Paroxysmal nocturnal hemoglobinuria (PNH) is caused by a genetic mutation that occurs in a single blood-forming stem cell in the bone marrow. This mutation affects a gene called **PIGA**, which is located on the X chromosome. The PIGA gene is responsible for producing a critical enzyme involved in the synthesis of a molecule called glycosylphosphatidylinositol (GPI) anchor. This GPI anchor is essential because it attaches certain protective proteins to the surface of blood cells, especially red blood cells.
When the PIGA gene is mutated, the affected stem cell and all its descendants produce blood cells that lack these GPI-anchored proteins. Among the missing proteins are CD55 and CD59, which normally protect red blood cells from being destroyed by the body’s own immune system, specifically the complement system. The complement system is part of the immune defense that helps clear pathogens and damaged cells, but without these protective proteins, red blood cells become vulnerable to attack.
Because the red blood cells lack CD55 and CD59, the complement system mistakenly targets and destroys them in a process called **hemolysis**. This destruction releases hemoglobin into the bloodstream, which can cause symptoms such as dark-colored urine (especially noticeable in the morning), fatigue, shortness of breath, abdominal pain, and anemia. The breakdown of red blood cells also releases substances that can damage organs like the kidneys.
The mutation in PIGA is **acquired**, not inherited, meaning it happens spontaneously in a single stem cell during a person’s life rather than being passed down from parents. This mutated stem cell gains a growth advantage and expands, leading to a population of blood cells that all share this defect.
In addition to red blood cells, other blood cells like white blood cells and platelets can also be affected because they come from the same mutated stem cell. This can lead to complications such as increased risk of blood clots (thrombosis), which is a major cause of morbidity and mortality in PNH patients. The excessive activation of the complement system not only destroys red blood cells but also activates platelets, making them more likely to form clots.
The exact trigger for why the PIGA mutation occurs in the first place is not fully understood, but it is known to be a **somatic mutation**—a change in the DNA that happens after conception in a single cell. This mutation leads to a clone of abnormal blood cells that can outcompete normal cells in the bone marrow.
To summarize the cause in simple terms:
– A **mutation in the PIGA gene** in a bone marrow stem cell prevents the production of protective proteins on blood cells.
– Without these protective proteins, red blood cells are attacked and destroyed by the immune system’s complement pathway.
– This destruction causes the symptoms and complications of PNH, including anemia, fatigue, and risk of blood clots.
– The mutation is acquired during life and leads to a clone of defective blood cells expanding in the bone marrow.
This process explains why PNH is a rare, acquired blood disorder characterized by episodes of red blood cell destruction, often worse at night or early morning, hence the name “nocturnal hemoglobinuria.” The disease is complex because it involves both genetic mutation and immune system dysfunction, leading to a cascade of effects on blood cells and overall health.
