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 protein s is the most reliable diagnostic criterion of the disease and is responsib le for many of the clinical manifestations of PNH. The current hypothesis e xplaining the disorder suggests that there are two components: (1) hematopo ietic stem cells with the characteristic defect are present in the marrow o f many if not all normal individuals in very small numbers; (2) some aplast ogenic influence suppresses the normal stem cells but does not suppress the defective stem cells, thus allowing the proportion of these cells to incre ase. Current research attempts to substantiate this hypothesis and design t herapy consistent with the hypothesis. Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired stem cell disorder characterized by intravascular hemo lysis, hypercoagulability, and relative bone marrow failure [1]. It is char acterized by a somatic mutation in the gene encoding the alpha1-6-N-acetyl- glucosaminyltransferase necessary for the formation of the glycosylphosphat idylinositol (GPI) anchor that binds certain proteins to the membrane surfa ce (Fig. 1) [2,3(.)]. Whereas many of the manifestations can be accounted f or by the absence of these proteins on the cells of the hematopoietic syste m, it is not entirely clear whether this defect is sufficient to make the d isease manifest. In this paper, the author reviews recent clinical observat ions and relates them to the underlying pathophysiology of the disease. (C) 2001 Lippincott Williams & Wilkins, Inc.