Beta thalassemia
Beta-thalassemia is an inherited blood disorder, a form of thalassemia resulting in variable outcomes ranging from clinically asymptomatic to severe anemia individuals. It is caused by reduced or absent synthesis of the beta chains of hemoglobin, the molecule that carries oxygen in the blood. Symptoms depend on the extent to which hemoglobin is deficient, and include anemia, pallor, tiredness, enlargement of the spleen, jaundice, and gallstones. In severe cases death ensues.
Beta thalassemia occurs due to a mutation of the HBB gene leading to deficient production of the hemoglobin subunit beta-globin; the severity of the disease depends on the nature of the mutation, and whether or not the mutation is homozygous. The body's inability to construct beta-globin leads to reduced or zero production of adult hemoglobin thus causing anemia. The other component of hemoglobin, alpha-globin, accumulates in excess leading to ineffective production of red blood cells, increased hemolysis, and iron overload. Diagnosis is by checking the medical history of near relatives, microscopic examination of blood smear, ferritin test, hemoglobin electrophoresis, and DNA sequencing.
As an inherited condition, beta thalassemia cannot be prevented although genetic counselling of potential parents prior to conception can propose the use of donor sperm or eggs. Patients may require repeated blood transfusions throughout life to maintain sufficient hemoglobin levels; this in turn may lead to severe problems associated with iron overload. Medication includes folate supplementation, iron chelation, bisphosphonates, and removal of the spleen. Beta thalassemia can also be treated by bone marrow transplant from a well matched donor, or by gene therapy.
Thalassemias were first identified in severely sick children in 1925, with identification of alpha and beta subtypes in 1965. Beta-thalassemia tends to be most common in populations originating from the Mediterranean, the Middle East, Central and Southeast Asia, the Indian subcontinent, and parts of Africa. This coincides with the historic distribution of Plasmodium falciparum malaria, and it is likely that a hereditary carrier of a gene for beta-thalassemia has some protection from severe malaria. However, because of population migration, β-thalassemia can be found around the world. In 2005, it was estimated that 1.5% of the world's population are carriers and 60,000 affected infants are born with the thalassemia major annually.
Signs and symptoms
Symptoms depend on the type and severity of thalassemia. Carriers of thalassemia genes may have no symptoms or very mild symptoms with occasional crisis ; individuals who are homozygous for the mutation have severe and life threatening symptoms.Individuals with beta-thalassemia major usually present within the first two years of life with symptomatic severe anemia, poor growth, and skeletal abnormalities. Untreated thalassemia major eventually leads to death, usually by heart failure.
Those with beta-thalassemia intermedia usually present later in life with mild to moderate symptoms of anemia.
Beta thalassemia trait involves heterozygous inheritance of a beta-thalassemia mutation. Individuals usually have microcytosis with mild anemia; they are usually asymptomatic or have mild symptoms. Beta thalassemia minor can also present as beta-thalassemia silent carriers; those who inherit a beta thalassemic mutation but have no hematologic abnormalities or symptoms.
Individuals with thalassemia thalassemia major and intermedia are susceptible to health complications that involve the spleen and gallstones. Additional symptoms of beta-thalassemia major or intermedia include the classic symptoms of anemia including fatigue, developmental delay in childhood, leg ulcers, and organ failure. Ineffective erythropoiesis can lead to expansion of the bone marrow in compensation; this can then lead to deformity, bone pain, and craniofacial abnormalities. Organs such as the liver and spleen that can also become enrolled in red blood cell production, leading to hepatosplenomegaly.
People with thalassemia can get too much iron in their bodies, either from the disease itself as RBCs are destroyed, or as a consequence of frequent blood transfusions. Excess iron is not excreted, but forms toxic non-transferrin-bound iron. This can lead to organ damage, potentially affecting the heart, liver, endocrine system, bones and spleen. Symptoms include an irregular heartbeat, cardiomyopathy, cirrhosis of the liver, hypothyroidism, delayed puberty and fertility problems, brittle and deformed bones, and an enlarged spleen.
For clinical purposes, thalassemia is categorised as either transfusion-dependent thalassemia or non-transfusion-dependent thalassemia are used. Patients are usually considered as having NTDT if they have received fewer than 6 red blood cell units in the past 6 months and none in the preceding 2 months.
Cause
Mutations
β-globin chains are encoded by the HBB gene on chromosome 11; in a healthy person with two copies on each chromosome, two loci encode the β chain. In beta thalassemia, a single faulty gene can be either asymptomatic or cause mild disease; if both genes are faulty this causes moderate to severe disease.More than 350 mutations have been identified which can cause beta thalassemia; 20 of these account for 80% of beta-thalassemia cases.
Two major groups of mutations can be distinguished:
- Nondeletion forms: These defects, in general, involve a single base-pair substitution or small insertions near or upstream of the HBB gene.
- Deletion forms: base-pair deletions of different sizes involving the HBB gene produce syndromes such as hereditary persistence of fetal hemoglobin syndrome.
| Name | Older synonyms | Description | Alleles |
| Heterozygous form: Only one of the β globin alleles bears a mutation. Affected individuals will develop microcytic anemia. Detection usually involves a lower than normal mean corpuscular volume value. | β+/β βo/β | ||
| 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+ βo/β+ | ||
| Mediterranean anemia; Cooley anemia | Homozygous form: Occurs when both alleles have thalassemia mutations. Untreated, it causes severe anemia, splenomegaly and bone deformities, and progresses to death before age 20. Treatment consists of periodic blood transfusion; splenectomy for splenomegaly and chelation of transfusion-related iron overload. | βo/βo |
Due to globin defects, beta thalassemia patients do not have normal levels of adult hemoglobin, and instead have elevated levels of HbA2. Production of this form of hemoglobin may increase as a consequence of stress erythropoiesis.
Prevention
Risk factors
Family history and ancestry are factors that increase the risk of beta-thalassemia. Depending on family history, if a person's parents or grandparents had beta thalassemia major or intermedia, there is a 75% probability of the mutated gene being inherited by an offspring. Even if a child does not have symptomatic beta thalassemia they can still be a carrier, leading to an increased risk in future generations of their offspring having beta-thalassemia.Beta thalassemia occurs most often in people of Mediterranean, Middle Eastern, Southern Asian, and African ancestry.
Counselling and screening
The American College of Obstetricians and Gynecologists recommends all people thinking of becoming pregnant should be offered testing to see if they have thalassemia trait. Genetic counseling and genetic testing are recommended for families who carry a thalassemia trait. Understanding the genetic risk, ideally before a family is started, would hopefully allow families to understand more about the condition and make an informed decision that is best for their family.A number of countries have programs aimed at reducing the incidence of beta-thalassemia:-
- Cyprus has one of the highest carrier rates in the world. A program of premarital screening and counselling has, since the program's implementation in the 1970s, reduced the number of children born with thalassemia major from one of every 158 births to almost zero. Greece also has a screening program to identify people who are carriers.
- In Iran as a premarital screening, the man's red cell indices are checked first. If he has microcytosis, the woman is tested. When both are microcytic, their hemoglobin A2 concentrations are measured. If both have a concentration above 3.5% they are referred to the local designated health post for genetic counseling.
- Large-scale awareness campaigns are being organized in India both by government and non-government organizations to promote voluntary premarital screening, with marriage between carriers strongly discouraged.
Combination hemoglobinopathies
A combination hemoglobinopathy occurs when someone inherits two different abnormal hemoglobin genes. If these are different versions of the same gene, one having been inherited from each parent it is an example of compound heterozygosity.Some examples of clinically significant combinations involving beta thalassemia include:
- Hemoglobin C/ beta thalassemia: common in Mediterranean and African populations generally results in a moderate form of anemia with splenomegaly.
- Hemoglobin D/ beta thalassemia: common in the northwestern parts of India and Pakistan.
- Hemoglobin E/ beta thalassemia: common in Cambodia, Thailand, and parts of India, it is clinically similar to β thalassemia major or β thalassemia intermedia.
- Hemoglobin S/ beta thalassemia: common in African and Mediterranean populations, it is clinically similar to sickle-cell anemia.
- Delta-beta thalassemia is a rare form of thalassemia in which there is a reduced production of both the delta and beta globins. It is generally asymptomatic.