Haemaglobinopathies Flashcards
What is Hb made up of?
4 subunit proteins which each have an haem prosthetic group containing iron, subunits are alpha beta and gamma
What is adult Hb made up of?
2 x alpha
2 x beta
What are the genes for the alpha subunit?
2 genes on chromosome 16
What are the genes for the beta subunit?
5 genes on chromosome 11
Why is fetal haemoglobin more efficient than adult Hb? What is the significance of this?
Fetal Hb can bind oxygen more efficiently than adult Hb hence has a greater affinity for oxygen
Allows transfer of oxygen from mother to fetus
Fetal myoglobin has even higher affinity for oxygen so molecules pass from fetal Hb for storage and use in muscle
What is the first form of Hb produced in the embryonic yolk sac? When does this happen?
zeta 2 epsilon 2 (Hb Gower- 1)
up to 6 weeks
has a very high oxygen affinity
What happens to fetal Hb after 6 weeks of gestation?
zeta gene is switched off and fetal Hb (HbF) is made up of 2 alpha and 2 gamma subunits, made in the liver and spleen
Compare HbF with zeta 2 epsilon 2?
HbF has a lower affinity for oxygen but still higher than maternal Hb
When does HbA replace HbF?
3-6 months after birth
What are the normal Hb proportions in a neonate compared to an adult?
HbA - 10% vs 96-97%
HbA2 - <1% vs 2-3.5%
HbF - 90% vs. <1%
What is thalassaemia?
genetic defect resulting in inadequate quantities of one or other of the subunits making up Hb
What is the difference in types of thalassaemia?
alpha thalassaemia - one or more of the alpha genes on chromosome 16 is deleted or faulty
beta thalassaemia - point mutation on chromosome 11
When does alpha thalassemia manifest?
Immediately at birth
What does the severity of alpha thalassaemia depend on?
Number of gene alleles defective/missing
How does alpha thalassaemia minima present?
one alpha gene defective, minimal effect on Hb synthesis, 3 alpha globin genes enough to permit normal Hb production, no clinical symptoms, silent carriers, slightly reduced MCV and MCHb
How does alpha thalassemia minor present?
2 alpha genes defective,2 permit nearly normal RBC production, mild microcytic hypochromic anaemia, can be mistaken for iron deficiency anaemia and treated inappropriately with iron
How does haemoglobin H disease present?
3 alpha genes defective, 2 unstable Hb present (haemoglobin Barts and haemoglobin H) which have higher affinity for oxygen than hormal Hb, poor release of oxygen in tissues, microcytic hypochromic anaemia
How does four alpha genes defected present?
fetus cannot live once outside uterus, may not survive gestation, most stillborn with hydrops fetalis, those born alive die shortly after birth, edematous, little circulating Hb, all Hb is Hb Barts
What is the inheritance pattern of beta thalassaemia?
autosomal recessive
What are the 2 main genotypes for beta thalassemia?
Heterozygous - thalassemia trait, beta thalassemia minor
Homozygous - beta thalassemia major
(+ beta thalassemia intermedia, both beta globin genes mutated but still able to make some beta chains)
When does beta thalassemia manifest itself?
When the switch from gamma to beta subunits occur from HbF to HbA several months after birth
What is the compensatory mechanism for beta thalassemia?
More gamma and alpha chain synthesis resulting in increased HbF and A2 levels
How does beta thalassemia lead to severe hypochromic microcytic anaemia?
Loss of beta globin synthesis, excess alpha produced in developing erythroblasts in marrow, alpha tetramers unstable and precipitate on erythrocyte membrane, intra-medullary destruction of developing erythroblasts = erythroid hyperplasmia = ineffective erythropoiesis = severe hypochromic microcytic anaemia
What are the effects of untreated beta thalassemia major?
- hypochromic microcytic anaemia
- bone marrow expansion, splenomegaly
- bone deformity, extramedullary erythropoietic masses
- failure to thrive from 6 months of age
- heart failure and death by age 3-4
- facial bone abnormalities (skull bossing, maxilla hypertrophy, upper teeth exposed, nasal bridge depression, periorbital puffiness)
- B thalassemia major: pallor, short stature, massive hepatosplenomegaly, wasted limbs
