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Molecular Genetics & Genomic Medicine Dec 2021Thalassemia is an inherited hematological disorder categorized by a decrease or absence of one or more of the globin chains synthesis. Beta-thalassemia is caused by one... (Review)
Review
BACKGROUND
Thalassemia is an inherited hematological disorder categorized by a decrease or absence of one or more of the globin chains synthesis. Beta-thalassemia is caused by one or more mutations in the beta-globin gene. The absence or reduced amount of beta-globin chains causes ineffective erythropoiesis which leads to anemia.
METHODS
Beta-thalassemia has been further divided into three main forms: thalassemia major, intermedia, and minor/silent carrier. A more severe form among these is thalassemia major in which individuals depend upon blood transfusion for survival. The high level of iron deposition occurs due to regular blood transfusion therapy.
RESULTS
Overloaded iron raises the synthesis of reactive oxygen species (ROS) that are noxious and prompting the injury to the hepatic, endocrine, and vascular system. Thalassemia can be analyzed and diagnosed via prenatal testing (genetic testing of amniotic fluid), blood smear, complete blood count, and DNA analysis (genetic testing). Treatment of thalassemia intermediate is symptomatic; however; it can also be accomplished by folic supplementation and splenectomy.
CONCLUSION
Thalassemia major can be cured through regular transfusion of blood, transplantation of bone marrow, iron chelation management, hematopoietic stem cell transplantation, stimulation of fetal hemoglobin production, and gene therapy.
Topics: Alleles; Animals; Clinical Decision-Making; Combined Modality Therapy; Disease Management; Disease Susceptibility; Genetic Testing; Genotype; Humans; Incidence; Mutation; Phenotype; Prevalence; Prognosis; Severity of Illness Index; Treatment Outcome; beta-Globins; beta-Thalassemia
PubMed: 34738740
DOI: 10.1002/mgg3.1788 -
Genetics in Medicine : Official Journal... Jun 2017β-Thalassemia is caused by reduced (β) or absent (β) synthesis of the β-globin chains of hemoglobin. Three clinical and hematological conditions of increasing... (Review)
Review
β-Thalassemia is caused by reduced (β) or absent (β) synthesis of the β-globin chains of hemoglobin. Three clinical and hematological conditions of increasing severity are recognized: the β-thalassemia carrier state, thalassemia intermedia, and thalassemia major, a severe transfusion-dependent anemia. The severity of disease expression is related mainly to the degree of α-globin chain excess, which precipitates in the red blood cell precursors, causing both mechanic and oxidative damage (ineffective erythropoiesis). Any mechanism that reduces the number of unbound α-globin chains in the red cells may ameliorate the detrimental effects of excess α-globin chains. Factors include the inheritance of mild/silent β-thalassemia mutations, the coinheritance of α-thalassemia alleles, and increased γ-globin chain production. The clinical severity of β-thalassemia syndromes is also influenced by genetic factors unlinked to globin genes as well as environmental conditions and management. Transfusions and oral iron chelation therapy have dramatically improved the quality of life for patients with thalassemia major. Previously a rapidly fatal disease in early childhood, β-thalassemia is now a chronic disease with a greater life expectancy. At present, the only definitive cure is bone marrow transplantation. Therapies undergoing investigation are modulators of erythropoiesis and stem cell gene therapy.Genet Med advance online publication 03 November 2016.
Topics: Animals; Diagnosis, Differential; Female; Humans; Mass Screening; Pregnancy; beta-Thalassemia
PubMed: 27811859
DOI: 10.1038/gim.2016.173 -
European Journal of Haematology Dec 2020β-thalassemia major is an inherited hemoglobinopathy that requires lifelong red blood cell transfusions and iron chelation therapy to prevent complications due to iron... (Review)
Review
β-thalassemia major is an inherited hemoglobinopathy that requires lifelong red blood cell transfusions and iron chelation therapy to prevent complications due to iron overload. Traditionally, β-thalassemia has been more common in certain regions of the world such as the Mediterranean, Middle East, and Southeast Asia. However, the prevalence of β-thalassemia is increasing in other regions, including Northern Europe and North America, primarily due to migration. This review summarizes the available data on the changing incidence and prevalence of β-thalassemia as well as factors influencing disease frequency. The data suggest that the epidemiology of β-thalassemia is changing: Migration has increased the prevalence of the disease in regions traditionally believed to have a low prevalence, while, at the same time, prevention and screening programs in endemic regions have reduced the number of affected individuals. Various approaches to prevention and screening have been used. Region-specific prevention and treatment programs, customized to align with local healthcare resources and cultural values, have been effective in identifying patients and carriers and providing information and care. Significant challenges remain in universally implementing these programs.
Topics: Disease Management; Disease Susceptibility; Emigration and Immigration; Geography, Medical; Global Health; Humans; Incidence; Population Surveillance; Prevalence; Public Health Surveillance; Risk Factors; beta-Thalassemia
PubMed: 32886826
DOI: 10.1111/ejh.13512 -
Cells Jun 2022Autologous hematopoietic stem cell (HSC)-targeted gene therapy provides a one-time cure for various genetic diseases including sickle cell disease (SCD) and... (Review)
Review
Autologous hematopoietic stem cell (HSC)-targeted gene therapy provides a one-time cure for various genetic diseases including sickle cell disease (SCD) and β-thalassemia. SCD is caused by a point mutation (20A > T) in the β-globin gene. Since SCD is the most common single-gene disorder, curing SCD is a primary goal in HSC gene therapy. β-thalassemia results from either the absence or the reduction of β-globin expression, and it can be cured using similar strategies. In HSC gene-addition therapy, patient CD34+ HSCs are genetically modified by adding a therapeutic β-globin gene with lentiviral transduction, followed by autologous transplantation. Alternatively, novel gene-editing therapies allow for the correction of the mutated β-globin gene, instead of addition. Furthermore, these diseases can be cured by γ-globin induction based on gene addition/editing in HSCs. In this review, we discuss HSC-targeted gene therapy in SCD with gene addition as well as gene editing.
Topics: Anemia, Sickle Cell; Gene Editing; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; beta-Globins; beta-Thalassemia
PubMed: 35681538
DOI: 10.3390/cells11111843 -
American Family Physician Mar 2022Thalassemia is a group of autosomal recessive hemoglobinopathies affecting the production of normal alpha- or beta-globin chains that comprise hemoglobin. Ineffective...
Thalassemia is a group of autosomal recessive hemoglobinopathies affecting the production of normal alpha- or beta-globin chains that comprise hemoglobin. Ineffective production of alpha- or beta-globin chains may result in ineffective erythropoiesis, premature red blood cell destruction, and anemia. Chronic, severe anemia in patients with thalassemia may result in bone marrow expansion and extramedullary hematopoiesis. Thalassemia should be suspected in patients with microcytic anemia and normal or elevated ferritin levels. Hemoglobin electrophoresis may reveal common characteristics of different thalassemia subtypes, but genetic testing is required to confirm the diagnosis. Thalassemia is generally asymptomatic in trait and carrier states. Alpha-thalassemia major results in hydrops fetalis and is often fatal at birth. Beta-thalassemia major requires lifelong transfusions starting in early childhood (often before two years of age). Alpha- and beta-thalassemia intermedia have variable presentations based on gene mutation or deletion, with mild forms requiring only monitoring but more severe forms leading to symptomatic anemia and requiring transfusion. Treatment of thalassemia includes transfusions, iron chelation therapy to correct iron overload (from hemolytic anemia, intestinal iron absorption, and repeated transfusions), hydroxyurea, hematopoietic stem cell transplantation, and luspatercept. Thalassemia complications arise from bone marrow expansion, extramedullary hematopoiesis, and iron deposition in peripheral tissues. These complications include morbidities affecting the skeletal system, endocrine organs, heart, and liver. Life expectancy of those with thalassemia has improved dramatically over the past 50 years with increased availability of blood transfusions and iron chelation therapy, and improved iron overload monitoring. Genetic counseling and screening in high-risk populations can assist in reducing the prevalence of thalassemia.
Topics: Child, Preschool; Hematologic Diseases; Humans; Infant, Newborn; Iron; Iron Overload; Thalassemia; beta-Globins; beta-Thalassemia
PubMed: 35289581
DOI: No ID Found -
Drugs Jul 2020Hemoglobinopathies are among the most common monogenic diseases worldwide. Approximately 1-5% of the global population are carriers for a genetic thalassemia mutation.... (Review)
Review
Hemoglobinopathies are among the most common monogenic diseases worldwide. Approximately 1-5% of the global population are carriers for a genetic thalassemia mutation. The thalassemias are characterized by autosomal recessive inherited defects in the production of hemoglobin. They are highly prevalent in the Mediterranean, Middle East, Indian subcontinent, and East and Southeast Asia. Due to recent migrations, however, the thalassemias are now becoming more common in Europe and North America, making this disease a global health concern. Currently available conventional therapies in thalassemia have many challenges and limitations. A better understanding of the pathophysiology of β-thalassemia in addition to key developments in optimizing transfusion programs and iron-chelation therapy has led to an increase in the life span of thalassemia patients and paved the way for new therapeutic strategies. These can be classified into three categories based on their efforts to address different features of the underlying pathophysiology of β-thalassemia: correction of the globin chain imbalance, addressing ineffective erythropoiesis, and improving iron overload. In this review, we provide an overview of the novel therapeutic approaches that are currently in development for β-thalassemia.
Topics: Blood Transfusion; Genetic Therapy; Humans; Iron Chelating Agents; Iron Overload; Molecular Targeted Therapy; beta-Thalassemia
PubMed: 32557398
DOI: 10.1007/s40265-020-01341-9 -
Blood Reviews Sep 2019Patients with β-thalassemia major (BTM) require regular blood transfusions, supported by appropriate iron chelation therapy (ICT), throughout their life. β-thalassemia... (Review)
Review
Patients with β-thalassemia major (BTM) require regular blood transfusions, supported by appropriate iron chelation therapy (ICT), throughout their life. β-thalassemia is a global disease that is most highly prevalent in Southeast Asia, Africa, and Mediterranean countries. However, the global distribution of patients with β-thalassemia is changing due to population migration, and Northern European countries now have significant thalassemia populations. Globally, many patients with BTM have limited access to regular and safe blood transfusions. A lack of voluntary nonremunerated blood donors, poor awareness of thalassemia, a lack of national blood policies, and fragmented blood services contribute to a significant gap between the timely supply of, and demand for, safe blood. In many centers, there is inadequate provision of antigen testing, even for common red cell antigens such as CcEe and Kell. Policies to raise awareness and increase the use of red blood cell antigen testing and requesting of compatible blood in transfusion centers are needed to reduce alloimmunization (the development of antibodies to red blood cell antigens), which limits the effectiveness of transfusions and the potential availability of blood. Patients with BTM are also at risk of transfusion-transmitted infections unless appropriate blood screening and safety practices are in place. Hence, many patients are not transfused or are undertransfused, resulting in decreased health and quality-of-life outcomes. Hemovigilance, leukoreduction, and the ability to thoroughly investigate transfusion reactions are often lacking, especially in resource-poor countries. ICT is essential to prevent cardiac failure and other complications due to iron accumulation. Despite the availability of potentially inexpensive oral ICT, a high proportion of patients suffer complications of iron overload and die each year due to a lack of, or inadequate, ICT. Increased awareness, training, and resources are required to improve and standardize adequate blood transfusion services and ICT among the worldwide population of patients with BTM. ICT needs to be available, affordable, and correctly prescribed. Effective, safe, and affordable new treatments that reduce the blood transfusion burden in patients with β-thalassemia remain an unmet need.
Topics: Blood Transfusion; Humans; beta-Thalassemia
PubMed: 31324412
DOI: 10.1016/j.blre.2019.100588 -
American Journal of Hematology Nov 2021The treatment landscape for patients with β-thalassemia is witnessing a swift evolution, yet several unmet needs continue to persist. Patients with... (Review)
Review
The treatment landscape for patients with β-thalassemia is witnessing a swift evolution, yet several unmet needs continue to persist. Patients with transfusion-dependent β-thalassemia (TDT) primarily rely on regular transfusion and iron chelation therapy, which can be associated with considerable treatment burden and cost. Patients with non-transfusion-dependent β-thalassemia (NTDT) are also at risk of significant morbidity due to the underlying anemia and iron overload, but treatment options in this patient subgroup are limited. In this review, we provide updates on clinical trials of novel therapies targeting the underlying pathology in β-thalassemia, including the α/non-α-globin chain imbalance, ineffective erythropoiesis, and iron dysregulation.
Topics: Blood Transfusion; Clinical Trials as Topic; Drug Discovery; Erythropoiesis; Humans; Iron; Iron Chelating Agents; alpha-Globins; beta-Thalassemia
PubMed: 34347889
DOI: 10.1002/ajh.26316 -
Blood Apr 2022The erythroid marrow and circulating red blood cells (RBCs) are the key components of the human erythron. Abnormalities of the erythron that are responsible for anemia...
The erythroid marrow and circulating red blood cells (RBCs) are the key components of the human erythron. Abnormalities of the erythron that are responsible for anemia can be separated into 3 major categories: erythroid hypoproliferation, ineffective erythropoiesis, and peripheral hemolysis. Ineffective erythropoiesis is characterized by erythropoietin-driven expansion of early-stage erythroid precursors, associated with apoptosis of late-stage precursors. This mechanism is primarily responsible for anemia in inherited disorders like β-thalassemia, inherited sideroblastic anemias, and congenital dyserythropoietic anemias, as well as in acquired conditions like some subtypes of myelodysplastic syndrome (MDS). The inherited anemias that are due to ineffective erythropoiesis are also defined as iron-loading anemias because of the associated parenchymal iron loading caused by the release of erythroid factors that suppress hepcidin production. Novel treatments specifically targeting ineffective erythropoiesis are being developed. Iron restriction through enhancement of hepcidin activity or inhibition of ferroportin function has been shown to reduce ineffective erythropoiesis in murine models of β-thalassemia. Luspatercept is a transforming growth factor-β ligand trap that inhibits SMAD2/3 signaling. Based on preclinical and clinical studies, this compound is now approved for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions. Luspatercept is also approved for the treatment of transfusion-dependent anemia in patients with MDS with ring sideroblasts, most of whom carry a somatic SF3B1 mutation. While the long-term effectiveness and safety of luspatercept need to be evaluated in β-thalassemia and MDS, defining the molecular mechanisms of ineffective erythropoiesis in different disorders might allow the discovery of new effective compounds.
Topics: Adult; Humans; Mice; Animals; Hepcidins; Erythropoiesis; beta-Thalassemia; Iron; Anemia, Sideroblastic; Myelodysplastic Syndromes
PubMed: 34932791
DOI: 10.1182/blood.2021011045 -
Medicine Nov 2021β-thalassemia is a hereditary hematological disease caused by over 350 mutations in the β-globin gene (HBB). Identifying the genetic variants affecting fetal... (Review)
Review
β-thalassemia is a hereditary hematological disease caused by over 350 mutations in the β-globin gene (HBB). Identifying the genetic variants affecting fetal hemoglobin (HbF) production combined with the α-globin genotype provides some prediction of disease severity for β-thalassemia. However, the generation of an additive composite genetic risk score predicts prognosis, and guide management requires a larger panel of genetic modifiers yet to be discovered.Presently, using data from prior clinical trials guides the design of further research and academic studies based on gene augmentation, while fundamental insights into globin switching and new technology developments have inspired the investigation of novel gene therapy approaches.Genetic studies have successfully characterized the causal variants and pathways involved in HbF regulation, providing novel therapeutic targets for HbF reactivation. In addition to these HBB mutation-independent strategies involving HbF synthesis de-repression, the expanding genome editing toolkit provides increased accuracy to HBB mutation-specific strategies encompassing adult hemoglobin restoration for personalized treatment of hemoglobinopathies. Allogeneic hematopoietic stem cell transplantation was, until very recently, the curative option available for patients with transfusion-dependent β-thalassemia. Gene therapy currently represents a novel therapeutic promise after many years of extensive preclinical research to optimize gene transfer protocols.We summarize the current state of developments in the molecular genetics of β-thalassemia over the last decade, including the mechanisms associated with ineffective erythropoiesis, which have also provided valid therapeutic targets, some of which have been shown as a proof-of-concept.
Topics: Fetal Hemoglobin; Gene Editing; Hemoglobinopathies; Humans; Molecular Biology; beta-Thalassemia
PubMed: 34766559
DOI: 10.1097/MD.0000000000027522