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Hematological problems in the neonate
Published in Prem Puri, Newborn Surgery, 2017
Andrea M. Malone, Owen P. Smith
Hereditary elliptocytosis is also a disease of autosomal dominant inheritance caused by defects in various structural proteins, resulting in elliptical shaped red cells. The elliptocytes are unstable and nondeformable, and thus hemolyzed by the reticuloendothelial system. It is straightforward to diagnose by the presence of elliptocytes on the peripheral blood smear.43
Inherited Disorders of Red Cell Membrane Proteins
Published in Ronald L. Nagel, Genetically Abnormal Red Cells, 2019
“Hereditary elliptocytosis” is a diagnosis applied to a heterogeneous group of clinical conditions which share a common red cell morphology — elliptocytes. In its most common form, hereditary elliptocytosis is an autosomal-dominant disorder characterized by mild or no anemia, minimum or no reticulocytosis, normal mean corpuscular volume, normal osmotic fragility, and peripheral smear striking in the predominance of regular-contoured, biconcave elliptocytes.57,58 Occasionally, family studies reveal that “carriers” may even have normal red cell morphology.59 Some newborns who ultimately develop classical hereditary elliptocytosis as older children have a transient hemolytic anemia associated with bizarre morphology consisting of fragmented and poikilocytic red cells, putting them into the general category of “infantile pyknocytosis”.60-62 Older individuals with hereditary elliptocytosis may also have transient episodes of intense hemolysis, especially with intercurrent infections.63 In some kindreds with classical hereditary elliptocytosis, an occasional family member will have a more severe disease with impressive chronic hemolysis. Although there is usually no obvious explanation for this clinical disparity,64 some of the individuals are clearly double heterozygotes.65 In some families, the red cell morphology has a mixture of elliptocytes and spherocytes, and the osmotic fragility is increased.66 In Melanesians, there is a variety of hereditary elliptocytosis where the elliptocytes have a stomatocytic appearance.67 These various clinical manifestations of hereditary elliptocytosis are not each associated with a specific molecular defect, as will be discussed in the following section.
Screening tools for hereditary hemolytic anemia: new concepts and strategies
Published in Expert Review of Hematology, 2021
Elisa Fermo, Cristina Vercellati, Paola Bianchi
RBC membrane defects are characterized by qualitative or quantitative abnormalities of the erythrocyte cytoskeletal proteins, which constitute a complex structure that determines the erythrocyte shape and deformability, and regulates the hydration state and cell volume. These alterations result in typical abnormalities in RBC morphology that can be observed at peripheral blood smear examination. The most common defects involve alterations in the membrane structural organization; in hereditary spherocytosis (HS), defects of ankyrin, spectrin, protein band 3, and band 4.2 impair the vertical linkage between the cytoskeleton and the membrane lipidic bilayer, leading to the release of microvesicles and loss of surface; conversely, impairment of the horizontal associations of the RBC cytoskeleton due to alterations in spectrin dimers or spectrin-actin-protein 4.1 complexes, results in hereditary elliptocytosis (HE) or hereditary pyropoikilocytosis (HPP). Given the constitutional expression and the double function (structural and membrane channel) of band 3, abnormalities in this protein may be associated to the severe form of distal renal tubular acidosis (dRTA), with or without HS [1,2].
A novel EPB41 p.Trp704* mutation in a Korean patient with hereditary elliptocytosis: a case report
Published in Hematology, 2020
Soyoung Shin, Kyung-Ah Hwang, Kyuhyun Paik, Joonhong Park
Hereditary elliptocytosis (HE) is a hematologic disorder characterized by elliptically-shaped erythrocytes and a variable degree of hemolytic anemia. The clinical phenotype is usually mild with peripheral blood elliptocytes, but it can be moderately severe. In severe forms that achieve hereditary poikilocytosis, large red cell fragments are torn off, leaving erythrocytes with marked poikilocytosis. Usually inherited as an autosomal dominant trait, elliptocytosis results from mutation in any one of several genes encoding proteins of the red cell membrane skeleton [1]. HE-1 is caused by heterozygous or homozygous mutation in the gene encoding erythrocyte membrane protein 4.1 (EPB41) on chromosome 1p35 [2]. HE-2 is caused by mutation in the SPTA1 gene [3]. HE-3 is caused by mutation in the SPTB gene [4]. HE-4, also known as Southeast Asian ovalocytosis, is caused by mutation in the SLC4A1 gene [5]. Particularly, the complex EPB41 gene encodes a diverse family of protein 4.1R isoforms which are key components of the erythroid membrane skeleton that regulates red cell morphology and mechanical stability [6].
Hereditary red blood cell membrane defects. Detection of PIEZO1 mutations associated with SPTA1 mutations. An unusual clinical case of hereditary xerocytosis
Published in Pediatric Hematology and Oncology, 2020
Carmelo Fortugno, Eulalia Galea, Renato Cantaffa, Francesco Gigliotti, Rachele Lucia Fabiano, Valentina Talarico, Giuseppe Raiola, Maria Concetta Galati
Hereditary spherocytosis is the most common red blood cell (RBC) membrane disorder causing hereditary hemolytic anemia characterized by sphere-shaped erythrocytes (spherocytes) with increased osmotic fragility. Hereditary spherocytosis can affect all ethnic groups but is more common in people of northern European ancestry where the prevalence is 1 in 1000–2500. Spherocytes are formed because of loss of membrane due to quantitative defects in proteins that link the cytoskeleton to the lipid bilayer (“vertical” linkages). The scaffolding network of the RBC cytoskeleton is assembled by α- and β-spectrin heterodimers self-associating in a head-to-head fashion to form tetramers, bound to the lipid membrane via the anchoring complex of ankyrin, protein 4.2, and band 3. In autosomal dominant Hereditary spherocytosis, which accounts for approximately 75% of cases, mutations of ankyrin (ANK1), band 3 (SLC4A1), and β-spectrin (SPTB) genes predominate. Recessive Hereditary spherocytosis is most often due to compound heterozygosity for defects in the genes encoding ankyrin, α-spectrin (SPTA1), or protein 4.2 (EPB42). Two SPTA1 low expression alleles were identified early-on to be associated with RBC membrane disorders and their study helped to determine the quantitative requirements of the RBC cytoskeleton for α-spectrin. αLELY(Low Expression LYon) has a minor allele frequency (MAF) of 25.5% and consists of the mutation c.6531-12C > T in intron 45, causing partial skipping of exon 46 in half of the transcripts and consequently a 50% decrease in the amount of α-spectrin. αLELYin trans to an SPTA1 allele with a hereditary elliptocytosis (HE)-associated mutation modifies the phenotype from HE to hereditary pyropoikilocytosis. In contrast, αLELYin trans to a null SPTA1 allele causes no disease, indicating that production of ∼25% of normal α-spectrin is enough for normal RBC cytoskeleton assembly.7–9 The severity of Hereditary spherocytosis is directly related to the extent of the surface loss and consequently to the degree of spherocytosis: among the RBC indices, the percentage of microcytes is the best indicator of the disease severity.