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Hereditary Red Cell Membrane Disorders and Laboratory Diagnostic Testing M.-J.KING*,A.ZANELLA†

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Hereditary Red Cell Membrane Disorders and Laboratory Diagnostic Testing M.-J.KING*,A.ZANELLA† International Journal of Laboratory Hematology The Official journal of the International Society for Laboratory Hematology REVIEW INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY Hereditary red cell membrane disorders and laboratory diagnostic testing M.-J.KING*,A.ZANELLA† *Membrane Biochemistry, NHS SUMMARY Blood and Transplant, Bristol, UK This overview describes two groups of nonimmune hereditary † Hematology Unit, Foundation hemolytic anemias caused by defects in membrane proteins located IRCCS Ca Granda Ospedale Maggiore Policlinico, Milan, in distinct layers of the red cell membrane. Hereditary spherocyto- Italy sis (HS), hereditary elliptocytosis (HE), and hereditary pyropoikilo- cytosis (HPP) represent disorders of the red cell cytoskeleton. Correspondence: Hereditary stomatocytoses represents disorders of cation permeabil- May-Jean King, Membrane Bio- chemistry, NHS Blood and ity in the red cell membrane. The current laboratory screening tests Transplant, 500 North Bristol for HS are the osmotic fragility test, acid glycerol lysis time test Park, Northway, Filton, Bristol, (AGLT), cryohemolysis test, and eosin-5′-maleimide (EMA)-binding UK. Tel.: +44-(0)117-921-7601; test. For atypical HS, SDS-polyacrylamide gel electrophoresis of Fax: +44-(0)117-912-5782; E-mail: may-jean.king@nhsbt. erythrocyte membrane proteins is carried out to confirm the diag- nhs.uk nosis. The diagnosis of HE/HPP is based on abnormal red cell mor- phology and the detection of protein 4.1R deficiency or spectrin doi:10.1111/ijlh.12070 variants using gel electrophoresis. None of screening tests can detect all HS cases. Some testing centers (a survey of 25 laborato- Received 22 December 2012; ries) use a combination of tests (e.g., AGLT and EMA). No specific accepted for publication 16 Jan- uary 2013 screening test for hereditary stomatocytoses is available. The preli- minary diagnosis is based on presenting a compensated hemolytic Keywords anemia, macrocytosis, and a temperature or time dependent Hereditary spherocytosis, pseudohyperkalemia in some patients. Both the EMA-binding test eosin-5′-maleimide binding, and the osmotic fragility test may help in differential diagnosis of hereditary pyropoikilocytosis, hereditary stomatocytosis, acid HS and hereditary stomatocytosis. glycerol lysis time test integral membrane proteins (band 3 and glycophorin INTRODUCTION C) embedded in the lipid bilayer and specific regions The human erythrocyte membrane is a laminated of spectrin proteins in the cytoskeleton (Figure 1a). structure consisting of an outer lipid bilayer and a Yet the process maintaining the biconcave shape of two dimensional network of spectrin-based cytoskel- human red cell remains unclear (4, 5). Most often, eton (1–3). Connections of the two layers depend an erythrocyte membrane defect is suspected when on different linker proteins with binding sites, the blood smear of a patient with a nonimmune respectively, for the cytoplasmic domains of the hemolytic anemia presents with red cells of different © 2013 Blackwell Publishing Ltd, Int. Jnl. Lab. Hem. 1 2 M.-J. KING AND A. ZANELLA | LABORATORY DIAGNOSIS OF MEMBRANOPATHIES (a) Red blood cell membrane Glycophorin A Hereditary spherocytosis Band 3 RhAG Band 3 tetramer CD47 dimer Rh protein Glycophorin C/D Hereditary elliptocytosis Lipid bilayer ~75 Å Hereditary pyropoikilocytosis 4.2 Protein HE HPP Cytoplasmic Cp55 4.1 R side Adducin Sp dimer Actin Spectrin-based Ankyrin Sp variants Yes Yes β cytoskeleton Spectrin Dematin αSp content Normal slight α Spectrin Nucleation Spectrin self site association site (b) Ion transport in red cells Defects in Hereditary stomatocytoses “Diffusional” permeability to Na+ and K+ Na+ Na+ ? Baseline “Leak” OHSt DHSt Cryohydrocytosis K+ ATP dependent Na+/K+ pump RhAG Piezo1 Band 3 (SLC4A1) Cell mmol/L cells Long-term volume regulation [K+] 100 + with “passive” leak” Glut-1 (SLC2A1) [Na+] 8 K Plasma mmol/L ±stomatin [K+] 3.5 –5.3 [Na+] 133–146 – CI K+ Neurological disorders K+Cl– co-transporter HCO3 CI– in subsets Band 3 anion Carbonic Minor role in short-term exchanger anhydrase volume regulation; activated CO2 Hb by cell swelling Figure 1. Erythrocyte membrane, ion transport, and associated membrane protein defects. Panel (a): The assembly of red cell cytoskeletal proteins showing the band 3 macro-complex comprising of band 3 (exisiting as dimer and tetramer), CD47, Rh protein, and Rh-associated glycoprotein (RhAG) in the lipid layer. Protein 4.2 and ankyrin (on the cytoplasmic side) form a bridge between the Band 3 macro-complex and the spectrin-based network. The GPC-P55-protein 4.1R-actin form a junctional complex. Panel (b): Selected ion pumps and passive diffusion of cations that maintain the red cell volume and intracellular Na+/K+ gradients. The concentrations of intracellular K+ and Na+ in red cells are reversed in plasma. DHSt, dehydrated hereditary stomatocytosis; Glut1, Glucose transporter 1; Hb, hemoglobin; OHSt, overhydrated hereditary stomatocytosis; RhAG, Rh-associated glycoprotein; Sp, spectrin. sizes and shapes. The results of patient studies and HEMOLYTIC ANEMIAS CAUSED BY basic research in the period of 1980–1990s had DEFECTIVE RED CELL SKELETON given us a good understanding on the pathophysiol- ogy of hereditary spherocytosis (HS), hereditary This category of red cell disorders arises from either a elliptocytosis (HE), and hereditary pyropoikilocytosis quantitative or a qualitative defect in the membrane (HPP) (6). protein(s) constituting the red cell cytoskeleton (Fig- In the last 15 years, the research on rare red cell ure 1a). Hereditary spherocytosis occurs at a higher disorders has made progress in two fronts. The identi- incidence among Northern Europeans (1 in 2000–5000 fication of genes responsible for type I and type II of births) than in other ethnic groups. Seventy-five per- congenital dyserythropoietic anemia (CDA)(7) has cent of the cases have a dominant mode of inheritance. allowed confirmation of their diagnoses in addition to Some HS patients can have asymptomatic parents. HS electron microscopic examination of the erythroblasts is heterogeneous in every aspect: clinically (asymptom- in the bone marrow (8, 9). Research into hereditary atic, mild, moderate, to severe hemolysis requiring stomatocytoses (Figure 1b) has revealed the involve- blood transfusion), biochemically, and genetically (15). ment of very different transmembrane proteins local- Asymptomatic or mild HS condition can be exacerbated ized to the lipid bilayer (10–12), and the molecular by an infection (e.g., Parvovirus B19, Herpes 6, CMV, basis of monovalent cation transport in this group of or gastroenteritis) or pregnancy. On postpartum, the rare red cell disorders (13, 14). HS patient’s condition will return to baseline level. © 2013 Blackwell Publishing Ltd, Int. Jnl. Lab. Hem. M.-J. KING AND A. ZANELLA | LABORATORY DIAGNOSIS OF MEMBRANOPATHIES 3 Despite accumulation of massive data from biochemi- regulated by the actions of a passive leak process and cal and molecular analyses on membrane protein the ATP-driven Na/K pump (Figure 1b). Earlier stud- defects, it remains difficult to delineate the basis of vari- ies could not delineate an association of membrane able clinical expression occasionally observed in a family protein defects in HS red cells with the altered cation or kindred (16). Co-inheritance of a low expression spec- permeability (19, 20). A subset of spherocytosis with trin polymorphism SpaLEPRA allele was found to have low temperature leak (also having a band 3 defi- contributed to a more severe hemolysis in HS patients ciency) was found to have a series of mutations in the havingaHSaSp allele. Membrane proteins involved with intramembrane domain of band 3 protein. The the vertical interaction of the red cell membrane are mutated band 3 protein had reduced anion transport affected, namely spectrin (a and b chain), ankyrin, band together with an additional unregulated cation trans- 3 (anion exchanger), and protein 4.2 (Figure 1a). port activity (21). Hereditary elliptocytosis is a dominantly inherited Unlike the low-temperature HS, sickle cell disease, condition caused by either a protein 4.1R deficiency or thalassemia, and pyruvate kinase deficiency, heredi- spectrin abnormalities (17), affecting the horizontal tary stomatocytoses (HSt) represent a category of interaction of the red cell cytoskeleton (Figure 1a). diverse red cell disorders with a common lesion, a sig- A milder hemolytic anemia is often found in patients nificantly altered Na+/K+ fluxes or ‘leaky’ red cells. with a partial protein 4.1R reduction than in those The incidence of HSt in a population is estimated patients having spectrin variant(s) (18). A complete about 40- to 50-fold lower than HS. Although isolated absence of protein 4.1R (null phenotype) is expected to variants of hereditary stomatocytosis have been result in a severe hemolytic anemia. A high proportion reported (14, 22), four main types are identified: over- of HE patients with spectrin defects are of African origin. hydrated (OHSt), dehydrated (DHSt), cryohydrocytosis A majority of the spectrin mutations are localized to the (CHC), and Familial Pseudohyperkalemia (FP). Only spectrin self-association site, where spectrin heterodi- FP has almost normal routine hematology, but a blood mers cross-link to form tetramers and higher oligomers. specimen will give a raised plasma K+ level after Hereditary pyropoikilocytosis is a severe form of HE, standing at room temperature for a few hours. The and it is often diagnosed in early
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