Paroxysmal nocturnal haemoglobinuria (PNH) is unique because it is an acquired haemolytic anaemia, resulting from an intrinsic red cell membrane disorder. The disease has been shown to be due to a somatic mutation of the phosphatidylinositol glycan complementation class A (pig-a) gene at the level of the haemopoietic stem cell. The defect in synthesis of the glycosylphosphatidylinositol (GPI) anchor results in a deficiency of all proteins that are GPI-bound to red cell, leucocyte and platelet membranes. The function of these proteins is extremely varied but a critical role is the protection of the cell from complement and it is the unopposed action of the complement cascade that results in the intravascular haemolysis and venous thrombosis which are hallmarks of the disease. The relationship between PNH and aplastic anaemia remains intriguing. It appears likely that an insult to a haemopoietic progenitor alters it in such a way that it becomes vulnerable to immune-mediated attack by cytotoxic T cells and/or cytokines. This attack requires one or more GPI-anchored molecules to be effective. Thus a GPI-negative clone would be at a relative advantage, and it is the balance between bone marrow impairment and proliferation of the GPI-negative clone(s) that determines the clinical picture. Prospects for molecular therapy continue to improve. Cell-to-cell transfer of GPI-linked proteins has been demonstrated in murine studies and recombinant CD59 has been expressed on GPI-deficient lymphocytes in vitro. Gene therapy remains a tantalising possibility, although a greater understanding of the pathophysiology of PNH is required, as well as advances in gene therapy techniques, before such an approach can be seriously considered.
Copyright 2002 S. Karger AG, Basel