Haemoglobinopathies Flashcards
How are most haemoglobinopathies inherited?
AR
On which Ch are the a-globin genes located?
Ch 16
On which Ch are the B-globin genes located?
Ch 11
What are the a-globin genes?
ζ
a1
a2
What are pseudogenes?
Non-functional genes which are not transcribed
Includes φζ and φα on Ch 16, and φβ on Ch 11
What are the B-globin genes?
ε Gγ Aγ δ β
What is the difference between Gγ and Aγ?
Functionally identical (difference of 1 residue)
Where is Hb synthesised in the embryo and foetus?
Embryo: yolk sac
Foetus: liver and spleen
What are the 3 types of embryonic Hb?
ζ2ε2
ζ2γ2
a2ε2
What is the foetal form of Hb?
a2γ2
What is the normal types and proportions of Hb in the adult?
97.5% HbA
2% HbA2
0.5% HbF
NB: proportions may change in carriers or those with a haemoglobinopathy
What is the globin chain composition of HbA?
a2B2
What is the globin chain composition of HbA2?
a2δ2
In what order do the globin chains switch throughout development?
In order of physical location on Ch (proximal to LCR, to distal from LCR)
What is LCR?
Locus control region (for regulation of globin gene expression)
What are the 3 main types of haemoglobinopathies?
Thalassaemias
Structural variants
Hereditary persistence of foetal Hb (HPFH)
What is the basis of thalassaemias?
Decreased or absent synthesis of 1 or more globin chains
What is the basis of structural variants of Hb?
Altered globin polypeptide without altering rate of synthesis
How many Hb structural variants are there?
> 500
Give an example of a haemoglobinopathy which is the result of a Hb structural variant
Sickle cell disease
What is HPFH?
Clinically benign condition in which HbF continues to be produced in adulthood
Describe the distribution of a-thalassaemias
Global, but high in SE Asia
Describe the distribution of B-thalassaemias
Global, but high in Southern Europe, Middle Eastern, North African and SE Asian countries, as well as the Indian subcontinent
Describe the distribution of sickle cell disease
West and Central Africa, Middle East, Indian subcontinent
What is the main problem in thalassaemias: the reduced synthesis or the resulting imbalance in Hb structure?
Imbalance in globin chains (e.g. homotetramers vs. heterotetramers)
What is the most common causative mutation in a-thalassaemia?
Large deletions
What is the most common causative mutation in B-thalassaemia?
Point mutations
Where do point mutations causing B-thalassaemia most commonly occur?
Promoter RNA splicing sites mRNA capping or polyA tailing sites Nonsense mutations Frameshift mutations
What is the result of nonsense or frameshift mutations in B-thalassaemias?
Non-functional mRNA or a short, unstable polypeptide is produced; this product is degraded
What is B+ thalassaemia?
B-thalassaemia with reduced synthesis of B-globins
What is B0 thalassaemia?
B-thalassaemia with no synthesis of B-globins
What causes the haemolytic anaemia associated with B-thalassaemia?
No B-globin chains can be produced, so Hb is synthesised as a4
a4 forms insoluble aggregates in RBCs which then accumulate and precipitate to cause damage; RBCs are then destroyed
What type of anaemia is caused by B-thalassaemia?
Microcytic hypochromic haemolytic anaemia
What are the clinical repercussions of the ineffective erythropoiesis in B-thalassaemia?
Erythropoiesis is ineffective, stimulating organs not normally associated with haemopoiesis in adults (including the spleen and liver) to start the process
Bone marrow also expands to accommodate increased erythropoiesis
Causes hepatosplenomegaly and skeletal abnormalities including frontal bossing (overgrowth of bones in forehead and maxilla), thinning of long bones and cranial bones leading to a “hair-on-end” appearance of skull (also confers increased risk of fracture)
What causes splenomegaly in B-thalassaemia?
Increased RBC turnover due to RBC damage from a4 precipitates
Extramedullary erythropoiesis in the spleen
What aspect of the disease pathogenesis is overwhelmingly responsible for the morbidity and mortality in B-thalassaemia?
Iron overload caused by release by iron in haem during RBC breakdown (body lacks effective means of eliminating excess iron)
In what organs does excess iron accumulate and what are some of the complications?
Pancreas: DM
Heart: HF
Liver: cirrhosis
Endocrine organs: hypo-hyperthyroidism and other complications
List 5 features that can be seen on a blood film in homozygous B-thalassaemia
Microcytic, hypochromic RBCs Anisocytotic cells (irregular in size) Tear-drop shaped cells Characteristic "target" cells Poikilocytotic cells (abnormally shaped)
What causes the tear-drop shaped cells in B-thalassaemia?
Inclusions of a4 aggregates
What is the general pattern of blood parameters in homozygous B-thalassaemia?
Decreased Hb Decreased MCV/MCH Decreased (B+) or absent (B0) HbA Normal or moderately elevated HbA2 Greatly elevated HbF
How are the individual Hbs measured?
Hb electrophoresis/HPLC
How is B-thalassaemia treated?
Blood transfusions
Chelation therapy to remove excess iron
Splenectomy for splenomegaly
HRT (iron overload causes early onset menopause)
How often are blood transfusions given for patients with B0-thalassaemia?
Every 3-4 weeks
How was iron chelation therapy previously administered? How has this changed?
Traditionally SC via pump (6-7 nights/week) Now orally (once daily)
How is B-thalassaemia cured?
Only with a bone marrow transplant
What are the 4 a-thalassaemia genotypes and their corresponding phenotypes?
a-/aa: silent carrier
a-/a- OR aa/–: a-thalassaemia trait (mild anaemia)
a-/–: HbH disease (mild to moderate anaemia)
–/–: HbBart (hydrops foetalis, fatal before or around birth)
What is the importance of the carrier genotype in a-thalassaemia?
If SE Asian mutation (aa/–), 1 in 4 chance of child having HbBart and developing hydrops foetalis
If Mediterranean mutation (a-/a-), no chance of HbBart
What is the globin chain composition of HbBart?
γ4
What is the globin chain composition of HbB?
B4
What is the point mutation in sickle cell?
Glycine>valine
List 5 symptoms of sickle cell disease
Anaemia and weakness Failure to thrive Splenomegaly Repeated infections Crises (ischaemia, thrombosis, infarctions especially in spleen, brain, lungs and kidneys)
How is sickle cell disease treated?
Drug reduces synthesis of abnormal B globin
What causes the symptoms of sickle cell disease?
Repeated cycles of deoxygenation result in an irreversibly sickled cell (exacerbated by stress, e.g. exercise)
Sickling causes increased adherence to endothelium and results in thrombosis
Also diminished O2-carrying capacity (causes anaemia)
What blood parameters are seen in sickle cell disease?
Decreased or normal MCV/MCH (may be dependent on whether patient is in crisis)
Significantly decreased Hb
HbS seen on Hb electrophoresis/HPLC
HbA absent
What is a double heterozygote in the context of haemoglobinopathies? How is this different to a compound heterozygote?
Mutation in B-globin AND a-globin
Compound heterozygote has 2 different mutations, typically within the same gene
What is the aim of future therapies for haemoglobinopathies?
Gene therapy
What are 3 possible mechanisms of gene therapy for haemoglobinopathies?
Aim to alter imbalance of chains (e.g. with RNAi)
Epigenetic modifications by small molecules to induce HbF (i.e. induce HPFH) in thalassaemia and sickle cell disease
Using induced pluripotent SCs
What is heterozygote advantage?
Selection advantage; heterozygosity for a mutation in globin genes may confer resistance to other disease states (e.g. haemoglobinopathies and malaria)
Selective advantage may be the reason for high carrier frequency in areas where malaria is endemic
