Haemoglobinopathies Flashcards
What is the inheritance pattern for the majority of haemoglobinopathies?
Autosomal recessive
Are alpha and beta globin genes on the same or different chromosomes?
Different.
Alpha: 16
Beta: 11
What is the structure of Foetal Haemoglobin?
alpha2gamma2
What are three different embryonic Haemoglobins?
ζ2ε2
ζ2γ2
α2ε2
Name three broad types of haemoglobinopathies.
Alpha and beta Thalassaemias
Structural variants
Hereditary persistence of fetal haemoglobin (HPFH)
What happens in alpha and beta thalassaemia?
Reduced synthesis of one or more globin chains.
How many different structural variants are there in the haemoglobinopathies?
> 500 different variants.
What is the effect of Hereditary persistence of foetal haemoglobin?
Nothing. It is clinically benign.
What is the main cause of problems in the thalassaemias?
Relative imbalance between alpha and beta globin.
What is the biggest physiological problem caused by thalassaemia?
Iron overload.
How is iron overload caused in thalassaemia?
Abnormal erythroblasts die in the bone marrow causing release and breakdown of protein and therefore release of iron. There’s no effective mechanism for removing excess iron so it accumulates in organs leading to systemic overload.
What gives the ‘hair on end’ appearance to the skull of someone with thalassaemia?
Thinning of skull, caused by increased erythropoiesis and expansion of the marrow.
Why do people with thalassaemia often have to get splenectomies?
Because the hypochromic red cells that manage to get out of the bone marrow are destroyed in the spleen, which leads to splenomegaly.
What mutation causes the majority of alpha-thalassaemias?
Large deletions
What mutation causes the majority of beta-thalassaemias?
Point mutations.
Which types of point mutations would result in degradation of the polypeptide produced by the beta-globin gene?
Nonsense and frames shift mutations
What sort of mutation causes sickle-cell disease?
Point mutations
What causes destruction of RBCs in Beta-thalassaemia (homozygous, also, incorrectly, called thalassaemia major)?
Produce only alpha globin chains, not beta, forming alpha4 globulin. These form aggregates, accumulate and precipitate in RBCs, causing damage.
What type of anaemia is caused by beta-thalassaemia?
Haemolytic anaemia
What effect does extramedullary erythropoiesis have on the liver and spleen?
Hepatomegaly
Splenomegaly
What causes skeletal deformities in Beta-thalassaemia?
Anaemia -> Tissue anoxia -> Erythropoietin increase -> marrow expansion -> skeletal deformities
Describe the red blood cells seen in Beta-thalassaemia.
Anisocytotic - irregular in size
Poikilocytotic - abnormal in shape
Microcytic (small)
Hypochromic (pale) RBCs
What happens to other types of haemoglobin in homozygous beta-thalassaemia?
HbA2 is normal or moderately elevated
HbF is greatly elevated
What does the treatment of beta-thalassaemia involve?
Blood transfusions every 3-4 weeks
Iron chelation therapy
Splenectomy
Hormone replacement therapy (women go through menopause at about 18years old)
Bone marrow transplant - cure (not everyone can do this though…)
What is the phenotype of alpha-thalassaemia with only 2 functional genes?
Alpha-thalassaemia trait - mild anaemia.
What is the phenotype of alpha-thalassaemia with only 1 functional gene?
HbH disease - mild to moderately severe anaemia.
What is the phenotype of alpha-thalassaemia with no functional alpha-thalassaemia genes?
HbBart - hydrops fetalis, which is fatal before or around birth.
What is the ‘South East Asian’ mutation for Alpha thalassaemia?
aa/–
What is the ‘mediterranian’ mutation for alpha thalassaemia?
a-/a-
What amino acid substitution is involved in sickle-cell anaemia?
Glu is substituted for Val
Are all RBCs containing HbS tetramers sickled in shape?
No, red blood cells first become reversibly sickled When a biconcave erythrocyte becomes deoxygenated. After repeated cycles of deoxygenation, the erythrocyte becomes irreversibly sickled.
What is the phenotype of Sickle Cell Disease (i.e. Homozygous, HbSS)
MCV/MCH may be normal or reduced
Hb significantly decreased. e.g. 60-80 g/L.
What is the phenotype of Sickle cell train (i.e. Heterozygous, HbAS)
MCV/MCH may be normal or reduced.
Hb slightly or moderately reduced.
What is an example of a double heterozygote?
e.g. a beta and alpha-globulin mutation. i.e. heterozygous for both.
What is the aim of Gene therapy in Beta-thalassaemia?
Aim is to alter the imbalance of alpha and beta chains by using RNAi (interfering RNA) to reduce alpha-globin mRNA.
How could epigenetic modifications be used as a gene therapy for the treatment of thalassaemia and sickle cell disease?
Small molecules could be used to induce HbF.
