β-Thalassemia

Abstract

β-Thalassemia is caused by reduced (β) or absent (β) synthesis of the β-globin chains of hemoglobin. Three clinical and hematological conditions of increasing severity are recognized: the β-thalassemia carrier state, thalassemia intermedia, and thalassemia major, a severe transfusion-dependent anemia. The severity of disease expression is related mainly to the degree of α-globin chain excess, which precipitates in the red blood cell precursors, causing both mechanic and oxidative damage (ineffective erythropoiesis). Any mechanism that reduces the number of unbound α-globin chains in the red cells may ameliorate the detrimental effects of excess α-globin chains. Factors include the inheritance of mild/silent β-thalassemia mutations, the coinheritance of α-thalassemia alleles, and increased γ-globin chain production. The clinical severity of β-thalassemia syndromes is also influenced by genetic factors unlinked to globin genes as well as environmental conditions and management. Transfusions and oral iron chelation therapy have dramatically improved the quality of life for patients with thalassemia major. Previously a rapidly fatal disease in early childhood, β-thalassemia is now a chronic disease with a greater life expectancy. At present, the only definitive cure is bone marrow transplantation. Therapies undergoing investigation are modulators of erythropoiesis and stem cell gene therapy.Genet Med advance online publication 03 November 2016.

The role of iron repletion in adult iron deficiency anemia and other diseases

“…Thalassemia syndromes are heritable disorders with a broad range of clinical manifestations caused by mutations in genes responsible for alpha‐ or beta‐globin synthesis, ultimately leading to ineffective erythropoiesis, hemolysis, and splenic sequestration of erythrocytes . Management of severe thalassemia generally consists of chronic blood transfusions and iron chelation therapy when serum ferritin exceeds 800‐1000 ng/mL . Splenectomy may be indicated, particularly in beta‐thalassemias if the patient experiences poor growth, increased transfusion demands, or sequestration crises .…”

p53 tumor suppressor and iron homeostasis

“…For example, decreased FPN activity, led by high levels of hepcidin, is found in iron‐restriction syndromes, including iron‐refractory iron deficiency anemia (IRIDA) or anemia of inflammation , in which iron accumulates in recycling macrophages and enterocytes, but may become insufficient in other tissues. In contrast, hyperactive FPN, usually as a result of hepcidin deficiency, is found in hereditary hemochromatosis or β‐thalassemia intermedia , in which excessive iron absorption and toxic iron deposition are found in hepatocytes and other parenchymal cells, but relative iron depletion occurs in macrophages.…”

A computational model to understand mouse iron physiology and diseases

“…β-thalassemia is a hereditary disease caused by reduced or absent production of hemoglobin's βglobin chain. This results in a defective erythropoiesis where α-globin tetramers precipitate and cause oxidative membrane damage leading to apoptosis of a large proportion of RBC precursor cells (Origa, 2017). It also results in shorter lifespan of mature RBC due to their increased catabolism by splenic macrophages (Skow et al, 1983;Yang et al, 1995;Mathias et al, 2000).…”