Alpha globin gene triplication and quadruplication may be detected by the MPLA procedure. Definition of coinherited HPFH determinants can be useful in predicting the severity of the phenotype of an affected fetus. As mentioned above, in fact, on increasing the gamma chain output, coinherited HPFH with homozygous beta-thalassemia may lead to a milder phenotype. The presence of high HbF in the parents may lead to the suspicion of double heterozygosity for beta-thalassemia and HPFH.
If targeted mutation analysis fails to detect the mutation, mutation scanning or sequence analysis can be used to detect mutations in the HBB coding region mutations in the noncoding region would not be detected by this analysis. Deletions of variable extent of the beta gene or of the HBB cluster that result in beta-thalassemia or in the complex beta-thalassemias, called gammadeltabeta-thalassemia and deltabeta-thalassemia, are rare causes of beta-thalassemia and testing that deletions is available clinically by using MPLA.
When the hematological analysis indicates a beta-thalassemia carrier state, molecular genetic testing of HBB can be performed to identify a disease-causing mutation. Through genetic counseling and the option of prenatal testing, such a couple can opt to bring to term only those pregnancies in which the fetus is unaffected. The optimal time for the assessment of genetic risk, definition of carrier status, and genetic counseling is before pregnancy.
It is appropriate to offer genetic counseling including discussion on the availability of prenatal diagnosis, potential risks to offspring, and reproductive options to young adults who are carriers. Population screening associated with genetic counseling is extremely useful by allowing couples at risk to make informed decision on their reproductive choices.
Furthermore, in the population at risk targeted by screening, a consistent reduction of the birth rate of affected children was registered, as shown in the Sardinian population. In high-risk pregnancies in which both members are defined carriers for beta-thalassemia, prenatal diagnosis is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis, usually performed at approximately 15—18 weeks' gestation, or chorionic villus sampling at approximately 10—12 weeks' gestation.
Both disease-causing alleles must be identified before prenatal testing can be performed. Alternatively, following an accurate genetic counseling explaining the pros and cons of the procedure preimplantation genetic diagnosis may be considered. Prenatal diagnosis by analysis of fetal cells in maternal blood is not yet available but is being investigated on a research basis. This testing is not yet clinically available but under investigation on a research basis with promising results.
In indeterminate-risk pregnancies, either one parent is a definite heterozygote and the other parent has a beta-thalassemia-like hematologic picture, but no HBB mutation has been identified by sequence analysis, or a mother is a known heterozygote and the father is unknown or unavailable for testing, especially if the father belongs to a population at risk.
In either instance, the options for prenatal testing should be discussed in the context of formal genetic counseling. In indeterminate-risk pregnancies, the prenatal testing strategy is the analysis for the known HBB mutation. If the known HBB mutation is present, analysis of globin chain synthesis is performed on a fetal blood sample obtained by percutaneous umbilical blood sampling at approximately 18—21 weeks' gestation.
A comprehensive review of the management of thalassemia major and thalassemia intermedia has been published by Thalassemia International Federation and is available at the Thalassemia International Federation Web site. In thalassemia major, regular transfusions correct the anemia, suppress erythropoiesis, and inhibit increased gastrointestinal absorption of iron.
Before starting the transfusions, it is absolutely necessary to carry out hepatitis B vaccination and perform extensive red blood cell antigen typing, including Rh, Kell, Kidd, and Duffy and serum immunoglobulin determination, the latter of which detects individuals with IgA deficiency who need special repeatedly washed blood unit preparation before each transfusion. Transfusions are usually given every 2—3 weeks. Treatment of individuals with thalassemia intermedia is symptomatic and based on splenectomy and folic acid supplementation.
Treatment of extramedullary erythropoietic masses is based on radiotherapy, transfusions, or, in selected cases, hydroxyurea with a protocol similar to that used for sickle cell disease. Hydroxyurea also increases globin gamma chains and may have other undefined mechanisms. The most common secondary complications are those related to transfusional iron overload, which can be prevented by adequate iron chelation. After 10—12 transfusions, chelation therapy is initiated with desferrioxamine B DFO , administered 5—7 days a week by hour continuous subcutaneous infusion via a portable pump.
Recommended dosage depends on the individual's age and the serum ferritin concentration. The dose may be reduced if serum ferritin concentration is low. By maintaining the total body iron stores below critical values i. Side effects of DFO are more common in the presence of relatively low iron burden and include ocular and auditory toxicity, growth retardation, and, rarely, renal impairment and interstitial pneumonitis. DFO administration also increases susceptibility to Yersinia infections.
The major drawback of DFO chelation therapy is low compliance resulting from complications of administration. In clinical practice, the effectiveness of DFO chelation therapy is monitored by routine determination of serum ferritin concentration. However, serum ferritin concentration is not always reliable for evaluating iron burden, because it is influenced by other factors, the most important being the extent of liver damage. Determination of liver iron concentration in a liver biopsy specimen shows a high correlation with total body iron accumulation and is the gold standard for evaluation of iron overload.
However, 1 liver biopsy is an invasive technique involving the possibility though low of complications; 2 liver iron content can be affected by hepatic fibrosis, which commonly occurs in individuals with iron overload and hepatitis C virus infection; and 3 irregular iron distribution in the liver can lead to possible false-negative results.
In recent years, magnetic resonance imaging MRI techniques for assessing iron loading in the liver and heart have improved. Magnetic biosusceptometry SQUID , which gives a reliable measurement of hepatic iron concentration, is another option ; however, magnetic susceptometry is currently available only in a limited number of centers worldwide. The main side effects of deferiprone therapy include neutropenia, agranulocytosis, arthropathy, and gastrointestinal symptoms that demand close monitoring.
However, results from independent studies suggest that deferiprone may be more cardioprotective than DFO. Compared with those being treated with DFO, individuals on treatment with deferiprone have better myocardial MRI pattern and less probability of developing or worsening preexisting cardiac disease. Deferasirox became recently available for clinical use in patients with thalassemia.
It is effective in adults and children and has a defined safety profile that is clinically manageable with appropriate monitoring. The most common treatment-related adverse events are gastrointestinal disorders, skin rash, and a mild, nonprogressive increase in serum creatinine concentration. New strategies of chelation using a combination of DFO and deferiprone have been effective in individuals with severe iron overload; toxicity was manageable. Assessment of myocardial siderosis and monitoring of cardiac function combined with intensification of iron chelation result in excellent long-term prognoses.
For individuals with thalassemia major, follow-up to monitor the effectiveness of transfusion therapy and chelation therapy and their side effects includes the following:. Physical examination every month by a physician familiar with the affected individual and the disease;. Complete cardiac evaluation and evaluation of thyroid, endocrine pancreas, parathyroid, adrenal, and pituitary function usually after 10 years ;.
Liver ultrasound evaluation, determination of serum alpha-fetoprotein concentration in adults with hepatitis C and iron overload for early detection of hepatocarcinoma; and.
Assessment for liver and heart iron with MRI should be in general recommended after 10 years of age and repeated according to the severity of iron overload, transfusion, and chelation regimes ; and. Regular gallbladder echography for early detection of cholelithiasis, 70 particularly in individuals with the Gilbert syndrome genotype i. Bone marrow transplantation BMT from an HLA-identical sib represents an alternative to traditional transfusion and chelation therapy.
If BMT is successful, iron overload may be reduced by repeated phlebotomy, thus eliminating the need for iron chelation. The outcome of BMT is related to the pretransplantation clinical conditions, specifically the presence of hepatomegaly, extent of liver fibrosis, and magnitude of iron accumulation. BMT from unrelated donors has been performed on a limited number of individuals with beta-thalassemia. Provided that selection of the donor is based on stringent criteria of HLA compatibility and that individuals have limited iron overload, results are comparable with those obtained when the donor is a compatible sib.
Cord blood transplantation from a related donor offers a good probability of a successful cure and is associated with a low risk of graft-versus-host disease. New chelation strategies, including the combination or alternate treatment with the available chelators, are under investigation. Induction of HbF synthesis can reduce the severity of beta-thalassemia by improving the imbalance between alpha and nonalpha globin chains. Several pharmacologic compounds including 5-azacytidine, decytabine, and butyrate derivatives have had disappointing results in clinical trials.
Their potential in the management of beta-thalassemia syndromes is still under investigation. The studies on BCL11 pave the way to develop a therapy based on down-regulation of this gene, which may lead to an increase of HbF level, thereby ameliorating the clinical severity of the disease. The efficacy of hydroxyurea treatment in individuals with thalassemia is still unclear. Hydroxyurea is used in persons with thalassemia intermedia to reduce extramedullary masses, to increase Hb levels, and, in some cases, to improve leg ulcers.
A good response, correlated with particular polymorphisms in the beta globin cluster i. The possibility of correction of the molecular defect in hematopoietic stem cells by transfer of a normal gene via a suitable vector or by homologous recombination is being actively investigated.
Hematopoietic stem cells, derived from the corrected embryonic stem cells ex vivo, were able to produce HbA and HbS, thereby leading to a phenotype similar to human sickle cell trait.
This and other similar experiments indicate the possibility of curing inherited hemoglobinopathies by homologous recombination in embryonic stem cells.
A new opportunity in the field of stem cell research has been recently determined by the discovery that transfection of four transcription factors Oct 3—4, Sox 2, cMyc, and Klf4 in several types of adult cells e. Based on this technology, Hanna et al. The iPSs were corrected ex vivo by homologous recombination. Hematopoietic stem cells derived from ex vivo-corrected iPS were able to cure the affected mouse.
This experiment offers proof of principle that genetically corrected iPS cells may lead to a cure for the inherited hemoglobinopathies. The thalassemia syndromes. Oxford, England: Blackwell Science Ltd, The hemoglobinopathies. Chapter Available at: www.
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Two additional variants of alpha thalassemia are related to a reduced amount of alpha-globin. Because cells still produce some normal hemoglobin, these variants tend to cause few or no health problems. A loss of two of the four alpha-globin alleles results in alpha thalassemia trait. People with alpha thalassemia trait may have unusually small, pale red blood cells and mild anemia. A loss of one alpha-globin allele is found in alpha thalassemia silent carriers. These individuals typically have no thalassemia-related signs or symptoms.
The inheritance of alpha thalassemia is complex. Each person inherits two alpha-globin alleles from each parent. If both parents are missing at least one alpha-globin allele, their children are at risk of having Hb Bart syndrome, HbH disease, or alpha thalassemia trait.
The precise risk depends on how many alleles are missing and which combination of the HBA1 and HBA2 genes is affected. Genetics Home Reference has merged with MedlinePlus. Learn more. The information on this site should not be used as a substitute for professional medical care or advice. Thousands of infants with beta thalassemia are born each year.
Mutations in the HBB gene cause beta thalassemia. The HBB gene provides instructions for making a protein called beta-globin.
Beta-globin is a component subunit of hemoglobin. Hemoglobin consists of four protein subunits, typically two subunits of beta-globin and two subunits of another protein called alpha-globin. Some mutations in the HBB gene prevent the production of any beta-globin. Other HBB gene mutations allow some beta-globin to be produced but in reduced amounts. A lack of beta-globin leads to a reduced amount of functional hemoglobin.
Without sufficient hemoglobin, red blood cells do not develop normally, causing a shortage of mature red blood cells. The low number of mature red blood cells leads to anemia and other associated health problems in people with beta thalassemia. Thalassemia major and thalassemia intermedia are inherited in an autosomal recessive pattern , which means both copies of the HBB gene in each cell have mutations.
The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Sometimes, however, people with only one HBB gene mutation in each cell develop mild anemia.
These mildly affected people are said to have thalassemia minor. Preview the new GARD site. Blood Diseases.
Alpha-thalassemia ; Alpha-thalassemia-abnormal morphogenesis ; Beta-thalassemia ; Alpha-thalassemia ; Alpha-thalassemia-abnormal morphogenesis ; Beta-thalassemia ; Sickle beta thalassemia ; Sickle delta beta thalassemia See More. Summary Summary. Symptoms Symptoms. The signs and symptoms vary depending on the severity of the thalassemia. For example, people affected by milder forms of thalassemia can develop mild anemia or may have no signs or symptoms of the condition at all.
In addition to the signs and symptoms seen in intermediate thalassemia, people with severe forms of thalassemia may also experience severe anemia, poor appetite, paleness, dark urine, yellow discoloration of skin jaundice , and enlarged liver or heart.
Do you have updated information on this disease? We want to hear from you. Cause Cause. There are two main types of thalassemia, alpha thalassemia and beta thalassemia , which each affect a different part of hemoglobin the protein in red blood cells that carries oxygen. Hemoglobin is made up of two different components subunits : beta globin and alpha globin.
Each person has two copies of each of these genes, one inherited from the mother and one from the father. Changes mutations in the HBB gene lead to reduced levels of beta globin and cause beta thalassemia. Inheritance Inheritance. In general, thalassemia is inherited in an autosomal recessive manner; however, the inheritance can be quite complex as multiple genes can influence the production of hemoglobin.
The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition; although some carriers of beta thalassemia develop mild anemia. For each gene, one copy is inherited from the mother and one is inherited from the father. If each parent is missing at least one gene copy, their children are at risk for having alpha thalassemia.
However, the exact risk and the severity of each child's condition depends on how many gene copies are lost deleted and which combination of the HBA1 and HBA2 genes are affected. Diagnosis Diagnosis. It has additional information on genetic testing for alpha thalassemia and beta thalassemia. The intended audience for the GTR is health care providers and researchers.
Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional. Treatment Treatment.
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