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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 -
Orphanet Journal of Rare Diseases May 2010Beta-thalassemias are a group of hereditary blood disorders characterized by anomalies in the synthesis of the beta chains of hemoglobin resulting in variable phenotypes... (Review)
Review
Beta-thalassemias are a group of hereditary blood disorders characterized by anomalies in the synthesis of the beta chains of hemoglobin resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. The total annual incidence of symptomatic individuals is estimated at 1 in 100,000 throughout the world and 1 in 10,000 people in the European Union. Three main forms have been described: thalassemia major, thalassemia intermedia and thalassemia minor. Individuals with thalassemia major usually present within the first two years of life with severe anemia, requiring regular red blood cell (RBC) transfusions. Findings in untreated or poorly transfused individuals with thalassemia major, as seen in some developing countries, are growth retardation, pallor, jaundice, poor musculature, hepatosplenomegaly, leg ulcers, development of masses from extramedullary hematopoiesis, and skeletal changes that result from expansion of the bone marrow. Regular transfusion therapy leads to iron overload-related complications including endocrine complication (growth retardation, failure of sexual maturation, diabetes mellitus, and insufficiency of the parathyroid, thyroid, pituitary, and less commonly, adrenal glands), dilated myocardiopathy, liver fibrosis and cirrhosis). Patients with thalassemia intermedia present later in life with moderate anemia and do not require regular transfusions. Main clinical features in these patients are hypertrophy of erythroid marrow with medullary and extramedullary hematopoiesis and its complications (osteoporosis, masses of erythropoietic tissue that primarily affect the spleen, liver, lymph nodes, chest and spine, and bone deformities and typical facial changes), gallstones, painful leg ulcers and increased predisposition to thrombosis. Thalassemia minor is clinically asymptomatic but some subjects may have moderate anemia. Beta-thalassemias are caused by point mutations or, more rarely, deletions in the beta globin gene on chromosome 11, leading to reduced (beta+) or absent (beta0) synthesis of the beta chains of hemoglobin (Hb). Transmission is autosomal recessive; however, dominant mutations have also been reported. Diagnosis of thalassemia is based on hematologic and molecular genetic testing. Differential diagnosis is usually straightforward but may include genetic sideroblastic anemias, congenital dyserythropoietic anemias, and other conditions with high levels of HbF (such as juvenile myelomonocytic leukemia and aplastic anemia). Genetic counseling is recommended and prenatal diagnosis may be offered. Treatment of thalassemia major includes regular RBC transfusions, iron chelation and management of secondary complications of iron overload. In some circumstances, spleen removal may be required. Bone marrow transplantation remains the only definitive cure currently available. Individuals with thalassemia intermedia may require splenectomy, folic acid supplementation, treatment of extramedullary erythropoietic masses and leg ulcers, prevention and therapy of thromboembolic events. Prognosis for individuals with beta-thalassemia has improved substantially in the last 20 years following recent medical advances in transfusion, iron chelation and bone marrow transplantation therapy. However, cardiac disease remains the main cause of death in patients with iron overload.
Topics: Genetic Counseling; Humans; Prenatal Diagnosis; beta-Thalassemia
PubMed: 20492708
DOI: 10.1186/1750-1172-5-11 -
British Journal of Clinical Pharmacology Aug 2022Beta-thalassaemia, including sickle cell anaemia and thalassaemia E, is most common in developing countries in tropical and subtropic regions. Because carriers have... (Review)
Review
Beta-thalassaemia, including sickle cell anaemia and thalassaemia E, is most common in developing countries in tropical and subtropic regions. Because carriers have migrated there owing to demographic migration, β-thalassaemia can now be detected in areas other than malaria-endemic areas. Every year, an estimated 300 000-500 000 infants, the vast majority of whom are from developing countries, are born with a severe haemoglobin anomaly. Currently, some basic techniques, which include iron chelation therapy, hydroxyurea, blood transfusion, splenectomy and haematopoietic stem cell transplantation, are being used to manage thalassaemia patients. Despite being the backbone of treatment, traditional techniques have several drawbacks and limitations. Ineffective erythropoiesis, correction of globin chain imbalance and adjustment of iron metabolism are some of the innovative treatment methods that have been developed in the care of thalassaemia patients in recent years. Moreover, regulating the expression of B-cell lymphoma/leukaemia 11A and sex-determining region Y-box through the enhanced expression of micro RNAs can also be considered putative targets for managing haemoglobinopathies. This review focuses on the biological basis of β-globin gene production, the pathophysiology of β-thalassaemia and the treatment options that have recently been introduced.
Topics: Blood Transfusion; Humans; Infant; Iron; Iron Chelating Agents; Thalassemia; beta-Thalassemia
PubMed: 35373382
DOI: 10.1111/bcp.15343 -
Hematology (Amsterdam, Netherlands) Apr 2012Thalassemia is the most common form of inherited anemia worldwide. The World Health Organization reports suggest that about 60,000 infants are born with a major...
Thalassemia is the most common form of inherited anemia worldwide. The World Health Organization reports suggest that about 60,000 infants are born with a major thalassemia every year. Although individuals originating from the tropical belt are most at risk, it is a growing global health problem due to extensive population migrations. Despite important advances on curative approaches such as stem cell transplantation and promising results of gene therapy, blood transfusions and iron chelation still remain as cornerstones of disease management. The purpose of this article is to focus on mainly the clinical aspects and management of beta-thalassemia major.
Topics: Blood Transfusion; Genetic Therapy; Humans; Infant; Iron Chelating Agents; Iron Overload; Stem Cell Transplantation; beta-Thalassemia
PubMed: 22507773
DOI: 10.1179/102453312X13336169155295 -
British Journal of Clinical Pharmacology Jun 2022Beta-thalassaemia is one of the most significant haemoglobinopathies worldwide resulting in the synthesis of little or no β-globin chains. Without treatment,... (Review)
Review
Beta-thalassaemia is one of the most significant haemoglobinopathies worldwide resulting in the synthesis of little or no β-globin chains. Without treatment, β-thalassaemia major is lethal within the first decade of life due to the complex pathophysiology, which leads to wide clinical manifestations. Current clinical management for these patients depends on repeated transfusions followed by iron-chelating therapy. Several novel approaches to correct the resulting α/β-globin chain imbalance, treat ineffective erythropoiesis and improve iron overload are currently being developed. Up to now, the only curative treatment for β-thalassemia is haematopoietic stem-cell transplantation, but this is a risky and costly procedure. Gene therapy, gene editing and base editing are emerging as a powerful approach to treat this disease. In β-thalassaemia, gene therapy involves the insertion of a vector containing the normal β-globin or γ-globin gene into haematopoietic stem cells to permanently produce normal red blood cells. Gene editing and base editing involves the use of zinc finger nucleases, transcription activator-like nucleases and clustered regularly interspaced short palindromic repeats/Cas9 to either correct the causative mutation or else insert a single nucleotide variant that will increase foetal haemoglobin. In this review, we will examine the current management strategies used to treat β-thalassaemia and focus on the novel therapies targeting ineffective erythropoiesis, improving iron overload and correction of the globin chain imbalance.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Iron Chelating Agents; Iron Overload; beta-Globins; beta-Thalassemia
PubMed: 34004015
DOI: 10.1111/bcp.14918 -
Bailliere's Clinical Haematology Mar 1998A complete spectrum of genetic lesions affecting the beta-globin gene giving rise to a complete spectrum of phenotypic severity is described. Although most of the... (Review)
Review
A complete spectrum of genetic lesions affecting the beta-globin gene giving rise to a complete spectrum of phenotypic severity is described. Although most of the molecular lesions involve the structural beta gene directly, some down regulate the gene through in-cis effects at a distance while trans-acting factors are implicated in a few cases. The remarkable phenotypic diversity can be related ultimately to the degree of alpha-globin-beta-globin chain imbalance and arises from variability of mutations affecting the beta gene itself and from interactions with other genetic loci, such as the alpha- and gamma-globin genes. The presence of other interacting loci is implicated by their interactions in increasing gamma gene expression or by an increased proteolytic capacity of the erythroid precursors. It is hoped that observations from the genotype-phenotype relationship might form the basis for a comprehensive diagnostic database that will be useful not only for genetic counselling and prenatal diagnosis but also for providing prognostic information for decision making in bone marrow transplantation and gene therapy programmes in the future. However, it is clear from recent analyses that, apart from the two categories of triplicated alpha genes with heterozygous beta-thalassaemia and inheritance of mild beta(+)-thalassaemia alleles, it is still not possible to predict consistently phenotype from alpha and beta genotypes alone owing to the influence of the other modulating factors, some implicated (such as inheritance of hereditary persistence of fetal haemoglobin) and others as yet unidentified.
Topics: Amino Acid Sequence; Base Sequence; Gene Deletion; Genotype; Globins; Humans; Molecular Sequence Data; Mutation; Phenotype; beta-Thalassemia
PubMed: 10872474
DOI: 10.1016/s0950-3536(98)80071-1 -
Orphanet Journal of Rare Diseases Sep 2013Thalassemia syndrome has diverse clinical presentations and a global spread that has far exceeded the classical Mediterranean basin where the mutations arose. The... (Review)
Review
Thalassemia syndrome has diverse clinical presentations and a global spread that has far exceeded the classical Mediterranean basin where the mutations arose. The mutations that give rise to either alpha or beta thalassemia are numerous, resulting in a wide spectrum of clinical severity ranging from carrier state to life-threatening, inherited hemolytic anemia that requires regular blood transfusion. Beta thalassemia major constitutes a remarkable challenge to health care providers. The complications arising due to the anemia, transfusional iron overload, as well as other therapy-related complications add to the complexity of this condition. To produce this consensus opinion manuscript, a PubMed search was performed to gather evidence-based original articles, review articles, as well as published work reflecting the experience of physicians and scientists in the Arabian Gulf region in an effort to standardize the management protocol.
Topics: Arabia; Consensus; Humans; beta-Thalassemia
PubMed: 24044606
DOI: 10.1186/1750-1172-8-143 -
The Medical Journal of Malaysia Dec 2010The haemoglobinopathies and thalassemias represent the most common inherited monogenic disorders in the world. Beta-thalassaemia major is an ongoing public health... (Review)
Review
The haemoglobinopathies and thalassemias represent the most common inherited monogenic disorders in the world. Beta-thalassaemia major is an ongoing public health problem in Malaysia. Prior to 2004, the country had no national policy for screening and registry for thalassemia. In the absence of a national audit, the true figure of the extent of thalassemia in the Malaysian population was largely presumptive from micro-mapping studies from various research workers in the country. The estimated carrier rate for beta-thalassemia in Malaysia is 3.5-4%. There were 4768 transfusion dependent thalassemia major patients as of May 2010 (Data from National Thalassemia Registry).
Topics: Anemia; Genotype; Malaysia; Phenotype; beta-Thalassemia
PubMed: 21901940
DOI: No ID Found -
Bailliere's Clinical Haematology Mar 1993
Review
Topics: Gene Deletion; Genetics, Population; Hemoglobin A2; Humans; Mutation; beta-Thalassemia
PubMed: 8353313
DOI: 10.1016/s0950-3536(05)80069-1 -
Indian Journal of Pediatrics Aug 2017Thalassemia is a common genetic disorder. It has been estimated that in India nearly 5 crore people are thalassemia carriers. They are asymptomatic and are detected on... (Review)
Review
Thalassemia is a common genetic disorder. It has been estimated that in India nearly 5 crore people are thalassemia carriers. They are asymptomatic and are detected on blood tests. These people are at same risk of developing iron deficiency anemia as general population and need iron therapy in the presence of iron deficiency anemia. Nearly 12,000 children with thalassemia major (Homozygous state) are born every year. These children often present with significant anemia along with hepatosplenomegaly during infancy and require early diagnosis and institution of therapy with repeated blood transfusions and chelation therapy. Adequate dose of chelation therapy is essential to maintain serum ferritin around 1000 ng/ml. With present protocol of management, thalassemic children have near normal life. Bone marrow transplantation offers cure for these children; results of bone marrow transplantation are best when performed below 7 y of age.
Topics: Blood Transfusion; Bone Marrow Transplantation; Chelation Therapy; Child; Humans; beta-Thalassemia
PubMed: 28435994
DOI: 10.1007/s12098-017-2325-1