L46. Haemoglobinopathies Flashcards Preview

02. Cardiovascular > L46. Haemoglobinopathies > Flashcards

Flashcards in L46. Haemoglobinopathies Deck (23):

Children with haemoglobinopathies exhibit...

Failure to thrive
Lack of appetite
Lethargy and Irritability


How do we test for anaemia?

Iron Studies
Hb testing (MCV and MCH)


What are the vast majority of haemoglobinopathies classified as?

Autosomal recessive disorders


Describe the structure of haemoglobin

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


Describe the genetic components of haemoglobin (encoding regions)

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


Describe the changes to Hb synthesis through development

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


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

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


What are the 3 types of haemoglobinopathies?

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


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

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


What causes the pathogenesis in thalassemia diseases?

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


What is the difference between thalassemia major and thalassemia minor?

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


Describe alpha thalassemia

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

These appear in development


Which type of Hb does it affect? Why?

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


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

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


Describe beta thalassemia

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



Why is beta thalassemia fatal if not treated?

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


What do blood films show in beta thalassemia?

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


What are the treatments of beta thalassemia?

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)


What is sickle cell disease?

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


What do blood films show in sickle cell disease?

1. Normocytic or macrocytic cells
2. Sickling of cells


What is the difference between compound heterozygotes and double heterozygotes?

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


What are some future therapies for Haemoglobinopatheies?

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


What is the heterozygote advantage?

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

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