A New Inherited Abnormality of Hemoglobin and Its Interaction with Sickle Cell Hemoglobin

Abstract

Abstract Through clinical, genetic and physicochemical studies a new inherited abnormality of hemoglobin has been recognized in American Negroes. The new hemoglobin, provisionally called hemoglobin III, can be separated from both normal and sickle cell hemoglobin by electrophoretic analysis. The structural anomaly of the hemoglobin molecule is determined by a gene inherited as a simple Mendelian dominant. A distinct hemolytic syndrome which is intermediate between the benign sickle cell trait and sickle cell anemia results from the combination of the new hemoglobin with sickle cell hemoglobin. A tentative characterization of the syndrome is presented. In contrast to classical sickle cell anemia this form of sickle cell disease is characterized by a mild hemolytic anemia with slowly progressive splenomegaly in the absence of cardiac or musculo-skeletal manifestations. In vitro, the erythrocytes sickle like those of sickle cell anemia. The bone marrow shows erythroid hyperplasia, fecal urobilinogen excretion is increased, and the survival time of the erythrocytes in normal recipients is shortened, but in the patients the red cell count and hemoglobin concentration are only slightly depressed. Reticulocytosis is slight and icterus is not observed. Whereas in sickle cell anemia both parents are expected to have the sickle trait, only one parent of these individuals shows sickling, while the nonsickling parent is a carrier of the hemoglobin III. The new syndrome does not appear to be identical with that resulting from the simultaneous presence of the sickling gene and the thalassemiagene. The presence of hemoglobin III when combined with structurally normal hemoglobin is expressed as an asymptomatic carrier state. The erythrocytes do not sickle but have a high incidence of target cell deformity and increased resistance to hypotonic saline. Although there is no evidence of hemolysis in such individuals their erythrocytes are eliminated with abnormal rapidity from the circulation of normal recipients. The homozygous state with respect to this new hemoglobin has not yet been identified but may well be some already recognized atypical form of chronic hemolytic anemia. Studies are now in progress to determine the incidence of this new molecular abnormality of hemoglobin.