Background: Common HE is the most prevalent clinical form of hereditary elliptocytosis; its clinical findings vary considerably, ranging from an asymptomatic carrier state to a severe, even life-threatening hemolytic disorder. Structural modification and reduction of 4.1 protein, or abnormalities at the spectrin self-association site could lead to elliptocytes.
Methods: Sixty-one Italian HE patients belonging to 28 families were studied. Analysis of red blood cell cytoskeleton was performed by means of SDS-PAGE, and spectrin dimer percentage was assessed by non denaturing polyacrylamide gel electrophoresis. Limited tryptic digestion of spectrin was employed in patients showing an abnormal dimer increase, and the amount of abnormal alpha I peptide was estimated. Molecular defects were detected by means of PCR of alpha and beta spectrin genes and direct sequencing of genomic DNA.
Results: We found a very heterogeneous spectrum of cytoskeletal alterations: 18 (29%) subjects showed partial protein 4.1 deficiency, whereas 31 (51%) displayed an increased amount of spectrin dimers; we were not able to detect any alteration in 12 (20%) HE patients. Patients enrolled in this study were widely distributed throughout Italy.
Conclusions: The subgroup of HE patients related to 4.1 deficiency is homogeneously asymptomatic, whereas forms due to disruption of the spectrin tetramerization site are very heterogeneous, and clinical severity appears to be related to spectrin dimers and especially to spectrin content. These two parameters in turn are related to the presence of a low expression alpha allele in trans and to the degree of disruption of head-to-head contact between alpha and beta chains.