Hemoglobinopathies

Question 1

Hb S

Answer 1

Glutamate –> Valine 6th position in Chrm 11 of Beta globin chain

Question 2

Hb C

Answer 2

Glutamate —> Lysine in 6th position

Question 3

Hb Hammersmith

Answer 3

Phe –> Ser at 42nd position
Unstable with lower O2 affinity
Hemolysis and cyanosis

Question 4

Methemeglobins (Hb M)

Answer 4

Heme iron in ferric form (Fe3+) instead of ferrous (Fe2+)
Chocolate cyanosis
Deficiency of methemoglobin reductase
Tx: Methylene blue (reduces Fe3+ to Fe2+)

Question 5

*Hb Hyde Park (example of Hb M)

Answer 5

Pt mut, Histidine –> Tyrosine at 92nd position in B globin gene

Autosomal dominant

Question 6

Hb Kempsey

Answer 6

pt mut, Asp –> Asn at 99th position of Beta globin
Locks Hb into RELAXED (R)
Hb has higher affinity for O2 (so impaired O2 delivery to tissues)
Polycythemia

Question 7

Thalassemias (general)

Answer 7

Imbalanced synthesis of globin chains
Carriers: protected against malaria
Excess, NORMAL chains eventually get precipitated in cell
Consequences include Heinz bodies and hemolytic anemia

Question 8

Alpha Thalassemias (4 causes)

Answer 8

1 gene defective: silent carrier
2 genes: alpha-thalessemia trait
3 genes: HbH (Beta 4) Disease: moderately severe hemolytic anemia, beta tetramers accumulates (inclusion bodies in RBCs)

4 genes: Hb Bart (Y4): hydrops fetalis (severe intrauterine hypoxia and infant is born with massive fluid accumulation

Question 9

Other Alpha-thalessemias

Answer 9

Due to ZF deletion: anti-sense RNA

ATRX syndrome from mut in X-linked ATRX gene, codes for chromatin re-modeling gene

Question 10

Beta Thalessemias

Answer 10

Single base pair substitution (pt mut)
Microcytic, hypochromic anemia
Increase in HbF and HbA2 (alpha 2, sigma 2)

1 gene defective: beta-thal trait
Both genes defective: Beta-thal MANOR

Severely anemic, skeletal changes

Question 11

Complex Beta Thalassemia

Answer 11

Large deletions that remove Beta globin gene PLUS:
one or more other genes from LCR from b globin cluster

Disoders named according to genes deleted

Gamma squiggly beta thal
squiggly beta thal

Question 12

Hereditary Persistence of Fetal Hb

Answer 12

Disruption of perinatal globin switch from γ globin to β globin (Possibly due to deletion at β globin gene cluster)

γ Globin gene remains intact, however, thereby continuing postnatal Hb F synthesis and compensating for the deficiency of Hb A

Question 13

Thalassemia associated with Hb E

Answer 13

Glutamate –> Lysine at 26th position

Question 14

Compounds that increase HbF Production

Answer 14

Hydoxyurea
Decitabine (a cytidine analogue): This drug stimulates (by    hypomethylation) the gene coding for the synthesis of HbF.

Coexistence of HbF is also reported to reduce the severity of complications in β- thalassemia

Question 15

LCR

Answer 15

Maintains open chromatin configuration, which facilitates access for transcriptional factors to bind at regulatory elements

May help in tx with Beta-thal