Beta-thalassemia
Encyclopedia
Beta-thalassemias are a group of inherited
blood disorders
caused by reduced or absent 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. Three main forms have been described: thalassemia major, thalassemia intermedia and thalassemia minor. Individuals with beta thalassemia major usually present within the first two years of life with severe anemia, poor growth, and skeletal abnormalities during infancy. Affected children will require regular lifelong blood transfusions
. Beta thalassemia intermedia is less severe than beta thalassemia major and may require episodic blood transfusions. Transfusion-dependent patients will develop iron overload and require chelation
therapy to remove the excess iron. Bone marrow transplants can be curative for some children with beta thalassemia major. Transmission is autosomal recessive; however, dominant mutations
have also been reported. Genetic counseling is recommended and prenatal diagnosis may be offered.
Note that βo/β can be associated with β thalassemia minor or β thalassemia intermedia, and β+/β+ with thalassemia major or intermedia.
The genetic mutations present in β thalassemias are very diverse, and a number of different mutations can cause reduced or absent β globin synthesis. Two major groups of mutations can be distinguished:
(or folate, a B-complex vitamin) and iron deficiency
(only in thalassemia minor).
, maxillary hyperplasia, dental malocclusion, cholelithiasis, systolic ejection murmur in the presence of severe anemia
, and pathologic fractures. Based on a number of key symptoms tests are ordered for the differential diagnosis. These tests include CBC; Hemoglobin electrophoresis
; Serum Transferin, Ferritin, Fe Binding Capacity; Urine urobilin & Urobilogen; Peripheral Blood Smear; Hematocrit
; Serum Bilirubin. Further genetic analysis may include HPLC should routine electrophoresis prove difficult. But, before any of these tests are ordered, a physician should inquire into a detailed family history..
and deferiprone
. Of the two, deferoxamine is preferred; it is more effective and is associated with fewer side-effects
.
The most common complaint by patients receiving deferoxamine is that it is difficult to comply with the subcutaneous chelation treatments because they are painful and inconvenient. The oral chelator deferasirox
(marketed as Exjade by Novartis) was approved for use in 2005 in some countries. It offers some hope with compliance but is very expensive (~US$100 per day) and has been associated with deaths from toxicity.
Untreated thalassemia major eventually leads to death usually by heart failure; therefore, birth screening is very important. Bone marrow transplant
ation is the only cure for thalassemia, and is indicated for patients with severe thalassemia major. Transplantation can eliminate a patient's dependence on transfusions. If there is no matching donor for a child with thalassemia, a savior sibling
can be conceived by preimplantation genetic diagnosis
(PGD) to be free of the disease as well as match the recipient's human leucocyte antigen (HLA) type in order to be a donor for the sick child.
Thalassemia intermedia patients vary a lot in their treatment needs, depending on the severity of their anemia. All thalassemia patients are susceptible to health complications that involve the spleen
(which is often enlarged and frequently removed) and gall stones. These complications are mostly prevalent to thalassemia major and intermedia patients.
test can determine what their iron levels are and guide them to further treatment if necessary. Thalassemia minor, although not life-threatening on its own, can affect quality of life due to the effects of a mild to moderate anemia
. Studies have shown that thalassemia minor often coexists with other diseases such as asthma
, and mood disorders.
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
blood disorders
Hemoglobinopathy
Hemoglobinopathy is a kind of genetic defect that results in abnormal structure of one of the globin chains of the hemoglobin molecule. Hemoglobinopathies are inherited single-gene disorders; in most cases, they are inherited as autosomal co-dominant traits. Common hemoglobinopathies include...
caused by reduced or absent synthesis of the beta chains
HBB
Beta globin Beta globin Beta globin (HBB, β-globinprotin that, along with alpha globin (HBA), makes up the most common form of hemoglobin in adult humans. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains.-Gene locus:...
of hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
resulting in variable phenotypes
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
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. Three main forms have been described: thalassemia major, thalassemia intermedia and thalassemia minor. Individuals with beta thalassemia major usually present within the first two years of life with severe anemia, poor growth, and skeletal abnormalities during infancy. Affected children will require regular lifelong blood transfusions
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
. Beta thalassemia intermedia is less severe than beta thalassemia major and may require episodic blood transfusions. Transfusion-dependent patients will develop iron overload and require chelation
Chelation
Chelation is the formation or presence of two or more separate coordinate bonds between apolydentate ligand and a single central atom....
therapy to remove the excess iron. Bone marrow transplants can be curative for some children with beta thalassemia major. Transmission is autosomal recessive; however, dominant mutations
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
have also been reported. Genetic counseling is recommended and prenatal diagnosis may be offered.
Types
Any given individual has two β globin alleles:| Name | Description | Alleles |
|---|---|---|
| Thalassemia minor | Only one of β globin alleles bears a mutation. Individual will suffer microcytic anemia Microcytic anemia Microcytic anemia is a generic term for any type of anemia characterized by small red blood cells. The normal mean corpuscular volume is 76-100 fL, with smaller cells as macrocytic.... . Detection usually involves lower than normal MCV Mean corpuscular volume The mean corpuscular volume, or "mean cell volume" , is a measure of the average red blood cell size that is reported as part of a standard complete blood count.... value (<80 fL). Plus an increase in fraction of Hemoglobin A2 Hemoglobin A2 Hemoglobin A2 is a normal variant of hemoglobin A that consists of two alpha and two delta chains and is found in small quantity in normal human blood. Hemoglobin A2 may be increased in beta thalassemia or to people who are heterozygous to beta thalassemia gene.... (>3.5%) and a decrease in fraction of Hemoglobin A Hemoglobin A Hemoglobin A or adult hemoglobin is the most common human hemoglobin tetramer, comprising over 97% of the total red cell hemoglobin. It consists of two alpha chains and two beta chains .... (<97.5%). |
β+/β or βo/β |
| Thalassemia intermedia | A condition intermediate between the major and minor forms. Affected individuals can often manage a normal life but may need occasional transfusions, e.g., at times of illness or pregnancy, depending on the severity of their anemia. | β+/β+ or βo/β |
| Thalassemia major | If both alleles have thalassemia mutations. This is a severe microcytic, hypochromic anemia Anemia Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin... . Untreated, it causes anemia Anemia Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin... , splenomegaly Splenomegaly Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any... , and severe bone deformities. It progresses to death before age 20. Treatment consists of periodic blood transfusion Blood transfusion Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood... ; splenectomy if splenomegaly is present, and treatment of transfusion-caused iron overload. Cure is possible by bone marrow transplantation. Cooley's anemia is named after Thomas Benton Cooley Thomas Benton Cooley Thomas Benton Cooley was an American pediatrician and hematologist and professor of hygiene and medicine at the University of Michigan and Wayne State University. He was the director of the Pasteur Institute at the University of Michigan from 1903 to 1904. He worked in private practice in... . |
β+/βo or βo/βo or β+/β+ |
Note that βo/β can be associated with β thalassemia minor or β thalassemia intermedia, and β+/β+ with thalassemia major or intermedia.
The genetic mutations present in β thalassemias are very diverse, and a number of different mutations can cause reduced or absent β globin synthesis. Two major groups of mutations can be distinguished:
- Nondeletion forms: These defects, in general, involve a single base substitution or small deletion or inserts near or upstream of the β globin gene. Most often, mutations occur in the promoter regions preceding the beta-globin genes. Less often, abnormal splice variants are believed to contribute to the disease.
- Deletion forms: Deletions of different sizes involving the β globin gene produce different syndromes such as (βo) or hereditary persistence of fetal hemoglobinHereditary persistence of fetal hemoglobinHereditary persistence of fetal hemoglobin is a benign condition in which significant fetal hemoglobin production continues well into adulthood, disregarding the normal shutoff point after which only adult-type hemoglobin should be produced.-Causes:This is usually caused by mutations in the...
syndromes.
Testing, Treatment, and Complications
Thalassemia may co-exist with other deficiencies such as folic acidFolic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
(or folate, a B-complex vitamin) and iron deficiency
Iron deficiency (medicine)
Iron deficiency is one of the most common of the nutritional deficiencies. Iron is present in all cells in the human body, and has several vital functions...
(only in thalassemia minor).
DNA analysis
This test is used to investigate deletions and mutations in the alpha- and beta-globin-producing genes. Family studies can be done to evaluate carrier status and the types of mutations present in other family members. DNA testing is not routinely done but can be used to help diagnose thalassemia and to determine carrier status. In most cases it is likely the treating physician will use a clinical prediagnosis by symptoms of anemia: tiredness, breathlessness, and poor exercise tolerance. Furthermore, abdominal pain due to hypersplenism and splenic infarction may occur and right-upper quadrant pain caused by gallstones may occur are major clinical manifestations. However, to coin thalassemiæ under signs and symptoms would be misleading when giving a diagnosis. Physicians will note these signs as associative due to the complexity of the nature of this disease. The following are also associative signs that can attest to the severity of the phenotype: pallor, poor growth, inadequate food intake, splenomegaly, jaundiceJaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
, maxillary hyperplasia, dental malocclusion, cholelithiasis, systolic ejection murmur in the presence of severe anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, and pathologic fractures. Based on a number of key symptoms tests are ordered for the differential diagnosis. These tests include CBC; Hemoglobin electrophoresis
Hemoglobin electrophoresis
Hemoglobin electrophoresis is a blood test that can detect different types of hemoglobin. It uses the principles of gel electrophoresis to separate out the various types of hemoglobin and is a type of native gel electrophoresis...
; Serum Transferin, Ferritin, Fe Binding Capacity; Urine urobilin & Urobilogen; Peripheral Blood Smear; Hematocrit
Hematocrit
The hematocrit or packed cell volume or erythrocyte volume fraction is the percentage of the concentration of red blood cells in blood. It is normally about 45% for men and 40% for women...
; Serum Bilirubin. Further genetic analysis may include HPLC should routine electrophoresis prove difficult. But, before any of these tests are ordered, a physician should inquire into a detailed family history..
Thalassemia Major and Intermedia
Thalassemia major patients receive frequent blood transfusions that lead to iron overload. Iron chelation treatment is necessary to prevent iron overload damage to the internal organs in patients with Thalassemia Major. Because of recent advances in iron chelation treatments, patients with thalassemia major can live long lives if they have access to proper treatment. Popular chelators include deferoxamineDeferoxamine
Deferoxamine is a bacterial siderophore produced by the actinobacteria Streptomyces pilosus. It has medical applications as a chelating agent used to remove excess iron from the body...
and deferiprone
Deferiprone
Deferiprone is an oral drug that chelates iron and is used to treat thalassaemia major.It has been licensed for use in Europe and Asia for many years while awaiting approval in Canada and the United States. On October 14, 2011, however, "the U.S...
. Of the two, deferoxamine is preferred; it is more effective and is associated with fewer side-effects
Adverse effect (medicine)
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
.
The most common complaint by patients receiving deferoxamine is that it is difficult to comply with the subcutaneous chelation treatments because they are painful and inconvenient. The oral chelator deferasirox
Deferasirox
Deferasirox is a rationally-designed oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving long-term blood transfusions for conditions such as beta-thalassemia and other chronic anemias...
(marketed as Exjade by Novartis) was approved for use in 2005 in some countries. It offers some hope with compliance but is very expensive (~US$100 per day) and has been associated with deaths from toxicity.
Untreated thalassemia major eventually leads to death usually by heart failure; therefore, birth screening is very important. Bone marrow transplant
Bone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...
ation is the only cure for thalassemia, and is indicated for patients with severe thalassemia major. Transplantation can eliminate a patient's dependence on transfusions. If there is no matching donor for a child with thalassemia, a savior sibling
Savior sibling
A savior sibling is a child who is born to provide an organ or cell transplant to a sibling that is affected with a fatal disease, such as cancer or Fanconi anemia, that can best be treated by hematopoietic stem cell transplantation....
can be conceived by preimplantation genetic diagnosis
Preimplantation genetic diagnosis
In medicine and genetics pre-implantation genetic diagnosis refers to procedures that are performed on embryos prior to implantation, sometimes even on oocytes prior to fertilization. PGD is considered another way to prenatal diagnosis...
(PGD) to be free of the disease as well as match the recipient's human leucocyte antigen (HLA) type in order to be a donor for the sick child.
Thalassemia intermedia patients vary a lot in their treatment needs, depending on the severity of their anemia. All thalassemia patients are susceptible to health complications that involve the spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
(which is often enlarged and frequently removed) and gall stones. These complications are mostly prevalent to thalassemia major and intermedia patients.
Thalassemia Minor
Thalassemia minor is not always actively treated. Contrary to popular belief, thalassemia minor patients should not avoid iron-rich foods by default. A serum ferritinFerritin
Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...
test can determine what their iron levels are and guide them to further treatment if necessary. Thalassemia minor, although not life-threatening on its own, can affect quality of life due to the effects of a mild to moderate anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
. Studies have shown that thalassemia minor often coexists with other diseases such as asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
, and mood disorders.