L46. Haemoglobinopathies

Question 1

Children with haemoglobinopathies exhibit…

Answer 1

Failure to thrive
Lack of appetite
Pale
Lethargy and Irritability

Question 2

How do we test for anaemia?

Answer 2

FBE
Iron Studies
Hb testing (MCV and MCH)

Question 3

What are the vast majority of haemoglobinopathies classified as?

Answer 3

Autosomal recessive disorders

Question 4

Describe the structure of haemoglobin

Answer 4

A tetramer

2 alpha and 2 beta subunits each with a central haem molecule

Question 5

Describe the genetic components of haemoglobin (encoding regions)

Answer 5

ALPHA: alpha and alpha like genes cluster on chromosome 16 with 2 copies of the alpha gene both are transcribed
BETA: beta and beta like genes cluster on chromosome 11 (more beta like genes exist)

There is complex regulation of gene expression with a Locus Control region (LCR) that is essential to the regulation

Question 6

Describe the changes to Hb synthesis through development

Answer 6

Development: Hb synthesis is in the yolk sac then to the liver, spleen and then to the bone marrow

Embryonic: 3 forms produced: zeta2epsilon2, zeta2gamma2 and alpha2epsilon2

Then after the first trimester the HbF begins to be made: alpha2gamma2

Late pregnancy then another switch occurs to HbA2 (alpha2delta2)

Adulthood: switch to alpha2beta2

Question 7

What is the approximate ratio of Hb proportions in the blood?

Answer 7

HbA: 97.5%
HbA2: 2%
HbF: 0.5%

Question 8

What are the 3 types of haemoglobinopathies?

Answer 8

1. Thalassemias: alpha and beta (decreased synthesis of one or more globin chains)
2. Structural variants (altered globin polypeptide without synthesis alteration)
3. Hereditary persistence of foetal Hb (HPFH) and is clinically benign

Question 9

What is the global distribution of the different types of haemoglobinopathies?

Answer 9

alpha thalassemia: globally but particularly high in SE Asia
beta thalassemia: globally but high in S. Europe, Middle east, N africa, SE asia and indian subcontinant
Sickle cell disease: W and central africa, middle east and indian subcontinant

Question 10

What causes the pathogenesis in thalassemia diseases?

Answer 10

Failure of synthesis of one or more types of globin chains leading to an IMBALANCE of the chains leading to HOMOTETRAMERS and the imbalance is the problem

Question 11

What is the difference between thalassemia major and thalassemia minor?

Answer 11

Major = have the disease (homozygous recessive)
Minor = carriers (heterozygous)

Question 12

Describe alpha thalassemia

Answer 12

Deficiency in alpha chains meaning only gamma Y4 (HbBart) or beta B4 (Beta4) homotetramers that are LESS SOLUBLE

These appear in development
Caused by LARGE DELETIONS

Question 13

Which type of Hb does it affect? Why?

Answer 13

Affects both adult and foetal because both of them are supposed to have 2 alpha chains

Question 14

There are 4 copies of the alpha gene (2 on each chromosome) - what does this mean about the phenotype of the disease?

Answer 14

Varies in severity depending on the genotype from 4 normally functioning genes (normal) to 0
a-/aa = minor
a-/a- or aa/– = mild anaemia
a-/– = HbH diseasemoderate to severe
–/– = Hb Bart: fatal before or around birth

Question 15

Describe beta thalassemia

Answer 15

Deficiency in beta chains leading to alpha4 homotetramers
Only manifests after birth (HbF doesn’t need beta)

alpha4 aggregate and accumulate causing precipitation of RBCs causing damage and destruction called HAEMOLYTIC ANAEMIA

Caused by POINT MUTATIONS

Question 16

Why is beta thalassemia fatal if not treated?

Answer 16

RBC production becomes aberrant
Most RBCs die as erythroblasts in the bone marrow
Anaemia causes more RBC to be produced in the bone marrow: high marrow volume = deformities like thinning of bones
Dietary Iron cannot be excreted: accumulation leading to organ failure
Re-recruit liver and spleen to make RBCs = hepatosplenomegaly

Question 17

What do blood films show in beta thalassemia?

Answer 17

1. Microcytic RBCs
2. Hypochromic (pale)
3. Anisocytotic (irregular in size)
4. Tear Drop shapes due to alpha4 aggregates
5. Polkilocytotic (abnormal shape)
6. Target cells characteristic of thalassemia

Question 18

What are the treatments of beta thalassemia?

Answer 18

Treated but not cured
Splenectomy (management)
Blood transfusions every 3-4 weeks but risk of infection is high and iron overload high (chelation) - expensive
Hormone replacement therapy
Bone marrow transplants (possible cure for future in stem cells)

Question 19

What is sickle cell disease?

Answer 19

Different point mutations (highly variant)
Glutamate acid point mutation to Valine = sticky protein aggregates in the deoxy form leading to irreversible sickling to block capillaries

Question 20

What do blood films show in sickle cell disease?

Answer 20

1. Normocytic or macrocytic cells

2. Sickling of cells

Question 21

What is the difference between compound heterozygotes and double heterozygotes?

Answer 21

Compound: have 2 different mutations
Double: mutation in both alpha and beta genes but they cancel each other out

Question 22

What are some future therapies for Haemoglobinopatheies?

Answer 22

1. Gene therapy to alter imbalance (gene knockdowns)
2. Epigenetic modifications
3. Induced pluripotent stem cells

Question 23

What is the heterozygote advantage?

Answer 23

High frequency of heterozygotes have a selection advantage (carriers of sickle cell anaemia are resistant to malaria)