PNH: “plus ça change, plus c'est la même chose”

A condition of being given a gentlemen's C to complete my undergraduate language requirement was that I would never use French in public. With apologies to Mademoiselle Ashrifé (my French 31 instructor), the findings of Horikawa and colleagues (page 24) proved irresistible as they reminded me that, with PNH as with most other of life's enduring dilemmas, “the more things change, the more they remain the same.” The changes in PNH this time are mutations in the X-chromosomal gene HGPRT. Unlike in PIG-A, mutations in HGPRT do not contribute to the pathophysiology of PNH; rather, they serve as surrogate markers for the frequency of somatic mutations occurring in hematopoietic cells. The authors report that peripheral blood T lymphocytes resistant to 6-TG (an indicator of mutant HGPRT) were found in 8 of 12 patients with PNH (67%) but in only 3 of 17 age-matched healthy volunteers (18%). More remarkably, the incidence of resistant clones was more than 20 times greater in the PNH patients than in the control group. Analysis of 6-TG resistance in the bone marrow supported the interpretation that the frequency of somatic mutations in hematopoietic stem cells is abnormally high in patients with PNH. Others have reported evidence of a higher mutational frequency in PNH although the magnitude was less than that of the current report. Horikawa and colleagues also found that the types of mutations in HGPRT in PNH patients (primarily large deletions) were different than in the healthy controls (single base-pair substitutions).

One of the most remarkable features of PNH is the coexistence in the same patient of multiple hematopoietic stem cell clones with discrete mutations in PIG-A. The studies of Dr Nakakuma's group provide a plausible explanation for why PNH is often an oligoclonal, rather than monoclonal, disease. But a higher mutational frequency alone is insufficient to account for the outgrowth of multiplePIG-A mutant stem cells characteristic of PNH. Principles of Darwinian evolution must contribute to the process. A powerful selection pressure is at work for multiple PIG-A mutant stem cells to emerge from the background of an injured bone marrow. Almost certainly the type of injury is specific (immune-mediated), and the mutant cells have a growth or survival advantage in this setting because of deficiency of one or more glycosyl phosphatidylinositol–anchored proteins. Delineating the nature of the selection process will allow us to understand the unique relationship between PNH and certain other bone marrow failure syndromes, particularly aplastic anemia. Changes in how we think about PNH continue to evolve, but our enduring fascination with the intricate pathophysiology of this elegant disease remains the same.