Pyruvate kinase deficiency

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.

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).

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.