Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired (not inherited) disorder that leads to the premature death and impaired production of blood cells. The disorder affects red blood cells (erythrocytes), which carry oxygen; white blood cells (leukocytes), which protect the body from infections; and platelets (thrombocytes), which are involved in blood clotting. PNH can occur at any age, although it is most often diagnosed in young adulthood.

People with PNH have sudden, recurring episodes of symptoms (paroxysmal symptoms), which may be triggered by stresses on the body, such as infections or physical exertion. During these episodes, red blood cells are broken down earlier than they should be (hemolysis). Affected individuals may pass dark-colored urine because of the presence of hemoglobin, the oxygen-carrying protein in blood. The abnormal presence of hemoglobin in the urine is called hemoglobinuria. In many, but not all cases, hemoglobinuria is most noticeable early in the morning, upon passing urine that has accumulated in the bladder during the night (nocturnal).

The premature breakdown of red blood cells results in a shortage of these cells in the blood (hemolytic anemia), which can cause signs and symptoms such as fatigue, weakness, abnormally pale skin (pallor), shortness of breath, and an increased heart rate (tachycardia). People with PNH may also be prone to infections because of a shortage of white blood cells (leukopenia).

Abnormal platelets associated with PNH can cause problems in the blood clotting process. As a result, people with this disorder may experience abnormal blood clotting (thrombosis), especially in large abdominal veins; or, less often, episodes of severe bleeding (hemorrhage).

Individuals with PNH are at increased risk of developing cancer in blood-forming cells (leukemia). In some cases, people who have or have been treated for another blood disease called aplastic anemia may develop PNH. In a small number of affected individuals, the signs and symptoms of PNH disappear on their own.

A very rare form of PNH involves abnormal inflammation in addition to the typical features described above. Inflammation is a normal immune system response to injury and foreign invaders (such as bacteria). In people with this rare form of PNH, the immune response is turned on (activated) abnormally and can cause recurrent aseptic meningitis (which is inflammation of the membranes surrounding the brain and spinal cord that is not related to infection); a red, itchy rash (known as hives or urticaria); joint pain (arthralgia); or inflammatory bowel disease. The inflammatory disorders usually begin earlier than the blood cell problems.

Variants (also known as mutations) in the PIGA gene cause almost all cases of PNH. Variants in the PIGT gene cause the rare, inflammatory form of the condition. The proteins produced from both genes are involved in a multistep process that connects particular proteins to the surface of cells. These proteins are attached to the cell by a specialized molecule called GPI anchor and are known as GPI-anchored proteins. The PIG-A protein helps produce the GPI anchor, and the PIG-T protein helps attach the GPI anchor to proteins. Anchored proteins have a variety of roles, including sticking cells to one another, relaying signals into cells, and protecting cells from destruction.

In people with PNH, variants of the PIGA gene occur during a person’s lifetime and are present only in certain cells. These changes, which are called somatic variants, are not inherited. In contrast, people with the inflammatory form of the condition inherit one altered copy of the PIGT gene. However, for the condition to occur, they need to also acquire a somatic variant that deletes the other copy of the PIGT gene and other genes around it.

PNH occurs when a somatic variant of the PIGA gene or PIGT gene occurs in a blood-forming cell called a hematopoietic stem cell. Hematopoietic stem cells are found mainly in the bone marrow and give rise to the various types of blood cells. These genetic variants severely reduce or eliminate the function of the PIG-A protein or PIG-T protein, respectively, in affected cells. Blood cells that arise from the abnormal stem cells also have the variant and are abnormal. As the abnormal hematopoietic stem cells multiply, more abnormal blood cells are formed, alongside normal blood cells produced by normal hematopoietic stem cells.

Cells with no PIG-A protein do not produce GPI anchor, and therefore are missing GPI-anchored proteins at the surface. Cells with no PIG-T protein produce GPI anchor but cannot attach proteins to it. As a result, these cells have GPI anchor on the surface, but no attached proteins. Two important GPI-anchored proteins on red blood cells protect them from being broken down by the immune system. Without these proteins, the abnormal red blood cells are prematurely destroyed, leading to hemolytic anemia. Studies show that GPI anchors with no attached proteins trigger inflammation in the body, leading to the inflammatory features in individuals with PIGT-related PNH. It is unclear how changes in the PIGA or PIGT gene affect other types of blood cells.

In individuals with either form of PNH, the proportion of abnormal blood cells can vary. It is unclear why the population of cells that grow from the hematopoietic stem cell with a PIGA gene variant may be larger than the population of normal cells in some affected individuals and smaller in others. Research suggests that certain abnormal white blood cells that are also part of the immune system may mistakenly attack normal blood-forming cells, in a malfunction called an autoimmune process. In addition, abnormal hematopoietic stem cells in people with PNH may be less susceptible than normal cells to a process called apoptosis, which causes cells to self-destruct when they are damaged or unneeded.

In abnormal blood cells with PIGT gene variants, the somatic variant in the PIGT gene deletes other nearby genes that control cell growth and development. Researchers suggest that loss of these genes allows the abnormal cells to grow or survive better than normal cells, increasing the proportion of abnormal blood cells in the body. The proportion of abnormal blood cells affects the severity of the signs and symptoms of PNH, including the risk of hemoglobinuria and thrombosis.

Normal Function

The PIGA gene provides instructions for making a protein called phosphatidylinositol glycan class A (shortened to PIG-A). The PIG-A protein takes part in a series of steps that produce a molecule called glycophosphatidylinositol (GPI) anchor. Specifically, the PIG-A protein is one piece of a group of proteins (a complex) that performs the first step of the series, which produces an intermediate molecule called N-acetylglucosaminyl phosphatidylinositol, or GlcNAc-PI.

The GPI anchor, the ultimate product of the series of steps, attaches many different proteins to the cell membrane. These proteins are known as GPI-anchored proteins. Anchored proteins have a variety of roles, including sticking cells to one another, relaying signals into cells, and protecting cells from destruction.

Health Conditions Related to Genetic Changes

Paroxysmal nocturnal hemoglobinuria

Variants (also known as mutations) in the PIGA gene cause a condition called paroxysmal nocturnal hemoglobinuria (PNH). People with this condition have episodes of blood in the urine (hemoglobinuria) that results from the breakdown of red blood cells. A tendency to develop blood clots (thrombosis) and other blood-cell abnormalities also occur in this condition.

In people with PNH, variants of the PIGA gene occur during a person’s lifetime and are present only in certain cells. These changes, which are called somatic variants, are not inherited. For the condition to develop, one or more somatic PIGA gene variants occur in blood-forming cells called hematopoietic stem cells. Hematopoietic stem cells produce red blood cells, which carry oxygen; white blood cells, which protect the body from infections; and platelets, which are involved in blood clotting. As the abnormal hematopoietic stem cells multiply, populations of abnormal blood cells are formed, alongside normal blood cells produced by normal hematopoietic stem cells that do not have the genetic alteration. The proportion of abnormal blood cells in the body affects the severity of the signs and symptoms of PNH.

Some of the PIGA gene variants alter the numbers or types of protein building blocks (amino acids) in the PIG-A protein, impairing its function. Other variants result in the insertion of a premature stop signal in the genetic instructions for making PIG-A. As a result, an abnormally small protein, which is usually unstable and easily broken down, is produced. A single variant in the PIGA gene can severely reduce or eliminate the function of PIG-A, because people have only one active copy of the PIGA gene in each cell. (The PIGA gene is located on the X-chromosome. Males have only one X chromosome. In females, who have two X chromosomes, a normal process called X-inactivation turns off one copy of the X chromosome, so that females also have only one active copy of the X chromosome in each body cell.)

Cells with little or no functional PIG-A protein do not produce GPI anchors, and therefore are missing GPI-anchored proteins at the surface. Two important GPI-anchored proteins normally found on the surface of red blood cells protect them from being broken down during immune reactions. Without these proteins, the abnormal red blood cells are prematurely destroyed, leading to hemoglobinuria and other features of PNH. It is unclear how changes in the PIGA gene affect other types of blood cells.

Other disorders

Inherited (germline) variants in the PIGA gene can cause a disorder called PIGA deficiency, which refers to a spectrum of conditions with varied features and severity. Severely affected individuals typically have profound intellectual disability, seizures known as infantile spasms, weak muscle tone (hypotonia), distinctive facial features, and abnormalities of the brain and spinal cord (central nervous system) and other body systems. Less severely affected individuals have mild to moderate intellectual disability, infantile spasms, and other seizures that can typically be treated.

Germline variants are present in every cell of the body (in contrast to somatic variants that cause PNH [described above], which are only found in certain cells). Variants in the PIGA gene that cause PIGA deficiency reduce the function of the PIG-A protein in cells. Studies suggest that the amount of remaining PIG-A function determines the severity of the condition: very little PIG-A function causes more severe signs and symptoms. The changes reduce the number of GPI-anchored proteins, possibly on some cells but not others. Researchers suspect that a shortage (deficiency) of PIG-A function impairs the activity of cell structures called mitochondria, which are the energy-producing centers of cells, although the mechanism is not clear. Researchers are still determining how PIGA gene variants lead to the features of PIGA deficiency.

Simpson-Golabi-Behmel syndrome

MedlinePlus Genetics provides information about Simpson-Golabi-Behmel syndrome

Other Names for This Gene

• GLCNAC-PI synthesis protein
• GPI anchor biosynthesis
• GPI3
• phosphatidylinositol glycan anchor biosynthesis, class A
• phosphatidylinositol glycan anchor biosynthesis, class A (paroxysmal nocturnal hemoglobinuria)
• phosphatidylinositol glycan, class A (paroxysmal nocturnal hemoglobinuria)
• phosphatidylinositol N-acetylglucosaminyltransferase subunit A
• phosphatidylinositol-glycan biosynthesis, class A protein
• PIG-A
• PIGA_HUMAN

Genomic Location

PNH is acquired, rather than inherited. Most cases result from new variants in the PIGA gene, and generally occur in people with no previous history of the disorder in their family. This form of the condition is not passed down to children of affected individuals.

The PIGA gene is located on the X chromosome, which is one of the two sex chromosomes. Males have only one X chromosome, and a variant in the only copy of the PIGA gene in each cell is sufficient to cause the condition. Females have two X chromosomes. However, early in embryonic development in females, one of the two X chromosomes is permanently inactivated in somatic cells (cells other than egg and sperm cells). This process, called X-inactivation, ensures that females, like males, have only one active copy of the X chromosome in each body cell. In females, a variant in the active copy of the PIGA gene is sufficient to cause the condition.

The risk of developing PIGT-related PNH follows an autosomal dominant pattern of inheritance, which means 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.

PNH is a rare disorder, estimated to affect between 1 and 5 per million people. The inflammatory form of the disorder is extremely rare and has been identified in a very small number of individuals.