Etiopathogenesis and Clinical Manifestations of Thalassemia Major

Genetic Basis and Pathophysiology

Thalassemia major is an autosomal recessive genetic disorder caused by mutations in the β-globin gene (HBB) located on chromosome 11, resulting in severe reduction or complete absence of functional β-globin chain synthesis 1, 2
The condition results from homozygosity or compound heterozygosity for β-thalassemia mutations, leading to severe reduction or complete absence of functional β-globin chain synthesis 1, 2
The severity is determined by whether the mutation causes β+ (reduced production) or β0 (absent production) phenotypes 3

Infants with thalassemia major are healthy at birth because fetal hemoglobin (HbF, composed of α2γ2 chains) does not require β-globin chains, but symptoms emerge at approximately 1-2 years of age as fetal hemoglobin production declines and the switch to adult hemoglobin (requiring β-chains) occurs 1, 2
Thalassemia major is characterized by the requirement for more than 8 transfusion events per year in adults over 16 years of age 1, 2
The American Heart Association recommends lifelong regular red blood cell transfusions as mandatory for survival, and lifelong iron chelation therapy to prevent or reverse iron-related organ damage 1, 4

Each unit of transfused blood contains approximately 200-250 mg of elemental iron, and humans lack physiological mechanisms for iron excretion, leading to iron overload 1, 2
Cardiac iron loading becomes the leading cause of death, accounting for approximately 70% of mortality in transfusion-dependent patients 4