New insights into paroxysmal nocturnal hemoglobinuria.
The characteristic, defining defect in paroxysmal nocturnal hemoglobinuria is the somatic mutation of the PIG-A gene (essential to the biosynthesis of the glycosylphosphatidylinositol moiety that affixes a number of proteins to the cellular surface) in hematopoietic cells. These cells thus lack the proteins usually held in place by this anchor. The absence of these proteins is the most reliable diagnostic criterion of the disease and is responsible for many of the clinical manifestations of PNH. The current hypothesis explaining the disorder suggests that there are two components: (1) hematopoietic stem cells with the characteristic defect are present in the marrow of many if not all normal individuals in very small numbers; (2) some aplastogenic influence suppresses the normal stem cells but does not suppress the defective stem cells, thus allowing the proportion of these cells to increase. Current research attempts to substantiate this hypothesis and design therapy consistent with the hypothesis. Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired stem cell disorder characterized by intravascular hemolysis, hypercoagulability, and relative bone marrow failure [1]. It is characterized by a somatic mutation in the gene encoding the alpha1-6-N-acetylglucosaminyltransferase necessary for the formation of the glycosylphosphatidylinositol (GPI) anchor that binds certain proteins to the membrane surface (Fig. 1) [2,3*]. Whereas many of the manifestations can be accounted for by the absence of these proteins on the cells of the hematopoietic system, it is not entirely clear whether this defect is sufficient to make the disease manifest. In this paper, the author reviews recent clinical observations and relates them to the underlying pathophysiology of the disease.
Rosse
W F
WF
Florence McAlister Professor of Medicine Emeritus, Department of Medicine, Duke University, Durham, North Carolina, USA. rosse001@mc.duke.edu
D000818:Animals; D017261:Glycosylphosphatidylinositols / Q000096:biosynthesis; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation
D017261:Glycosylphosphatidylinositols; D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein