date=2003-01-01|publisher=Lippincott Williams & Wilkins|isbn=9780781730631|page=496|language=en}} 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. Furthermore, tests to determine bile salts (bilirubin) can be used to see whether the gall bladder has been compromised.

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.{{Cite book|url=https://books.google.com/books?id=qN6VebjNBfgC|title=Medicine at a Glance|last=Davey|first=Patrick|date=2010-02-01|publisher=John Wiley & Sons|isbn=9781405186162|page=341|language=en}}

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.{{Cite journal|last1=Zanella|first1=A.|last2=Bianchi|first2=P.|last3=Fermo|first3=E.|date=2007-06-01|title=Pyruvate kinase deficiency|journal=Haematologica|language=en|volume=92|issue=6|pages=721–723|doi=10.3324/haematol.11469|pmid=17550841|issn=0390-6078|doi-access=free}} The transplantation of bone marrow has also been conducted as a treatment option.{{Cite journal|last1=Zanella|first1=Alberto|last2=Fermo|first2=Elisa|last3=Bianchi|first3=Paola|last4=Valentini|first4=Giovanna|date=2005-07-01|title=Red cell pyruvate kinase deficiency: molecular and clinical aspects|journal=British Journal of Haematology|language=en|volume=130|issue=1|pages=11–25|doi=10.1111/j.1365-2141.2005.05527.x|pmid=15982340|issn=1365-2141|doi-access=free}}

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.{{Cite journal|last1=Wijk|first1=Richard van|last2=Solinge|first2=Wouter W. van|date=2005-12-15|title=The energy-less red blood cell is lost: erythrocyte enzyme abnormalities of glycolysis|journal=Blood|language=en|volume=106|issue=13|pages=4034–4042|doi=10.1182/blood-2005-04-1622|issn=0006-4971|pmid=16051738|doi-access=free}} 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.

Mitapivat was approved for medical use in the United States in February 2022.{{cite press release | title=Agios Announces FDA Approval of Pyrukynd (mitapivat) as First Disease-Modifying Therapy for Hemolytic Anemia in Adults with Pyruvate Kinase Deficiency | publisher=Agios Pharmaceuticals | via=GlobeNewswire | date=17 February 2022 | url=https://www.globenewswire.com/news-release/2022/02/17/2387542/31990/en/Agios-Announces-FDA-Approval-of-PYRUKYND-mitapivat-as-First-Disease-Modifying-Therapy-for-Hemolytic-Anemia-in-Adults-with-Pyruvate-Kinase-Deficiency.html | access-date=19 February 2022}}

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).{{Cite web|title = Pyruvate Kinase Deficiency. Information about PKD {{!}} Patient|url = http://patient.info/doctor/Pyruvate-Kinase-Deficiency.htm#ref-3|website = Patient| date=19 August 2011 |access-date = 2015-11-11|language = en-GB}}{{Cite journal|last1=Beutler|first1=Ernest|last2=Gelbart|first2=Terri|year=2000|title=Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population|url=http://www.bloodjournal.org/content/bloodjournal/95/11/3585.full.pdf?sso-checked=true|journal=Blood|volume=95|issue=11|pages=3585–3588|doi=10.1182/blood.V95.11.3585|pmid=10828047|access-date=2016-11-25|archive-url=https://web.archive.org/web/20170821164829/http://www.bloodjournal.org/content/bloodjournal/95/11/3585.full.pdf?sso-checked=true|archive-date=2017-08-21|url-status=dead}}

In addition to humans, several other animals are known to be susceptible to pyruvate kinase deficiency, including dogs and cats.{{Cite journal |last=Whitney |first=K. M. |last2=Goodman |first2=S. A. |last3=Bailey |first3=E. M. |last4=Lothrop |first4=C. D. |date=August 1994 |title=The molecular basis of canine pyruvate kinase deficiency |url=https://pubmed.ncbi.nlm.nih.gov/7520391/ |journal=Experimental Hematology |volume=22 |issue=9 |pages=866–874 |issn=0301-472X |pmid=7520391}}{{Cite web |title=Somali - Pyruvate Kinase Deficiency |url=https://www.ufaw.org.uk/cats/somali---pyruvate-kinase-deficiency- |access-date=2025-02-01 |website=www.ufaw.org.uk |language=english}}

• List of hematologic conditions

{{Reflist}}

• {{Cite book|title = Hematology: Diagnosis and Treatment|url = https://books.google.com/books?id=NIjCabJ2FQcC|publisher = Elsevier Health Sciences|date = 2013-02-12|isbn = 978-1455776887|language = en|first1 = Ronald|last1 = Hoffman|first2 = Edward J. Jr.|last2 = Benz|first3 = Leslie E.|last3 = Silberstein|first4 = Helen|last4 = Heslop|first5 = Jeffrey|last5 = Weitz|first6 = John|last6 = Anastasi}}
• {{Cite journal|title = Prenatal Diagnosis of Pyruvate Kinase Deficiency|last = Baroncian|first = Luciano|date = 1994|journal = Blood|volume = 84|issue = 7|pages = 2354–2356|doi = 10.1182/blood.V84.7.2354.2354|pmid = 7919353|doi-access = free}}

{{Medical resources

| DiseasesDB = 11090

| ICD10 = {{ICD10|D|55|2|d|55}}

| ICD9 = {{ICD9|282.3}}

| ICDO =

| OMIM = 266200

| MedlinePlus = 001197

| eMedicineSubj = med

| eMedicineTopic = 1980

| MeshID =

}}

{{Commons}}

{{Scholia|topic}}

{{Diseases of RBCs}}

{{Inborn errors of carbohydrate metabolism}}

{{DEFAULTSORT:Pyruvate Kinase Deficiency}}

Category:Inborn errors of carbohydrate metabolism

Category:Hereditary hemolytic anemias