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Beta-Thalassemia: An Inherited Blood Disorder


Beta-thalassemia is an inherited blood disorder in which the body fails to produce healthy "beta" globin chains of hemoglobin. Hemoglobin (Hb) is an oxygen-carrying protein in red blood cells, which gives your blood its red color. When this protein is defective, your body’s red blood cells die before the end of their natural lifespan. Thus, in its major form, β-thalassemia leads to excessive destruction of red blood cells and severe anemia that requires frequent blood transfusions.

At what age does beta-thalassemia present?

Most children manifest the symptoms after six months of life when the adult hemoglobin replaces the fetal hemoglobin (Hb-gamma).

Which ethnicity is most prone to beta-thalassemia?

Traditionally, thalassemia has been relatively rare in the United States. Traits for beta-thalassemia have been more common in people of Mediterranean, Southeast Asian, African, and Middle Eastern descent. That said, cases in the U.S. have risen by approximately 7.5% over the last 50 years. This change in beta-thalassemia patterns is due to people moving from countries with high thalassemia prevalence.

What causes Beta-thalassemia?

Beta-thalassemia stems from an inherited mutation (alteration or deletion) of the beta-globin genes of hemoglobin (HBB). You inherit this defect from your parents.

In a healthy human, adult hemoglobin has two alpha-and beta-globin chains, coded by two alpha and two beta-globin genes. However, in beta-thalassemia, there’s a genetic mutation of the HBB located on chromosome 11. This HBB mutation causes either partial or complete deficiency of the beta-globin chains of Hb.

On the other hand, the α-chain (alpha) production within the red blood cells (RBCs) goes unleashed. Below is the sequence of steps that follows uncontrolled α-chain production:

  1. The α-chains form aggregates, which trigger premature breakdown (medically known as hemolysis) and death of red blood cells.
  2. The hemoglobin contained within the RBCs then leaks into the bloodstream.
  3. Your body recycles hemoglobin’s heme component into iron and a yellow pigment called bilirubin.
  4. With time, the bilirubin buildup leads to jaundice, and the iron accumulation in various organs gives rise to the clinical consequences of iron overload.
  5. The spleen then sequesters the damaged red blood cells from the blood and itself enlarges.
  6. The bone marrow starts churning red blood cells to compensate for lost cells and expands. Bone marrow is where blood cells, including RBCs, typically develop.
  7. When the marrow reserves of RBCs are exhausted, sites outside the marrow begin producing these cells. These sites include the spleen, liver, joints, heart, skin, lymph nodes, lungs, spinal cord, etc. This process is known as extramedullary hematopoiesis.

What are the different types of Beta-thalassemia?

Depending upon the severity of the disease, β–thalassemia has two primary forms.

β-thalassemia major (Cooley’s anemia)

In this form of thalassemia, you inherit two mutated or defective beta-globin genes from your parents, and thus your body fails to produce any β-globin. This form of thalassemia leads to life-threatening symptoms calling for lifelong transfusions.

β-thalassemia minor (Thalassemia carrier or trait)

In this type, you inherit one altered β-globin gene. The other gene is normal. Therefore, the anemia is mild and usually does not require transfusion.

Signs and symptoms of Beta-thalassemia

Signs and symptoms of beta-thalassemia depend on its types and clinical severity. For thalassemia major, we can divide the symptoms into those related to:

Symptoms of anemia

  • Skin pallor
  • Feeling tired most of the time
  • Weakness
  • Dizziness or lightheadedness
  • Shortness of breath
  • Rapid heartbeat

Symptoms of extramedullary hematopoiesis

  • Enlarged spleen
  • Enlarged liver
  • An atypical facial appearance with prominent cheekbones and a flat nasal bridge due to expansion of the marrow within the bones of the skull and face
  • Nodules on the skin
  • Tumor-like masses
  • Back pain, tingling, numbness, muscle weakness, and other nerve deficits as a result of spinal cord compression

Symptoms of iron overload

  • Joint pain
  • Increased blood sugar levels leading to diabetes
  • Enlarged heart resulting in heart failure
  • Liver failure
  • Bronze or gray skin color

Treatment options for Beta-thalassemia

Treatment depends on the clinical severity of the disease. Primary treatments include:

Blood transfusions

Severe degrees of thalassemia require frequent blood transfusions, often every two to four weeks. The goal is to maintain hemoglobin at 9 to 10 g/dl to treat the symptoms of anemia and simultaneously suppress the excess red blood cell formation outside the bone marrow.

Iron chelation

To counter iron overload occurring as a result of thalassemia itself as well as transfusion-related complications, your doctor will also use iron chelators. The two iron chelators approved by the U.S. Food and Drug Administration (FDA) are:

  • Deferoxamine (Desferal), given as a subcutaneous (under the skin) injection in an infusion pump form
  • Deferasirox (Exjade or Jadenu), given as once-daily dispensable or film-coated tablets

Bone marrow/stem cell transplantation

If successful, stem cell transplantation offers a disease-free survival rate of over 90%. It is a potentially curative option for people with severe beta-thalassemia. The benefits, however, come at the expense of calculated risks.

Gene therapy

Recently, a red cell-based gene therapy named Zynteglo, Beti-cel (short for betibeglogene autotemcel), has won FDA approval for adults and children with transfusion-dependent beta-thalassemia. Zynteglo is one of the most cutting-edge treatments, offering long-lasting transfusion independence with normal hemoglobin levels. The one-time Beti-cel gene therapy carries a whopping price tag of US$2.8 million.

Each dose of Zynteglo is a bespoke therapy that involves:

  1. Harvesting a patient's bone marrow stem cells.
  2. Genetically engineering the harvested stem cells using a carrier or viral vector to create functional beta-globin genes.
  3. Inserting the modified stem cells carrying a workable beta-globin gene back into your body after removal of the abnormal stem cells from your body via chemotherapy.

Conclusion

In its major form, beta thalassemia leads to excessive destruction of red blood cells and severe anemia that requires frequent blood transfusions.

Key takeaways

Beta-thalassemia is an inherited blood disorder resulting from a mutation in the beta globin-gene of hemoglobin.

The condition exists in two primary forms: β-thalassemia major (Cooley’s anemia) and β-thalassemia minor.

Beta-thalassemia manifests as life-threatening anemia that calls for lifelong blood transfusions.

Frequent blood transfusions lead to several complications, in particular, iron overload.

Gene therapy offers durable transfusion independence.

References:

National Center for Biotechnology Information (US). (1998). Thalassemia.

Bajwa, H., Basit, H. (2022). Thalassemia. Treasure Island (FL): StatPearls Publishing.

Galanello, R., and Origa, R. (2010). Beta-thalassemia. Orphanet Journal of Rare Diseases.

Moukalled, N.M., Bou-Fakhredin, R., and Taher, A.T. (2018). Deferasirox: Over a Decade of Experience in Thalassemia. Mediterranean Journal of Hematology and Infectious Diseases.

Kattamis, A., Forni, G.L., Aydinok, Y., and Viprakasit, V. (2020). Changing patterns in the epidemiology of β-thalassemia. European Journal of Haematology.

Yamamoto, K., Miwa, Y., Abe-Suzuki, S., Abe, S., Kirimura, S., Onishi, I., Kitagawa, M., and Kurata, M. (2016). Extramedullary hematopoiesis: Elucidating the function of the hematopoietic stem cell niche (Review). Molecular Medicine Reports.

Porter, J.L., Rawla, P. (2022). Hemochromatosis. StatPearls Publishing.

U.S. Food and Drug Administration. FDA Approves First Cell-Based Gene Therapy to Treat Adult and Pediatric Patients with Beta-thalassemia Who Require Regular Blood Transfusions.

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