Elsevier

Blood Reviews

Volume 27, Issue 4, July 2013, Pages 167-178
Blood Reviews

REVIEW
Hereditary spherocytosis, elliptocytosis, and other red cell membrane disorders

https://doi.org/10.1016/j.blre.2013.04.003Get rights and content

Abstract

Hereditary spherocytosis and elliptocytosis are the two most common inherited red cell membrane disorders resulting from mutations in genes encoding various red cell membrane and skeletal proteins. Red cell membrane, a composite structure composed of lipid bilayer linked to spectrin-based membrane skeleton is responsible for the unique features of flexibility and mechanical stability of the cell. Defects in various proteins involved in linking the lipid bilayer to membrane skeleton result in loss in membrane cohesion leading to surface area loss and hereditary spherocytosis while defects in proteins involved in lateral interactions of the spectrin-based skeleton lead to decreased mechanical stability, membrane fragmentation and hereditary elliptocytosis. The disease severity is primarily dependent on the extent of membrane surface area loss. Both these diseases can be readily diagnosed by various laboratory approaches that include red blood cell cytology, flow cytometry, ektacytometry, electrophoresis of the red cell membrane proteins, and mutational analysis of gene encoding red cell membrane proteins.

Introduction

A number of inherited red cell disorders due to altered membrane function have been identified. These include hereditary spherocytosis (HS), hereditary elliptocytosis (HE), hereditary ovalocytosis (SAO), and hereditary stomatocytosis (HSt).

HS and HE [1], [2], [3], [4], [5], [6] are the most common red cell membrane disorders in the world with a prevalence of 1 out of 2000 affected cases in North America and Northern European countries and are likely to be even higher due to underdiagnosis of asymptomatic forms. Both diseases result from defects in genes encoding various membrane and skeletal proteins that play a role in regulating membrane cohesion and membrane mechanical stability [1], [2], [3], [4], [5], [6]. In both HS and HE, red cell life span is shortened as result of splenic sequestration of red cells. The abnormal red cells with decreased membrane surface area and increased sphericity are trapped in the billroth canals in the spleen and phagocytozed by the splenic reticulo-endothelial system [7], [8] resulting in regenerative hemolytic anemia, splenomegaly, and ictera with increased free bilirubin level. The severity of the disease depends on the extent of surface area loss and ranges from asymptomatic forms to severe neonatal or prenatal forms responsible for rare hydrops fetalis cases requiring transfusion in utero. In this review, we will summarize the substantial progress that has been made in our understanding of i) structural organization of the red cell membrane including comprehensive characterization of a large number of membrane proteins, ii) structural basis for the interactions between various membrane and skeletal proteins and how defects in these interactions due to mutations in genes encoding the various proteins lead to defective membrane function, and iii) appropriate methodologies including genetic analysis that enable the diagnosis of various red cell membrane disorders.

Section snippets

Red cell membrane structure

The red cell membrane is a composite structure consisting of a lipid bilayer anchored to the spectrin-based membrane skeleton through linking proteins interacting with cytoplasmic domains of membrane proteins embedded in the lipid bilayer. In addition, anionic phospholipids in the inner lipid monolayer interact directly with skeletal proteins spectrin and protein 4.1 and these interactions modulate membrane function [9], [10], [11], [12], [13]. In addition to phospholipids, the red cell

Hereditary spherocytosis

Hereditary spherocytosis (HS) (known as well as the Minkowski Chauffard disease) is the most common inherited red cell membrane disorder with one case out of 2000–3000 individuals, and probably even higher prevalence due to underdiagnosis of minor or moderate forms of HS (Table 1). Although more often diagnosed in Europe and North America, HS is reported in other continents and countries, without a founder effect. The inheritance is dominant in 75% of cases.

Hereditary elliptocytosis (HE), pyropoikilocytosis (HPP), South East Asian ovalocytosis (SAO)

Hereditary elliptocytosis is another red cell membrane disorder characterized by mutations in genes encoding membrane or skeletal proteins, which alters membrane function and reduces red cell deformability. HE is due to defects in the horizontal protein connections of the red cell membrane skeletal network including the spectrin dimer–dimer interaction or the spectrin–actin–protein 4.1R junctional complex. The genes mutated in HE are thus the α-spectrin (SPTA1), the β-spectrin (SPTB) or protein

Stomatocytosis

This rare red cell disorder is divided into two different entities: the xerocytosis or dehydrated hereditary stomatocytosis (DHSt) and the overhydrated hereditary stomatocytosis (OHS) [1], [2], [4], [41], [130]. Both exhibit a cation leak to the univalent cations Na+ and K+ resulting in altered intracellular cation content and cell volume alterations. The inheritance of stomatocytosis is autosomal dominant. The phenotype can vary from asymptomatic to severe hemolytic form.

In the DHSt, the most

Conflict of interest statement

None of the authors have any conflicts of interest to declare.

Acknowledgments

We would like to acknowledge D. Biallez for providing some of the ektacytometer data, Y. Colin, INTS, Paris and the Université Paris VII-Denis Diderot, Sorbonne Paris Cité for the funding of the red cell membrane diagnosis in the hematology lab of R. Debré Hospital.

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    Author contributions: L. Da Costa wrote the article. J. Galimand acquired the ektacytometer data. O. Fenneteau performed microscopic analysis of the red cells. N. Mohandas worked on the article with L. Da Costa.

    1

    Service d'Hématologie Biologique, Hôpital R. Debré, 48 boulevard Sérurier, Paris, France, F-75019. Tel.: + 33 1 40 03 41 94; fax: + 33 1 40 03 47 95.

    2

    Red Cell Physiology Laboratory, New York Blood Center, 310 East 67th street, New York, 10021, NY, USA. Tel.: + 1 212 570 3056; fax: + 1 212 570 3264.

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