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Pediatr Blood Cancer 2019 Feb 4;66(2):e27531. Epub 2018 Nov 4.

Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

The broad phenotypic variability among individuals with sickle cell disease (SCD) suggests the presence of modifying factors. We identified two unrelated SCD patients with unusually severe clinical and laboratory phenotype that were found to carry the hereditary elliptocytosis-associated alpha-spectrin mutation c.460_462dupTTG (p. Read More

Clin Chim Acta 2018 Dec 11;487:311-317. Epub 2018 Oct 11.

Department of Laboratory Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan; Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan; Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan; Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan. Electronic address:

Purpose: Congenital hemolytic anemia caused by red blood cell (RBC) membrane defects is a heterogeneous group of disorders. The present study aimed to search the causative gene mutations in patients with RBC membrane disorders in Taiwan.

Materials And Methods: Next-generation sequencing approach using whole-exome sequencing (WES) was performed. Read More

Br J Haematol 2019 May 10;185(3):578-582. Epub 2018 Sep 10.

Center of Excellence for Medical Genomics, Department of Paediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Am J Hematol 2018 Oct 26;93(10):E340-E342. Epub 2018 Sep 26.

Service d'Hématologie Biologique, CHU Bicêtre, AP-HP, Le Kremlin-Bicêtre, France.

Blood 2018 01;131(1):153

Children's Mercy Hospital.

Blood 2017 12;130(25):2808

Centre Hospitalier Universitaire Nancy.

Am J Hematol 2017 10 29;92(10):E607-E609. Epub 2017 Jul 29.

Department of Molecular Medicine and Medical Biotechnology, University Federico II, Naples, Italy.

Clin Pediatr (Phila) 2018 Jan 15;57(1):19-26. Epub 2017 Jan 15.

1 University of Utah, Salt Lake City, UT, USA.

Various mutations in the genes encoding alpha spectrin (SPTA1) or beta spectrin (SPTB) are known to cause erythrocyte membrane disorders, sometimes associated with severe neonatal jaundice and anemia. We used a next-generation sequencing panel to evaluate 3 unrelated neonates who had puzzling cases of nonimmune hemolytic jaundice. In each case, we identified novel mutations in either SPTA1 or SPTB. Read More

Blood Cells Mol Dis 2016 10 17;61:4-9. Epub 2016 Jul 17.

Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are heterogeneous red blood cell (RBC) membrane disorders that result from mutations in the genes encoding α-spectrin (SPTA1), β-spectrin (SPTB), or protein 4.1R (EPB41). The resulting defects alter the horizontal cytoskeletal associations and affect RBC membrane stability and deformability causing shortened RBC survival. Read More

S D Med 2016 May;69(5):208-209

Department of Pathology, University of South Dakota Sanford School of Medicine.

J La State Med Soc 2016 Jan-Feb;168(1):6-7. Epub 2016 Feb 15.

Dr. Cotelingam is associated with the Department of Pathology.

A seven-year-old African-American male presented with a history of hematuria, proteinuria, jaundice, and anemia occasionally treated with transfusions since early childhood. The family history included a father and sister with similar symptoms of anemia, both of which had been diagnosed with hereditary pyropoikilocytosis. Due to the patient's family history and symptoms indicating a possible hematologic problem, a blood draw was performed. Read More

Clin Genet 2016 07 15;90(1):69-78. Epub 2016 Mar 15.

Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

The aim of this study was to describe the mutational characteristics in Korean hereditary spherocytosis (HS) patients. Relevant literatures including genetically confirmed cases with well-documented clinical summaries and relevant information were also reviewed to investigate the mutational gene- or domain-specific laboratory and clinical association. Twenty-five HS patients carried one heterozygous mutation of ANK1 (n = 13) or SPTB (n = 12) but not in SPTA1, SLC4A1, or EPB42. Read More

Biomed Res Int 2015 18;2015:451861. Epub 2015 Oct 18.

Department of Laboratory Medicine, Kawasaki Medical School, Kurashiki, Japan.

Flow cytometric test for analyzing the eosin-5-maleimide (EMA) binding to red blood cells has been believed to be a specific method for diagnosing hereditary spherocytosis (HS). However, it has been reported that diseases other than HS, such as hereditary pyropoikilocytosis (HPP) and Southeast Asian ovalocytosis (SAO), which are forms in the category of hereditary elliptocytosis (HE), show decreased EMA binding to red blood cells. We analyzed EMA binding to red blood cells in 101 healthy control subjects and 42 HS patients and obtained a mean channel fluorescence (MCF) cut-off value of 36. Read More

Turk J Haematol 2016 Mar 6;33(1):86-7. Epub 2015 Aug 6.

Hacettepe University Faculty of Medicine, Department of Pediatric Hematology, Ankara, Turkey. E-mail:

Int J Lab Hematol 2015 Jun 18;37(3):304-25. Epub 2015 Mar 18.

Membrane Biochemistry, NHS Blood and Transplant, Bristol, UK.

Introduction: Hereditary spherocytosis (HS), hereditary elliptocytosis (HE), and hereditary stomatocytosis (HSt) are inherited red cell disorders caused by defects in various membrane proteins. The heterogeneous clinical presentation, biochemical and genetic abnormalities in HS and HE have been well documented. The need to raise the awareness of HSt, albeit its much lower prevalence than HS, is due to the undesirable outcome of splenectomy in these patients. Read More

Pediatr Clin North Am 2013 Dec 15;60(6):1349-62. Epub 2013 Oct 15.

Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, PO Box 208064, New Haven, CT 06520-8064, USA. Electronic address:

Primary abnormalities of the erythrocyte membrane are characterized by clinical, laboratory, and genetic heterogeneity. Among this group, hereditary spherocytosis patients are more likely to experience symptomatic anemia. Treatment of hereditary spherocytosis with splenectomy is curative in most patients. Read More

Neonatology 2014 31;105(1):1-4. Epub 2013 Oct 31.

Department of Women and Newborns, Intermountain Healthcare, Salt Lake City, Utah, USA.

We cared for a neonate who had problematic hyperbilirubinemia born into a family where nine first-degree relatives had hereditary elliptocytosis (HE). As neonates, the nine relatives did not have any significant jaundice or anemia that was recognizable. Blood films on the proband suggested a diagnosis of pyropoikilocytosis. Read More

Haematologica 2013 Dec 27;98(12):1972-9. Epub 2013 Sep 27.

Hereditary pyropoikilocytosis is a severe hemolytic anemia caused by spectrin deficiency and defective spectrin dimer self-association, typically found in African populations. We describe two Utah families of northern European ancestry including 2 propositi with atypical non-microcytic hereditary pyropoikilocytosis, 7 hereditary elliptocytosis members and one asymptomatic carrier. The underlying molecular defect is a novel mutation in the alpha(α) spectrin gene, SPTA(R34P) that impairs spectrin tetramer formation. Read More

Blood 2013 Oct 23;122(17):3045-53. Epub 2013 Aug 23.

The Center for Systems and Computational Biology and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA;

Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are common disorders of erythrocyte shape primarily because of mutations in spectrin. The most common HE/HPP mutations are located distant from the critical αβ-spectrin tetramerization site, yet still interfere with formation of spectrin tetramers and destabilize the membrane by unknown mechanisms. To address this question, we studied the common HE-associated mutation, αL260P, in the context of a fully functional mini-spectrin. Read More

Blood Rev 2013 Jul 9;27(4):167-78. Epub 2013 May 9.

AP-HP, Service d'Hématologie Biologique, Hôpital R. Debré, Paris, F-75019, France.

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. Read More

Int J Lab Hematol 2013 Jun 11;35(3):237-43. Epub 2013 Mar 11.

Membrane Biochemistry, NHS Blood and Transplant, Bristol, UK.

This overview describes two groups of nonimmune hereditary hemolytic anemias caused by defects in membrane proteins located in distinct layers of the red cell membrane. Hereditary spherocytosis (HS), hereditary elliptocytosis (HE), and hereditary pyropoikilocytosis (HPP) represent disorders of the red cell cytoskeleton. Hereditary stomatocytoses represents disorders of cation permeability in the red cell membrane. Read More

Ann Acad Med Singapore 2012 Jul;41(7):305-8

Children's Haematology and Cancer Centre, Mount Elizabeth Hospital, Singapore.

Introduction: The underlying diagnosis of severe anaemic illnesses in children may not be easy to identify at times, especially when regular blood transfusion has been started.

Materials And Methods: International children patients attending a haematology clinic for diagnostic evaluation were identified retrospectively if they had to receive repeated blood transfusions with an undiagnosed illness or an incorrect diagnosis. Their demographic data, presenting features, and eventual diagnosis were described. Read More

Transfusion 2012 Aug;52(8):1646

Service d'Hématologie Biologique, Centre Hospitalier Universitaire, Nancy, France.

Ann Biol Clin (Paris) 2012 Jul-Aug;70(4):483-8

Service d'hématologie biologique, Centre hospitalier universitaire, Nancy.

We report on a case of hereditary pyropoïkilocytosis fortuitously diagnosed in a 34-year old woman issued from Benin. Laboratory tests indicated a moderate haemolytic anaemia with a marked microcytosis. Blood film examination revealed a striking anisopoikilocytosis characterized by elliptocytes, numerous red blood cells (RBC) fragments and microspherocytes. Read More

Int J Lab Hematol 2011 Apr 3;33(2):205-11. Epub 2010 Nov 3.

International Blood Group Reference Laboratory, NHS Blood & Transplant, Bristol, UK.

Introduction: Hereditary spherocytosis (HS) and hereditary pyropoikilocytosis (HPP, severe form of hereditary elliptocytosis) are unrelated red cell disorders caused by defects in distinct regions of the red cell cytoskeleton. The high predictive value of the eosin-5-maleimide (EMA)-binding test for the diagnosis of HS is because of its interaction with transmembrane proteins band 3, Rh protein, Rh glycoprotein and CD47, which are reduced on HS red cells. Our study was undertaken to determine why EMA-labelled HPP red cells were previously found to give much lower fluorescence readings than HS. Read More

Blood 2010 Jun 2;115(23):4843-52. Epub 2010 Mar 2.

Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, IL 60208, USA.

As the principal component of the membrane skeleton, spectrin confers integrity and flexibility to red cell membranes. Although this network involves many interactions, the most common hemolytic anemia mutations that disrupt erythrocyte morphology affect the spectrin tetramerization domains. Although much is known clinically about the resulting conditions (hereditary elliptocytosis and pyropoikilocytosis), the detailed structural basis for spectrin tetramerization and its disruption by hereditary anemia mutations remains elusive. Read More

Br J Haematol 2009 Nov 31;147(3):392-5. Epub 2009 Aug 31.

Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.

The functional roles of residues 21-43 and 55-59 in the alpha-spectrin N-terminal region in forming tetramers were determined by the introduction of mutations at each of these positions. We measured association affinities for tetramer formation (K(d)), which can be used to predict clinical severity, of these mutants. A total of nine residues critical for association with beta-spectrin were found. Read More

Blood 2009 Jun 15;113(24):6237-45. Epub 2009 Apr 15.

Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.

Membrane-spanning proteins may interact with a variety of other integral and peripheral membrane proteins via a diversity of protein-protein interactions. Not surprisingly, defects or mutations in any one of these interacting components can impact the physical and biological properties on the entire complex. Here we use quantum dots to image the diffusion of individual band 3 molecules in the plasma membranes of intact human erythrocytes from healthy volunteers and patients with defects in one of their membrane components, leading to well-known red cell pathologies (hereditary spherocytosis, hereditary elliptocytosis, hereditary hydrocytosis, Southeast Asian ovalocytosis, and hereditary pyropoikilocytosis). Read More

Haematologica 2008 Nov 24;93(11):1752-4. Epub 2008 Sep 24.

Br J Haematol 2008 Jun 19;142(2):315-7. Epub 2008 May 19.

Cytometry B Clin Cytom 2008 Jul;74(4):244-50

Membrane Biochemistry, International Blood Group Reference Laboratory, Bristol, United Kingdom.

Background: Flow cytometric analysis of eosin-5-maleimide (EMA)-labeled red blood cells (RBCs) has been used as a screening test for the diagnosis of patients with hereditary spherocytosis (HS). We assessed the fluorescence profiles for patients having HS and hereditary pyropoikilocytosis (HPP) together with their red cell indices.

Methods: Flow cytometry was used to analyze EMA-labeled RBCs. Read More

Blood 2008 Jun 24;111(12):5712-20. Epub 2008 Jan 24.

The Wistar Institute, Philadelphia, PA 19104, USA.

The most common hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) mutations are alpha-spectrin missense mutations in the dimer-tetramer self-association site. In this study, we systematically compared structural and functional properties of the 14 known HE/HPP mutations located in the alpha-spectrin tetramer binding site. All mutant alpha-spectrin recombinant peptides were well folded, stable structures, with only the R34W mutant exhibiting a slight structural destabilization. Read More

J Biochem Biophys Methods 2007 Jun 1;70(4):641-8. Epub 2007 Mar 1.

Department of Physics, Biophysics, Roentgenology and Radiology, Medical Faculty, Thracian University, Stara Zagora 6000, Bulgaria.

Hereditary hemolytic anemias originate mainly from defects in hemoglobin and plasma membrane proteins. Here, we propose a new method, thermal analysis of impedance, sensitive to membrane defects. It detects three processes in erythrocyte membrane; fall in membrane capacity at 49. Read More

J Pediatr Hematol Oncol 2007 Feb;29(2):128-9

Department of Pathology, Division of Hematopathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Hereditary pyropoikilocytosis is an inherited red cell membrane disorder with characteristic morphology: striking anisopoikilocytosis with red cell fragmentation and microspherocytes. Clinical and laboratory physicians must be aware of the potential impact of this disorder on accuracy of complete blood count results reported by automated hematology instruments. Recognition of the morphologic and laboratory findings are important for recognizing this potentially severe anemia. Read More

Blood 2007 Apr 27;109(8):3538-43. Epub 2006 Dec 27.

Molecular and Cell Biophysics Laboratory, University of Pennsylvania, 3699 Market Street, Philadelphia, PA 19104, USA.

Pathogenic mutations in alpha and beta spectrin result in a variety of syndromes, including hereditary elliptocytosis (HE), hereditary pyropoikilocytosis (HPP), and hereditary spherocytosis (HS). Although some mutations clearly lie at sites of interaction, such as the sites of spectrin alpha-betatetramer formation, a surprising number of HE-causing mutations have been identified within linker regions between distal spectrin repeats. Here we apply solution structural and single molecule methods to the folding and stability of recombinant proteins consisting of the first 5 spectrin repeats of alpha-spectrin, comparing normal spectrin with a pathogenic linker mutation, Q471P, between repeats R4 and R5. Read More

Int J Clin Pract 2006 Nov;60(11):1513-4

Department of Newborn Care, Royal Hospital for Women, Sydney, NSW, Australia.

We report two neonates, one with Rh anti-C isoimmunisation and the other with hereditary pyropoikilocytosis. Both presented with severe, early onset conjugated hyperbilirubinaemia. Read More

Hematology Am Soc Hematol Educ Program 2005 :13-8

Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, P. O. Box 208064, New Haven, CT 06520-8064, USA.

Disorders of the erythrocyte membrane, including hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis, and hereditary stomatocytosis, comprise an important group of inherited hemolytic anemias. These syndromes are characterized by marked clinical and laboratory heterogeneity. Recent molecular studies have revealed that there is also significant genetic heterogeneity in these disorders. Read More

Blood 2005 Dec 8;106(13):4367-9. Epub 2005 Sep 8.

Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.

Hereditary pyropoikilocytosis (HPP) is a severe hemolytic anemia due to abnormalities of the red blood cell (RBC) membrane skeleton. In the original HPP kindred, there is compound heterozygosity for an allele encoding a structural variant of alpha-spectrin (L207P) and an alpha-spectrin allele associated with a defect in alpha-spectrin production. To identify the molecular defect in the production-defective allele, reticulocyte alpha-spectrin cDNA from one of the original HPP patients was analyzed. Read More

J Biol Chem 2004 Dec 27;279(53):55024-33. Epub 2004 Sep 27.

Department of Pediatrics and Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8021, USA.

Alpha-spectrin is a membrane protein critical for the flexibility and stability of the erythrocyte. We are attempting to identify and characterize the molecular mechanisms controlling the erythroid-specific expression of the alpha-spectrin gene. Previously, we demonstrated that the core promoter of the human alpha-spectrin gene directed low levels of erythroid-specific expression only in the early stages of erythroid differentiation. Read More

Curr Hematol Rep 2004 Mar;3(2):85-91

Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.

Disorders of the red blood cell membrane, such as hereditary spherocytosis, hereditary elliptocytosis, and hereditary pyropoikilocytosis, are characterized by heterogeneity in their clinical and laboratory manifestations. Advances in molecular biology have allowed determination of the precise genetic defect in many cases of membrane-associated anemia and have revealed significant genetic heterogeneity. Six genetic loci have been identified and many defects, including gene deletions and insertions, missense and nonsense mutations, and splicing mutations, have been found. Read More

Rev Clin Exp Hematol 2003 Mar;7(1):22-56

Institute for Pediatrics, University of Foggia, Viale Pinto, 71100 Foggia, Italy.

We present an overview of the currently known molecular basis of red cell membrane disorders. A detailed discussion of the structure of the red cell membrane and the pathophysiology and clinical aspects of its disorders is reported. Generally speaking, hereditary spherocytosis (HS) results from a loss of erythrocyte surface area. Read More

Br J Haematol 2004 Jan;124(2):251-2

Leukemia 2001 Mar;15(3):440-4

Dipartimento di Pediatria, II Università di Napoli, Italy.

The erythrocyte skeleton plays an essential role in determining the shape and deformability of the red cell. Disruption of the interaction between components of the red cell membrane skeleton may cause loss of structural and functional integrity of the membrane. Several observations based on studies in vitro strongly suggest that phosphorylation may modify interactions between proteins, leading to a reduced affinity. Read More

Br J Haematol 1999 Jan;104(1):2-13

Division of Hematology/Oncology, Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.

The recent discovery of the specific molecular defects in many patients with hereditary spherocytosis and hereditary elliptocytosis/pyropoikilocytosis partially clarifies the molecular pathology of these diseases. HE and HPP are caused by defects in the horizontal interactions that hold the membrane skeleton together, particularly the critical spectrin self-association reaction. Single gene defects cause red cells to elongate as they circulate, by a unknown mechanism, and are clinically harmless. Read More

Am J Hematol 1997 Oct;56(2):107-11

Department of Pediatrics, Internal Medicine and Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

Defects of alpha spectrin have been identified in many cases of hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP). To aid in the genetic analysis of families with these disorders, the locations of three alpha-spectrin gene polymorphisms were mapped, the genetic basis of these polymorphisms identified, and PCR-based assays designed for their identification. The frequencies of these polymorphisms were determined in two populations and in patients with alphaI/50a HE and HPP. Read More

Curr Opin Hematol 1997 Mar;4(2):128-35

Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.

Disorders of the erythrocyte membrane, such as hereditary spherocytosis, hereditary elliptocytosis, and hereditary pyropoikilocytosis, are characterized by heterogeneity in their clinical and laboratory manifestations. Recent work has shown that these disorders also exhibit marked genetic heterogeneity. Multiple genetic loci have been implicated, and various genetic defects, including gene deletions, point mutations, and defects in mRNA processing, have been described. Read More

J Clin Pathol 1996 Sep;49(9):772-3

Department of Haematology, St Mary's Hospital Medical School, London.

The blood films both of patients with hereditary pyropoikilocytosis and of those with severe thermal burns are characterised by budding erythrocytes and the presence of microspherocytes. Recently, a fourth example of similar morphological features, caused by overheating of a blood specimen in a motor vehicle during transport to the laboratory, has been observed. It is important to be aware of this artefact as failure to recognise it is likely to lead to diagnostic confusion and unnecessary further testing, causing inconvenience to the patient. Read More

Am J Hum Genet 1996 Aug;59(2):351-9

Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520-8061, USA.

Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are inherited disorders of erythrocyte shape that are frequently associated with abnormalities in alpha-spectrin, one of the principal structural proteins of the erythrocyte membrane skeleton. Five polymorphisms of the alpha-spectrin gene, located in a 6-kb interval of genomic DNA, were identified and analyzed in normal and mutant alpha-spectrin alleles. Three of these polymorphisms are due to single nucleotide substitutions in the alpha-spectrin gene coding region that lead to changes in the amino acid sequence. Read More

Blood Cells Mol Dis 1996 ;22(3):254-8

Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520-8064, USA.

Hum Mutat 1996 ;8(2):97-107

Laboratoire de Génétique Moléculaire Humaine CNRS URA 1171, Institut Pasteur de Lyon, France.

Hereditary elliptocytosis (HE), its aggravated form hereditary pyropoikilocytosis (HPP), and hereditary spherocytosis (HS) designate a set of congenital hemolytic syndromes. The responsible mutations lie in several genes encoding proteins of the red cell membrane. In particular, they involve the SPTA1 and SPTB genes that encode erythroid spectrin alpha- and beta-chains, respectively. Read More