Hemoglobinopathies

Question 1

describe hemoglobin S

Answer 1

• single point mutation in the B-globin gene
• glutamic acid is substituted by valine at position 6
• HbS moves slower to the anode than HbA in hemoglobin electrophoresis
  
  • homozygous = sickle cell disease, no HbA formation

Question 2

describe fetal hemoglobin inducers

Answer 2

• normal changes in gene expression through methylation of CpG islands in the DNA of promoters suppresses transcription of fetal globin after birth
• drugs that increase expression of fetal globins are 5-azacytidine (Decitabine), hydroxyurea, butyrate compounds (inhibit histone deacetylation)
• these drugs are epigenetic gene regulatory mechanisms
  
  • turn on fetal globin genes

Question 3

describe a heterogenous carrier sickle cell (HbAS)

Answer 3

• those who are heterozygous for the sickle cell allele produce both normal and abnormal hemoglobin
• sickle cell trait has a hemoglobin genotype AS and is generally regarded as benign
  
  • they can develop clinical problems of sickle crisis in low O2 saturation
    
    • deep sea diving
    • extreme exercise

Question 4

describe hemoglobin C

Answer 4

• hemoglobin C has a point mutation at the 6th codon position of the B-globin gene resulting in a missense mutation (Glu –> lysine)
• HbC moves slowest to the anode (positive electrode)
• person that are homozygous for HbC have mild hemolysis
• HbC has a lower solubility than HbA and tends to crystallize in RBCs

Question 5

describe thalassemias

Answer 5

• disorders in which the rate of synthesis of a globin chain is reduced
  
  • alpha = reduced alpha chain synthesis
  • beta = reduced beta chain synthesis
• there is an imbalance in the alpha:beta chain ratio (normally 1:1)

Question 6

describe how alpha-thalasemmia can occur

Answer 6

• most likely occurs during misalignment during meiosis, which leads to defective crossing over
  
  • entire alpha gene deleted

Question 7

describe the genetic basis of alpha-thalassemia

Answer 7

• cis: 2 deletions on the same chromosome (chr. 16)
  
  • potentially more severe to offspring
• trans: 2 deletion on different chromosomes

Question 8

describe hemoglobin Bart hydrops fetalis (Hb Bart) syndrome

Answer 8

• most severe form of alpha-thalassemia
• Hb Bart: aggregation of gamma-globin (absence of alpha-globin chains)
• characterized by fetal onset of generalized edema, ascites, pleural and pericardial effusions and severe hypochromic anemia
  
  • death is inevitable
• all 4 alpha-globin alleles are deleted (inactivated) and no HbF or HbA

Question 9

describe hemoglobin H (HbH) disease

Answer 9

• only has 1 working copy of the alpha globin gene
  
  • one chromosome is cis (both alpha globin genes deleted)
  • one chromosome trans (only one globin gene deleted)
• presents in infancy or childhood with mild to moderate microcytic hypochromic hemolytic anemia
• HbH: aggregation of 4 beta globin genes
  
  • result of deletion of 3/4 alpha globin genes

Question 10

describe beta-thalassemia

Answer 10

• B-thalassemia is an AR disorder
• allelic heterogeneity
  
  • B+ mutation: reduced gene expression
    
    • less severe
  • B⁰ mutation: complete suppression of gene expression
    
    • most severe
• the net effect = less B-globin production
• excessive alpha-globin chains precipitate and result in severe hemolytic anemia

Question 11

decribe the 3 B-thalassemia mutations

Answer 11

• B-thalassemia major
  
  • homozygotes or compound heterozygotes for B0 or B+ genes
  • very low or absent HbA levels (high HbA2 and HbF)
• B-thalassemia intermedia
  
  • mostly homozygotes or compound heterozygotes (different B+ mutations on the B-globin genes); one severe mutation, second mutation is less severe or 2 less severe mutations
  • low HbA levels as there is some B globin synthesis
• B-thalassemia minor
  
  • mostly heterozygotes (one normal and one mutant B-globin gene)
  • almost normal HbA levels

Question 12

describe the molecular basis for B-thalassemia

Answer 12

• B-thalassemia is due to mutations in the HBB (B-globin) gene on chr. 11 (2 copies in an individual)
• inherited in an autosomal recessive fashion
• there is a relative excess of alpha chains that do not form tetramers; they bind to the RBC membranes and form toxic aggregates that results in hemolysis

Question 13

describe the treatment of B-thalassemia

Answer 13

• B* homozygotes (thalassemia major) present at ~6 months since gamma-globin (HbF) genes are switched off
• regular transfusions correct the anemia and suppress erythropoiesis but lead to iron deposition
  
  • iron chelation and dietary control
• the only available definitive cure is bone marrow transplantation from an HLA-identical sibling

Question 14

describe hemophilia A and the genetic basis

Answer 14

• genes for both Factor 8 and factor 9 are located on the long arm of X-chromosome
• the gene for factor 8 (F8C) is unusually large
  
  • approximately 40% of cases of severe FVIII deficiency arise from a large inversion that disrupts the FVIII gene
  • deletions, insertions and point mutation account for the remaining 50-60% of hemophilia A mutations (allelic heterogeneity)

Question 15

describe the intron inversion that occurs in hemophilia A

Answer 15

• the repeat sequences on the same chromosome misalign aberrantly and then recombination occurs
  
  • part of factor VIII gene is lost

Question 16

describe hemophilia A in carrier females

Answer 16

• carrier females are generally asymptomatic bc of random X inactivation/Lyonization
• in some carrier females, a lower level of clotting factor is seen and manifestations resemble affected males (manifesting heterozygote)
  
  • this is attributed to the skewed X-chromosome inactivation leading to a higher % of inactivation of the normal X-chromosome