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Hannah's Intersystem > Haemoglobinopathies > Flashcards

Haemoglobinopathies Flashcards

1
Q

How are most haemoglobinopathies inherited?

A

AR

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2
Q

On which Ch are the a-globin genes located?

A

Ch 16

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3
Q

On which Ch are the B-globin genes located?

A

Ch 11

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4
Q

What are the a-globin genes?

A

ζ
a1
a2

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5
Q

What are pseudogenes?

A

Non-functional genes which are not transcribed

Includes φζ and φα on Ch 16, and φβ on Ch 11

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6
Q

What are the B-globin genes?

A 
ε
Gγ
Aγ
δ
β
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7
Q

What is the difference between Gγ and Aγ?

A

Functionally identical (difference of 1 residue)

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8
Q

Where is Hb synthesised in the embryo and foetus?

A

Embryo: yolk sac
Foetus: liver and spleen

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9
Q

What are the 3 types of embryonic Hb?

A

ζ2ε2
ζ2γ2
a2ε2

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10
Q

What is the foetal form of Hb?

A

a2γ2

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11
Q

What is the normal types and proportions of Hb in the adult?

A

97.5% HbA
2% HbA2
0.5% HbF
NB: proportions may change in carriers or those with a haemoglobinopathy

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12
Q

What is the globin chain composition of HbA?

A

a2B2

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13
Q

What is the globin chain composition of HbA2?

A

a2δ2

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14
Q

In what order do the globin chains switch throughout development?

A

In order of physical location on Ch (proximal to LCR, to distal from LCR)

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15
Q

What is LCR?

A

Locus control region (for regulation of globin gene expression)

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16
Q

What are the 3 main types of haemoglobinopathies?

A

Thalassaemias
Structural variants
Hereditary persistence of foetal Hb (HPFH)

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17
Q

What is the basis of thalassaemias?

A

Decreased or absent synthesis of 1 or more globin chains

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18
Q

What is the basis of structural variants of Hb?

A

Altered globin polypeptide without altering rate of synthesis

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19
Q

How many Hb structural variants are there?

A

> 500

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20
Q

Give an example of a haemoglobinopathy which is the result of a Hb structural variant

A

Sickle cell disease

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21
Q

What is HPFH?

A

Clinically benign condition in which HbF continues to be produced in adulthood

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22
Q

Describe the distribution of a-thalassaemias

A

Global, but high in SE Asia

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23
Q

Describe the distribution of B-thalassaemias

A

Global, but high in Southern Europe, Middle Eastern, North African and SE Asian countries, as well as the Indian subcontinent

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24
Q

Describe the distribution of sickle cell disease

A

West and Central Africa, Middle East, Indian subcontinent

25
Q

What is the main problem in thalassaemias: the reduced synthesis or the resulting imbalance in Hb structure?

A

Imbalance in globin chains (e.g. homotetramers vs. heterotetramers)

26
Q

What is the most common causative mutation in a-thalassaemia?

A

Large deletions

27
Q

What is the most common causative mutation in B-thalassaemia?

A

Point mutations

28
Q

Where do point mutations causing B-thalassaemia most commonly occur?

A 
Promoter
RNA splicing sites
mRNA capping or polyA tailing sites
Nonsense mutations
Frameshift mutations
29
Q

What is the result of nonsense or frameshift mutations in B-thalassaemias?

A

Non-functional mRNA or a short, unstable polypeptide is produced; this product is degraded

30
Q

What is B+ thalassaemia?

A

B-thalassaemia with reduced synthesis of B-globins

31
Q

What is B0 thalassaemia?

A

B-thalassaemia with no synthesis of B-globins

32
Q

What causes the haemolytic anaemia associated with B-thalassaemia?

A

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

33
Q

What type of anaemia is caused by B-thalassaemia?

A

Microcytic hypochromic haemolytic anaemia

34
Q

What are the clinical repercussions of the ineffective erythropoiesis in B-thalassaemia?

A

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)

35
Q

What causes splenomegaly in B-thalassaemia?

A

Increased RBC turnover due to RBC damage from a4 precipitates
Extramedullary erythropoiesis in the spleen

36
Q

What aspect of the disease pathogenesis is overwhelmingly responsible for the morbidity and mortality in B-thalassaemia?

A

Iron overload caused by release by iron in haem during RBC breakdown (body lacks effective means of eliminating excess iron)

37
Q

In what organs does excess iron accumulate and what are some of the complications?

A

Pancreas: DM
Heart: HF
Liver: cirrhosis
Endocrine organs: hypo-hyperthyroidism and other complications

38
Q

List 5 features that can be seen on a blood film in homozygous B-thalassaemia

A 
Microcytic, hypochromic RBCs
Anisocytotic cells (irregular in size)
Tear-drop shaped cells
Characteristic "target" cells
Poikilocytotic cells (abnormally shaped)
39
Q

What causes the tear-drop shaped cells in B-thalassaemia?

A

Inclusions of a4 aggregates

40
Q

What is the general pattern of blood parameters in homozygous B-thalassaemia?

A 
Decreased Hb
Decreased MCV/MCH
Decreased (B+) or absent (B0) HbA
Normal or moderately elevated HbA2
Greatly elevated HbF
41
Q

How are the individual Hbs measured?

A

Hb electrophoresis/HPLC

42
Q

How is B-thalassaemia treated?

A

Blood transfusions
Chelation therapy to remove excess iron
Splenectomy for splenomegaly
HRT (iron overload causes early onset menopause)

43
Q

How often are blood transfusions given for patients with B0-thalassaemia?

A

Every 3-4 weeks

44
Q

How was iron chelation therapy previously administered? How has this changed?

A 
Traditionally SC via pump (6-7 nights/week)
Now orally (once daily)
45
Q

How is B-thalassaemia cured?

A

Only with a bone marrow transplant

46
Q

What are the 4 a-thalassaemia genotypes and their corresponding phenotypes?

A

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)

47
Q

What is the importance of the carrier genotype in a-thalassaemia?

A

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

48
Q

What is the globin chain composition of HbBart?

A

γ4

49
Q

What is the globin chain composition of HbB?

A

B4

50
Q

What is the point mutation in sickle cell?

A

Glycine>valine

51
Q

List 5 symptoms of sickle cell disease

A 
Anaemia and weakness
Failure to thrive
Splenomegaly
Repeated infections
Crises (ischaemia, thrombosis, infarctions especially in spleen, brain, lungs and kidneys)
52
Q

How is sickle cell disease treated?

A

Drug reduces synthesis of abnormal B globin

53
Q

What causes the symptoms of sickle cell disease?

A

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)

54
Q

What blood parameters are seen in sickle cell disease?

A

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

55
Q

What is a double heterozygote in the context of haemoglobinopathies? How is this different to a compound heterozygote?

A

Mutation in B-globin AND a-globin

Compound heterozygote has 2 different mutations, typically within the same gene

56
Q

What is the aim of future therapies for haemoglobinopathies?

A

Gene therapy

57
Q

What are 3 possible mechanisms of gene therapy for haemoglobinopathies?

A

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

58
Q

What is heterozygote advantage?

A

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

Hannah's Intersystem (16 decks)

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