Thalassemias

Question 1

What are the major categories of thallasemia?

Answer 1

• A group of disorders in which one or more copies of the globin genes are defective, resulting in decreased globin production – (Quantitative hemoglobinopathies)
• Among the most common genetic disorders worldwide: nearly 5% of the world population carry a globin variant, including 1.67% who are carriers for thalassemia
  
  • Alpha-Thalassemia is a deficiency of a-globin production
  • Beta-Thalassemia is a deficiency of b-globin production

Question 2

What is the epidemiology of thalassemias?

Answer 2

• While thalassemia syndromes are relatively rare conditions in the U.S., they are highly prevalent in geographic regions where historically malaria was endemic:
  
  • Mediterranean
  • sub-Saharan Africa
  • the Middle East
  • the Asian-Indian subcontinent
  • Southeast Asia
• Red blood cells of thalassemia carriers (heterozygotes) are less susceptible to invasion by Plasmodium falciparum, thus conferring a survival advantage

Question 3

Describe the molecular genetics of alpha-thalassemia.

Answer 3

• Alpha thalassemia results from mutations of the alpha globin gene complex on chromosome 16, which can be deletional or non-deletional
  
  • Deletional mutations are more common, but non-deletional forms of alpha thalassemia tend to be more severe
• Defects of all 4 genes lead to the severe intrauterine anemia, “Hydrops Fetalis” and often, fetal demise
• When 3 of 4 alpha genes are defective, Hemoglobin H (Hb H) forms (b-tetramer), which is non-functional
• Hb Bart’s (g tetramer) forms in varying amounts transiently in newborns with 2, 3 or 4 defective alpha globin genes

Question 4

Describe the molecular genetics of beta-thalassemia.

Answer 4

• In Beta Thalassemia, most gene defects are point mutations involving the regulatory regions or coding sequences of the beta globin gene complex on human chromosome 11
• Mutations occur in regulatory, coding and noncoding regions of the gene and cause decreased globin chain production
  
  • b0 mutations are associated with absent expression, and b+ are associated with reduced expression, however, the genotype does not always predict genotype
  • Deletional mutants are uncommon

Question 5

What are some other compound heterozygous thalassemia syndrome and how do they present?

Answer 5

• Other compound heterozygous thalassemia syndromes result from the coinheritance of a thalassemia mutant allele and a structural globin variants
• Examples on thalassemia due to compound heterozygous defects include HbE/beta thalassemia and HbH/Constant Spring
  
  • Hb E is a very common structural beta globin mutation found in Southeast Asians
  • The HbE defect is the result of a mutation in exon 1 which activates a cryptic splice site
  • Anemia in HbE/beta thalassemia can be moderate to severe
• Hb Constant Spring is a non-deletional alpha globin mutation that results in elongation of the 3’ end of mRNA and an unstable protein product
  
  • HbH/Constant Spring results from compound heterozygous mutations in alpha globin alleles that can also cause a clinically significant condition

Question 6

What is the relationship between the molecular genetics and clinical phenotype in thallasemias?

Answer 6

• The molecular genetics of the alpha and beta globin genes does not necessarily predict the clinical phenotype
  
  • Likely due to alterations in genetic modifier genes, such as polymorphisms in Bcl11A, gamma globin, HBS1L-MYB intergenic sequences and AHSP

Question 7

What is the cellular physiology of thalassemias?

Answer 7

• Unbalanced globin chain synthesis leads to precipitation of excess unpaired chains and formation of intracellular inclusion bodies
  
  • Adherence of excess chains to red cell cytoskeleton causes membrane damage and early cell death in the marrow (ineffective erythropoiesis) or increased destruction in the peripheral blood (hemolysis)
• Quantitative hemoglobinopathies result in:
  
  • reduced amounts of hemoglobin per red cell
  • compensatory overproduction of immature red cells
  • shortened red cell survival
• Defective red cells are sequestered in the spleen
  
  • Profound anemia causes tissue hypoxia which stimulates erythropoietin production, causing marrow expansion

Question 8

What are the key features regarding the pathophysiology of thalassemias?

Answer 8

• Chronic anemia with compensatory increase in red cell production (ineffective erythropoiesis) leads to:
  
  • poor growth
  • splenomegaly
  • increased intestinal iron absorption
  • cardiomyopathy
• Hemolysis results in increased release of heme which is converted to bilirubin
  
  • Patients with thalassemia may have pigmented gall stones and jaundice
• Marrow expansion with thinning of cortical bone causes:
  
  • skeletal deformities
  • osteopenia
  • pathological fractures
• Extramedullary hematopoiesis, results in hepatosplenomegaly and less commonly paravertebral masses
• Enhanced GI iron absorption combined with transfusional iron overload causes:
  
  • endocrinopathies
    
    • hypogonadism
    • growth hormone deficiency
    • hypothyroidism
    • hypoparathryoidism
    • diabetes mellitus
  • hepatic fibrosis
  • cardiac failure

Question 9

What are the major methods of diagnosis for thalassemias?

Answer 9

• Newborn screening with HPLC, isoelectric focusing or hemoglobin electrophoresis:
  
  • a thalassemia: HbF, Hb Bart’s (g4), Hb H (ß4)
  • b thalassemia: Hb F only
  • Hb E/b thalassemia: Hb F and Hb E present, no Hb A
• Post neonatal testing utilizing CBC and hemoglobin electrophoresis:
  
  • Microcytic, hypochromic anemia with increased RBC count
  • Hb H disease: increased Hb F, reduced Hb A, Hb H inclusion bodies
  • b thalassemia: Hb F, increased Hb A2 in most cases, reduced or absent Hb A

Question 10

List the major treatment modalities for thalassemias.

Answer 10

• Transfusion support
• Iron overload management - chelation therapy
• Surveillance and other supportive care
• Stem cell transplantation

Question 11

Describe the use of transfusion support in the management of thalassemias.

Answer 11

• Usually initiated by 1 year of age in beta thalassemia major
• Every 3-4 weeks to maintain pre transfusion Hb > 9 gm/dl
• Intermittent or variable transfusion requirements for Hb H disease, Hb H/Constant Spring, Hb E/b thalassemia

Question 12

Describe the use of iron overload management - chelation therapy in the treatment of thalassemias.

Answer 12

• Required for most patients to control transfusional iron overload
• Usually started when serum ferritin consistently >1000ng/ml
• Treatment options:
  
  • Deferoxamine subcutaneous infusion 8-12 hours, 5-7 nights/wk
  • Deferasirox 20-30mg/kg daily oral suspension
  • Deferiprone 75mg/kg divided 3 times a day tablets
• Monitoring important to avoid overchelation and underchelation

Question 13

Describe the use of surveillance and other supportive care in the treatment of thalassemias.

Answer 13

• Splenectomy
• Blood borne infection monitoring
• Hormone replacement
• Bone mineral density scans, osteoporosis prevention or treatment
• Cardiac monitoring with ECGs, echocardiograms and MRI
• Fetal Hb inducers

Question 14

Describe the use of stem cell transplantation in the treatment of thalassemias.

Answer 14

• Only curative treatment option
• Most commonly HLA-matched sibling donor with myeloablative pre-transplant conditioning
• Improving results with reduced intensity/non-myeloablative conditioning and alternative donor stem cell transplant
• Early data on gene therapy for thalassemia promising