What causes Paroxysmal Nocturnal Hemoglobinuria (PNH)?

From the Guidelines

Paroxysmal nocturnal hemoglobinuria (PNH) is caused by a genetic mutation in the PIGA gene in bone marrow stem cells, leading to a lack of protective proteins on blood cells and making them vulnerable to destruction by the complement system. This mutation is acquired, not inherited, and occurs randomly in a small population of blood-forming cells 1. The PIGA gene is responsible for producing a protein that helps attach certain protective proteins to cell surfaces, such as CD55 and CD59. When this gene is mutated, blood cells lack these protective proteins, making them vulnerable to premature destruction by the complement system, which is part of the body's immune defense. Without these protective proteins, red blood cells are broken down too easily, leading to hemolysis (cell destruction) and the release of hemoglobin into the urine, especially at night - hence the name "nocturnal hemoglobinuria" 1.

Some key points to consider about PNH include:

• The condition is rare and can develop at any age, though it's most commonly diagnosed in young adults 1
• The mutation is not hereditary but occurs spontaneously in the body, making PNH an acquired stem cell disorder rather than an inherited disease
• PNH has been associated with a high propensity for venous thrombosis, particularly in the splanchnic vasculature 1
• Testing for PNH should routinely be performed in all patients with suspected vascular diseases of the liver, such as Budd-Chiari syndrome 1

Overall, the genetic mutation in the PIGA gene is the primary cause of PNH, leading to a lack of protective proteins on blood cells and making them vulnerable to destruction by the complement system.

From the Research

Causes of Paroxysmal Nocturnal Hemoglobinuria (PNH)

• PNH is a rare disorder of complement regulation due to somatic mutation of the PIGA (phosphatidylinositol glycan anchor) gene 2.
• The PIGA gene products are crucial for biosynthesis of glycosylphosphatidylinositol (GPI) anchors, which attach a number of proteins to the plasma membrane of the cell, including the complement regulatory proteins CD55 and CD59 2, 3, 4, 5, 6.
• The loss of complement regulatory protein renders the red cell susceptible to complement-mediated lysis leading to intravascular and extravascular hemolysis 2, 3, 4, 5, 6.
• Somatic mutation of the PIGA gene in one or several hematopoietic stem cells can cause PNH, and recently, PNH caused by somatic mutation of one allele of the PIGT gene in combination with a germline mutation of the other allele has been reported 5.
• Clonal expansion of PIGA deficient cells does not occur with PIGA deficiency alone, and it is hypothesized that PIGA deficient cells acquire a proliferative phenotype via additional gene mutations within the associated environment of bone marrow failure 5.

Molecular Basis of PNH

• The molecular basis of PNH is a somatic mutation of the PIGA gene, which causes a lack of glycosyl phosphatidyl inositol that binds many important antigens to the cell surface membrane, including inhibitors of activated complement CD59 and CD55 antigens 4.
• The CD55 inhibits C3 convertase, whereas the CD59 blocks the membrane attack complex (MAC) by inhibiting the incorporation of C9 to MAC 2.
• The lack of CD55 and CD59 on the surface of red blood cells makes them susceptible to complement-mediated lysis 2, 3, 4, 5, 6.

Clinical Manifestations of PNH

• The clinical manifestations of PNH are intravascular hemolysis, thrombophilia, and bone marrow failure 3, 4.
• The clinical features of PNH include recurrent hemolytic episodes, thrombosis, smooth muscle dystonia, and bone marrow failure, as well as other important complications such as renal failure, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) 2.