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Flashcards in Thalassemias Deck (14):
1

What are the major categories of thallasemia?

  • 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

2

What is the epidemiology of thalassemias?

  • 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

3

Describe the molecular genetics of alpha-thalassemia.

  • 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

4

Describe the molecular genetics of beta-thalassemia.

  • 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

5

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

  • 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

6

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

  • 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

7

What is the cellular physiology of thalassemias?

  • 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

8

What are the key features regarding the pathophysiology of thalassemias?

  • 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

9

What are the major methods of diagnosis for thalassemias?

  • 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

10

List the major treatment modalities for thalassemias.

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

11

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

  • 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

12

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

  • 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

13

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

  • 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

14

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

  • 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