SNP Shot: Genomic Insights

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired blood disorder, meaning it's not inherited. In PNH, blood cells die prematurely, and the body doesn't produce enough of them. This affects red blood cells (erythrocytes), responsible for carrying oxygen; white blood cells (leukocytes), which fight infections; and platelets (thrombocytes), essential for blood clotting. PNH can develop at any age, but it's most frequently diagnosed in young adults.

Individuals with PNH experience sudden, recurring episodes of symptoms (paroxysmal symptoms) often triggered by bodily stresses like infections or strenuous activity. During these episodes, red blood cells are broken down too early (hemolysis). This can lead to dark-colored urine due to the presence of hemoglobin, the oxygen-carrying protein from red blood cells. This condition, where hemoglobin is present in the urine, is called hemoglobinuria. Hemoglobinuria is frequently more noticeable in the first urine of the morning (nocturnal), after urine has collected in the bladder overnight.

The early breakdown of red blood cells results in hemolytic anemia, a condition where the blood lacks sufficient red blood cells. This shortage causes symptoms like fatigue, weakness, pale skin (pallor), shortness of breath, and a rapid heartbeat (tachycardia). Furthermore, due to a deficiency in white blood cells (leukopenia), individuals with PNH are more susceptible to infections.

PNH affects platelets, leading to problems with blood clotting. This can manifest as abnormal blood clots (thrombosis), particularly in large veins in the abdomen. Less commonly, patients might experience severe bleeding episodes (hemorrhage).

People with PNH have an elevated risk of developing blood cancers (leukemia). In some instances, PNH can develop in individuals who have or have been treated for aplastic anemia, another blood disorder. Rarely, the signs and symptoms of PNH resolve spontaneously.

A very rare variant of PNH includes unusual inflammation in addition to the typical symptoms. Inflammation is a normal immune response to injury and foreign invaders. However, in this rare form of PNH, the immune system becomes abnormally activated, leading to recurrent aseptic meningitis (inflammation of the membranes surrounding the brain and spinal cord not caused by infection), a red, itchy rash (hives or urticaria), joint pain (arthralgia), or inflammatory bowel disease. Typically, the inflammatory symptoms appear before the blood cell problems.

Inheritance:

PNH is an acquired condition, not inherited. Most cases are caused by new mutations in the PIGA gene and typically occur in individuals with no family history of the disorder. This form is not passed on to children. The PIGA gene is located on the X chromosome, one of the two sex chromosomes. Males have one X chromosome, and a mutation in their single copy of the PIGA gene is enough to cause the condition. Females have two X chromosomes, but one is inactivated early in embryonic development in somatic cells (cells other than egg and sperm cells). This X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each body cell. In females, a mutation in the active copy of the PIGA gene can also cause the condition.

The risk of developing PIGT-related PNH follows an autosomal dominant pattern of inheritance, meaning one copy of the altered gene in each cell is sufficient to increase a person’s chance of developing the condition. Affected individuals inherit one altered copy of the PIGT gene from a parent. However, the condition is acquired when a second alteration occurs in the other copy of the PIGT gene.