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Blood Dec 2017
Topics: Blood Platelets; Burns; Child, Preschool; Diagnostic Imaging; Elliptocytosis, Hereditary; Erythrocytes; Humans; Leukocytosis; Male; Spherocytes; Thrombocytosis
PubMed: 29269532
DOI: 10.1182/blood-2017-08-802678 -
American Journal of Hematology Oct 2018
Topics: Blood Transfusion; Combined Modality Therapy; Elliptocytosis, Hereditary; Ferritins; Follow-Up Studies; Hemoglobins; Humans; Infant; Organ Size; Platelet Count; Reoperation; Retrospective Studies; Spleen; Splenectomy; Treatment Outcome
PubMed: 30035308
DOI: 10.1002/ajh.25223 -
British Journal of Haematology Oct 2019Hereditary erythrocyte membrane disorders are caused by mutations in genes encoding various transmembrane or cytoskeletal proteins of red blood cells. The main... (Review)
Review
Hereditary erythrocyte membrane disorders are caused by mutations in genes encoding various transmembrane or cytoskeletal proteins of red blood cells. The main consequences of these genetic alterations are decreased cell deformability and shortened erythrocyte survival. Red blood cell membrane defects encompass a heterogeneous group of haemolytic anaemias caused by either (i) altered membrane structural organisation (hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis and Southeast Asian ovalocytosis) or (ii) altered membrane transport function (overhydrated hereditary stomatocytosis, dehydrated hereditary stomatocytosis or xerocytosis, familial pseudohyperkalaemia and cryohydrocytosis). Herein we provide a comprehensive review of the recent literature on the molecular genetics of erythrocyte membrane defects and their reported clinical consequences. We also describe the effect of low-expression genetic variants on the high inter- and intra-familial phenotype variability of erythrocyte structural defects.
Topics: Alleles; Anemia, Hemolytic, Congenital; Elliptocytosis, Hereditary; Erythrocyte Membrane; Erythrocytes, Abnormal; Humans; Membrane Proteins; Spherocytosis, Hereditary
PubMed: 31364155
DOI: 10.1111/bjh.16126 -
Blood Cells, Molecules & Diseases Oct 2016Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are heterogeneous red blood cell (RBC) membrane disorders that result from mutations in the genes...
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. The clinical diagnosis of HE and HPP relies on identifying characteristic RBC morphology on peripheral blood smear and specific membrane biomechanical properties using osmotic gradient ektacytometry. However, this phenotypic diagnosis may not be readily available in patients requiring frequent transfusions, and does not predict disease course or severity. Using Next-Generation sequencing, we identified the causative genetic mutations in fifteen patients with clinically suspected HE or HPP and correlated the identified mutations with the clinical phenotype and ektacytometry profile. In addition to identifying three novel mutations, gene sequencing confirmed and, when the RBC morphology was not evaluable, identified the diagnosis. Moreover, genotypic differences justified the phenotypic differences within families with HE/HPP.
Topics: Adolescent; Child; Child, Preschool; Cytoskeletal Proteins; DNA Mutational Analysis; Elliptocytosis, Hereditary; Erythrocyte Membrane; Female; Genetic Association Studies; Humans; Infant; Male; Medical History Taking; Membrane Proteins; Mutation; Pedigree; Spectrin
PubMed: 27667160
DOI: 10.1016/j.bcmd.2016.07.003 -
Pediatric Clinics of North America Dec 2013Primary abnormalities of the erythrocyte membrane are characterized by clinical, laboratory, and genetic heterogeneity. Among this group, hereditary spherocytosis... (Review)
Review
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. Growing recognition of the long-term risks of splenectomy has led to re-evaluation of the role of splenectomy. Management guidelines acknowledge these considerations and recommend discussion between health care providers, patient, and family. The hereditary elliptocytosis syndromes are the most common primary disorders of erythrocyte membrane proteins. However, most elliptocytosis patients are asymptomatic and do not require therapy.
Topics: Anemia, Hemolytic, Congenital; Elliptocytosis, Hereditary; Erythrocyte Membrane; Erythrocytes; Humans; Spherocytosis, Hereditary; Splenectomy
PubMed: 24237975
DOI: 10.1016/j.pcl.2013.09.001 -
British Journal of Haematology Jan 1999The recent discovery of the specific molecular defects in many patients with hereditary spherocytosis and hereditary elliptocytosis/pyropoikilocytosis partially... (Review)
Review
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. The combination of two defective genes or one severe alpha spectrin defect and a thalassaemia-like defect in the opposite allele (alphaLELY) results in fragile cells that fragment into bizarre shapes in the circulation, with haemolysis and sometimes life-threatening anaemia. A few of the alpha spectrin defects are common, suggesting they provide an advantage against malaria or some other threat. HS, in contrast, is nearly always caused by family-specific private mutations. These involve the five proteins that link the membrane skeleton to the overlying lipid bilayer: alpha and beta spectrin, ankyrin, band 3 and protein 4.2. Somehow, perhaps through loss of the anchorage band 3 provides its lipid neighbours (Peters et al, 1996), microvesiculation of the membrane surface ensues, leading to spherocytosis, splenic sequestration and haemolysis. Future research will need to focus on how each type of defect causes its associated disease, how the spleen aggravates membrane skeleton defects (a process termed 'conditioning'), how defective red, cells are recognized and removed in the spleen, and why patients with similar or even identical defects can have different clinical severity. Emphasis also needs to be given to improving diagnostic tests, particularly for HS, and exploring new options for therapy, like partial splenectomy, which can ameliorate symptoms while better protecting patients from bacterial sepsis and red cell parasites, and perhaps from atherosclerosis (Robinette & Franmeni, 1977) and venous thrombosis (Stewart et al, 1996).
Topics: Blood Platelet Disorders; Cell Membrane; Humans; Membrane Proteins; Mutation
PubMed: 10027705
DOI: 10.1111/j.1365-2141.1999.01130.x -
American Journal of Hematology Apr 2022
Topics: Elliptocytosis, Hereditary; Humans; Infant, Newborn; Jaundice, Neonatal; Spherocytosis, Hereditary
PubMed: 34553410
DOI: 10.1002/ajh.26358 -
Turkish Journal of Haematology :... Mar 2016
Topics: Consanguinity; Elliptocytosis, Hereditary; Erythrocyte Transfusion; Erythrocytes, Abnormal; Humans; Infant, Newborn; Jaundice, Neonatal; Male; Phototherapy
PubMed: 26377499
DOI: 10.4274/tjh.2015.0054 -
The Journal of Clinical Investigation Jun 1983The structural and functional properties of spectrin from normal and hereditary pyropoikilocytosis (HPP) donors from the two unrelated families were studied. The...
The structural and functional properties of spectrin from normal and hereditary pyropoikilocytosis (HPP) donors from the two unrelated families were studied. The structural domains of the spectrin molecule were generated by mild tryptic digestion and analyzed by two-dimensional electrophoresis (isoelectric focusing; sodium dodecyl sulfate-polyacrylamide gel electrophoresis). The alpha I-T80 peptide (Mr 80,000) is not detectable in two related HPP donors; instead, two new peptides (Mr 50,000 and 21,000) are generated and have been identified as fragments of the normal alpha I-T80. A third sibling has reduced levels of both the normal alpha I-T80 and the two new peptides. A similar analysis of spectrin from another HPP family indicates that their spectrins contain reduced amounts of the alpha I-T80 and the 50,000 and 21,000 fragments of the alpha I domain. The HPP donor also has other structural variations in the alpha I, alpha II, and alpha III domains. The alpha I-T80 domain of normal spectrin has been shown to be an important site for spectrin oligomerization (J. Morrow and V.T. Marchesi. 1981. J. Cell Biol. 88: 463-468), and in vitro assays indicate that HPP spectrin has an impaired ability to oligomerize. Ghost membranes from HPP donors are also more fragile than membranes from normal erythrocytes when measured by ektacytometry. In both the oligomerization and fragility assays, the degree of impairment is correlated with the amount of normal alpha I-T80 present in the spectrin molecule. We believe that a structural alteration in the alpha I-T80 domain perturbs normal in vivo oligomerization of spectrin, producing a marked decrease in erythrocyte stability.
Topics: Adult; Anemia, Hemolytic, Congenital; Erythrocytes; Female; Hot Temperature; Humans; Macromolecular Substances; Male; Membrane Proteins; Peptide Fragments; Protein Denaturation; Spectrin; Trypsin
PubMed: 6863544
DOI: 10.1172/jci110942