The molecular lesion of hereditary spherocytosis (HS): a continuing enigma [Editorial]

V ERY FEW, if any, abnormalities of the human erythrocyte have been studied with such diligence as those associated with hereditary spherocytosis (HS). Not only has the small, round, densely staining spherocyte provided a long-recognized morphologic benchmark, but its inordinate susceptibility to lysis in hypotonic saline has been clearly documented for 75 years.’ Forty years ago, Haden (cited above) and Castle and Daland2 related the latter to loss of the usual discoidal form of the erythrocyte, and to a probable structural abnormality resulting in a decreased surface area/volume ratio. The unique role ofthe spleen in recognizing, sequestering, and finally destroying the abnormal cell, and the effect of splenectomy in correcting clinical manifestations were investigated in great detail in the 1940’s and early l95O’s.�� The assumption that a genetically determined, usually dominantly transmitted7”#{176} abnormality of the red cell membrane lies at the heart of the disorder has pervaded studies of its pathophysiobogyand, in the past 20 years, has fostered many investigations of red cell membrane structure and function. While these studies have added much to our understanding of red cell physiology, the secret of the ultimate molecular lesion still remains locked within the osmotically fragile spherocyte. These investigations have defined a variety of abnormal properties in HS red cells. These cells are abnormally permeable to sodium and this “sodium leak”2 necessitates an increased glycolytic rate to support greater-thannormal adenosine triphosphate-adenosine triphosphatase (ATP-ATPase)dependent pumping of sodium from the cell’s interior.’2’4 While total lipids have been reported to be relatively somewhat decreased both before’5”6 and after’7 splenectomy, and abnormalities of phospholipid turnover have been suggested,’t no consistently demonstrable data thus far support specific abnormalities in membrane lipid structure. However, under conditions of glucose deprivation, HS membrane lipid is abnormally unstable, and is released by a budding process, thus contributing to a still greater deficit in surface area.’5”9’2#{176}