th;lessemi

• Thalassemia syndromes are among the most common genetic disorders worldwide
• Normal adult hemoglobin (HbA)


  Consists of a heme molecule linked to two α-globin and two β-globin chains (α2β2)
• Alpha thalassemia


  Caused by deletions or mutations that reduce the rate of α-globin chain production
• Beta thalassemia


  Caused by deletions or mutations that reduce the rate of β-globin chain production
• Thalassemia is usually asymptomatic in carriers, or presents with anemia of varying degrees in patients with more severely impaired globin-chain production
• Patients with thalassemia trait may be at risk of having a severely affected child and should be referred for genetic counseling
• Patients with severe beta thalassemia are dependent on regular or intermittent red cell transfusions
• Patients with severe thalassemia should be followed at a thalassemia comprehensive care center under the care of a hematologist
• Thalassemia syndromes are among the most common genetic disorders worldwide
• Curative therapy such as bone marrow transplantation may be an option for some patients, and novel agents, as well as gene therapy, are in the pipeline
• Severe forms of beta thalassemia


  • Severe pallor, scleral icterus
  • Enlarged abdomen due to hepatosplenomegaly
  • Severe bony changes due to ineffective erythroid production
  • Neuropathy/paralysis due to extramedullary hematopiesis
  • Growth retardation and short stature
• Patients with alpha thalassemia

  • Pallor, scleral icterus
  • Splenomegaly (hepatomegaly is less common)
  • Absence of bony deformities
• Complete blood count (CBC) results and red cell indices, along with peripheral blood film examination, are usually sufficient to suspect a diagnosis of thalassemia
• Hb electrophoresis can usually confirm the diagnosis of beta thalassemia, HbH disease, and HbE/β-thalassemia
• Polymerase chain reaction (PCR) assay techniques and next-generation sequencing (NGS) have allowed noninvasive screening to be done on fetal DNA obtained from maternal plasma
• Splenectomy


  The principal surgical procedure used for some patients with thalassemia
• PRBC transfusions


  Routine administration, up to 20 mL/kg every 3-4 weeks, aiming for a 9-10 g/dL hemoglobin level prior to the next transfusion
• Routine administration of iron chelation is essential to avoid transfusion-related iron overload and multiorgan toxicity
• In 2019, the European Union conditionally approved the use of betibeglogene autotemcel (Zynteglo), the first gene therapy for the treatment of transfusion-dependent beta thalassemia
• Normal adult hemoglobin (HbA)


  Consists of a heme molecule linked to two α-globin and two β-globin chains (α2β2)
• The US Food and Drug Administration (FDA) approved the betibeglogene autotemcel in August 2022
• A second gene therapy, exagamglogene autotemcel (Casgevy), was approved by the FDA for transfusion-dependent beta thalassemia in 2024
• Beta thalassemia was first described by Thomas Cooley, a Detroit pediatrician


  1925
• Ingram and Stratton postulated that decrease in β-globin or α-globin production led to a transfusion-dependent anemia


  1959
• Alpha thalassemia


  Deletions or mutations of one or more of the α-globin genes on chromosome 16 result in reduced α-globin chain production
• Lie-injo Luan Eng, an Indonesian pathologist, described a stillbirth with Hb Bart hydrops fetalis


  1962
• HbA


  Consists of heme combined with two α-globin and two β-globin chains (α2β2)
• Beta thalassemia


  Deletions or mutations of the β-globin genes on chromosome 11 result in reduced β-globin chain production
• Chromosome 16


  Each DNA strand has two α-globin genes
• Chromosome 11


  Has a single pair of β-globin genes
• Thalassemia is usually asymptomatic in carriers, or presents with anemia of varying degrees in patients with more severely impaired globin-chain production
• In the thalassemia syndromes, mutations affecting either gene affect the balanced production of α-globin and β-globin chains, resulting in decreased hemoglobin and varying degrees of anemia
• Patients with thalassemia trait may be at risk of having a severely affected child and should be referred for genetic counseling
• Fetal hemoglobin (HbF)


  α2γ2, produced during fetal development
• Adult hemoglobin (HbA)


  α2β2, produced after birth
• HbA2


  α2δ2, small amounts produced after birth
• Globin genes


  Consist of three coding exons and two noncoding introns (IVS)
• Beta thalassemia mutations


  Severe (β0) mutations result in complete absence of β-globin production, less severe (β+) mutations reduce β-globin production
• Splice-site mutations


  Change the critical GT/AG bases around the splice site, rendering the splice site unrecognizable by the normal splicing process
• Nonsense mutations


  Single base change in the exon generates a stop codon in the mRNA, resulting in premature termination of the globin chain