The disease begins with the expansion of a hematopoietic stem cell that has a severe deficiency or absence for GPI, a glycolipid moiety that anchors >150 different proteins to the cell surface ( Figure 1). Hemolysis in PNH is complement mediated and is a direct result of PNH cells acquiring a deficiency of complement regulatory proteins. A few years later, a genetic mutation (phosphatidylinositol glycan class A ) responsible for the GPI anchor protein deficiency was discovered, 8-11 and most recently, a humanized monoclonal antibody that inhibits terminal complement activation has been shown to ameliorate hemolysis and thrombosis and improve quality of life in PNH patients. Two of the missing GPI anchored proteins (CD55 and CD59) regulate complement. In the 1980s, it was discovered that PNH cells display a global deficiency in a group of proteins affixed to the cell surface by a glycosylphosphatidylinositol (GPI) anchor. The cell lysis following acidified serum appeared to be complement dependent because heat inactivation abrogated the reaction however, it was not until 1954, with the discovery of the alternative pathway of complement activation, that complement was formally proven to cause the hemolysis of PNH red cells. 7 This seminal discovery resulted in the first diagnostic test for PNH, the acidified serum (Ham) test. 6 In 1937, Thomas Ham reported that PNH erythrocytes were hemolyzed when incubated with normal, acidified serum. Later reports by Marchiafava and Micheli led to the eponym, Marchiafava-Micheli syndrome, but it was Enneking, in 1925, who introduced the term paroxysmal nocturnal hemoglobinuria. 5 Strübing deduced that the hemolysis was occurring intravascularly as the patient’s plasma turned red following severe attacks of hemoglobinuria. 1-4 One of the earliest descriptions of PNH was by Dr Paul Strübing, who in 1882 described a 29-year-old man who presented with fatigue, abdominal pain, and severe nocturnal paroxysms of hemoglobinuria. Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disorder that manifests with hemolytic anemia, bone marrow failure, and thrombosis. Bone marrow transplantation remains the only cure for PNH but should be reserved for patients with suboptimal response to eculizumab. Eculizumab, a first-in-class monoclonal antibody that inhibits terminal complement, is the treatment of choice for patients with severe manifestations of PNH. In addition, hypomorphic germ-line PIGA mutations that do not cause PNH have been shown to be responsible for a condition known as multiple congenital anomalies-hypotonia-seizures syndrome 2. GPI anchor protein deficiency is almost always due to somatic mutations in phosphatidylinositol glycan class A ( PIGA), a gene involved in the first step of GPI anchor biosynthesis however, alternative mutations that cause PNH have recently been discovered. The absence of two glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that accounts for hemolysis and other PNH manifestations. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare bone marrow failure disorder that manifests with hemolytic anemia, thrombosis, and peripheral blood cytopenias.
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