Haemoglobinopathies

Question 1

What chains make up adult haemoglobin?

What is it also known as?

Answer 1

2 alpha and 2 beta

Haemoglobin A

Question 2

Where are the gene(s) for alpha subunit found

Answer 2

Chromosome 16

2 genes on each chromosome so 4 altogether

Question 3

Where are the gene(s) for beta subunit found?

Answer 3

5 genes for beta subunit on chromosome 11

Question 4

Name the 5 genes that can produce beta chain (5’ to 3’ direction)

Answer 4

Epsilon
gamma A
gamma G
delta
beta

Question 5

Is adult or foetal haemoglobin better at binding oxygen?

Answer 5

Foetal

Question 6

What is the first form of haemoglobin formed in the embryonic yolk sac

Answer 6

Hb Gower-1, also called Zeta 2 Epsilon 2

Question 7

What haemoglobin is made after week 6 of gestation

Answer 7

HbF (foetal haemoglobin)

Alpha 2 gamma 2

Question 8

Where in the foetus is HbF made?

Answer 8

Liver and spleen

Question 9

Does HbA, HbF or Hb Gower-1 have higher affinity?

Answer 9

H Gower-1

Question 10

When does HbA start to replace HbF

Answer 10

3-6 months after birth

Question 11

What is HbA2

Answer 11

alpha 2 delta 2

Question 12

What % of each haemoglobin type are present in adult

Answer 12

96-97% HbA
2-3.5% HbA2
<1% HbF

Question 13

What % of each haemoglobin types are found in neonate

Answer 13

10% HbA
<1% HbA2
90% Hbf

Question 14

Define thalassaemia

Answer 14

Genetic defect resulting in inadequate quantities of one of the haemoglobin subunits

Question 15

What is alpha thalassaemia

Answer 15

Results when one or more alpha genes of chromosome 16 is deleted or faulty

Question 16

What is beta thalassaemia

Answer 16

Results when there is a point mutation of chromosome 11

Question 17

When does alpha thalassaemia manifest

Answer 17

Immediately at birth

Question 18

What happens if one alpha gene is defective

Answer 18

Alpha thalassaemia minima
Minimal effect on synthesis
Silent carriers

Question 19

What happens if two alpha genes are defective?

Answer 19

Alpha thalassaemia minor
Mild microcytic anaemia
Can be mistaken for iron deficiency anaemia

Question 20

What happens if three alpha genes are defective?

Answer 20

Haemoglobin H disease
2 unstable haemoglobins present in blood: Hb Barts (y4) and haemoglobin H (beta 4)
Microcytic hypochromic anaemia

Question 21

What happens if four alpha genes are defective

Answer 21

Foetus can’t live outside uterus
Many stillborn, rest die after birth
Circulating haemoglobin is barts- tetrameric gamma chains

Question 22

How is beta thalassaemia inhertited

Answer 22

Autosomal recessive

Question 23

What are the 2 main genotypes of beta thalassaemia

Answer 23

Heterozygous (beta thalassaemia minor)

Homozygous (major/ Cooleys anaemia)

Question 24

When does beta thalassaemia manifest

Answer 24

Several months after bith when switch from gamma to beta chains begins

Question 25

Describe the pathological effects of beta thalassaemia

Answer 25

Excess alpha globins produced which are unstable and cause intra-medullary destruction of developing erythroblasts, erythroid hyperplasia and ineffective erythropoiesis

Question 26

How does HbF levels present in beta thalassaemia major

Answer 26

High

Question 27

Effects of untreated beta thalassemia major (5)

Answer 27

- Hypochromic, microcytic anaemia - Bone marrow expansion - Bone deformity - Splenomegaly - Failure to thrive by 6 months, death aged 3-4

Question 28

Usual treatments for thalassamia major

Answer 28

Regular transfusions with iron chelating therapy to prevent overload Bone marrow transplant HbF modulating treatments

Question 29

What do iron chelating compounds do

Answer 29

Bind free iron and prevent Fenton reaction

Question 30

What is the fenton reaction and what does it cause?

Answer 30

Free iron reacts with hydrogen peroxide producing free radicals Responsible for cirrhosis, diabetes, glandular synfunction

Question 31

Name an oral iron chelation therapy

Answer 31

Deferiprone

Question 32

Side effects of desferoxamine

Answer 32

Toxicity- diarrhoea, vomiting, fever, hearing and eye probs

Question 33

Side effects of deferasirox

Answer 33

GI bleeding, kidney and liver failure

Question 34

What is problem with having sickle shaped red cells?

Answer 34

Can block capillaries, restrict blood flow to organ and cause ischaemia, pain and organ damage

Question 35

Signs of sickle cell disease

Answer 35

Haemolytic anaemia (Hb 6-8) Microvascular occlusion Large vessel damage

Question 36

What mutation occurs in sickle cell anaemia | What does this produce?

Answer 36

GAG--> GTG Glutamic acid--> valine Abnormal beta chain

Question 37

What is the haemoglobin in sickle cell called

Answer 37

Haemoglobin S | alpha 2 beta S 2

Question 38

How does survival time differ in sickle cells

Answer 38

It is decreased

Question 39

4 major clinical consequences of sickle cell disease

Answer 39

- Anaemia - Increased infection risk - Vaso-occlusive crises - Chronic tissue damage

Question 40

How can sickle cell be managed

Answer 40

``` Analgesics for painful crises Transfusion Hyroxyurea increases HbF Bone marrow transplant Infection prophylaxis ```

Question 41

How can couples be screened for sickle cell

Answer 41

Simple blood analysis (full blood count and haemoglobinopathy screen)

Question 42

When is the highest risk time for sickle cell complication

Answer 42

6 months- 2 years

Question 43

How is neonatal screening carried out

Answer 43

Heel prick | Implemented in UK since 2006

Question 44

What is haemoglobin C?

Answer 44

Mutation causing abnormal Beta subunit Reduced plasticity and flexibility--> haemolysis Homo- mild haemolytic anaemia

Question 45

What is haemoglobin E?

Answer 45

Single point mutation in Beta | 3-6 months fetal haemoglobin disappears, HbE increases mild beta thalassamia

Question 46

Which gene is switched off after 6 weeks of gestation

Answer 46

Zeta gene

Question 47

Where is the first form of haemoglobin produced

Answer 47

Embryonic solk sac

Question 48

Where is HbF produced

Answer 48

Liver/ spleen

Question 49

What variants of Gower haemoglobin can occur in the early weeks

Answer 49

- Gower 2 alpha episilon 2 | Portland

Question 50

How does beta thalassaemia major lead to microcytic anaemia

Answer 50

Bodys inability to construct beta-globins--> underproduction of haemoglobin A. Reduction in HBA available to fill red blood cells leads to microcytic anaemia

Question 51

Describe the blood results of a heterozygous character of beta thalassaemia

Answer 51

- Mildly low Hb - Low MCV - Normal HbA - High HBA2 - Normal HbF

Question 52

How may HbS behave in deoxygenated blood

Answer 52

Precipitate or cystallise, distorting the cells and making them fragile and easily destroyed