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?
Hb testing (MCV and MCH)
What are the vast majority of haemoglobinopathies classified as?
Autosomal recessive disorders
Describe the structure of haemoglobin
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?
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
Caused by LARGE DELETIONS
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
Caused by POINT MUTATIONS
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
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