What is Beta -Thalassemia?
Beta (β) Thalassemia is an inherited blood disorder that often evolves from a reduced or absent production of the beta globin chain of hemoglobin. Hemoglobin is a protein in blood cells that helps carry oxygen through the body. When genetic differences in the globin gene lead to structural variants, many physiological processes can be affected. The frequency of β thalassemia varies regionally with the highest prevalence in people of Mediterranean, Middle Eastern and Asian descent. Approximately 68000 children are born annually worldwide with β-thalassemia, with 80-90 million estimated carriers. Over 200 thalassemia causing mutations in the beta gene have been identified thus far and contribute to the wide genomic and phenotypic variability of the disease.1
How does it occur?
Beta thalassemia occurs with the variant production of the beta chains of hemoglobin and can result in a range of outcomes from severe anemia to clinically asymptomatic. β-thalassemia is classified as minor, intermedia, or major, based on clinical presentations from asymptomatic or mild symptoms to severe anemia requiring blood transfusions for life. Interestingly, some gene mutations that cause thalassemia have been phylogenetically tied to partial protection against malaria. As an inherited disorder, it’s been linked to parts of the world where malaria is prevalent as an evolutionary need against the parasite.
Genetically, everyone inherits two beta-globin genes, one from each parent. Depending on which parts of each gene are mutated, thalassemia can manifest in a range of symptoms depending on type and severity. One mutated/ defective or missing beta-chain gene can cause mild symptoms and is often classified as β thalassemia minor. Individuals with β thalassemia minor can have no clinical symptoms or appear to have noticeably smaller red blood cells, but no significant clinical impacts. If both genes are defective or missing, moderate to severe symptoms can appear. Mild to moderate symptoms include growth problems, delayed puberty, bone abnormalities, and enlarged spleen. Severe symptoms include poor appetite, pale or yellowish skin, irregular bone structures, and lifelong severe anemia that manifest early in life.2
Hemoglobin is a tetramer made of two alpha chains and two non-alpha chains. Adult hemoglobin A1 (two alpha and beta chains) is the primary hemoglobin after 6 months from birth and hemoglobin A2 – a smaller component (comprised of two alpha and delta chains) is also produced. With β-thalassemia the overall pathology is two-fold. First, there is a decrease in hemoglobin synthesis causing anemia. During early development, the body compensates for the reduction of β-globulin with an increase in fetal hemoglobin, which typically goes down after 6-24 months of age. Overtime fetal hemoglobin production halts and the production of hemoglobin A1 continues leading to an excess of alpha chain components. Second, this excess leads to the formation of an insoluble aggregates of the globulin chain causing red blood lysis and/or ineffective red blood cell production, triggering bone marrow expansion due to red blood cell hyperplasia. The pathology can manifest as hypercoagulability (deformed cells cause clotting in circulation), chronic anemia, and iron overload. In extreme cases, classified as β thalassemia major, inadequately treated patients and transfusion dependent patients are at risk for organ damage.1,2
In general, there is significant inconsistency in size and shape of blood cells in cases of β-thalassemia depending on genetic variability and zygosity. β-thalassemia minor is often discovered incidentally during routine blood work when patients present with anemia or blood smears appear abnormal. Individuals with β-thalassemia intermedia or major often present clinical symptoms between 6-24 months of age when fetal to adult hemoglobin production transitions, if not detected during pre-natal screenings. Mild forms of β-thalassemia can present in adults when symptoms like fatigue and pallor arise along with variable physical exam findings.
Are there comorbidities with β-thalassemia?
Since β-thalassemia impacts blood circulation, complications with heart disease, vascular, liver, kidney, bone, and endocrine disorders can arise. Insulin sensitivity and secretion as well as deterioration of glucose tolerance has been seen to manifest over time.3 Iron overload often from ineffective blood cell production or in cases where blood transfusions are part of the treatment paradigm, can often cause several morbidities including hepatic fibrosis, thrombosis, pulmonary hypertension, endocrinopathies, osteoporosis, and cardiovascular and cerebrovascular disease. Other morbidities associated with ineffective blood cell production can lead to progressive bone marrow expansion and changes in bone structure and mineral densities. Without intervention, patients wild mild to moderate β-thalassemia often experience increased morbidities as they advance in age. In patients with non-transplant dependent β-thalassemia, the quality of life has been directly linked to age and multiplicity of morbidity. Patients are often encouraged to focus on appropriate management of physical symptoms and psychological care.4
Treatment and management of β-thalassemia
In the carrier state, most individuals remain asymptomatic, and genetic counseling and prenatal screenings are recommended when family planning. With individuals with mild or moderate symptoms (intermedia), treatments focus on clinical manifestations and involve care teams with multiple specialists. Treatments may include iron chelation therapy, folic acid supplements, Luspatraceot (injectable that promotes red blood cell production), blood transfusions, bone marrow and stem cell transplants. An interdisciplinary care team is needed to manage severe symptoms associated with β-thalassemia major. Treatment primarily involves red blood cell transfusions, and as regular transfusions pose additional complications, risks for iron overload, transfusion reactions, and development of autoantibodies are closely monitored. Currently, bone marrow or cord blood transplants offer the only potential cure for beta-thalassemia.5 In certain qualifying cases (based on HLA-compatibility) stem-cell transplantation has shown promise with 90% disease free survival.6
β-thalassemia is treatable. Patients with mild and moderate forms can expect an average lifespan with proper management and adherence to medical guidance. Unfortunately, the prognosis for β-thalassemia major remains poor and can significantly impact quality of life and life-span, with patients often developing heart failure from iron overload. Understanding the prognosis and severity can help manage the disease burden. Each individual’s experience dealing with β-thalassemia is unique depending on severity, and it is important to work with specialists with experience diagnosing, treating, and managing the disease.
Recognizing future prospects
Several novel therapies are being developed for patients with β-thalassemia. Gene therapies replacing defective β-globin are already in progress with promising results in patients with β-thalassemia major.7 Additionally, drugs like JAK2 inhibitors are being considered for use to ameliorate symptoms of splenomegaly as well as ligand traps sotatercept and luspatercep, for reducing transfusion requirements. While the only known cure for β-thalassemia is bone marrow and stem cell transplants from compatible donors, many developing therapies show great promise for patients.
References
1. Needs T, Gonzalez-Mosquera LF, Lynch DT. Beta Thalassemia. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK531481/
2. Hemolysis and ineffective erythropoiesis are the primary drivers of downstream complications, including chronic anemia. Complications of Thalassemia, Rething Thalassemia, Agios Pharmaceuticals, Inc. © 2025
3. De Sanctis V, Soliman A, Tzoulis P, et al. The clinical characteristics, biochemical parameters and insulin response to oral glucose tolerance test (OGTT) in 25 transfusion dependent β-thalassemia (TDT) patients recently diagnosed with diabetes mellitus (DM). Acta Biomed. 2022;92(6):e2021488. Published 2022 Jan 19. doi:10.23750/abm.v92i6.12366
4. Ali T. Taher, Maria Domenica Cappellini; How I manage medical complications of β-thalassemia in adults. Blood 2018; 132 (17): 1781–1791. doi: https://doi.org/10.1182/blood-2018-06-818187
5. Schrier SL, Angelucci E. New strategies in the treatment of the thalassemias. Annu Rev Med. 2005;56:157-71
6. Gaziev J, Lucarelli G. Stem cell transplantation for hemoglobinopathies. Curr Opin Pediatr. 2003 Feb;15(1):24-31
7. Thompson AA, Walters MC, Kwiatkowski J, et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2018;378(16):1479-1493.
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