Haemoglobinopathies Flashcards
What is the structure of adult haemoglobin?
2 alpha and 2 beta chains
On which chromosome are the genes for the alpha chain located?
Chromosome 16 (2 genes) zeta gene also found here
On which chromosome are the genes for the beta chain located?
chromosome 11 (5 genes)
What is the structure of embryonic haemoglobin?
2 zeta chains and 2 epsilon chains
called Hb Gower 1
Stays in this form for up to 6 weeks
What is the structure of foetal haemoglobin?
Zeta gene is switched off
Now in the form of 2 alpha and 2 gamma chains
What is the structure of haemoglobin 3-6 months after birth?
2 alpha and 2 delta chains
What is thalassaemia?
Reduced production of function haemoglobin
due to underproduction of either alpha or beta subunit
therefore there are 2 subtypes: alpha or beta thalassaemia
What are the different kinds of alpha thalassaemia?
- 1 gene is defective = alpha thalassaemia minima
- 3 normal alpha genes –> can have normal Hb production and no clinical symptoms
- may have slightly reduced MCV
- silent carriers - 2 alpha genes are defective = alpha thalassaemia minor
- mild microcytic, hypochromic anaemia –> can be mistaken for iron deficiency - 3 alpha genes defective = haemoglobin H disease
- 2 unstable haemoglobins produced: Hb Barts (gamma 4) and Hb H (beta 4)
- increased free O2 = reduced O2 delivery to tissues
- microcytic hypochromic anaemia - 4 alpha genes defective = incompatible with life
- Hb Barts produced = unstable
- infants are stillborn = hydrops fetalis
What is the cause of beta thalassaemia and when does the condition manifest? What is the inheritance pattern?
Caused by a point mutation of chromosome 11
Occurs during the transition from HbF to HbA
Inherited in an autosomal recessive pattern
What are the two main genotypes of beta thalassaemia?
Homozygous: beta thalassaemia major/Cooley’s anaemia
Heterozygous: thalassaemia trait/beta thalassaemia minor
there is also beta thalassaemia intermedia (beta globin genes are mutated)
What is the result of underproduction of HbA? How do individuals compensate for this underproduction?
Underproduction = hypochromic, microcytic anaemia
Compensatory increase in gamma and delta chain synthesis
What are the pathological effects of beta-thalassaemia?
- reduced beta globin synthesis = increase alpha globins; alpha tetramers are unstable and therefore precipitate on erythrocyte membrane –> this causes erythrocyte membrane = hepatosplenomegaly and jaundice
- intramedullary destruction (of erythroblasts) leading to erythroid hyperplasia and ineffective erythropoiesis
- -> leads to hepatosplenomegaly and facial bone abnormalities - Result = severe hypochromic microcytic anaemia (reduced Hb, MCV and MCH)
What are the effects of untreated beta-thalassaemia major?
- hypochromic, microcytic anaemia
- bone marrow expansion, splenomegaly
- bone deformity, extramedullary erythropoietic masses
- failure to thrive from about 6 months of age
- heart failure and death by age 3-4
- facial bone abnormalities, hypertrophy of maxilla, exposing upper teeth, depression of nasal bridge and periorbital puffiness
- pallor, short, hepatosplenomegaly and wasted limbs
How is thalassaemia treated?
- regular transfusions (must be careful of iron overload)
- iron chelation therapy (bind free iron) –> desferoxamine, deferiprone , deferasirox
- splenectomy
- allogenic bone marrow transplant
What is sickle cell anaemia and how does it arise? What is the inheritance pattern?
mutated beta chain, but still have 2 alpha and 2 beta chains
occurs when there is a missense point mutation in the beta globin chain
glutamic acid –> valine (GAG –> GTG)
