Pyruvate kinase deficiency

The enzyme pyruvate kinase or PK is an enzyme involved in glycolysis, a metabolic pathway in which energy is obtained from glucose, and whose deficiency can lead to alterations in red blood cells causing hemolytic anemia.

Pyruvate kinase deficiency (PKD) is a genetic blood disorder that causes chronic nonspherocytic hemolytic anemia and is the most common enzymatic defect of the glycolytic pathway. The glycolytic pathway is a metabolic process of generating energy from glucose.In red blood cells, glycolysis plays an important role in the maintenance of their structure and functions and it has been observed that deficient PK activity leads to premature destruction of red blood cells in the spleen and liver.

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.

Symptoms

The clinical presentation of PKD is quite variable and the severity of symptoms varies widely, from patients with few or no symptoms to patients who develop severe hemolytic anemia requiring treatment with regular red blood cell transfusions.

It usually appears in the neonatal period; however, it is not uncommon for some patients to go undiagnosed until adulthood. Symptoms include mild to severe hemolytic anemia, jaundice, enlargement of the spleen (splenomegaly) and increased numbers of reticulocytes or immature red blood cells (reticulocytosis).

Disease management

Neonatal jaundice is usually treated with phototherapy and hydration, which can help avoid exchange transfusion. However, neonates without evidence of jaundice and/or with mild anemia are sometimes not diagnosed until hemolysis or more profound symptoms occur.

Patients with mild PKD usually do not require treatment. Patients with severe PKD are usually treated with blood transfusions, surgical removal of the spleen (splenectomy) and medications to remove excess iron from the blood (chelation therapy). Promising new treatments are emerging such as the use of a small molecule known as AG-348 allosteric activator of PK that is under development, with safety and efficacy demonstrated in phase I and II trials.

Genes analyzed

PKLR

Bibliography

Al-Samkari H, Van Beers EJ, Kuo KHM, et al . The variable manifestations of disease in pyruvate kinase deficiency and their management. Haematologica. 2020 Sep 1;105(9):2229-2239.

Bianchi P, Fermo E.Molecular heterogeneity of pyruvate kinase deficiency. Haematologica. 2020 Sep 1;105(9):2218-2228.

Grace RF, Barcellini W . Management of pyruvate kinase deficiency in children and adults. Blood. 2020 Sep 10;136(11):1241-1249.

Enegela OA, Anjum F . Pyruvate Kinase Deficiency. 2021 Jun 4. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-.

Montllor L, Mañú-Pereira MD, Llaudet-Planas E, et al . Red cell pyruvate kinase deficiency in Spain: A study of 15 cases. Med Clin (Barc). 2017 Jan 6;148(1):23-27. English, Spanish.

Warang P, Kedar P, Ghosh K, et al . Molecular and clinical heterogeneity in pyruvate kinase deficiency in India. Blood Cells Mol Dis. 2013 Oct;51(3):133-7.

Zanella A, Fermo E, Bianchi P, et al . Pyruvate kinase deficiency: the genotype-phenotype association. Blood Rev. 2007 Jul;21(4):217-31.

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