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CR2 > Haemoglobinopathies > Flashcards

Haemoglobinopathies Flashcards

1
Q

What does mean corpuscular haemoglobin (MCH) indicate? [1]

A

What does mean corpuscular haemoglobin (MCH) indicate? [1]

Amount of Hb per red blod cell (usually 29 picograms per cell)

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2
Q

Describe structure of Hb [2]

A

Tetramer: 4 subunits (of two identical dimers) [1]

Each subunit contains a haem and globin protein chain

Has just the right pocket size containing iron to allow oxygen to fit and form a partial bond with the valence electron on iron

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3
Q

What is haem metabolised to? [1]

A

Bilirubin

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4
Q

What are the two products of the alpha globin gene? [2]

What are the products of beta globin genes? [4]

How do the above interact? [1]

A

What are the two products of the alpha globin gene? [2]
Alpha globin chain
Zeta globin chain

What are the products of beta globin genes? [4]
Epsilon (e) globin
Gamma globin
Delta globin
Beta globin

To form Hb: need interaction of one component of alpha globin chain and beta chain (could be alpha and delta etc)

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5
Q

Alpha globin gene is found on:

Chromosome 12
Chromosome 8
Chromsome 15
Chromosome 16
Chromsome 4

A

Alpha globin gene is found on:

Chromosome 12
Chromosome 8
Chromsome 15
Chromosome 16
Chromsome 4

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6
Q

What are the 3 functional genes found on a-Globin gene? [3]

When are each expressed? [1]

A

Embryonic: zeta [1] HbZ gene

Fetal / Adult: Alpha 1 / 2 [2] HbA1 and HbA2

α-globin gene expression begins in early fetal life and is predominant throughout fetal and adult life

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7
Q

Beta globin gene is found on:

Chromosome 11
Chromosome 14
Chromsome 9
Chromosome 16
Chromsome 2

A

Beta globin gene is found on:

Chromosome 11
Chromosome 14
Chromsome 9
Chromosome 16
Chromsome 2

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8
Q

What are the 5 functional genes found on beta-Globin gene? [3]

When are each expressed? [1]

A

Embryonic: HBE gene / e-globin gene

Fetal: HBG2 and HBG1 genes Gy and Ay globin gene (The γ-globin genes (Gγ and Aγ) are the major β-like genes expressed in most of fetal life)

Adult: HBD and HBB genes delta and B- globin

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9
Q

Name the different places that haematopoiesis occurs in from embryo to neotate [4]

A

Embryo (3 weeks): Yolk sac

Fetus (6 weeks): Liver

Fetus (8 weeks): Spleen =

Neonate: Bone marrow

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9
Q

Name the different places that haematopoiesis occurs in from embryo to neotate [4]

A

Embryo (3 weeks): Yolk sac

Fetus (6 weeks): Liver

Fetus (8 weeks): Spleen =

Neonate: Bone marrow

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10
Q

Label the type of Hb that are dominant in each stage of life [3]

A

Yolk Sac / A: Z2, E2

Fetal liver / B: A2, γ2

Bone marrow / C: A2, B2

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11
Q

Which of the following represents the structure of fetal Hb?

  • α2, β2
  • α2, ζ2
  • α2, Y2
  • α2, δ2
  • δ2, β2
A

Which of the following represents the structure of fetal Hb?

  • α2, β2
  • α2, ζ2
    - α2, Y2 (alpha 2, gamma 2)
  • α2, δ2
  • δ2, β2
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12
Q

Which of the following represents the structure of adult Hb A?

  • α2, β2
  • α2, ζ2
  • α2, Y2
  • α2, δ2
  • δ2, β2
A

Which of the following represents the structure of adult Hb A?

- α2, β2
- α2, ζ2
- α2, Y2
- α2, δ2
- δ2, β2

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13
Q

Which of the following represents the structure of adult Hb A2?

  • α2, β2
  • α2, ζ2
  • α2, Y2
  • α2, δ2
  • δ2, β2
A

Which of the following represents the structure of adult Hb A2?

  • α2, β2
  • α2, ζ2
  • α2, Y2
    - α2, δ2
  • δ2, β2
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14
Q

What are the normal variants of Hb? [3]

A
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15
Q

Haemoglobinopathies arised from mutations or deletions in which gene? [1]

A

Globin gene

Abnormal structure or Abnormal production

16
Q

What is the inheritance patten of thalassaemias? [1]

What is the cause of thalassaemias [1]

What are the two types and how do they arise? [2]

A

Autosomal recessive

Abnormal production of globins:
the red blood cells are more fragile and break down more easily.

Alpha thalassaemia: deletion of HBA1 & HBA2 genes ( alpha-globin chains) (two copies on each chromosome - so have 4 genes. can have deletion of 1-4 of those genes)

Beta thalassaemia: mutations in HBB (beta-globin chains) genes (normally B genes)

17
Q

Explain the 4 different types of alpha thalassaemias

A

o1 defective alpha subunit: alpha thalassemia minima
· Minimal effect on Hb synthesis
· The other alpha globin genes produce enough subunits
· No clinical symptoms
· Slightly reduced MCV
· ‘silent carriers’

o2 alpha subunits missing or defective: alpha thalassemia minor
· Mild microcytotic hypochromic anaemia
· The remaining 2 alpha genes produce nearly normal levels of RBCs
· Can be mistaken for iron deficiency anaemia.

o3 alpha subunits missing or defective: Haemoglobin H disease (HbH)
Deletion of three alpha genes
Haemoglobin H (B4)
Moderate microcytic hypochromic anaemia
Excess beta chains cause damage by:
i) damage the red blood cell membrane, resulting in intramedullary hemolysis
ii) HbH has very high affinity for oxygen, and doesn’t release oxygen to the tissues. And a consequence of hypoxia is that it signals the bone marrow, as well as extramedullary tissues like the liver and spleen, to increase production of red blood cells.

o4 alpha subunits missing or defective:
· Foetus cannot live outside of uterus
· May not survive gestation
· Hydrops fetalis: Haemoglobin Barts (γ4) - super high affinity to O2.
Incompatible with life

18
Q

Why does Hb Bart’s hydrops foetalis syndrome arise? [1]

Describe the structure of Hb in Hb Bart’s hydrops foetalis syndrome in fetus [1]

Describe the structure of Hb in Hb Bart’s hydrops foetalis syndrome in embryo [1]

A

Hemoglobin Bart’s results from deletion of all four α-globin genes, with the subsequent inability to produce any α-globin chains, leading to failure of synthesis ofHb A, F, or A2. In the fetus, an excess number of γ-globin chains join together to form unstabletetramersknown as Hb Bart’s (γ4)

Haemoglobin in in erythrocytes contain
non-functional homotetramers γ4 (Hb γ4)

, or if in embryo: embryonic Hb Portland (ζ2γ2)

Die in utero (23-38 weeks or shortly after birth)

19
Q

Describe how Beta-thalassemias occur [2] (be specific)

A

Beta-thalassemias: occur from mutations within the B-gene [1]

Characterised by a reduced or absent production of haemoglobin A (which contains a2,B2)

As a result: excess α-chains precipitate in red cell precursors (as theres no beta chains) causing ineffective erythropoiesis as well as in mature red cells causing hemolysis.

Ineffective erythropoiesis and hemolysis cause anaemia

When there’s a β-globin chain deficiency, free α-chains accumulate within red blood cells, and they clump together to form intracellular inclusions, which damage the red blood cell’s cell membrane. This causes hemolysis,

20
Q

What are the three different types of Beta-thalaseemia and what do they arise from? [3]

A

There is one copy of Beta gene on each chromsome (but alpha gene, have 2)

Thalassaemia minor: Mutation in one HBB gene
( β/βo or β/β+ genotype)
* They have one abnormal and one normal gene.
* mild microcytic anaemia

Thalassaemia intermedia: Mutation in two HBB genes ((β+/βo or β+/β+ genotype)
* This can be either two defective genes or one defective gene and one deletion gene.
* more significant microcytic anaemia

Thalassaemia major: Mutations in both HBB genes (βo/βo genotype)
* major are homozygous for the deletion genes. They have no functioning beta-globin genes at all.
* Severe microcytic anaemia

21
Q

Explain why Thalassaemia minor & Thalassaemia intermedia & Thalassaemia major have different symptoms [3]

A

There is one copy of Beta gene on each chromsome (but alpha gene, have 2)

Thalassaemia minor: Mutation in one HBB gene
( β/βo or β/β+ genotype):
causes - reduced or no production of beta chains from one gene, but normal beta globin produced from other gene to form HbA: asymptomatic

Thalassaemia intermedia: Mutation in two HBB genes*
*- significantly reduced levels of beta chains. can form some HbA, but present with microcytic hypochromic anaema

Thalassaemia major: Mutations in both HBB genes (βo/βo genotype)
- No beta chains formed: No HbA formed –> HbF and HbA2 increased instead, get accumulation of a-globin chains: which causes aggregations in rbc

22
Q

How would you distinguish between anaemia from ID versus thalassemia?

A

In thalassaemia, although red cells are microcytic, serum iron and ferritin are normal (as iron absorption is normal )

23
Q

How do you treat a/b thalassemia?

What is an issue with this treatment?

A

Thalassaemia major (a+b) treatment:

Regular blood transfusion

BUT: can get Iron overload from constant blood transfusion: this happens because excess haemolysis can lead to excess free iron in blood (usually bound to ferritin in the spleen), which is oxidising

24
Q

what is the mutation the that causes SCA ? [3]

what does is the name of the Hb this mutation leads to? [1]

A

Single base mutation of Adenine to Thymine. Produces a substitution of valine for glutamic acid at the sixth codon of the beta-globin chain. Hb gene found on chromosome 11

Creates a hydrophobic spot on the outside of the protein that sticks to the hydrophobic region of an adjacent haemoglobin molecule’s beta chain: intracellular hemoglobin polymerization, loss of deformability and changes in cell morphology

Repeated sickling / non sickling causes change in membrane to permenant sickled

25
Q

What are the clinical features of SCA? [4]

A

(haemolytic) Anaemia
Jaundice (increased bilirubin due to shorter lifespan)
Increased susceptibility to infection (particularly encapsulated bacteria)
Vaso-occlusive crises (pain due to hypoxia in tissue where capillaries occluded)
Chronic tissue damage (eg stroke, avascular necrosis of hip, retinopathy

26
Q

What are treatment options for SCA?

A

Analgesics for painful ‘vaso-occlusive crises” where blood vessels become blocked by sickle cells

o Prophylaxis antibiotics - as suffers usually have poor immune systems.

o Bone marrow transplantation

o Possible transfusion

27
Q

Why does hemoglobin H, or HbH, disease lead to splenomagaly or hepatomegaly? [3]

A

HbH = Hb β4. This form of Hb causes

Damage to the red blood cell membrane, resulting in intramedullary hemolysis, or red blood cell breakdown in the bone marrow; or extravascular hemolysis, when red blood cells are destroyed by macrophages in the spleen.

Second, HbH has very high affinity for oxygen, and doesn’t release oxygen to the tissues. And a consequence of hypoxia is that it signals the bone marrow, as well as extramedullary tissues like the liver and spleen, to increase production of red blood cells. This may cause the bones that contain bone marrow, as well as the liver and spleen, to enlarge.

28
Q

Why does beta thalassamia minor symptoms only appear after 3-6 months?

A

Symptoms are produced by alh

During the first 3 to 6 months of life, fetal hemoglobin is still produced, and that process uses up some of the free α-chains

29
Q

What are the mising alpha globins replaced with in HbH as a fetus and adult? [2]

A

Hemoglobin H forms when only one normal alpha gene has been inherited. This causes significantly impaired alpha globin production. In the neonatal period, this will cause an excess of gamma, and in adults, this leaves an excess of beta-globin chains

30
Q

3 symptoms of beta thal. major? [3]

A

Severe microcytic anaemia
Splenomegaly
Bone deformities

CR2 (59 decks)

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