Handbook of Genetic Counseling/Beta-Thalassemia

Beta-Thalassemia (Also called Cooley's Anemia, Beta-Thalassemia is an inherited blood disorder that manifests as an absent or decreased production of normal hemoglobin.)

Genetics

• Caused by a mutation in the gene encoding the Hemoglobin beta chain (HBB)
• Normal hemoglobin has two alpha and two beta peptide chains. Beta-Thalassemia results from reduced synthesis of the hemoglobin beta chain. This disorder is caused by mutations in the beta chain of the hemoglobin molecule.
• Chromosomal locus of the HBB gene is 11p15.5
• Over 200 different HBB gene mutations are known. In each at risk population, though, four to ten mutations usually account for a large majority of HBB disease-causing alleles.
• HBB gene is 1.6Kb and has 3 exons

Incidence and Carrier Frequency

• Overall gene frequency is 1/300
• B-thal is more prevalent in Meditarranean, Middle Eastern, Transcaucasus, Central Asia, Indian and Far Eastern populations.
• Ex.: People with Mediterranean ancestry (Greek or Italian) have a 1/30 carrier risk

Inheritance/Risks

• Autosomal recessive inheritance
• Parents of an affected child are heterozygotes. They are clinically asymptomatic but may be slightly anemic.They are referred to as having beta-thalassemia minor.

Beta-Thalassemia Major

• Patients present with severe anemia and hepatosplenomegaly
• Patients with thalassemia major are usually picked up within the first 2 yrs of life. Babies may be pale, fussy, have poor appetite and infections
• If untreated, spleen, liver and heart become enlarged and bones can become thin and brittle. Buildup of iron may cause heart failure in teens or 20s.affected children have failure to thrive and shortened life expectancy. Many other complications can occur without treatment. Patients usually die before 30.
• Treatment involves chelation therapy (which removes excess iron) and blood transfusions

Thalassemia Intermedia

• Patients present at later age and have more mild anemia
• Liver and spleen are enlarged and iron overload may still occur
• Rarely requires transfusions

Thalassemia Minor or Thalassemia Trait

• Refers to carriers of one abnormal beta gene
• Sometimes results in anemia
• Few or no symptoms (thalassemia minima)

Diagnosis

• Red blood cell indices
  • Shows microcytic anemia (low mean corpuscular volume) and reduced content of Hb per red cell (low mean corpuscular hemoglobin).
  • Normal level of hemoglobin for males is 14-18 g/dl and 12-16 g/dl for females. Affected individuals have hemoglobin levels less than 7 g/dl and carrier level is 11-14 g/dl.
• Peripheral blood smear
  • Affected patients have microcytosis, hypochromia, anisocytosis, poikilocytosis and nucleated red blood cells (erythroblasts).
• Hemoglobin analysis
  • Identifies amount and type of hemoglobin present
  • This disorder characterized by decreased amounts of hemoglobin A (HbA)
• Bone marrow examination
  • In beta-thalassemia patients, bone marrow is extremely cellular due to erythroid hyperplasia
• Molecular Genetic testing
  • Mutations are detected by a number of different PCR-based procedures. The most common are reverse dot blot analysis or primer-specific amplification, with a set of probes complementary to the most common mutations in the population from which the patient originated.
  • There are known common mutations for Mediterranean, Middle Eastern, Indian, Thai, Chinese, and African/ African American populations.
  • Clinical testing is available

Carrier Testing

• Carriers identified by red blood cell indices, hemoglobin analysis and mutation analysis.
• Family members of an affected person, gamete donors and members of at-risk ethnic groups should consider carrier detection.
• Hematologic testing has several limitations: silent mutations, coinheritance of other thalassemias, and confusion with Alpha-thalassemia.
• Prenatal testing is available for couples who are both carriers and their mutations have been identified. Use CVS or amniocentesis.

Treatment

• Transfusion therapy
  • Corrects the anemia, suppresses erythropoiesis and inhibits increased gastrointestinal absorption of iron
  • Usually given every 2-3 weeks
• Chelation therapy
  • Used to maintain iron levels below critical values
  • DFO (desferrioxamine B)
• Bone marrow transplantation from an HLA identical sibling is an alternative

Resources

• www.geneclinics.org
• Children's Hospital of Philadelphia

Notes

The information in this outline was last updated in February 2003.