beta thalassemia beta thalassemia beta thalassemias (β thalassemias) are a group of inherited blood disorders. they are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. global annual incidence is estimated at one in 100,000. beta thalassemias occur due to malfunctions in the hemoglobin subunit beta or hbb. the severity of the disease depends on the nature of the mutation. beta-thalassemiaother namesmicrocytemia, beta typebeta thalassemia genetics, the picture shows one example of how beta thalassemia is inherited. the beta globin gene is located on chromosome 11. a child inherits two beta globin genes (one from each parent).specialtyhematologytypesthalassemia minor, intermediate and majorcausesmutations in the hbb genediagnostic methoddna analysistreatmentdepends on type (see types) hbb blockage over time leads to decreased beta-chain synthesis. the body's inability to construct new beta-chains leads to the underproduction of hba (adult hemoglobin). reductions in hba available overall to fill the red blood cells in turn leads to microcytic anemia. microcytic anemia ultimately develops in respect to inadequate hbb protein for sufficient red blood cell functioning. due to this factor, the patient may require blood transfusions to make up for the blockage in the beta-chains. repeated blood transfusions cause severe problems associated with iron overload. signs and symptoms the hand of a person with severe anemia (left, wearing ring) compared to one without three main forms have been described: thalassemia minor, thalassemia intermedia, and thalassemia major which vary from asymptomatic or mild symptoms to severe anemia requiring lifelong transfusions. individuals with beta thalassemia major (those who are homozygous for thalassemia mutations, or inheriting 2 mutations) 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; therefore, prenatal screening is very important. those with beta thalassemia intermedia (those who are compound heterozygotes for the beta thalassemia mutation) usually present later in life with mild to moderate symptoms of anemia. beta thalassemia trait (also known as beta thalassemia minor) involves heterozygous inheritance of a beta-thalassemia mutation and patients usually have borderline microcytic, hypochromic anemia and 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 nor symptoms. some people with thalassemia are susceptible to health complications that involve the spleen (hypersplenism) and gallstones (due to hyperbilirubinemia from peripheral hemolysis). these complications are mostly found in thalassemia major and intermedia patients. excess iron (from hemolysis or transfusions) causes serious complications within the liver, heart, and endocrine glands. severe symptoms include liver cirrhosis, liver fibrosis, and in extreme cases, liver cancer. heart failure, growth impairment, diabetes and osteoporosis are life-threatening conditions which can be caused by beta thalassemia major. the main cardiac abnormalities seen as a result of beta thalassemia and iron overload include left ventricular systolic and diastolic dysfunction, pulmonary hypertension, valvulopathy, arrhythmias, and pericarditis. increased gastrointestinal iron absorption is seen in all grades of beta thalassemia, and increased red blood cell destruction by the spleen due to ineffective erythropoiesis further releases additional iron into the bloodstream. additional symptoms of beta thalassemia major or intermedia include the classic symptoms of moderate to severe anemia including fatigue, growth and developmental delay in childhood, leg ulcers and organ failure. ineffective erythropoiesis (red blood cell production) can also lead to compensatory bone marrow expansion which can then lead to bony changes/deformities, bone pain and craniofacial abnormalities. extramedullary organs such as the liver and spleen that can also undergo erythropoiesis become activated leading to hepatosplenomegaly (enlargement of the liver and spleen). other tissues in the body can also become sites of erythropoiesis, leading to extramedullary hematopoietic pseudotumors which may cause compressive symptoms if they occur in the thoracic cavity or spinal canal. cause mutations two major groups of mutations can be distinguished: nondeletion forms: these defects, in general, involve a single base substitution or small insertions 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 hemoglobin syndromes. mutations are characterized as (βo) if they prevent any formation of β globin chains, mutations are characterized as (β+) if they allow some β globin chain formation to occur. name older synonyms description alleles thalassemia minor heterozygous form: only one of β globin alleles bears a mutation. affected individuals will develop microcytic anemia. detection usually involves lower than normal mean corpuscular volume value (<80 fl). β+/ββo/β thalassemia intermedia 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+ thalassemia major mediterranean anemia; cooley anemia homozygous form: occurs when both alleles have thalassemia mutations. this is a severe microcytic, hypochromic anemia. untreated, it causes anemia, splenomegaly and severe 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 mrna assembly protein hbb pdb 1a00. this is a healthy beta globin protein. beta thalassemia is a hereditary disease affecting hemoglobin. as with about half of all hereditary diseases, an inherited mutation damages the assembly of the messenger-type rna (mrna) that is transcribed from a chromosome. dna contains both the instructions (genes) for stringing amino acids together into proteins, as well as stretches of dna that play important roles in regulating produced protein levels. in thalassemia, an additional, contiguous length or a discontinuous fragment of non-coding instructions is included in the mrna. this happens because the mutation obliterates the boundary between the intronic and exonic portions of the dna template. because all the coding sections may still be present, normal hemoglobin may be produced and the added genetic material, if it produces pathology, instead disrupts regulatory functions enough to produce anemia. hemoblogin's normal alpha and beta subunits each have an iron-containing central portion (heme) that allows the protein chain of a subunit to fold around it. normal adult hemoglobin contains 2 alpha and 2 beta subunits. thalassemias typically affect only the mrnas for production of the beta chains (hence the name). since the mutation may be a change in only a single base (single-nucleotide polymorphism), on-going efforts seek gene therapies to make that single correction. 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% (3 out of 4) probability (see inheritance chart at top of page) of the mutated gene being inherited by an offspring. even if a child does not have beta thalassemia major or intermedia, they can still be a carrier, possibly resulting in future generations of their offspring having beta thalassemia. another risk factor is ancestry. beta thalassemia occurs most often in people of italian, greek, middle eastern, southern asian, and african ancestry. diagnosis peripheral blood smear from a person with beta thalassemia. the red blood cells vary greatly in shape and size and some look empty because of their low hemoglobin content (giemsa stain). abdominal pain due to hypersplenism, splenic infarction and right-upper quadrant pain caused by gallstones are major clinical manifestations. however, diagnosing thalassemia from symptoms alone is inadequate. physicians note these signs as associative due to this disease's complexity. the following associative signs can attest to the severity of the phenotype: pallor, poor growth, inadequate food intake, splenomegaly, jaundice, maxillary hyperplasia, dental malocclusion, cholelithiasis, systolic ejection murmur in the presence of severe anemia and pathologic fractures. based on symptoms, tests are ordered for a differential diagnosis. these tests include complete blood count; hemoglobin electrophoresis; serum transferrin, ferritin, total iron-binding capacity; urine urobilin and urobilogen; peripheral blood smear, which may show codocytes, or target cells; hematocrit; and serum bilirubin. the expected pattern on hemoglobin electrophoresis in people with beta-thalassemia is an increased level of hemoglobin a2 and slightly increased hemoglobin f. the diagnosis is confirmed with hemoglobin electrophoresis or high performance liquid chromatography. skeletal changes associated with expansion of the bone marrow: chipmunk facies: bossing of the skull, prominent malar eminence, depression of the bridge of the nose, tendency to a mongoloid slant of the eye, and exposure of the upper teeth due to hypertrophy of the maxillae. hair-on-end (or "crew cut") on skull x-ray: new bone formation due to the inner table. dna analysis all beta thalassemias may exhibit abnormal red blood cells; a family history is followed by 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 routine, but can help diagnose thalassemia and determine carrier status. in most cases the treating physician uses a clinical prediagnosis assessing anemia symptoms: fatigue, breathlessness and poor exercise tolerance. further genetic analysis may include hplc should routine electrophoresis prove difficult. prevention beta thalassemia is a hereditary disease allowing for a preventative treatment by carrier screening and prenatal diagnosis. it can be prevented if one parent has normal genes, giving rise to screenings that empower carriers to select partners with normal hemoglobin. a study aimed at detecting the genes that could give rise to offspring with sickle cell disease. patients diagnosed with beta thalassemia have mch ≤ 26 pg and an rdw < 19. of 10,148 patients, 1,739 patients had a hemoglobin phenotype and rdw consistent with beta thalassemia. after the narrowing of patients, the hba2 levels were tested presenting 77 patients with beta thalassemia. this screening procedure proved insensitive in populations of west african ancestry because of the indicators has high prevalence of alpha thalassemia. countries have programs distributing information about the reproductive risks associated with carriers of haemoglobinopathies. thalassemia carrier screening programs have educational programs in schools, armed forces, and through mass media as well as providing counseling to carriers and carrier couples. screening has shown reduced incidence; by 1995 the prevalence in italy reduced from 1:250 to 1:4000, and a 95% decrease in that region. the decrease in incidence has benefitted those affected with thalassemia, as the demand for blood has decreased, therefore improving the supply of treatment. treatment beta thalassemia major surgically removed spleen of a thalassemic child. it is about 15 times larger than normal. affected children require regular lifelong blood transfusions. bone marrow transplants can be curative for some children. patients receive frequent blood transfusions that lead to or potentiate iron overload. iron chelation treatment is necessary to prevent damage to internal organs in cases of iron overload. advances in iron chelation treatments allow patients with thalassemia major to live long lives with access to proper treatment. popular chelators include deferoxamine and deferiprone. the oral chelator deferasirox was approved for use in 2005 in some countries. bone marrow transplantation is the only cure and is indicated for patients with severe thalassemia major. transplantation can eliminate a patient's dependence on transfusions. absent a matching donor, a savior sibling can be conceived by preimplantation genetic diagnosis (pgd) to be free of the disease as well as to match the recipient's human leukocyte antigen (hla) type. serum ferritin (the storage form of iron) is routinely measured in those with beta thalassemia to determine the degree of iron overload; with increased ferritin levels directing the use of iron chelation therapy. the three iron chelators; subcutaneous deferoxamine, oral deferiprone and oral deferasirox can be used as monotherapy or in combination, they have all been shown to decrease serum/systemic iron levels, hepatic and cardiac iron levels as well as decreasing the risk of cardiac arrhythmia, heart failure and death. hepatic and myocardial mri is also used to quantify the iron deposition in target organs, especially the heart and liver, to guide therapy. scientists at weill cornell medical college have developed a gene therapy strategy that could feasibly treat both beta-thalassemia and sickle cell disease. the technology is based on delivery of a lentiviral vector carrying both the human β-globin gene and an