GENETIC-DEFECTS UNDERLYING PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA THAT ARISES OUT OF APLASTIC-ANEMIA

Treatment of severe aplastic anemia with antithymocyte globulin (ATG) and cyclosporin leads to clinical remission in a large proportion of patients. As many as 10% to 57% of these patients, however, develop paroxysmal nocturnal hemoglobinuria (PNH). We and others have observed that this secondary PNH appears to be more indolent than classical PNH, which results from an acquired mutation in the PIG-A gene. in the present study, we compared PIG-A mRNA transcripts in affected cells from patients with secondary PNH and patients with classical PNH. All four of our aplastic patients who developed PNH had a negative Ham test at diagnosis. Two of the four showed a positive Ham test within 3 months after ATG/cyclosporin administration, one developed a positive test at 6 months, and another at 18 months after immunosuppressive therapy. Ali four patients remain transfusion-independent with no thrombotic episodes after a mean follow-up of 30 months (range, 6 to 63 months). Reverse transcription-polymerase chain reaction (RT-PCR) of PIG-A transcripts in DAF(-)/CD59(-) neutrophils or lymphocyte lines of the four patients showed PIG-A abnormalities in all cases. Transition of C-163 to T was found in one, a 14-bp deletion (positions 1141 to 1154) was found in the second, deletion of C-39 was found in the third, and two mutations, transition of C-55 to T and transversion of T-762 to A, were found in the fourth. These abnormalities compared with findings of abnormal RNA splicing causing a 133-bp deletion, a 4-bp insertion (between positions 578 and 579), loss of A(767), and loss of C-575 in four patients with primary PNH. We conclude that secondary PNH that evolves out of aplastic anemia, like classical PNH, is associated with mutations in the PIG-A gene. The apparent indolent nature of this disease probably reflects early detection. (C) 1995 by The American Society of Hematology.