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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 -
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 -
Hematology. American Society of... Nov 2018Significant advances have been made in diagnosis and clinical management of inherited red cell membrane disorders that result in hemolytic anemia. Membrane structural... (Review)
Review
Significant advances have been made in diagnosis and clinical management of inherited red cell membrane disorders that result in hemolytic anemia. Membrane structural defects lead to hereditary spherocytosis (HS) and hereditary elliptocytosis (HE), whereas altered membrane transport function accounts for hereditary xerocytosis (HX) and hereditary overhydrated stomatocytosis (OHS). The degrees of membrane loss and resultant increases in cell sphericity determine the severity of anemia in HS and HE, and splenectomy leads to amelioration of anemia by increasing the circulatory red cell life span. Alterations in cell volume as a result of disordered membrane cation permeability account for reduced life span red cells in HX and OHS. Importantly, splenectomy is not beneficial in these 2 membrane transport disorders and is not recommended because it is ineffective and may lead to an increased risk of life-threatening thrombosis. Rational approaches are now available for the diagnosis and management of these inherited red cell disorders, and these will be discussed in this review.
Topics: Anemia, Hemolytic, Congenital; Elliptocytosis, Hereditary; Erythrocyte Membrane; Humans; Hydrops Fetalis; Risk Factors; Spherocytosis, Hereditary; Thrombosis
PubMed: 30504335
DOI: 10.1182/asheducation-2018.1.377 -
British Journal of Haematology May 2008Studies during the last three decades have enabled the development of detailed molecular insights into the structural basis of altered function in various inherited red... (Review)
Review
Studies during the last three decades have enabled the development of detailed molecular insights into the structural basis of altered function in various inherited red cell membrane disorders. This review highlights our current understanding of molecular and mechanistic insights into various inherited red cell membrane disorders involving either altered membrane structural organization (hereditary spherocytosis, hereditary elliptocytosis and hereditary ovalocytosis) or altered membrane transport function (hereditary stomatocytosis). The molecular basis for the vast majority of cases of hereditary spherocytosis, elliptocytosis and ovalocytosis have been fully defined while little progress has been made in defining the molecular basis for hereditary stomatocytosis. Mutations in a number of distinct genes account for hereditary spherocytosis and elliptocytosis, while a single genetic defect accounts for all cases of hereditary ovalocytosis. Based on these molecular insights, a comprehensive understanding of the structural basis for altered membrane function has been developed. Loss of vertical linkage between membrane skeleton and lipid bilayer leads to membrane loss in hereditary spherocytosis, while weakening of lateral linkages between skeletal proteins leads to membrane fragmentation and surface area loss in hereditary elliptocytosis. Importantly, the severity of anaemia in both these disorders is directly related to extent of membrane surface area loss. Splenectomy results in amelioration of anaemia.
Topics: Anemia, Hemolytic, Congenital; Elliptocytosis, Hereditary; Erythrocyte Membrane; Erythrocytes, Abnormal; Humans; Spherocytosis, Hereditary
PubMed: 18341630
DOI: 10.1111/j.1365-2141.2008.07091.x -
Blood Apr 2013
Topics: Elliptocytosis, Hereditary; Erythrocytes; Female; Hematologic Tests; Humans; Pregnancy; Pregnancy Complications, Hematologic; Young Adult
PubMed: 23729040
DOI: 10.1182/blood-2012-09-457788 -
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 -
PLoS Biology Jul 2019Cilia are remarkable cellular devices that power cell motility and transduce extracellular signals. To assemble a cilium, a cylindrical array of 9 doublet microtubules...
Cilia are remarkable cellular devices that power cell motility and transduce extracellular signals. To assemble a cilium, a cylindrical array of 9 doublet microtubules push out an extension of the plasma membrane. Membrane tension regulates cilium formation; however, molecular pathways that link mechanical stimuli to ciliogenesis are unclear. Using genome editing, we introduced hereditary elliptocytosis (HE)- and spinocerebellar ataxia (SCA)-associated mutations into the Caenorhabditis elegans membrane skeletal protein spectrin. We show that these mutations impair mechanical support for the plasma membrane and change cell shape. RNA sequencing (RNA-seq) analyses of spectrin-mutant animals uncovered a global down-regulation of ciliary gene expression, prompting us to investigate whether spectrin participates in ciliogenesis. Spectrin mutations affect intraflagellar transport (IFT), disrupt axonemal microtubules, and inhibit cilium formation, and the endogenous spectrin periodically distributes along cilia. Mammalian spectrin also localizes in cilia and regulates ciliogenesis. These results define a previously unrecognized yet conserved role of spectrin-based mechanical support for cilium biogenesis.
Topics: Animals; Animals, Genetically Modified; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Membrane; Cilia; Gene Expression Regulation, Developmental; Microscopy, Confocal; Microscopy, Electron, Transmission; Mutation; Sequence Analysis, RNA; Spectrin
PubMed: 31299042
DOI: 10.1371/journal.pbio.3000369 -
Journal of Biomechanical Engineering Feb 2017We review recent advances in multiscale modeling of the biomechanical characteristics of red blood cells (RBCs) in hematological diseases, and their relevance to the... (Review)
Review
We review recent advances in multiscale modeling of the biomechanical characteristics of red blood cells (RBCs) in hematological diseases, and their relevance to the structure and dynamics of defective RBCs. We highlight examples of successful simulations of blood disorders including malaria and other hereditary disorders, such as sickle-cell anemia, spherocytosis, and elliptocytosis.
Topics: Blood Flow Velocity; Cell Size; Compressive Strength; Computer Simulation; Elastic Modulus; Erythrocytes; Hematologic Diseases; Humans; Models, Cardiovascular; Rheology; Shear Strength; Stress, Mechanical; Tensile Strength
PubMed: 27814430
DOI: 10.1115/1.4035120 -
Orphanet Journal of Rare Diseases Oct 2021Congenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of... (Review)
Review
Congenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of erythropoiesis. These rare and heterogeneous conditions may generate several difficulties from the diagnostic point of view. Membrane defects include hereditary spherocytosis and elliptocytosis, and the group of hereditary stomatocytosis; glucose-6-phosphate dehydrogenase and pyruvate kinase, are the most common enzyme deficiencies. Among ultra-rare forms, it is worth reminding other enzyme defects (glucosephosphate isomerase, phosphofructokinase, adenylate kinase, triosephosphate isomerase, phosphoglycerate kinase, hexokinase, and pyrimidine 5'-nucleotidase), and congenital dyserythropoietic anemias. Family history, clinical findings (anemia, hemolysis, splenomegaly, gallstones, and iron overload), red cells morphology, and biochemical tests are well recognized diagnostic tools. Molecular findings are increasingly used, particularly in recessive and de novo cases, and may be fundamental in unraveling the diagnosis. Notably, several confounders may further challenge the diagnostic workup, including concomitant blood loss, nutrients deficiency, alterations of hemolytic markers due to other causes (alloimmunization, infectious agents, rare metabolic disorders), coexistence of other hemolytic disorders (autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, etc.). Additional factors to be considered are the possible association with bone marrow, renal or hepatic diseases, other causes of iron overload (hereditary hemochromatosis, hemoglobinopathies, metabolic diseases), and the presence of extra-hematological signs/symptoms. In this review we provide some instructive clinical vignettes that highlight the difficulties and confounders encountered in the diagnosis and clinical management of CHAs.
Topics: Anemia, Hemolytic, Congenital; Erythrocytes; Hemoglobinopathies; Humans; Pyruvate Kinase; Spherocytosis, Hereditary
PubMed: 34627331
DOI: 10.1186/s13023-021-02036-4