Paroxysmal nocturnal hemoglobinuria – PIG-A gene.

            Paroxysmal nocturnal hemoglobinuria is a disorder that results in altered production of erythrocytes, leukocytes and thrombocytes, and leads to early death. This disease affects both sexes equally, and can manifest at any age, although it is diagnosed more frequently in adulthood.       

Affected individuals manifest paroxysmal symptoms, which may be caused by stress on the body, such as infections or recurrent physical exertion. During these episodes, hemolysis occurs. In addition, affected people may manifest hemoglobinuria, which results in dark-colored urine due to the presence of hemoglobin, the protein that carries oxygen in the blood. In many, but not all cases, hemoglobinuria is most noticeable in the morning.

The early breakdown of red blood cells causes hemolytic anemia, which can cause signs and symptoms such as fatigue, weakness, paleness, shortness of breath, and an increased heart rate. People with paroxysmal nocturnal hemoglobinuria may also be prone to infections due to a deficiency of white blood cells. Additionally, abnormal thrombocytes associated with paroxysmal nocturnal hemoglobinuria can cause problems in the blood clotting process. As a consequence, affected individuals may experience thrombosis, especially in the large abdominal veins or less frequently, bleeding episodes. Individuals with paroxysmal nocturnal hemoglobinuria are at increased risk of developing leukemia. In some cases, people who have been treated for aplastic anemia may develop paroxysmal nocturnal hemoglobinuria.

This process is due to mutations in the PIG-A gene, located on the short arm of the X chromosome (Xp22.1). This gene encodes a protein called phosphatidylinositol glycan class A. This protein participates in a series of processes that encode a molecule called GPI anchoring. Specifically, phosphatidylinositol class A glycan is involved in the first step of the sequence that encodes an intermediate molecule called N-acetylglucosaminyl phosphatidylinositol or GlcNAc-PI. This step takes place in the endoplasmic reticulum of the cell. The PIG-A protein forms a complex with several other proteins, and this complex helps initiate the reaction that produces GlcNAc-PI. GPI anchoring attaches many different proteins to the cell membrane, thus ensuring that these proteins are available when needed on the cell surface.           

More than 100 somatic mutations have been identified in the PIG-A gene. Some of these mutations alter the amino acids in phosphatidylinositol class A glycan, impairing its function. Other mutations lead to the insertion of an early stop signal encoding phosphatidylinositol class A glycan. As a consequence, an abnormally small protein is encoded, which is usually unstable. In people with paroxysmal nocturnal hemoglobinuria, somatic mutations of the PIG-A gene occur in hematopoietic stem cells, which are primarily found in the bone marrow. These cells produce erythrocytes, leukocytes and thrombocytes. Individuals with paroxysmal nocturnal hemoglobinuria have one or more mutations in the PIG-A gene in their hematopoietic stem cells, leading to coding for abnormal blood cells. As abnormal hematopoietic stem cells multiply, populations of abnormal blood cells form, alongside the normal blood cells encoded by normal hematopoietic stem cells. Certain abnormal white blood cells are likely to initiate an autoimmune process. Additionally, abnormal hematopoietic stem cells in people with paroxysmal nocturnal hemoglobinuria may be more susceptible to apoptosis, causing the cells to self-destruct when damaged or not needed. The proportion of abnormal blood cells in the body affects the severity of the signs and symptoms of paroxysmal nocturnal hemoglobinuria, including the risk of thrombosis and hemoglobinuria.           

This disease is acquired, rather than inherited. The disease is due to new mutations in the PIG-A gene and is generally expressed in people with no history of the disease in their family. The disease is not transmitted to the children of affected people.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Paroxysmal nocturnal hemoglobinuria, by means of the complete PCR amplification of the exons of the PIGA gene, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).