Hereditary elliptocytosis: clinical, morphological and biochemical studies of 38 cases.

We report clinical, morphological and biochemical studies performed on 38 cases of hereditary elliptocytosis (HE). The major determinant of membrane shape and stability is a proteinaceous meshwork named membrane skeleton, composed mainly of spectrin, actin, protein 4.1 and ankyrin. Spectrin is a heterodimer composed of two chains alpha and beta. Two spectrin dimers associate head to head to form a tetramer. Spectrin tetramers are cross-linked by actin and protein 4.1 to form the skeletal meshwork. We observed two types of membrane defects in the 38 patients studied: 24 patients (13 kindreds) exhibited spectrin self-association defect (type I HE) and 14 patients (6 kindreds) displayed deficiency in protein 4.1. A mutation in the spectrin chain was mostly found in the cases of type I HE. These mutations were depicted on tryptic digest patterns of spectrin. Three pathological variants were thus identified and characterized by the appearance of an abnormal peptide, with a molecular weight of either 74,000 or 65,000, or 46,000 daltons. In one family, the spectrin self-association defect was related to a shortened spectrin beta chain. Deficiency in protein 4.1 was found in 14 patients by means of polyacrylamide gel electrophoresis of red cell membranes. In 12 heterozygous cases of HE, the decrease in the amount of protein band 4.1 was between 40% and 50%. In 2 homozygous HE cases, protein band 4.1 was totally absent. Immunoelectrotransfer blots of red cell membrane proteins using a monoclonal antibody against protein 4.1 allowed characterization of additional bands in two families. In some cases variations in the amount of glycophorin C were noticed. Comparative studies of the two types of membrane abnormalities in HE clearly showed the absence of correlation between clinical, morphological phenotypes, and specific molecular etiology. However, all HE patients with protein 4.1 deficiency were caucasian and most of the type I HE were of black extraction. A study of red cell deformability using an ektacytometer revealed that the cell deformability under isotonic conditions was decreased in all HE patients. When the deformability was studied as a function of the osmolality of the suspending medium, the curve obtained had a trapezoid shape. This typical profile appeared to be constant in type I HE. We showed that the molecular abnormalities of the spectrin alpha chain, found in most type I HE correlated well with the functional spectrin defect.(ABSTRACT TRUNCATED AT 400 WORDS)